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Postpartum depression

Postpartum depression (PPD), also called postnatal depression, is a type of mood disorder associated with childbirth, which can affect both sexes. Symptoms may include extreme sadness, low energy, anxiety, crying episodes, irritability, and changes in sleeping or eating patterns. Onset is typically between one week and one month following childbirth. PPD can also negatively affect the newborn child.While the exact cause of PPD is unclear, the cause is believed to be a combination of physical, emotional, genetic, and social factors. These may include factors such as hormonal changes and sleep deprivation. Risk factors include prior episodes of postpartum depression, bipolar disorder, a family history of depression, psychological stress, complications of childbirth, lack of support, or a drug use disorder. Diagnosis is based on a persons symptoms. While most women experience a brief period of worry or unhappiness after delivery, postpartum depression should be suspected when symptoms are severe and last over two weeks.Among those at risk, providing psychosocial support may be protective in preventing PPD. This may include community support such as food, household chores, mother care, and companionship. Treatment for PPD may include counseling or medications. Types of counseling that have been found to be effective include interpersonal psychotherapy (IPT), cognitive behavioral therapy (CBT), and psychodynamic therapy. Tentative evidence supports the use of selective serotonin reuptake inhibitors (SSRIs).Postpartum depression affects roughly 15% of women after childbirth. Moreover, this mood disorder is estimated to affect 1% to 26% of new fathers. Postpartum psychosis, a more severe form of postpartum mood disorder, occurs in about 1 to 2 per 1,000 women following childbirth. Postpartum psychosis is one of the leading causes of the murder of children less than one year of age, which occurs in about 8 per 100,000 births in the United States. Signs and symptoms Symptoms of PPD can occur any time in the first year postpartum. Typically, a diagnosis of postpartum depression is considered after signs and symptoms persist for at least two weeks. Emotional Persistent sadness, anxiousness or "empty" mood Severe mood swings Frustration, irritability, restlessness, anger Feelings of hopelessness or helplessness Guilt, shame, worthlessness Low self-esteem Numbness, emptiness Exhaustion Inability to be comforted Trouble bonding with the baby Feeling inadequate in taking care of the baby Thoughts of self-harm or suicide Behavioral Lack of interest or pleasure in usual activities Low libido Changes in appetite Fatigue, decreased energy and motivation Poor self-care Social withdrawal Insomnia or excessive sleep Worry about harming self, baby, or partner Neurobiology fMRI studies indicate differences in brain activity between mothers with postpartum depression and those without. Mothers diagnosed with PPD tend to have less activity in the left frontal lobe and increased activity in the right frontal lobe when compared with healthy controls. They also exhibit decreased connectivity between vital brain structures, including the anterior cingulate cortex, dorsal lateral prefrontal cortex, amygdala, and hippocampus. Brain activation differences between depressed and nondepressed mothers is more pronounced when stimulated by non-infant emotional cues. Depressed mothers show greater neural activity in the right amygdala toward non-infant emotional cues as well as reduced connectivity between the amygdala and right insular cortex. Recent findings have also identified blunted activity in anterior cingulate cortex, striatum, orbitofrontal cortex, and insula in mothers with PPD when viewing images of their own infants.More robust studies on neural activation regarding PPD have been conducted with rodents than humans. These studies have allowed for greater isolation of specific brain regions, neurotransmitters, hormones, and steroids. Onset and duration Postpartum depression onset usually begins between two weeks to a month after delivery. A study done at an inner-city mental health clinic has shown that 50% of postpartum depressive episodes there began prior to delivery. Therefore, in the DSM-5 postpartum depression is diagnosed under "depressive disorder with peripartum onset", in which "peripartum onset" is defined as anytime either during pregnancy or within the four weeks following delivery. PPD may last several months or even a year. Postpartum depression can also occur in women who have suffered a miscarriage. For fathers, several studies show that men experience the highest levels of postpartum depression between 3–6 months postpartum. Parent-infant relationship Postpartum depression can interfere with normal maternal-infant bonding and adversely affect acute and longterm child development. Postpartum depression may lead mothers to be inconsistent with childcare. These childcare inconsistencies may include feeding routines, sleep routines, and health maintenance.In rare cases, or about 1 to 2 per 1,000, the postpartum depression appears as postpartum psychosis. In these, or among women with a history of previous psychiatric hospital admissions, infanticide may occur. In the United States, postpartum depression is one of the leading causes of annual reported infanticide incidence rate of about 8 per 100,000 births.According to research published in the American Journal of Obstetrics and Gynecology, children can experience the effects of postpartum depression. If a mother experiences postpartum depression that goes untreated, it can have adverse effects on her children. When a child is in infancy, these problems can include unusual amounts of crying (colic) and not having normal sleeping patterns. These problems can have a cyclical effect, meaning that they can further agitate the mothers postpartum depression and can even lead to the mother further developing postpartum depression. These cyclical effects can affect the way the mother maintains her relationship with her child. These can include the stopping of breastfeeding, as well as negative emotions such as withdrawal, disengagement, and even hostility. If a mother develops a hostile relationship, it can lead to extreme outcomes such as infanticide. As the child grows older, postpartum depression can lead to the child experiencing irregularities in cognitive processes, behaviors, and emotions. In addition to these abnormalities, children who grew up around postpartum depression also are susceptible to developing violent tendencies. Postpartum Depression in Fathers Paternal postpartum depression has not been studied as intently as its maternal counterpart. However, postpartum depression affects 8 to 10% of fathers. In men, postpartum depression is typically defined as "an episode of major depressive disorder (MDD) occurring soon after the birth of a child". There are no set criteria for men to have postpartum depression. The cause may be distinct in males. Causes of paternal postpartum depression include hormonal changes during pregnancy, which can be indicative of father-child relationships. For instance, male depressive symptoms have been associated with low testosterone levels in men. Low prolactin, estrogen, and vasopressin levels have been associated with struggles with father-infant attachment, which can lead to depression in first-time fathers. Symptoms of postpartum depression in men are extreme sadness, fatigue, anxiety, irritability, and suicidal thoughts. Postpartum depression in men is most likely to occur 3–6 months after delivery, and is correlated with maternal depression, meaning that if the mother is experiencing postpartum depression, then the father is at a higher risk of developing the illness as well. Postpartum depression in men leads to an increase risk of suicide, while also limiting healthy infant-father attachment. Men who experience PPD can exhibit poor parenting behaviors, distress, and reduce infant interaction. Reduced paternal interaction can later lead to cognitive and behavioral problems in children. Children as young as 3.5 years old experience problems with internalizing and externalizing behaviors, indicating that paternal postpartum depression can have long-term consequences. Furthermore, if children as young as two are not frequently read to, this negative parent-child interaction can have a harmful impact on their expressive vocabulary. Causes The cause of PPD is unknown. Hormonal and physical changes, personal and family history of depression, and the stress of caring for a new baby all may contribute to the development of postpartum depression.Evidence suggests that hormonal changes may play a role. Understanding the neuroendocrinology characteristic of PPD has proven to be particularly challenging given the erratic changes to the brain and biological systems during pregnancy and postpartum. A review of exploratory studies in PPD have observed that women with PPD have more dramatic changes in HPA axis activity, however directionality of specific hormone increases or decreases remain mixed. Hormones which have been studied include estrogen, progesterone, thyroid hormone, testosterone, corticotropin releasing hormone, endorphins, and cortisol. Estrogen and progesterone levels drop back to pre-pregnancy levels within 24 hours of giving birth, and that sudden change may cause it. Aberrant steroid hormone–dependent regulation of neuronal calcium influx via extracellular matrix proteins and membrane receptors involved in responding to the cells microenvironment might be important in conferring biological risk. The use of synthetic oxytocin, a birth-inducing drug, has been linked to increased rates of postpartum depression and anxiety.Fathers, who are not undergoing profound hormonal changes, can also have postpartum depression. The cause may be distinct in males. Profound lifestyle changes that are brought about by caring for the infant are also frequently hypothesized to cause PPD. However, little evidence supports this hypothesis. Mothers who have had several previous children without experiencing PPD can nonetheless experience it with their latest child. Despite the biological and psychosocial changes that may accompany pregnancy and the postpartum period, most women are not diagnosed with PPD. Many mothers are unable to get the rest they need to fully recover from giving birth. Sleep deprivation can lead to physical discomfort and exhaustion, which can contribute to the symptoms of postpartum depression. Risk factors While the causes of PPD are not understood, a number of factors have been suggested to increase the risk. These risks can be broken down into two categories, biological and psychosocial: Biological Administration of labor-inducing medication synthetic oxytocin Chronic illnesses caused by neuroendocrine irregularities Genetic history of PPD Hormone irregularities Inflammatory illnesses (irritable bowel syndrome, fibromyalgia) Cigarette smokingThe risk factors for postpartum depression can be broken down into two categories as listed above, biological and psychosocial. Certain biological risk factors include the administration of oxytocin to induce labor. Chronic illnesses such as diabetes, or Addisons disease, as well as issues hypothalamic-pituitary-adrenal dysregulation (which controls hormonal responses), inflammatory processes like asthma or celiac disease, and genetic vulnerabilities such as a family history of depression or PPD. Chronic illnesses caused by neuroendocrine irregularities including irritable bowl syndrome and fibromyalgia typically put individuals at risk for further health complications. However, it has been found that these diseases do not increase risk for postpartum depression, these factors are known to correlate with PPD. This correlation does not mean these factors are causal. Cigarette smoking has been known to have additive effects. Some studies have found a link between PPD and low levels of DHA (an omega-3 fatty acid) in the mother. A correlation between postpartum thyroiditis and postpartum depression has been proposed but remains controversial. There may also be a link between postpartum depression and anti-thyroid antibodies. Psychosocial Prenatal depression or anxiety A personal or family history of depression Moderate to severe premenstrual symptoms Stressful life events experienced during pregnancy Postpartum blues Birth-related psychological trauma Birth-related physical trauma History of sexual abuse Childhood trauma Previous stillbirth or miscarriage Formula-feeding rather than breast-feeding Low self-esteem Childcare or life stress Low social support Poor marital relationship or single marital status Low socioeconomic status A lack of strong emotional support from spouse, partner, family, or friends Infant temperament problems/colic Unplanned/unwanted pregnancy Breastfeeding difficulties Maternal age, family food insecurity and violence against womenThe psychosocial risk factors for postpartum depression include severe life events, some forms of chronic strain, relationship quality, and support from partner and mother. There is a need for more research in regard to the link between psychosocial risk factors and postpartum depression. Some psychosocial risk factors can be linked to the social determinants of health. Women with fewer resources indicate a higher level of postpartum depression and stress than those women with more resources, such as financial.Rates of PPD have been shown to decrease as income increases. Women with fewer resources may be more likely to have an unintended or unwanted pregnancy, increasing risk of PPD. Women with fewer resources may also include single mothers of low income. Single mothers of low income may have more limited access to resources while transitioning into motherhood. These women already have fewer spending options, and having a child may spread those options even further. Low-income women are frequently trapped in a cycle of poverty, unable to advance, affecting their ability to access and receive quality healthcare to diagnose and treat postpartum depression.Studies have also shown a correlation between a mothers race and postpartum depression. African American mothers have been shown to have the highest risk of PPD at 25%, while Asian mothers had the lowest at 11.5%, after controlling for social factors such as age, income, education, marital status, and babys health. The PPD rates for First Nations, Caucasian and Hispanic women fell in between.Migration away from a cultural community of support can be a factor in PPD. Traditional cultures around the world prioritize organized support during postpartum care to ensure the mothers mental and physical health, wellbeing, and recovery.One of the strongest predictors of paternal PPD is having a partner who has PPD, with fathers developing PPD 50% of the time when their female partner has PPD.Sexual orientation has also been studied as a risk factor for PPD. In a 2007 study conducted by Ross and colleagues, lesbian and bisexual mothers were tested for PPD and then compared with a heterosexual sample group. It was found that lesbian and bisexual biological mothers had significantly higher Edinburgh Postnatal Depression Scale scores than did the heterosexual women in the sample. Postpartum depression is more common among lesbian women than heterosexual women, which can be attributed to lesbian womens higher depression prevalence. Lesbian women have a higher risk of depression because they are more likely to have been treated for depression and to have attempted or contemplated suicide than heterosexual women. These higher rates of PPD in lesbian/bisexual mothers may reflect less social support, particularly from their families of origin and additional stress due to homophobic discrimination in society.There is a call to integrate both a consideration of biological and psychosocial risk factors for PPD when treating and researching the illness. Violence A meta-analysis reviewing research on the association of violence and postpartum depression showed that violence against women increases the incidence of postpartum depression. About one-third of women throughout the world will experience physical or sexual violence at some point in their lives. Violence against women occurs in conflict, post-conflict, and non-conflict areas. The research reviewed only looked at violence experienced by women from male perpetrators. Further, violence against women was defined as "any act of gender-based violence that results in, or is likely to result in, physical, sexual, or psychological harm or suffering to women". Psychological and cultural factors associated with increased incidence of postpartum depression include family history of depression, stressful life events during early puberty or pregnancy, anxiety or depression during pregnancy, and low social support. Violence against women is a chronic stressor, so depression may occur when someone is no longer able to respond to the violence. Diagnosis Criteria Postpartum depression in the DSM-5 is known as "depressive disorder with peripartum onset". Peripartum onset is defined as starting anytime during pregnancy or within the four weeks following delivery. There is no longer a distinction made between depressive episodes that occur during pregnancy or those that occur after delivery. Nevertheless, the majority of experts continue to diagnose postpartum depression as depression with onset anytime within the first year after delivery.The criteria required for the diagnosis of postpartum depression are the same as those required to make a diagnosis of non-childbirth related major depression or minor depression. The criteria include at least five of the following nine symptoms, within a two-week period: Feelings of sadness, emptiness, or hopelessness, nearly every day, for most of the day or the observation of a depressed mood made by others Loss of interest or pleasure in activities Weight loss or decreased appetite Changes in sleep patterns Feelings of restlessness Loss of energy Feelings of worthlessness or guilt Loss of concentration or increased indecisiveness Recurrent thoughts of death, with or without plans of suicide Differential diagnosis Postpartum blues Postpartum blues, commonly known as "baby blues," is a transient postpartum mood disorder characterized by milder depressive symptoms than postpartum depression. This type of depression can occur in up to 80% of all mothers following delivery. Symptoms typically resolve within two weeks. Symptoms lasting longer than two weeks are a sign of a more serious type of depression. Women who experience "baby blues" may have a higher risk of experiencing a more serious episode of depression later on. Psychosis Postpartum psychosis is not a formal diagnosis, but is widely used to describe a psychiatric emergency that appears to occur in about 1 in a 1000 pregnancies, in which symptoms of high mood and racing thoughts (mania), depression, severe confusion, loss of inhibition, paranoia, hallucinations and delusions begin suddenly in the first two weeks after delivery; the symptoms vary and can change quickly. It is different from postpartum depression and from maternity blues. It may be a form of bipolar disorder. It is important not to confuse psychosis with other symptoms that may occur after delivery, such as delirium. Delirium typically includes a loss of awareness or inability to pay attention.About half of women who experience postpartum psychosis have no risk factors; but a prior history of mental illness, especially bipolar disorder, a history of prior episodes of postpartum psychosis, or a family history put some at a higher risk.Postpartum psychosis often requires hospitalization, where treatment is antipsychotic medications, mood stabilizers, and in cases of strong risk for suicide, electroconvulsive therapy.The most severe symptoms last from 2 to 12 weeks, and recovery takes 6 months to a year. Women who have been hospitalized for a psychiatric condition immediately after delivery are at a much higher risk of suicide during the first year after delivery.Birth-Related/Postpartum Posttraumatic Stress Disorder Although birth-related posttraumatic stress disorder is not recognized in the DSM-5, there is extensive research being conducted to bring awareness to the posttraumatic stress disorder symptoms one could experience following childbirth. Some research examines the differences and comorbidity when looking into birth-related posttraumatic stress disorder, or postpartum posttraumatic stress disorder, and postpartum depression. In the recent research, similarities and differences in symptoms have been identified when it comes to postpartum posttraumatic stress disorder and postpartum depression. Although both diagnoses have overlap in their diagnostic criteria, some of the criteria specific to postpartum depression include intense hopelessness and sadness, excessive worry or anxiety, intrusive thoughts of harm to oneself or harm to the baby, feelings of guilt or thoughts of worthlessness, and a change in appetite which could result in under-eating or overeating. On the other hand, diagnostic criteria specific to postpartum posttraumatic stress disorder includes being easily startled, recurring nightmares and flashbacks, avoiding the baby or anything that reminds one of birth, aggression, irritability, and panic attacks. Although these are the symptoms that often help differentiate between postpartum posttraumatic stress disorder and postpartum depression, it is important to note that some of these symptoms can cross over to the other diagnosis (e.g., someone meeting the diagnostic criteria of postpartum depression may also present with panic attacks, or someone meeting the diagnostic criteria for postpartum posttraumatic stress disorder may experience depressive episodes, etc.). Another crucial element in diagnosing postpartum posttraumatic stress disorder following childbirth is when there is a real or perceived trauma before, during, or following childbirth, which is not always required when it comes to diagnosing someone with postpartum depression. This real or perceived traumatic event that could happen before, during, or following labor and delivery could be toward the baby, mother, or both. These traumatic events could include, but are not limited to unplanned c-section, death, the baby going into the NICU, the use of the vacuum extractor, or forceps during delivery, lack of support and/or reassurance during the delivery (from friends, family, and/or the medical staff), or any other severe physical complication or injury related to childbirth such as preeclampsia, or an unexpected hysterectomy.Conclusions have been made related to the idea of childbirth stressors and the contribution those can play in an increased risk of developing comorbid birth-related posttraumatic stress disorder and postpartum depression rather than only a postpartum depression diagnosis. Findings like the one mentioned above are crucial in accurate diagnosis to provide the mothers with the most appropriate and effective treatment options, and to advance the validity and reliability of preventative assessments and strategies. Other studies have been able to identify obstetric and perinatal risk factors associated specifically with birth-related posttraumatic stress disorder including educational level, gestational age at delivery, number of prenatal care visits, pregnancy intervals, mode of delivery, any complications with pregnancy, and labor duration. Based on current meta-analytic research, it has been concluded that the prevalence of postpartum posttraumatic stress disorder was 3.1% in community settings and 15.7% in at-risk populations; however, those findings do state various limitations, including underreporting biases, across the examined studies which lead many researchers to believe the prevalence may be higher.As of right now, there are no widely recognized assessments that measure for postpartum posttraumatic stress disorder in clinical and medical settings. However, researchers and physicians will often use more reliable posttraumatic stress disorder questionnaires and assessments, which are unfortunately not always specific enough to the posttraumatic symptoms and experiences that are felt before, during, or after childbirth. One assessment for postpartum posttraumatic stress disorder, the City Birth Trauma Scale (CBTS), has been used in some research settings; however, it is not widely used in clinical and medical settings. The CBTS is a 29-item self-report questionnaire developed to measure birth-related posttraumatic stress disorder, according to the DSM-5 criteria of: symptoms of re-experiencing the event, avoidance, negative cognitions and mood, and hyperarousal, as well as the duration of ones symptoms and the amount of distress and impairment the symptoms have caused in the individuals life. The creators of the CTSB also added in two items from the DSM-IV that they felt were relevant to the population being assessed with this measure – that the mothers responded to the traumatic events during childbirth with intense fear, helplessness, or horror and that there were symptoms of emotional numbing. Although the emotional numbing component was excluded in the DSM-5 criteria for posttraumatic stress disorder, research has shown that when studying mothers who have been exposed to trauma, emotional numbing is more predictive of parenting stress than other posttraumatic stress disorder symptoms. Although this assessment shows strong reliability (Cronbachs alpha = 0.92), and participants from the pilot study found the measure to be easy to understand, this assessment is still not used in clinical or medical settings as often as it is used in research settings. The researchers that have utilized the CTSB have been able to identify various limitations with the pilot study, including the lack of diversity in the sample demographic characteristics (93% White postpartum women) as well as the self-report nature of the assessment which could lead to underreporting of symptoms. Another assessment that has also been used in research more often than in clinical or medical settings is the Perinatal Posttraumatic Stress Disorder Questionnaire (PPQ), which has since been modified into the Perinatal Posttraumatic Stress Disorder Questionnaire-II (PPQ-II), with the modified version being a 14-item scale which does not address all the necessary diagnostic criteria. Further research and development are needed to create a more accurate assessments and screening tools that can differentiate among posttraumatic stress disorders, postpartum/childbirth-related posttraumatic stress disorder, and postpartum depression so that the most adequate treatment interventions and options can be implemented as quickly as possible. Screening Screening for postpartum depression is critical as up to 50% of cases go undiagnosed in the US, emphasizing the significance of comprehensive screening measures. In the US, the American College of Obstetricians and Gynecologists suggests healthcare providers consider depression screening for perinatal women. Additionally, the American Academy of Pediatrics recommends pediatricians screen mothers for PPD at 1-month, 2-month and 4-month visits. However, many providers do not consistently provide screening and appropriate follow-up. For example, in Canada, Alberta is the only province with universal PPD screening. This screening is carried out by Public Health nurses with the babys immunization schedule. In Sweden, Child Health Services offer a free program for new parents that includes screening mothers for PPD at 2 months postpartum. However, there are concerns about adherence to screening guidelines regarding maternal mental health.The Edinburgh Postnatal Depression Scale, a standardized self-reported questionnaire, may be used to identify women who have postpartum depression. If the new mother scores 13 or more, she likely has PPD and further assessment should follow.Healthcare providers may take a blood sample to test if another disorder is contributing to depression during the screening.The Edinburgh Postnatal Depression Scale, is used within the first week of their newborn being admitted. If mothers receive a score less than 12 they are told to be reassessed because of the depression testing protocol. It is also advised that mothers in the NICU to get screened every four to six weeks as their infant remains in the neonatal intensive care unit. Mothers who score between twelve and nineteen on the EPDS are offered two types of support. The mothers are offered LV treatment provided by a nurse in the NICU and they can be referred to the mental health professional services. If a mother receives a three on item number ten of the EPDS they are immediately referred to the social work team as they may be suicidal.It is critical to acknowledge the diversity of patient populations diagnosed with postpartum depression and how this may impact the reliability of the screening tools used. There are cultural differences in how patients express symptoms of postpartum depression; those in non-western countries exhibit more physical symptoms, whereas those in western countries have more feelings of sadness. Depending on ones cultural background, symptoms of postpartum depression may manifest differently, and non-Westerners being screened in Western countries may be misdiagnosed because their screening tools do not account for cultural diversity. Aside from culture, it is also important to consider ones social context, as women with low socioeconomic status may have additional stressors that affect their postpartum depression screening scores. Prevention A 2013 Cochrane review found evidence that psychosocial or psychological intervention after childbirth helped reduce the risk of postnatal depression. These interventions included home visits, telephone-based peer support, and interpersonal psychotherapy. Support is an important aspect of prevention, as depressed mothers commonly state that their feelings of depression were brought on by "lack of support" and "feeling isolated."Across different cultures, traditional rituals for postpartum care may be preventative for PPD, but are more effective when the support is welcomed by the mother.In couples, emotional closeness and global support by the partner protect against both perinatal depression and anxiety. In 2014, Alasoom and Koura found that compared to 42.9 percent of women who did not get spousal support, only 14.7 percent of women who got spousal assistance had PPD. Further factors such as communication between the couple and relationship satisfaction have a protective effect against anxiety alone.In those who are at risk counselling is recommended. In 2018, 24% of areas in the UK have no access to perinatal mental health specialist services.Preventative treatment with antidepressants may be considered for those who have had PPD previously. However, as of 2017, the evidence supporting such use is weak. Treatments Treatment for mild to moderate PPD includes psychological interventions or antidepressants. Women with moderate to severe PPD would likely experience a greater benefit with a combination of psychological and medical interventions. Light aerobic exercise has been found to be useful for mild and moderate cases. Therapy Both individual social and psychological interventions appear equally effective in the treatment of PPD. Social interventions include individual counseling and peer support, while psychological interventions include cognitive behavioral therapy (CBT) and interpersonal therapy (IPT). Interpersonal therapy (IPT) has shown to be effective in focusing specifically on the mother and infant bond. Support groups and group therapy options focused on psychoeducation around postpartum depression have been shown to enhance the understanding of postpartum symptoms and often assist in finding further treatment options. Other forms of therapy, such as group therapy, home visits, counseling, and ensuring greater sleep for the mother may also have a benefit. While specialists trained in providing counseling interventions often serve this population in need, results from a recent systematic review and meta-analysis found that nonspecialist providers, including lay counselors, nurses, midwives, and teachers without formal training in counseling interventions, often provide effective services related to perinatal depression and anxiety.Internet-based cognitive behavioral therapy (iCBT) has shown promising results with lower negative parenting behavior scores and lower rates of anxiety, stress, and depression. iCBT may be beneficial for mothers who have limitations in accessing in person CBT. However, the long term benefits have not been determined. Medication A 2010 review found few studies of medications for treating PPD noting small sample sizes and generally weak evidence. Some evidence suggests that mothers with PPD will respond similarly to people with major depressive disorder. There is low-certainty evidence which suggests that selective serotonin reuptake inhibitors (SSRIs) are effective treatment for PPD. The first-line anti-depressant medication of choice is sertraline, an SSRI, as very little of it passes into the breast milk and, as a result, to the child. However, a recent study has found that adding sertraline to psychotherapy does not appear to confer any additional benefit. Therefore, it is not completely clear which antidepressants, if any, are most effective for treatment of PPD, and for whom antidepressants would be a better option than non-pharmacotherapy.Some studies show that hormone therapy may be effective in women with PPD, supported by the idea that the drop in estrogen and progesterone levels post-delivery contribute to depressive symptoms. However, there is some controversy with this form of treatment because estrogen should not be given to people who are at higher risk of blood clots, which include women up to 12 weeks after delivery. Additionally, none of the existing studies included women who were breastfeeding. However, there is some evidence that the use of estradiol patches might help with PPD symptoms.Oxytocin has been shown to be an effective anxiolytic and in some cases antidepressant treatment in men and women. Exogenous oxytocin has only been explored as a PPD treatment with rodents, but results are encouraging for potential application in humans.In 2019, the FDA approved brexanolone, a synthetic analog of the neurosteroid allopregnanolone, for use intravenously in postpartum depression. Allopregnanolone levels drop after giving birth, which may lead to women becoming depressed and anxious. Some trials have demonstrated an effect on PPD within 48 hours from the start of infusion. Other new allopregnanolone analogs under evaluation for use in the treatment of PPD include zuranolone and ganaxolone.Brexanolone has risks that can occur during administration, including excessive sedation and sudden loss of consciousness, and therefore has been approved under the Risk Evaluation and Mitigation Strategy (REMS) program. The mother is to enrolled prior to receiving the medication. It is only available to those at certified health care facilities with a health care provider who can continually monitor the patient. The infusion itself is a 60-hour, or 2.5 day, process. Peoples oxygen levels are to be monitored with a pulse oximeter. Side effects of the medication include dry mouth, sleepiness, somnolence, flushing and loss of consciousness. It is also important to monitor for early signs of suicidal thoughts or behaviors. Breastfeeding Caution should be exercised when administering antidepressant medications during breastfeeding. Most antidepressants are excreted in breast milk in low quantities which can have adverse effect on babies. Regarding allopregnanolone, very limited data did not indicate a risk for the infant. Other Electroconvulsive therapy (ECT) has shown efficacy in women with severe PPD that have either failed multiple trials of medication-based treatment or cannot tolerate the available antidepressants. Tentative evidence supports the use of repetitive transcranial magnetic stimulation (rTMS).As of 2013 it is unclear if acupuncture, massage, bright lights, or taking omega-3 fatty acids are useful. Resources International Postpartum Support International is the most recognized international resource for those with PPD as well as healthcare providers. It brings together those experiencing PPD, volunteers, and professionals to share information, referrals, and support networks. Services offered by PSI include the website (with support, education, and local resource info), coordinators for support and local resources, online weekly video support groups in English and Spanish, free weekly phone conference with chats with experts, educational videos, closed Facebook groups for support, and professional training of healthcare workers. United States Educational interventions Educational interventions can help women struggling with postpartum depression (PPD) to cultivate coping strategies and develop resiliency. The phenomenon of "scientific motherhood" represents the origin of womens education on perinatal care with publications like Ms. circulating some of the first press articles on PPD that helped to normalize the symptoms that women experienced. Feminist writings on PPD from the early seventies shed light on the darker realities of motherhood and amplified the lived experiences of mothers with PPD. Instructional videos have been popular among women who turn to the internet for PPD treatment, especially when the videos are interactive and get patients involved in their treatment plan. Since the early 2000s, video tutorials on PPD have been integrated into many web-based training programs for individuals with PPD and are often considered a type of evidence-based management strategy for individuals. This can take the form of objective-based learning, detailed exploration of case studies, resource guides for additional support and information, etc. Government-funded programs The National Child and Maternal Health Education Program functions as a larger education and outreach program supported by the National Institute of Child Health and Human Development (NICHD) and the National Institute of Health. The NICHD has worked alongside organizations like the World Health Organization to conduct research on the psychosocial development of children with part of their efforts going towards the support of mothers health and safety. Training and education services are offered through the NICHD to equip women and their health care providers with evidence-based knowledge on PPD.Other initiatives include the Substance Abuse and Mental Health Services Administration (SAMHSA) whose disaster relief program provides medical assistance at both the national and local level. The disaster relief fund not only helps to raise awareness of the benefits of having healthcare professionals screen for PPD, but also helps childhood professionals (home visitors and early care providers) develop the skills to diagnose and prevent PPD. The Infant and Early Childhood Mental Health Consultation (IECMH) center is a related technical assistance program that utilizes evidence-based treatments services in order to address issues of PPD. The IECMH facilitates parenting and home visit programs, early care site interventions with parents and children and a variety of other consultation-based services. The IECMHs initiatives seek to educate home visitors on screening protocols for PPD as well as ways to refer depressed mothers to professional help. Links to government-funded programs National Child and Maternal Health Education Program National Institute of Child Health and Human Development Substance Abuse and Mental Health Services Administration Infant and Early Childhood Mental Health Consultation Center Psychotherapy Therapeutic methods of intervention can begin as early as a few days post-birth when most mothers are discharged from hospitals. Research surveys have revealed a paucity of professional, emotional support for women struggling in the weeks following delivery despite there being a heightened risk for PPD for new mothers during this transitional period. Community-based support A lack of social support has been identified as a barrier to seeking help for postpartum depression. Peer-support programs have been identified as an effective intervention for women experiencing symptoms of postpartum depression. In-person, online, and telephone support groups are available to both women and men throughout the United States. Peer-support models are appealing to many women because they are offered in a group and outside of the mental-health setting. The website Postpartum Progress provides a comprehensive list of support groups separated by state and includes the contact information for each group. The National Alliance on Mental Illness lists a virtual support group titled "The Shades of Blue project," which is available to all women via the submission of a name and email address. Additionally, NAMI recommends the website "National Association of Professional and Peer Lactation Supports of Color" for mothers in need of a lactation supporter. Lactation assistance is available either online or in-person, if there is support nearby. Personal narratives & memoirs Postpartum Progress is a blog focused on being a community of mothers talking openly about postpartum depression and other mental health conditions associated. Story-telling and online communities reduce the stigma around PPD and promote peer-based care. Postpartum Progress is specifically relevant to people of color and queer folks due to an emphasis on cultural competency. Hotlines & telephone interviews Hotlines, chat lines, and telephone interviews offer immediate, emergency support for those experiencing PPD. Telephone-based peer support can be effective in the prevention and treatment of postpartum depression among women at high-risk. Established examples of telephone hotlines include: National Alliance on Mental Illness: 800-950-NAMI (6264), National Suicide Prevention Lifeline: 800-273-TALK (8255), Postpartum Support International: 800-944-4PPD (4773), and SAMHSAs National Hotline: 1-800-662-HELP (4357). Postpartum Health Alliance has an immediate, 24/7 support line in San Diego/San Diego Access and Crisis Line at (888) 724–7240, in which you can talk with mothers who have recovered from PPD and trained providers.However, hotlines can lack cultural competency which is crucial in quality healthcare, specifically for people of color. Calling the police or 911, specifically for mental health crises, is dangerous for many people of color. Culturally and structurally competent emergency hotlines are a huge need in PPD care. National Alliance on Mental Illness: 800-950-NAMI (6264) National Suicide Prevention Lifeline: 800-273-TALK (8255) Postpartum Support International: 800-944-4PPD (4773) SAMHSAs National Hotline: 1-800-662-HELP (4357) Self-care & well-being activities Women demonstrated an interest in self-care and well-being in an online PPD prevention program. Self-care activities, specifically music therapy, are accessible to most communities and valued among women as a way to connect with their children and manage symptoms of depression. Well-being activities associated with being outdoors, including walking and running, were noted amongst women as a way to help manage mood. Accessibility to care Those with PPD come across many help-seeking barriers, including lack of knowledge, stigma about symptoms, as well as health service barriers. There are also attitudinal barriers to seeking treatment, including stigma. Interpersonal relationships with friends and family, as well as institutional and financial obstacles serve as help-seeking barriers. The history of mistrust within the United States healthcare system or negative health experiences can influence ones willingness and adherence to seek postpartum depression treatment. Cultural responses must be adequate in PPD healthcare and resources. Representation and cultural competency are crucial in equitable healthcare for PPD. Different ethic groups may believe that healthcare providers will not respect their cultural values or religious practices, which influences their willingness to use mental health services or be prescribed antidepressant medications. Additionally, resources for PPD are limited and often dont incorporate what mothers would prefer. The use of technology can be a beneficial way to deliver mothers with resources because it is accessible and convenient. Epidemiology North America United States Within the United States, the prevalence of postpartum depression was lower than the global approximation at 11.5% but varied between states from as low as 8% to as high as 20.1%. The highest prevalence in the US is found among women who are American Indian/Alaska Natives or Asian/Pacific Islanders, possess less than 12 years of education, are unmarried, smoke during pregnancy, experience over two stressful life events, or whos full term infant is low-birthweight or was admitted to a Newborn Intensive Care Unit. While US prevalence decreased from 2004 to 2012, it did not decrease among American Indian/Alaska Native women or those with full term, low-birthweight infants.Even with the variety of studies, it is difficult to find the exact rate as approximately 60% of US women are not diagnosed and of those diagnosed approximately 50% are not treated for PPD. Cesarean section rates did not affect the rates of PPD. While there is discussion of postpartum depression in fathers, there is no formal diagnosis for postpartum depression in fathers. Canada Canada has one of the largest refugee resettlement in the world with an equal percentage of women to men. This means that Canada has a disproportionate percentage of women that develop post-partum depression since there is an increased risk among the refugee population. In a blind study, where women had to reach out and participate, around 27% of the sample population had symptoms consistent with post-partum depression without even knowing. Also found that on average 8.46 women had minor and major PPDS was found to be 8.46 and 8.69% respectively. The main factors that were found to contribute in this study were the stress during pregnancy, the availability of support after, and a prior diagnosis of depression were all found to be factors. Canada has the specific population demographics that also involve a large amount of immigrant and indigenous women which creates a specific cultural demographic localized to Canada. In this study researchers found that these two populations were at significantly higher risk compared to "Canadian born non-indigenous mothers". This study found that risk factors such as low education, low income cut off, taking antidepressants, and low social support are all factors that contribute to the higher percentage of these population in developing PPDS. Specifically, indigenous mothers had the most risk factors then immigrant mothers with non-indigenous Canadian women being closer to the overall population. South America A main issue surrounding PPD is the lack of study and the lack of reported prevalence that is based on studies developed in Western economically developed countries. In countries such as Brazil, Guyana, Costa Rica, Italy, Chile, and South Africa there is actually a prevalence of report, around 60%. In an itemized research analysis put a mean prevalence at 10-15% percent but explicitly stated that cultural factors such as perception of mental health and stigma could possibly be preventing accurate reporting. The analysis for South America shows that PPD occurs at a high rate looking comparatively at Brazil (42%) Chile (4.6-48%) Guyana and Colombia (57%) and Venezuela (22%). In most of these countries PPD is not considered a serious condition for women and therefore there is an absence of support programs for prevention and treatment in health systems. Specifically, in Brazil PPD is identified through the family environment whereas in Chile PPD manifests itself through suicidal ideation and emotional instability. In both cases most women feel regret and refuse to take care of the child showing that this illness is serious for both the mother and child. Asia From a selected group of studies found from a literature search, researchers discovered many demographic factors of Asian populations that showed significant association with PPD. Some of these include age of mother at the time of childbirth as well as older age at marriage. Being a migrant and giving birth to a child overseas has also been identified as a risk factor for PPD. Specifically for Japanese women who were born and raised in Japan but who gave birth to their child in Hawaii, USA, about 50% of them experienced emotional dysfunction during their pregnancy. In fact, all women who gave birth for the first time who were included in the study experienced PPD. In immigrant Asian Indian women, the researchers found a minor depressive symptomatology rate of 28% and an additional major depressive symptomatology rate of 24% likely due to different health care attitudes in different cultures and distance form family leading to homesickness.In the context of Asian countries, premarital pregnancy is an important risk factor for PPD. This is because it is considered highly unacceptable in most Asian culture as there is a highly conservative attitude toward sex among Asian people than people in the west. In addition, conflicts between mother and daughter-in-law are notoriously common in Asian societies as traditionally for them, marriage means the daughter-in-law joining and adjusting to the grooms family completely. These conflicts may be responsible for emergence of PPD. Regarding gender of the child, many studies have suggested dissatisfaction in infants gender (birth of a baby girl) is a risk factor for PPD. This is because in some Asian cultures, married couples are expected by the family to have at least one son to maintain the continuity of the bloodline which might lead a woman to experience PPD if she cannot give birth to a baby boy. Europe There is a general assumption that Western cultures are homogenous and that there are no significant differences in psychiatric disorders across Europe and the USA. However, in reality factors associated with maternal depression, including work and environmental demands, access to universal maternity leave, health care, and financial security, are regulated and influenced by local policies that differ across countries. For example, European social policies differ from country-to-country contrary to the US, all countries provide some form of paid universal maternity leave and free health care. Studies also found differences in symptomatic manifestations of PPD between European and American women. Women from Europe reported higher scores of anhedonia, self-blaming, and anxiety, while women from the USA disclosed more severe insomnia, depressive feelings, and thoughts of self-harming. Additionally, there are differences in prescribing patterns and attitudes towards certain medications between the US and Europe which are indicative of how different countries approach treatment, and their different stigmas. Africa Africa, like all other parts of the world struggles with a burden of postpartum depression. Current studies estimate the prevalence to be 15-25% but this is likely higher due to a lack of data and recorded cases. The magnitude of postpartum depression in South Africa is between 31.7% and 39.6%, in Morocco between 6.9% and 14%, in Nigeria between 10.7% and 22.9%, in Uganda 43%, in Tanzania 12%, in Zimbabwe 33%, in Sudan 9.2%, in Kenya between 13% and 18.7% and, 19.9% for participants in Ethiopia according to studies carried out in these countries among postpartum mothers between the ages of 17–49. This demonstrates the gravity of this problem in Africa, and the need for postpartum depression to be taken seriously as a public health concern in the continent. Additionally, each of these studies were conducted using Western developed assessment tools. Cultural factors can affect diagnosis and can be a barrier to assessing the burden of disease. Some recommendations to combat postpartum depression in Africa include considering postpartum depression as a public health problem that is neglected among postpartum mothers. Investing in research to assess the actual prevalence of postpartum depression, and encourage early screening, diagnosis and treatment of postpartum depression as an essential aspect of maternal care throughout Africa.Issues in Reporting Prevalence Most studies regarding PPD are done using self-report screenings which are less reliable than clinical interviews. This use of self-report may have results that underreport symptoms and thus postpartum depression rates. History Prior to the 19th century Western medical sciences understanding and construction of postpartum depression has evolved over the centuries. Ideas surrounding womens moods and states have been around for a long time, typically recorded by men. In 460 B.C., Hippocrates wrote about puerperal fever, agitation, delirium, and mania experienced by women after child birth. Hippocrates ideas still linger in how postpartum depression is seen today.A woman who lived in the 14th century, Margery Kempe, was a Christian mystic. She was a pilgrim known as "Madwoman" after having a tough labor and delivery. There was a long physical recovery period during which she started descending into "madness" and became suicidal. Based on her descriptions of visions of demons and conversations she wrote about that she had with religious figures like God and the Virgin Mary, historians have identified what Margery Kempe was experiencing as "postnatal psychosis" and not postpartum depression. This distinction became important to emphasize the difference between postpartum depression and postpartum psychosis. A 16th century physician, Castello Branco, documented a case of postpartum depression without the formal title as a relatively healthy woman with melancholy after childbirth, remained insane for a month, and recovered with treatment. Although this treatment was not described, experimental treatments began to be implemented for postpartum depression for the centuries that followed. Connections between female reproductive function and mental illness would continue to center around reproductive organs from this time all the way through to modern age, with a slowly evolving discussion around "female madness". 19th century and after With the 19th century came a new attitude about the relationship between female mental illness and pregnancy, childbirth, or menstruation. The famous short story, "The Yellow Wallpaper", was published by Charlotte Perkins Gilman in this period. In the story, an unnamed woman journals her life when she is treated by her physician husband, John, for hysterical and depressive tendencies after the birth of their baby. Gilman wrote the story to protest societal oppression of women as the result of her own experience as a patient.Also during the 19th century, gynecologists embraced the idea that female reproductive organs, and the natural processes they were involved in, were at fault for "female insanity." Approximately 10% of asylum admissions during this time period are connected to "puerperal insanity," the named intersection between pregnancy or childbirth and female mental illness. It wasnt until the onset of the twentieth century that the attitude of the scientific community shifted once again: the consensus amongst gynecologists and other medical experts was to turn away from the idea of diseased reproductive organs and instead towards more "scientific theories" that encompassed a broadening medical perspective on mental illness. Society and culture Legal recognition Recently, postpartum depression has become more widely recognized in society. In the US, the Patient Protection and Affordable Care Act included a section focusing on research into postpartum conditions including postpartum depression. Some argue that more resources in the form of policies, programs, and health objectives need to be directed to the care of those with PPD. Role of stigma When stigma occurs, a person is labelled by their illness and viewed as part of a stereotyped group. There are three main elements of stigmas, 1) problems of knowledge (ignorance or misinformation), 2) problems of attitudes (prejudice), 3) problems of behavior (discrimination). Specifically regarding PPD, it is often left untreated as women frequently report feeling ashamed about seeking help and are concerned about being labeled as a "bad mother" if they acknowledge that they are experiencing depression. Although there has been previous research interest in depression-related stigma, few studies have addressed PPD stigma. One study studied PPD stigma through examining how an education intervention would impact it. They hypothesized that an education intervention would significantly influence PPD stigma scores. Although they found some consistencies with previous mental health stigma studies, for example, that males had higher levels of personal PPD stigma than females, most of the PPD results were inconsistent with other mental health studies. For example, they hypothesized that education intervention would lower PPD stigma scores, but in reality there was no significant impact and also familiarity with PPD was not associated with ones stigma towards people with PPD. This study was a strong starting point for further PPD research, but clearly indicates more needs to be done in order to learn what the most effective anti-stigma strategies are specifically for PPD.Postpartum depression is still linked to significant stigma. This can also be difficult when trying to determine the true prevalence of postpartum depression. Participants in studies about PPD carry their beliefs, perceptions, cultural context and stigma of mental health in their cultures with them which can affect data. The stigma of mental health - with or without support from family members and health professionals - often deters women from seeking help for their PPD. When medical help is achieved, some women find the diagnosis helpful and encourage a higher profile for PPD amongst the health professional community. Cultural beliefs Postpartum depression can be influenced by sociocultural factors. There are many examples of particular cultures and societies that hold specific beliefs about PPD. Malay culture holds a belief in Hantu Meroyan; a spirit that resides in the placenta and amniotic fluid.When this spirit is unsatisfied and venting resentment, it causes the mother to experience frequent crying, loss of appetite, and trouble sleeping, known collectively as "sakit meroyan". The mother can be cured with the help of a shaman, who performs a séance to force the spirits to leave.Some cultures believe that the symptoms of postpartum depression or similar illnesses can be avoided through protective rituals in the period after birth. These may include offering structures of organized support, hygiene care, diet, rest, infant care, and breastfeeding instruction. The rituals appear to be most effective when the support is welcomed by the mother.Some Chinese women participate in a ritual that is known as "doing the month" (confinement) in which they spend the first 30 days after giving birth resting in bed, while the mother or mother-in-law takes care of domestic duties and childcare. In addition, the new mother is not allowed to bathe or shower, wash her hair, clean her teeth, leave the house, or be blown by the wind. Media Certain cases of postpartum mental health concerns received attention in the media and brought about dialogue on ways to address and understand more on postpartum mental health. Andrea Yates, a former nurse, became pregnant for the first time in 1993. After giving birth to five children in the coming years, she had severe depression and had many depressive episodes. This led to her believing that her children needed to be saved, and that by killing them, she could rescue their eternal souls. She drowned her children one by one over the course of an hour, by holding their heads under water in their family bathtub. When called into trial, she felt that she had saved her children rather than harming them and that this action would contribute to defeating Satan.This was one of the first public and notable cases of postpartum psychosis, which helped create dialogue on womens mental health after childbirth. The court found that Yates was experiencing mental illness concerns, and the trial started the conversation of mental illness in cases of murder and whether or not it would lessen the sentence or not. It also started a dialogue on women going against "maternal instinct" after childbirth and what maternal instinct was truly defined by.Yates case brought wide media attention to the problem of filicide, or the murder of children by their parents. Throughout history, both men and women have perpetrated this act, but study of maternal filicide is more extensive. See also Postpartum blues Antenatal depression Gender disappointment Psychiatric disorders of childbirth Sex after pregnancy Breastfeeding and mental health References External links Postpartum depression at Curlie "Depression during and after pregnancy fact sheet". Womenshealth.gov. 6 March 2009. Archived from the original on 1 March 2012. Postnatal Depression, information from the mental health charity The Royal College of Psychiatrists NHS Choices Health A-Z: Postnatal depression Postpartum Depression and the Baby Blues - HelpGuide.org

Cholesteatoma

Cholesteatoma is a destructive and expanding growth consisting of keratinizing squamous epithelium in the middle ear and/or mastoid process. Cholesteatomas are not cancerous as the name may suggest, but can cause significant problems because of their erosive and expansile properties. This can result in the destruction of the bones of the middle ear (ossicles), as well as growth through the base of the skull into the brain. They often become infected and can result in chronically draining ears. Treatment almost always consists of surgical removal. Signs and symptoms Other more common conditions (e.g. otitis externa) may also present with these symptoms, but cholesteatoma is much more serious and should not be overlooked. If a patient presents to a doctor with ear discharge and hearing loss, the doctor should consider cholesteatoma until the disease is definitely excluded. Other less common symptoms (all less than 15%) of cholesteatoma may include pain, balance disruption, tinnitus, earache, headaches and bleeding from the ear. There can also be facial nerve weakness. Balance symptoms in the presence of a cholesteatoma raise the possibility that the cholesteatoma is eroding the balance organs in the inner ear. Doctors initial inspections may only reveal an ear canal full of discharge. Until the doctor has cleaned the ear and inspected the entire tympanic membrane, cholesteatoma cannot be diagnosed. Once the debris is cleared, cholesteatoma can give rise to a number of appearances. If there is significant inflammation, the tympanic membrane may be partially obscured by an aural polyp. If there is less inflammation, the cholesteatoma may present the appearance of semolina discharging from a defect in the tympanic membrane. The posterior and superior parts of the tympanic membrane are most commonly affected. If the cholesteatoma has been dry, the cholesteatoma may present the appearance of wax over the attic. The attic is just above the eardrum. If untreated, a cholesteatoma can eat into the three small bones located in the middle ear (the malleus, incus and stapes, collectively called ossicles), which can result in nerve deterioration, deafness, imbalance and vertigo. It can also affect and erode, through the enzymes it produces, the thin bone structure that isolates the top of the ear from the brain, as well as lay the covering of the brain open to infection with serious complications (rarely even death due to brain abscess and sepsis). Both the acquired as well as the congenital types of the disease can affect the facial nerve that extends from the brain to the face and passes through the inner and middle ear and leaves at the anterior tip of the mastoid bone, and then rises to the front of the ear and extends into the upper and lower face. Cause Cholesteatomas occur in two basic classifications: Acquired cholesteatomas, which are more common, are usually caused by pathological alteration of the ear drum leading to accumulation of keratin within the middle ear. Congenital cholesteatomas are usually middle ear epidermal cysts that are identified deep within an intact ear drum. Congenital cholesteatoma Keratin-filled cysts that grow medial to the tympanic membrane are considered to be congenital if they fulfill the following criteria (Levensons criteria): mass medial to the tympanic membrane normal tympanic membrane no previous history of ear discharge, perforation or ear surgeryCongenital cholesteatomas occur at three important sites: the middle ear, the Petrous apex, and the cerebropontinio angle. They are most often found deep to the anterior aspect of the ear drum, and a vestigial structure, the epidermoid formation, from which congenital cholesteatoma may originate, has been identified in this area.Not all middle ear epidermal cysts are congenital, as they can be acquired either by metaplasia of the middle ear mucosa or by traumatic implantation of ear canal or tympanic membrane skin. In addition, cholesteatoma inadvertently left by a surgeon usually regrows as an epidermal cyst. Some authors have also suggested hereditary factors. Acquired cholesteatoma More commonly, keratin accumulates in a pouch of tympanic membrane which extends into the middle ear space. This abnormal folding or retraction of the tympanic membrane arises in one of the following ways: Jackler’s theory : Mucosal coupling with traction generated by interaction of migrating opposing surfaces leading to formation of cholesteatoma.Wittmaacks theory : Invagination of tympanic membrane from the attic or part of pars tensa in the form of retraction pockets lead to the formation of cholesteatoma. Ruedis theory : The basal cells of germinal layer of skin proliferate under the influence of infection and lay down keratinising squamous epithelium. Habermanns theory: The epithelium from the meatus or outer drum surface grows into the middle ear through a pre-existing perforation and form cholesteatoma.Cholesteatoma may also arise as a result of metaplasia of the middle ear mucosa or implantation following trauma. Diagnosis Cholesteatoma is diagnosed by a medical doctor by physical examination of the ear. A CT scan may help to rule out other, often more serious causes for the patients clinical presentation. Non-ionizing radiation imaging techniques (MRI) may be suitable to replace a CT scan, if determined necessary by a physician. Treatment Cholesteatoma is a persistent disease. Once the diagnosis of cholesteatoma is made in a patient who can tolerate a general anesthetic, the standard treatment is to surgically remove the growth. The challenge of cholesteatoma surgery is to permanently remove the cholesteatoma whilst retaining or reconstructing the normal functions of the structures housed within the temporal bone. The general objective of cholesteatoma surgery has two parts. It is both directed against the underlying pathology and directed towards maintaining the normal functions of the temporal bone. These aims are conflicting and this makes cholesteatoma surgery extremely challenging. Sometimes, the situation results in a clash of surgical aims. The need to fully remove a progressive disease like cholesteatoma is the surgeons first priority. Preservation of hearing is secondary to this primary aim. If the disease can be removed easily so that there is no increased risk of residual disease, then the ossicles may be preserved. If the disease is difficult to remove, so that there is an increased risk of residual disease, then removal of involved ossicles in order to fully clear cholesteatoma has generally been regarded as necessary and reasonable. In other words, the aims of cholesteatoma treatment form a hierarchy. The paramount objective is the complete removal of cholesteatoma. The remaining objectives, such as hearing preservation, are subordinate to the need for complete removal of cholesteatoma. This hierarchy of aims has led to the development of a wide range of strategies for the treatment of cholesteatoma. Surgery The variation in technique in cholesteatoma surgery results from each surgeons judgment whether to retain or remove certain structures housed within the temporal bone in order to facilitate the removal of cholesteatoma. This typically involves some form of mastoidectomy which may or may not involve removing the posterior ear canal wall and the ossicles. Removal of the canal wall facilitates the complete clearance of cholesteatoma from the temporal bone in three ways: It removes a large surface onto which cholesteatoma may be adherent; It removes a barrier behind which the cholesteatoma may be hidden; It removes an impediment to the introduction of instruments used for the removal of cholesteatoma.Thus removal of the canal wall provides one of the most effective strategies for achieving the primary aim of cholesteatoma surgery, the complete removal of cholesteatoma. However, there is a trade-off, since the functional impact of canal wall removal is also important. The removal of the ear canal wall results in: a space, the "mastoid cavity", which is less likely than the original ear canal to resist infection; exposure of the ossicles, which may allow the subsequent formation of a new cholesteatoma deep to the ossicles. To prevent this, these ossicles must be removed, which may diminish the patients hearing.The formation of a mastoid cavity by removal of the canal wall is the simplest and most effective procedure for facilitating the removal of cholesteatoma, but may bestow the most lasting infirmity due to loss of ear function upon the patient treated in this way. The following strategies are employed to mitigate the effects of canal wall removal: Careful design and construction of the mastoid cavity. This is essential for the health and integrity of the protective sheet of migrating, keratising epithelium which lines the distorted ear canal. This requires the surgeon to saucerise the cavity. A high facial ridge and an inappropriately small cartilaginous meatus are obstructions to epithelial migration and are particularly high risk factors for failure of the self-cleaning mechanism of the external ear. Partial obliteration of the mastoid cavity. This can be performed using a wide range of materials. Many of these resorb in time, which means that the long-term results of such surgery are poorer than the short-term results. Reconstruction of the ear canal wall. Canal wall reconstruction has been performed using ear canal skin alone, fascia, cartilage, titanium as well as by replacing the original intact wall. If the reconstruction is poorly performed, it may result in a high rate of recurrent cholesteatoma. Preservation of the ear canal wall. If poorly performed, it may result in a high rate of both residual and recurrent cholesteatoma. Reconstruction of the chain of hearing bones using a passive middle ear implant.Clearly, preservation and restoration of ear function at the same time as total removal of cholesteatoma requires a high level of surgical expertise. Endoscopic surgery Traditionally, ear surgery has been performed using the surgical microscope. The direct line of view dictated by that approach necessitates using the mastoid as the access port to the middle ear. It has long been recognized that failure in cholesteatoma surgery occurs in some of the out of view spaces of the tympanic cavity like the sinus tympani and facial recess that are out of view using the traditional microscopic technique. More recently, the endoscope has been increasingly utilized in the surgical management of cholesteatoma in one of two ways: Using the endoscope as an ancillary instrument to the microscope when trying to visualize areas that are hidden from the microscope such as the sinus tympani. This work was pioneered by Professor Thomassin. Using the endoscope as the main surgical instrument through the ear canal, or whats called: Endoscopic Ear Surgery, pioneered by Professor Tarabichi.There are multiple advantages for the use of the endoscope in cholesteatoma surgery: The endoscope wide angle of view and the ability to "see around the corner". The endoscope allows minimally invasive access through the natural ear canal, rather than through the usual 5 cm incision behind the ear utilized in traditional microscopic surgery. The 30 degrees endoscope allows access to the bony area of the Eustachian tube to address any obstructive pathologies. Prognosis It is important that the patient attend periodic follow-up checks, because even after careful microscopic surgical removal, cholesteatomas may recur. Such recurrence may arise many years, or even decades, after treatment. A residual cholesteatoma may develop if the initial surgery failed to completely remove the original; residual cholesteatomas typically become evident within the first few years after the initial surgery. A recurrent cholesteatoma is a new cholesteatoma that develops when the underlying causes of the initial cholesteatoma are still present. Such causes can include, for example, poor Eustachian tube function, which results in retraction of the ear drum, and failure of the normal outward migration of skin.In a retrospective study of 345 patients with middle ear cholesteatoma operated on by the same surgeon, the overall 5-year recurrence rate was 11.8%. In a different study with a mean follow-up period of 7.3 years, the recurrence rate was 12.3%, with the recurrence rate being higher in children than in adults. The use of the endoscope as an ancillary instrument has been shown to reduce the incidence of residual cholesteatoma. Although more studies are needed, so far, new techniques addressing underlying Eustachian tube dysfunction such as transtympanic dilatation of the Eustachian tube has not been shown to change outcomes of chronic ear surgery. Infections Recent findings indicate that the keratinizing squamous epithelium of the middle ear could be subjected to human papillomavirus infection. Indeed, DNA belonging to oncogenic HPV16 has been detected in cholesteatoma tissues, thereby underlining that keratinizing squamous epithelia could potentially be a target tissue for HPV infection. Epidemiology In one study, the number of new cases of cholesteatoma in Iowa was estimated in 1975–76 to be just under one new case per 10,000 citizens per year. Cholesteatoma affects all age groups, from infants through to the elderly. The peak incidence occurs in the second decade. See also Chronic suppurative otitis media Otic polyp Endoscopic ear surgery References External links Information on Cholesteatomas Laser Cholesteatoma Surgery

Lichen simplex chronicus

Lichen simplex chronicus (LSC) is thick leathery skin with exaggerated skin markings caused by sudden itching and excessive rubbing and scratching. It generally results in small bumps, patches, scratch marks and scale. It typically affects the neck, scalp, upper eyelids, ears, palms, soles, ankles, wrists, genital areas and bottom. It often develops gradually and the scratching becomes a habit. Signs and symptoms People burdened with LSC report pruritus, followed by uncontrollable scratching of the same body region, excessively. Most common sites of LSC are the sides of the neck, the scalp, ankles, vulva, pubis, scrotum, and extensor sides of the forearms. However, due to the stigma associated with chronic scratching, some patients will not admit to chronic rubbing or abrasion. The skin may become thickened and hyperpigmented (lichenified) as a direct result of chronic excoriation. Typically this period of increased scratching is associated with stressors. Causes This is a skin disorder characterized by a self-perpetuating scratch-itch cycle: It may begin with something that rubs, irritates, or scratches the skin, such as clothing. This causes the person to rub or scratch the affected area. Constant scratching causes the skin to thicken. The thickened skin itches, causing more scratching, causing more thickening. Affected area may spread rapidly through the rest of the body.Many hypothesize LSC has a psychosomatic origin. Those predisposed to itch as a response to emotional tensions may be more susceptible to the itch-scratch cycle. It may also be associated with nervousness, anxiety, depression, and other psychological disorders. Many people with LSC are aware of the scratching they do during the day, but they might not be aware of the scratching they do in their sleep. LSC is also associated with atopy, or atopic dermatitis (eczema) and an increase of histamine levels. Diagnosis LSC is typically diagnosed by careful observation and history taking. It is easily recognized (see signs and symptoms, and gallery). Biopsies are sometimes necessary to confirm the diagnosis and differentiate it from other similar appearing lesions. Treatment Treatment is aimed at reducing itching and minimizing existing lesions because rubbing and scratching exacerbate LSC. The itching and inflammation may be treated with a lotion or steroid cream (such as triamcinolone or Betamethasone) applied to the affected area of the skin. Night-time scratching can be reduced with sedatives and antihistamines. Doxepin is often prescribed, as it offers both antihistamine properties and is also effective at reducing the (itch scratch cycle) associated with the obsessive psychosomatic behavioral symptoms. Gallery See also List of cutaneous conditions References == External links ==

Plantar fasciitis

Plantar fasciitis or plantar heel pain (PHP) is a disorder of the plantar fascia, which is the connective tissue which supports the arch of the foot. It results in pain in the heel and bottom of the foot that is usually most severe with the first steps of the day or following a period of rest. Pain is also frequently brought on by bending the foot and toes up towards the shin. The pain typically comes on gradually, and it affects both feet in about one-third of cases.The cause of plantar fasciitis is not entirely clear. Risk factors include overuse, such as from long periods of standing, an increase in exercise, and obesity. It is also associated with inward rolling of the foot, a tight Achilles tendon, and a sedentary lifestyle. It is unclear if heel spurs have a role in causing plantar fasciitis even though they are commonly present in people who have the condition. Plantar fasciitis is a disorder of the insertion site of the ligament on the bone characterized by micro tears, breakdown of collagen, and scarring. Since inflammation plays either a lesser or no role, a review proposed it be renamed plantar fasciosis. The presentation of the symptoms is generally the basis for diagnosis; with ultrasound sometimes being useful if there is uncertainty. Other conditions with similar symptoms include osteoarthritis, ankylosing spondylitis, heel pad syndrome, and reactive arthritis.Most cases of plantar fasciitis resolve with time and conservative methods of treatment. For the first few weeks, those affected are usually advised to rest, change their activities, take pain medications, and stretch. If this is not sufficient, physiotherapy, orthotics, splinting, or steroid injections may be options. If these measures are not effective, additional measures may include extracorporeal shockwave therapy or surgery.Between 4% and 7% of the general population has heel pain at any given time: about 80% of these are due to plantar fasciitis. Approximately 10% of people have the disorder at some point during their life. It becomes more common with age. It is unclear if one sex is more affected than the other. Signs and symptoms When plantar fasciitis occurs, the pain is typically sharp and usually unilateral (70% of cases). Bearing weight on the heel after long periods of rest worsens heel pain in affected individuals. Individuals with plantar fasciitis often report their symptoms are most intense during their first steps after getting out of bed or after prolonged periods of sitting. Symptoms typically improve with continued walking. Rare, but reported symptoms include numbness, tingling, swelling, or radiating pain. Typically there are no fevers or night sweats.If the plantar fascia is overused in the setting of plantar fasciitis, the plantar fascia can rupture. Typical signs and symptoms of plantar fascia rupture include a clicking or snapping sound, significant local swelling, and acute pain in the bottom of the foot. Risk factors Identified risk factors for plantar fasciitis include excessive running, standing on hard surfaces for prolonged periods, high arches of the feet, the presence of a leg length inequality, and flat feet. The tendency of flat feet to excessively roll inward during walking or running makes them more susceptible to plantar fasciitis. Obesity is seen in 70% of individuals who present with plantar fasciitis and is an independent risk factor.Plantar fasciitis is commonly a result of some biomechanical imbalance that causes an increased amount of tension placed along the plantar fascia.Studies consistently find a strong association between increased body mass index and plantar fasciitis in the non-athletic population. This association between weight and plantar fasciitis is not present in the athletic population. Achilles tendon tightness and inappropriate footwear have also been identified as significant risk factors. Pathophysiology The cause of plantar fasciitis is poorly understood and appears to have several contributing factors. The plantar fascia is a thick fibrous band of connective tissue that originates from the medial tubercle and anterior aspect of the heel bone. From there, the fascia extends along the sole of the foot before inserting at the base of the toes and supports the arch of the foot.Plantar fasciitis is a non-inflammatory condition of the plantar fascia. Within the last decade, studies have observed microscopic anatomical changes indicating that plantar fasciitis is due to a non-inflammatory structural breakdown of the plantar fascia rather than an inflammatory process.Many in the academic community have stated the condition should be renamed plantar fasciosis in light of these newer findings. Repetitive microtrauma (small tears) appears to cause a structural breakdown of the plantar fascia. Microscopic examination of the plantar fascia often shows myxomatous degeneration, connective tissue calcium deposits, and disorganized collagen fibers.Disruptions in the plantar fascias normal mechanical movement during standing and walking (known as the Windlass mechanism) place excess strain on the calcaneal tuberosity and seem to contribute to the development of plantar fasciitis. Other studies have also suggested that plantar fasciitis is not due to the inflamed plantar fascia but maybe a tendon injury involving the flexor digitorum brevis muscle located immediately deep to the plantar fascia. Diagnosis Plantar fasciitis is usually diagnosed by a health care provider after consideration of a persons presenting history, risk factors, and clinical examination. Palpation along the inner aspect of the heel bone on the sole may elicit tenderness during the physical examination. The foot may have limited dorsiflexion due to excessive tightness of the calf muscles or the Achilles tendon. Dorsiflexion of the foot may elicit the pain due to stretching of the plantar fascia with this motion. Diagnostic imaging studies are not usually needed to diagnose plantar fasciitis. Occasionally, a physician may decide imaging studies (such as X-rays, diagnostic ultrasound, or MRI) are warranted to rule out serious causes of foot pain. Other diagnoses that are typically considered include fractures, tumors, or systemic disease if plantar fasciitis pain fails to respond appropriately to conservative medical treatments. Bilateral heel pain or heel pain in the context of a systemic illness may indicate a need for a more in-depth diagnostic investigation. Under these circumstances, diagnostic tests such as a CBC or serological markers of inflammation, infection, or autoimmune disease such as C-reactive protein, erythrocyte sedimentation rate, anti-nuclear antibodies, rheumatoid factor, HLA-B27, uric acid, or Lyme disease antibodies may also be obtained. Neurological deficits may prompt an investigation with electromyography to check for damage to the nerves or muscles.An incidental finding associated with this condition is a heel spur, a small bony calcification on the calcaneus (heel bone), which can be found in up to 50% of those with plantar fasciitis. In such cases, it is the underlying plantar fasciitis that produces the heel pain, and not the spur itself. The condition is responsible for the creation of the spur though the clinical significance of heel spurs in plantar fasciitis remains unclear. Imaging Medical imaging is not routinely needed. It is expensive and does not typically change how plantar fasciitis is managed. When the diagnosis is not clinically apparent, lateral view X-rays of the ankle are the recommended imaging modality to assess for other causes of heel pain, such as stress fractures or bone spur development.The plantar fascia has three fascicles-the central fascicle being the thickest at 4 mm, the lateral fascicle at 2 mm, and the medial less than a millimeter thick. In theory, plantar fasciitis becomes more likely as the plantar fascias thickness at the calcaneal insertion increases. A thickness of more than 4.5 mm ultrasound and 4 mm on MRI are useful for diagnosis. Other imaging findings, such as thickening of the plantar aponeurosis, are nonspecific and have limited usefulness in diagnosing plantar fasciitis.Three-phase bone scan is a sensitive modality to detect active plantar fasciitis. Furthermore, a 3-phase bone scan can be used to monitor response to therapy, as demonstrated by decreased uptake after corticosteroid injections. Differential diagnosis The differential diagnosis for heel pain is extensive and includes pathological entities including, but not limited to, the following: calcaneal stress fracture, septic arthritis, calcaneal bursitis, osteoarthritis, spinal stenosis involving the nerve roots of lumbar spinal nerve 5 (L5) or sacral spinal nerve 1 (S1), calcaneal fat pad syndrome, metastasized cancers from elsewhere in the body, hypothyroidism, gout, seronegative spondyloparthopathies such as reactive arthritis, ankylosing spondylitis, or rheumatoid arthritis (more likely if pain is present in both heels), plantar fascia rupture, and compression neuropathies such as tarsal tunnel syndrome or impingement of the medial calcaneal nerve.A determination about a diagnosis of plantar fasciitis can usually be made based on a persons medical history and physical examination. When a physician suspects a fracture, infection, or some other serious underlying condition, they may order an X-ray to investigate. X-rays are unnecessary to screen for plantar fasciitis for people who stand or walk a lot at work unless imaging is otherwise indicated. Treatment Non-surgical About 90% of plantar fasciitis cases improve within six months with conservative treatment, and within a year regardless of treatment.The recommended first treatment is a 4-6 week course which combines three elements: daily stretching, daily foot taping (using a special tape around the foot for supporting the arch) and individually tailored education on choosing footwear and other ways of managing the condition.If plantar fasciitis fails to respond to conservative treatment for at least three months, then extracorporeal shockwave therapy (ESWT) may be considered. Evidence from meta-analyses suggests significant pain relief lasts up to one year after the procedure. However, debate about the therapys efficacy has persisted. ESWT is performed with or without anesthesia though studies suggest giving anesthesia diminishes the procedures effectiveness. Complications from ESWT are rare and typically benign when present. Known complications of ESWT include the development of a mild hematoma or an ecchymosis, redness around the site of the procedure, or migraine. The third line of treatment, if shockwave therapy is not effective after around 8 weeks, is using customised foot orthoses which can offer short-term relief from pain.Affected people use further different treatments for plantar fasciitis but many have little evidence to support their use and are not adequately studied.Other conservative approaches include rest, massage, heat, ice, and calf-strengthening exercises, weight reduction in the overweight or obese, and nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin or ibuprofen. The use of NSAIDs to treat plantar fasciitis is common, but their use fails to resolve the pain in 20% of people.Corticosteroid injections are sometimes used for cases of plantar fasciitis that have proven resistant to more conservative measures. There is tentative evidence that injected corticosteroids are effective for short-term pain relief up to one month, but not after that.Another treatment technique is known as plantar iontophoresis. This technique involves applying anti-inflammatory substances such as dexamethasone or acetic acid topically to the foot and transmitting these substances through the skin with an electric current. Some evidence supports the use of night splints for 1–3 months to relieve plantar fasciitis pain that has persisted for six months. The night splints are designed to position and maintain the ankle in a neutral position, thereby passively stretching the calf and plantar fascia during sleep. Surgery Plantar fasciotomy is a surgical treatment and the last resort for refractory plantar fasciitis pain. If plantar fasciitis does not resolve after six months of conservative treatment, then the procedure is considered as a last resort. Minimally invasive and endoscopic approaches to plantar fasciotomy exist but require a specialist who is familiar with specific equipment. The availability of these surgical techniques is limited as of 2012. A 2012 study found 76% of people who underwent endoscopic plantar fasciotomy had complete relief of their symptoms and had few complications (level IV evidence). Heel spur removal during plantar fasciotomy does not appear to improve the surgical outcome.Plantar heel pain may occur for multiple reasons. In select cases, surgeons may perform a release of the lateral plantar nerve alongside the plantar fasciotomy. Possible complications of plantar fasciotomy include nerve injury, instability of the medial longitudinal arch of the foot, fracture of the calcaneus, prolonged recovery time, infection, rupture of the plantar fascia, and failure to improve the pain. Coblation surgery has recently been proposed as an alternative surgical approach for the treatment of recalcitrant plantar fasciitis. Unproven treatments Botulinum toxin A injections as well as similar techniques such as platelet-rich plasma injections and prolotherapy remain controversial.Dry needling is also being researched for treatment of plantar fasciitis. A systematic review of available research found limited evidence of effectiveness for this technique. The studies were reported to be inadequate in quality and too diverse in methodology to enable reaching a firm conclusion. Epidemiology Plantar fasciitis is the most common type of plantar fascia injury and is the most common reason for heel pain, responsible for 80% of cases. The condition tends to occur more often in women, military recruits, older athletes, dancers, the obese, and young male athletes.Plantar fasciitis is estimated to affect 1 in 10 people at some point during their lifetime and most commonly affects people between 40 and 60 years of age. In the United States alone, more than two million people receive treatment for plantar fasciitis. The cost of treating plantar fasciitis in the United States is estimated to be $284 million each year. References Further reading External links "Plantar fasciitis and bone spurs". American Academy of Orthopedic Surgeons.

Epidermolysis bullosa

Epidermolysis bullosa (EB) is a group of rare medical conditions that result in easy blistering of the skin and mucous membranes. Blisters occur with minor trauma or friction and are painful. Its severity can range from mild to fatal. Inherited EB is a rare disease with a prevalence in the United States of 8.2 per million live births. Those with mild cases may not develop symptoms until they start to crawl or walk. Complications may include esophageal narrowing, squamous cell skin cancer, and the need for amputations. EB is due to a mutation in at least one of 16 different genes. Some types are autosomal dominant while others are autosomal recessive. The underlying mechanism is a defect in attachment between or within the layers of the skin. Loss or diminished function of C7 leads to weakness in the structural architecture of the dermal–epidermal junction (DEJ) and mucosal membranes. There are four main types: epidermolysis bullosa simplex (EBS), dystrophic epidermolysis bullosa (DEB), junctional epidermolysis bullosa (JEB), and Kindler syndrome. The diagnosis is suspected based on symptoms and confirmed by skin biopsy or genetic testing. There is no cure for the condition. Management involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications. About half a million people are affected globally. It occurs equally commonly in males and females. Classification Epidermolysis bullosa refers to a group of disorders that involve the formation of blisters following trivial trauma. Over 300 mutations have been identified in this condition. They have been classified into the following types:: 596 Epidermolysis bullosa simplex Epidermolysis bullosa simplex (EBS) is a form of EB that causes blisters at the site of rubbing. It typically affects the hands and feet, and is typically inherited in an autosomal dominant manner, affecting the keratin genes KRT5 and KRT14. Therefore, there is a failure in keratinization, which affects the integrity and the ability of the skin to resist mechanical stresses. Junctional epidermolysis bullosa Junctional epidermolysis bullosa (JEB) is an inherited disease affecting laminin and collagen. This disease is characterized by blister formation within the lamina lucida of the basement membrane zone: 599  and is inherited in an autosomal recessive manner. It also presents with blisters at the site of friction, especially on the hands and feet, and has variants that can occur in children and adults. Less than one person per million people is estimated to have this form of EB. Dystrophic epidermolysis bullosa Dystrophic epidermolysis bullosa (DEB) is an inherited variant affecting the skin and other organs. DEB is caused by genetic defects (or mutations) within the human COL7A1 gene encoding the protein type VII collagen (collagen VII). DEB-causing mutations can be either autosomal dominant or autosomal recessive. Epidermis bullosa pruriginosa and albopapuloid epidermolysis bullosa (Pasinis disease) are rare subtypes of this disease. Other genetic Epidermolysis bullosa acquisita Acral peeling Pathophysiology The human skin consists of two layers: an outermost layer called the epidermis and a layer underneath called the dermis. In individuals with healthy skin, there are protein anchors between these two layers (Dermo epidermal junction) that prevent them from moving independently from one another (shearing). In people born with EB, the two skin layers lack the protein anchors that hold them together, resulting in extremely fragile skin—even minor mechanical friction (like rubbing or pressure) or trauma will separate the layers of the skin and form blisters and painful sores. EB individuals manifest unremitting skin blistering that evolves into chronic wounds, inflammation, and fibrosis.People with EB have compared the sores with third-degree burns. Furthermore, as a complication of the chronic skin damage, people with EB have an increased risk of malignancies (cancers) of the skin.Virtually any organ lined or covered by epithelium may be injured in inherited EB. External eye, esophagus, upper airway, and genitourinary tract are the epithelial surfaced tissues that are at particular risk. Diagnosis EB can be diagnosed either by a skin (punch) biopsy at the edge of a wound with immunofluorescent mapping, or via blood sample and genetic testing. Treatment The combination of birch bark extract from Betula pendula and Betula pubescens is used to treat epidermolysis bullosa.Research has focused on changing the mixture of keratins produced in the skin. There are 54 known keratin genes—of which 28 belong to the type I intermediate filament genes and 26 to type II—which work as heterodimers. Many of these genes share substantial structural and functional similarity, but they are specialized to cell type and/or conditions under which they are normally produced. If the balance of production could be shifted away from the mutated, dysfunctional keratin gene toward an intact keratin gene, symptoms could be reduced. For example, sulforaphane, a compound found in broccoli, was found to reduce blistering in a mouse model to the point where affected pups could not be identified visually, when injected into pregnant mice (5 μmol/day = 0.9 mg) and applied topically to newborns (1 μmol/day = 0.2 mg in jojoba oil).As of 2008 clinical research at the University of Minnesota has explored allogeneic bone marrow transplantation for RD and junctional EB, treating a two-year-old child who is one of two brothers with EB. A second transplant has also been performed on the childs older brother, and a third transplant is scheduled for a California baby. A clinical trial is planned for 30 subjects. However, the immune suppression that bone marrow transplantation requires causes a risk of serious infections with large scale blisters and skin erosion. Indeed, at least four people have died in the course of either preparation for or institution of bone marrow transplantation for EB, out of only a small group of patients treated so far. The mechanism of action of this therapy is unclear as hematopoietic stem cells are not thought to contribute to epithelial lineages. Rather, it is speculated that cross-correction from tissue-resident graft-derived immune cells contributes to the observed clinical benefit.A pilot study performed in 2015 suggests that systemic granulocyte-colony stimulating factor (G-CSF) may promote increased wound healing in people with dystrophic EB. Transplanting skin derived from genetically modified stem cells onto the wound surfaces has been studied with a report of improvements in one person.A 2017 clinical trial with male RDEB (recessive dystrophic EB) patients conducted successful grafting of type VII gene corrected keratinocytes (COL7A1 gene correction using retrovirus transduction), without any serious adverse effects. Type VII collage formation was observed at the dermis-epidermis junction in significant amounts.A 2020 study demonstrated the safe allogenic grafting of acellular dermal matrix/scaffolds in EB patients without any observed infection or necrosis and instead noted fewer required dressing changes, promoted wound healing, pain reduction, and an overall improvement in the quality of life of the patients. Monitoring The Epidermolysis Bullosa Disease Activity and Scarring index (EBDASI) is a scoring system that objectively quantifies the severity of EB. The EBDASI is a tool for clinicians and patients to monitor the severity of the disease. It has also been designed to evaluate the response to new therapies for the treatment of EB. The EBDASI was developed and validated by Professor Dedee Murrell and her team of students and fellows at the St George Hospital, University of New South Wales, in Sydney, Australia. It was presented at the International Investigative Dermatology congress in Edinburgh in 2013 and a paper-based version was published in the Journal of the American Academy of Dermatology in 2014. Prognosis A 2014 study classified cases into three types—EBS, JEB and DEB—and reviewed their times of death. The first two types tended to die in infancy and the last in early adulthood. In a survey of 11 families affected by the disease, lack of awareness of the disease by both the public and health care providers raised concerns about the care provided. Epidemiology An estimated 20 per million live births are diagnosed with EB, and 9 per million people in the general population have the condition. Of these cases, approximately 92% are EBS, 5% are DEB, 1% are JEB, and 2% are unclassified. Carrier frequency ranges from 1 in 333 for JEB, to 1 in 450 for DEB; the carrier frequency for EBS is presumed to be much higher than JEB or DEB.The disorder occurs in every racial and ethnic group and affects both sexes. Society and culture In 2010, Emma Fogarty, a campaigner for DEBRA Ireland (the EB charity) was awarded a People of the Year Award. Actor Colin Farrell has campaigned with Fogarty on behalf of affected people.In 2014, Pearl Jam lead vocalist Eddie Vedder together with his wife Jill McCormick co-founded the EB Research Partnership, a non-profit organization dedicated to finding a cure for EB. McCormick is childhood friends with Ryan Fullmer, whose son, Michael, was born with EB. Vedder, McCormick, Ryan Fullmer, and his wife, Heather founded Heal EB. In 2014, they merged Heal EB with the Jackson Gabriel Research Foundation to create the EB Research Partnership. The EBRP hosts several annual fundraising events. To date, they have raised $12 million to fund research to find a cure. On March 1, 2019, heavyweight boxer Luis Ortiz was named an honorary ambassador for the EB community by the EB Research Partnership. Ortizs daughter, Lismercedes, was born with EB. Movies The condition was brought to public attention in 2004 in the UK through the Channel 4 documentary The Boy Whose Skin Fell Off, chronicling the life and death of Jonny Kennedy, an Englishman with EB. In the United States, the same could be said of the HBO documentary My Flesh and Blood from 2003. Additionally, the film Butterfly Girl follows Abigail Evans with the disease. In Canada, The Sports Networks award-winning documentary on Jonathan Pitre led to extensive coverage on the boys disease, treatment, and death. Other names Other terms used to describe those affected include "butterfly children" as the skin is fragile as a butterflys wings, "cotton wool babies", or "crystal skin children". References External links GeneReviews/NCBI/UW/NIH entry on Epidermolysis Bullosa Simplex Questions and Answers about Epidermolysis Bullosa - US National Institute of Arthritis and Musculoskeletal and Skin Diseases

Organophosphate poisoning

Organophosphate poisoning is poisoning due to organophosphates (OPs). Organophosphates are used as insecticides, medications, and nerve agents. Symptoms include increased saliva and tear production, diarrhea, vomiting, small pupils, sweating, muscle tremors, and confusion. While onset of symptoms is often within minutes to hours, some symptoms can take weeks to appear. Symptoms can last for days to weeks.Organophosphate poisoning occurs most commonly as a suicide attempt in farming areas of the developing world and less commonly by accident. Exposure can be from drinking, breathing in the vapors, or skin exposure. The underlying mechanism involves the inhibition of acetylcholinesterase (AChE), leading to the buildup of acetylcholine (ACh) in the body. Diagnosis is typically based on the symptoms and can be confirmed by measuring butyrylcholinesterase activity in the blood. Carbamate poisoning can present similarly.Prevention efforts include banning very toxic types of organophosphates. Among those who work with pesticides the use of protective clothing and showering before going home is also useful. In those who have organophosphate poisoning the primary treatments are atropine, oximes such as pralidoxime, and diazepam. General measures such as oxygen and intravenous fluids are also recommended. Attempts to decontaminate the stomach, with activated charcoal or other means, have not been shown to be useful. While there is a theoretical risk of health care workers taking care of a poisoned person becoming poisoned themselves, the degree of risk appears to be very small.OPs are one of the most common causes of poisoning worldwide. There are nearly 3 million poisonings per year resulting in two hundred thousand deaths. Around 15% of people who are poisoned die as a result. Organophosphate poisoning has been reported at least since 1962. Signs and symptoms The symptoms of organophosphate poisoning include muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis. Other symptoms include hypertension, and hypoglycemia. Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur.The effects of organophosphate poisoning on muscarinic receptors are recalled using the mnemonic SLUDGEM (salivation, lacrimation, urination, defecation, gastrointestinal motility, emesis, miosis) An additional mnemonic is MUDDLES: miosis, urination, diarrhea, diaphoresis, lacrimation, excitation, and salivation.The onset and severity of symptoms, whether acute or chronic, depends upon the specific chemical, the route of exposure (skin, lungs, or GI tract), the dose, and the individuals ability to degrade the compound, which the PON1 enzyme level will affect. Reproductive effects Certain reproductive effects in fertility, growth, and development for males and females have been linked specifically to OP pesticide exposure. Most of the research on reproductive effects has been conducted on farmers working with pesticides and insecticides in rural areas. For those males exposed to OP pesticides, poor semen and sperm quality have been seen, including reduced seminal volume and percentage motility, as well as a decrease in sperm count per ejaculate. In females menstrual cycle disturbances, longer pregnancies, spontaneous abortions, stillbirths, and some developmental effects in offspring have been linked to OP pesticide exposure. Prenatal exposure has been linked to impaired fetal growth and development. The effects of OP exposure on infants and children are at this time currently being researched to come to a conclusive finding. Evidence of OP exposure in pregnant mothers are linked to several health effects in the fetus. Some of these effects include delayed mental development, Pervasive developmental disorder (PDD), morphological abnormalities in the cerebral surface. Neurotoxic effects Neurotoxic effects have also been linked to poisoning with OP pesticides causing four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides. Cholinergic syndrome occurs in acute poisonings with OP pesticides and is directly related to levels of AChE activity. Symptoms include miosis, sweating, lacrimation, gastrointestinal symptoms, respiratory difficulties, shortness of breath, slowed heart rate, cyanosis, vomiting, diarrhea, trouble sleeping, as well as other symptoms. Along with these central effects can be seen and finally seizures, convulsions, coma, respiratory failure. If the person survives the first day of poisoning, personality changes can occur, in addition to aggressive behavior, psychotic episodes, memory and attention disturbances, and other delayed effects. When death occurs, it is most commonly due to respiratory failure due to paralysis of respiratory muscles and depression of central nervous system, which is responsible for respiration. For people affected by cholinergic syndrome, atropine sulfate combined with an oxime is used to combat the effects of the acute OP poisoning. Diazepam is sometimes also administered.The intermediate syndrome (IMS) appears in the interval between the end of the cholinergic crisis and the onset of OPIDP. Symptoms associated with IMS manifest between 24 and 96 hours after exposure. The exact etiology, incidence, and risk factors associated with IMS are not well understood, but IMS is recognized as a disorder of neuromuscular junctions. IMS occurs when a person has a prolonged and severe inhibition of AChE. It has been linked to specific OP pesticides such as parathion, methylparathion, and dichlorvos. Patients generally present with increasing weakness in the facial, neck flexor, and respiratory muscles. OPIDP occurs in a small percentage of cases, roughly two weeks after exposure, where temporary paralysis occurs. This loss of function and ataxia of peripheral nerves and spinal cord is the phenomenon of OPIDP. Once the symptoms begin with shooting pains in both legs, the symptoms continue to worsen for 3–6 months. In the most severe cases quadriplegia has been observed. Treatment only affects sensory nerves, not motor neurons which may permanently lose function. The aging and phosphorylation of more than 70% of functional NTE in peripheral nerves is one of the processes involved in OPIDP. Standard treatments for OP poisoning are ineffective for OPIDP. COPIND occurs without cholinergic symptoms and is independent of AChE inhibition. COPIND appears with a delay and is long lasting. Symptoms associated with COPIND include cognitive deficit, mood changes, autonomic dysfunction, peripheral neuropathy, and extrapyramidal symptoms. The underlying mechanisms of COPIND have not been determined, but it is hypothesized that withdrawal of OP pesticides after chronic exposure or acute exposure could be a factor. Pregnancy Evidence of exposure to OP pesticides during gestation and early postnatal period have been linked to neurodevelopmental effects in animals, specifically rats. Animals exposed in utero to chlorpyrifos exhibited decreased balance, poorer cliff avoidance, decreased locomotion, delays in maze performance, and increased gait abnormalities. Early gestation is believed to be a critical time period for the neurodevelopmental effects of pesticides. OPs affect the cholinergic system of fetuses, so exposure to chlorpyrifos during critical periods of brain development potentially could cause cellular, synaptic, and neurobehavioral abnormalities in animals. In rats exposed to methylparathion, studies found reduced AChE activity in all brain regions and subtle alterations in behaviors such as locomotor activity and impaired cage emergence. Organophosphates as whole have been linked to decreases in the length of limbs, head circumference, and slower rates of postnatal weight gain in mice. Cancer The International Agency for Research on Cancer (IARC) found that organophosphate exposure may increase cancer risk. Tetrachlorvinphos and parathion were classified as "possibly carcinogenic", malathion, and diazinon. Cause OP pesticide exposure occurs through inhalation, ingestion and dermal contact. Because OP pesticides degrade quickly when exposed to air and light, they have been considered relatively safe to consumers. However, OP residues may linger on fruits and vegetables. Certain OP pesticides have been banned for use on some crops, For example, methyl parathion is banned from use on some crops and permitted on others. It can also occur through deliberate poisoning using nerve agents such as sarin and tabun. Examples Insecticides including malathion, parathion, diazinon, fenthion, dichlorvos, chlorpyrifos, ethion, trichlorfon Nerve agents including soman, sarin, tabun, VX Herbicides including tribufos [DEF], merphos are tricresyl phosphate–containing industrial chemicals.Exposure to any of the above-listed organophosphates may occur through inhalation, skin absorption, and ingestion, most commonly of food that has been treated with an OP herbicide or insecticide. Exposure to these chemicals can occur at public buildings, schools, residential areas, and in agricultural areas. Chlorpyrifos and Malathion have been linked to reproductive effects, neurotoxicity, kidney/liver damage, and birth defects. Dichlorvos has also been linked to reproductive effects, neurotoxicity, and kidney/liver damage. It is also recognized to be a possible carcinogen. Pathophysiology The health effects associated with organophosphate poisoning are a result of excess acetylcholine (ACh) present at different nerves and receptors in the body because acetylcholinesterase is blocked. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When there is an accumulation of ACh at autonomic ganglia synapses this causes overstimulation of muscarinic expression in the parasympathetic nervous system. Organophosphates irreversibly and non-competitively inhibit acetylcholinesterase, causing poisoning by phosphorylating the serine hydroxyl residue on AChE, which inactivates AChE. AChE is critical for nerve function, so the inhibition of this enzyme, which causes acetylcholine accumulation, results in muscle overstimulation. This causes disturbances across the cholinergic synapses and can only be reactivated very slowly, if at all. Paraoxonase (PON1) is a key enzyme involved in OP toxicity and has been found to be critical in determining an organisms sensitivity to OP exposure. PON1 can inactivate some OPs through hydrolysis. PON1 hydrolyzes the active metabolites in several OP insecticides such as chlorpyrifos oxon, and diazoxon, as well as, nerve agents such as soman, sarin, and VX. PON1 hydrolyzes the metabolites, not the parent compounds of insectides. The presence of PON1 polymorphisms causes there to be different enzyme levels and catalytic efficiency of this esterase, which in turn suggests that different individuals may be more susceptible to the toxic effect of OP exposure. Higher levels of PON1 plasma hydrolytic activity provide a greater degree of protection against OP pesticides. Rats injected with purified PON1 from rabbit serum were more resistant to acute cholinergic activity than the control rats. PON1 knockouts in mice are found to be more sensitive to the toxicity of pesticides, like chlorpyrifos. Animal experiments indicate that while PON1 plays a significant role in regulating the toxicity of OPs its degree of protection given depends on the compound (i.e. Chlorpyrifos oxon or diazoxon). The catalytic efficiency with which PON1 can degrade toxic OPs determines the degree of protection that PON1 can provide for organism. The higher the concentration of PON1 the better the protection provided. PON1 activity is much lower in neonates, so neonates are more sensitive to OP exposure. In 2006, reports up to a 13-fold variation was seen in PON1 levels in adults, as well as, specifically regarding sensitivity to diazoxon, a variation up to 26 and 14-fold was reported in a group of newborns and Latino mothers. This wide range in variability of enzyme levels determining a humans sensitivity to various OPs is being researched further. Diagnosis A number of measurements exist to assess exposure and early biological effects for organophosphate poisoning. Measurements of OP metabolites in both the blood and urine can be used to determine if a person has been exposed to organophosphates. Specifically in the blood, metabolites of cholinesterases, such as butyrylcholinesterase (BuChE) activity in plasma, neuropathy target esterase (NTE) in lymphocytes, and of acetylcholinesterase (AChE) activity in red blood cells. Due to both AChE and BuChE being the main targets of organophosphates, their measurement is widely used as an indication of an exposure to an OP. The main restriction on this type of diagnosis is that depending on the OP, the degree to which either AChE or BuChE are inhibited differs; therefore, measure of metabolites in blood and urine do not specify which OP agent is responsible for the poisoning. However, for fast initial screening, determining AChE and BuChE activity in the blood are the most widely used procedures for confirming a diagnosis of OP poisoning. The most widely used portable testing device is the Test-mate ChE field test,: 13  which can be used to determine levels of Red Blood Cells (RBC), AChE and plasma (pseudo) cholinesterase (PChE) in the blood in about four minutes. This test has been shown to be just as effective as a regular laboratory test and because of this, the portable ChE field test is frequently used by people who work with pesticides on a daily basis. Treatment Current antidotes for OP poisoning consist of a pretreatment with carbamates to protect AChE from inhibition by OP compounds and post-exposure treatments with anti-cholinergic drugs. Anti-cholinergic drugs work to counteract the effects of excess acetylcholine and reactivate AChE. Atropine can be used as an antidote in conjunction with pralidoxime or other pyridinium oximes (such as trimedoxime or obidoxime), though the use of "-oximes" has been found to be of no benefit, or to be possibly harmful, in at least two meta-analyses. Atropine is a muscarinic antagonist, and thus blocks the action of acetylcholine peripherally. These antidotes are effective at preventing lethality from OP poisoning, but current treatment lack the ability to prevent post-exposure incapacitation, performance deficits, or permanent brain damage. While the efficacy of atropine has been well-established, clinical experience with pralidoxime has led to widespread doubt about its efficacy in treatment of OP poisoning.Enzyme bioscavengers are being developed as a pretreatment to sequester highly toxic OPs before they can reach their physiological targets and prevent the toxic effects from occurring. Significant advances with cholinesterases (ChEs), specifically human serum BChE (HuBChE) have been made. HuBChe can offer a broad range of protection for nerve agents including soman, sarin, tabun, and VX. HuBChE also possess a very long retention time in the human circulation system and because it is from a human source it will not produce any antagonistic immunological responses. HuBChE is currently being assessed for inclusion into the protective regimen against OP nerve agent poisoning. Currently there is potential for PON1 to be used to treat sarin exposure, but recombinant PON1 variants would need to first be generated to increase its catalytic efficiency. Another potential treatment being researched is the Class III anti-arrhythmic agents. Hyperkalemia of the tissue is one of the symptoms associated with OP poisoning. While the cellular processes leading to cardiac toxicity are not well understood, the potassium current channels are believed to be involved. Class III anti-arrhythmic agents block the potassium membrane currents in cardiac cells, which makes them a candidate for become a therapeutic of OP poisoning.There is insufficient evidence to support using plasma alkalinisation to treat a person with organophosphate poisoning. Epidemiology Organophosphate pesticides are one of the top causes of poisoning worldwide, with an annual incidence of poisonings among agricultural workers varying from 3-10% per country. History Ginger Jake A striking example of OPIDN occurred during the 1930s Prohibition Era when thousands of men in the American South and Midwest developed arm and leg weakness and pain after drinking a "medicinal" alcohol substitute. The drink, called "Ginger Jake," contained an adulterated Jamaican ginger extract containing tri-ortho-cresyl phosphate (TOCP) which resulted in partially reversible neurologic damage. The damage resulted in the limping "Jake Leg" or "Jake Walk" which were terms frequently used in the blues music of the period. Europe and Morocco both experienced outbreaks of TOCP poisoning from contaminated abortifacients and cooking oil, respectively. Gulf War syndrome Research has linked the neurological abnormalities found in Persian Gulf War veterans who have chronic multisymptom illnesses to exposure to wartime combinations of organophosphate chemical nerve agents. Before, it was believed that veterans had a psychologically based disorder or depression, most likely post-traumatic stress disorder (PTSD). Many veterans were given pyridostigmine bromide (PB) pills to protect against nerve gas agents such as sarin and soman. During the war veterans were exposed to combinations of organophosphate pesticides and nerve agents, which produced symptoms associated with chronic organophosphate-induced delayed polyneuropathy (OPIDP) syndrome. Similar symptoms found in the veterans were the same symptoms reported for individuals in occupational settings who were acutely poisoned by organophosphates, such as chlorpyrifos. Studies found veterans experienced deficits in intellectual and academic abilities, simple motor skills, memory impairment, and impaired emotional function. These symptoms indicate brain damage, not a psychologically based disorder. Society and culture United States Under a 1988 amendment to the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), the U.S. Environmental Protection Agency (EPA) regulates organophosphate pesticides Its focus was initially on registering pesticides for use on food crops. No pesticide can be sold in the United States before the EPA has reviewed the manufacturers application for registration and determined that the use of the product will not present an unreasonable risk to the public or the environment. In 1996, with the passage of the Food Quality Protection Act, Congress required the EPA to reassess all existing pesticide tolerances with specific consideration for children. This resulted in a 10-year review process of the health and environmental effects of all pesticides, beginning with the organophosphates. As part of that process, in 1999 the EPA announced a ban the use of organophosphate pesticide methyl parathion and significant restrictions on the use of another OP, azinphos methyl, in what they called "kids food". The review process was concluded in 2006 and eliminated or modified thousands of other uses of pesticides. Other legislative action has been taken to protect children from the risks of organophosphates. Many non-governmental and research groups, as well as the EPAs Office of Inspector General, have expressed concerns that the review did not take into account possible neurotoxic effects on developing fetuses and children, an area of developing research. OIG report. A group of leading EPA scientists sent a letter to the chief administrator, Stephen Johnson, decrying the lack of developmental neurotoxicity data in the review process. EPA Letter EHP article New studies have shown toxicity to developing organisms during certain "critical periods" at doses much lower than those previously suspected to cause harm.Even the restrictions which did successfully pass have been controversial. For example, in 1999 the EPA restricted the use of chlorpyrifos in households (under the commercial name Dursban). However, the EPA did not limit its use in agriculture. Chlorpyrifos remains one of the most widely used pesticides. This may soon change. On February 8, 2013, the EPA requested comment on a preliminary evaluation of the potential risks to children and other bystanders from volatilization of chlorpyrifos from treated crops Vulnerable groups Some populations are more vulnerable to pesticide poisoning. In the United States, farmworkers can be exposed via direct spray, drift, spills, direct contact with treated crops or soil, or defective or missing protective equipment. Migrant workers may be at an especially high risk of chronic exposure as over the course of a growing season, they may work at multiple farms, thus increasing their exposure to pesticides. Farmworkers in more permanent positions may receive more safety training and/or more "consistent reinforcement of safety behaviors than seasonal farmworkers or day laborers." For migrant farmworkers, language barriers and/or education level could be a barrier to understanding posted warning signs, labels and safety warnings located on the pesticides, or understanding any safety training that is provided.Other factors that may lead to greater exposure for the migrant farmworker population include: limited or no access to safety equipment, little to no control over pesticide use, cultural factors, and fear of job loss if they report potential hazards. Studies have also shown that there are some key beliefs by farmworkers that may exacerbate pesticide exposure, including the belief that "pesticides must be felt, seen, tasted, or smelled to be present; the skin blocks absorption and body openings facilitate it; exposure occurs only when a pesticide is wet;…and acute, not low-level chronic exposure is the primary danger."This, coupled with the difficulty or uncertainty of recognizing and/or diagnosing chronic pesticide poisoning by the medical community, makes it difficult for exposed workers to receive an effective remedy. Migrant workers may also be hesitant to seek-out medical care due to lack of health insurance, language barriers, immigration status, cost, cultural factors, lack of transportation, fear of job loss, and lack of awareness of workers compensation benefits. Sergei and Yulia Skripal In March 2018, Sergei Skripal and his daughter were poisoned in Salisbury, England, with an organophosphate poison known as a Novichok agent. Both fell unconscious while sitting on a park bench. A first responder to the scene also became contaminated and had symptoms of organophosphate poisoning. All three survived after hospital treatment. Despite continually denying responsibility for the attack, Russia is suspected to be behind the poisonings. Alexei Navalny On 20 August 2020, Russian politician Alexei Navalny developed life-threatening acute poisoning symptoms on a flight. He was later transferred to Berlin, where poisoning by a cholinesterase inhibitor was diagnosed and confirmed by multiple tests in independent laboratories. == References ==

Retropharyngeal abscess

Retropharyngeal abscess (RPA) is an abscess located in the tissues in the back of the throat behind the posterior pharyngeal wall (the retropharyngeal space). Because RPAs typically occur in deep tissue, they are difficult to diagnose by physical examination alone. RPA is a relatively uncommon illness, and therefore may not receive early diagnosis in children presenting with stiff neck, malaise, difficulty swallowing, or other symptoms listed below. Early diagnosis is key, while a delay in diagnosis and treatment may lead to death. Parapharyngeal space communicates with retropharyngeal space and an infection of retropharyngeal space can pass down behind the esophagus into the mediastinum. RPAs can also occur in adults of any age. RPA can lead to airway obstruction or sepsis – both life-threatening emergencies. Fatalities normally occur from patients not receiving treatment immediately and suffocating prior to knowing that anything serious was wrong. Signs and symptoms Signs and symptoms may include the following stiff neck (limited neck mobility or torticollis), some form of palpable neck pain (may be in "front of the neck" or around the Adams Apple), malaise, difficulty swallowing, fever, stridor, drooling, croup-like cough or enlarged cervical lymph nodes. Any combination of these symptoms should arouse suspicion of RPA. Causes RPA is usually caused by a bacterial infection originating from the nasopharynx, tonsils, sinuses, adenoids, molar teeth or middle ear. Any upper respiratory infection (URI) can be a cause. RPA can also result from a direct infection due to penetrating injury or a foreign body. RPA can also be linked to young children who do not have adequate dental care or brush their teeth properly. Diagnosis A computed tomography (CT) scan is the definitive diagnostic imaging test.X-ray of the neck often (80% of the time) shows swelling of the retropharyngeal space in affected individuals. If the retropharyngeal space is more than half of the size of the C2 vertebra, it may indicate retropharyngeal abscess. Treatment RPAs frequently require surgical intervention. A tonsillectomy approach is typically used to access/drain the abscess, and the outcome is usually positive. Surgery in adults may be done without general anesthesia because there is a risk of abscess rupture during tracheal intubation. This could result in pus from the abscess aspirated into the lungs. In complex cases, an emergency tracheotomy may be required to prevent upper airway obstruction caused by edema in the neck.High-dose intravenous antibiotics are required in order to control the infection and reduce the size of the abscess prior to surgery. Chronic retropharyngeal abscess is usually secondary to tuberculosis and the patient needs to be started on anti-tubercular therapy as soon as possible. References == External links ==

Cryoglobulinemia

Cryoglobulinemia is a medical condition in which the blood contains large amounts of pathological cold sensitive antibodies called cryoglobulins – proteins (mostly immunoglobulins themselves) that become insoluble at reduced temperatures. This should be contrasted with cold agglutinins, which cause agglutination of red blood cells. Cryoglobulins typically precipitate (clumps together) at temperatures below normal body temperature – 37 degrees Celsius (99 degrees Fahrenheit) – and will dissolve again if the blood is heated. The precipitated clump can block blood vessels and cause toes and fingers to become gangrenous. While this disease is commonly referred to as cryoglobulinemia in the medical literature, it is better termed cryoglobulinemic disease for two reasons: 1) cryoglobulinemia is also used to indicate the circulation of (usually low levels of) cryoglobulins in the absence of any symptoms or disease and 2) healthy individuals can develop transient asymptomatic cryoglobulinemia following certain infections.In contrast to these benign instances of circulating cryoglobulins, cryoglobulinemic disease involves the signs and symptoms of precipitating cryoglobulins and is commonly associated with various pre-malignant, malignant, infectious, or autoimmune diseases that are the underlying cause for production of the cryoglobulins. Classification Since the first description of cryoglobulinemia in association with the clinical triad of skin purpura, joint pain, and weakness by Meltzer et al. in 1967, the percentage of cryoglobulinemic diseases described as essential cryoglobulinemia or idiopathic cryoglobulinemia, that is cryoglobulinemic disease that is unassociated with an underlying disorder, has fallen. Currently most cases of this disease are found to be associated with premalignant, malignant, infectious, or autoimmune disorders that are the known or presumed causes for the production of cryoglobulins. This form of non-essential or non-idiopathic cryoglobulinemic disease is classically grouped into three types according to the Brouet classification. The classification distinguishes three subtypes of cryoglobulinemic diseases based on two factors, the class of immunoglobulins in the cryoglobulin and the association of the cryoglobulinemic disease with other disorder. The following table lists these three types of cryoglobulinemic disease, characterized on the monoclonal immunoglobulin(s) comprising the involved cryoglobulin, percentage of total cryoglobulinemic disease cases, and class of disorders associated for each type. The monoclonal or polyclonal IgM proteins involved in Types II and III cryoglobulinemic disease have rheumatoid factor activity. That is, they bind to polyclonal immunoglobulins, activate the blood complement system, and thereby form tissue deposits that contain IgM, IgG (or, rarely, IgA), and components of the complement system, including in particular complement component 4. The vascular deposition of these types of cryoglobulin-containing immune complexes and complement can cause a clinical syndrome of cutaneous small-vessel vasculitis characterized by systemic vasculitis and inflammation termed cryoglobulinemic vasculitis. Accordingly, type II and type III cryoglobulinemic diseases are often grouped together and referred to as mixed cryoglobulinemia or mixed cryoglobulinemic disease. The monoclonal IgM involved in Type I cryoglobulinemic diseases lacks rheumatoid factor activity.More recent high resolution protein electrophoresis methods have detected a small monoclonal immunoglobulin component in type III cryoglobulins and/or a micro-heterogeneous composition of oligo-clonal (i.e., more than one monoclonal) immunoglobulin components or immunoglobulins with structures that do not fit into any classifications in the cryoglobulins of ≈10% of type II and III disease cases. It has been proposed that these cases be termed an intermediate type II-III variant of cryoglobulinemic disease and that some of the type III cases associated with the expression of low levels of a one or more isotypes of circulating monoclonal immunoglobulin(s) are in transition to type II disease. Signs and symptoms The clinical features of cryoglobulinemic disease can reflect those due not only to the circulation of cryoglobulins but also to any underlying hematological premalignant or malignant disorder, infectious disease, or autoimmune syndrome. The following sections of clinical features focuses on those attributed to the cryoglobulins. Cryoglobulins cause tissue damage by three mechanisms; they can: a) increase blood viscosity thereby reducing blood flow to tissues to cause the hyperviscosity syndrome (i.e., headache, confusion, blurry or loss of vision, hearing loss, and epistaxis; b) deposit in small arteries and capillaries thereby plugging these blood vessels and causing infarction and necrosis of tissues including in particular skin (e.g., ears), distal extremities, and kidneys; c) in type II and type III disease, deposit on the endothelium of blood vessels and activate the blood complement system to form pro-inflammatory elements such as C5a thereby initiating the systemic vascular inflammatory reaction termed cryoglobulinemic vasculitis. Essential cryoglobulinemic disease The signs and symptoms in the increasingly rare cases of cryoglobulinemic disease that cannot be attributed to an underlying disease generally resemble those of patients suffering Type II and III (i.e., mixed) cryoglobulinemic disease. Type I cryoglobulinemic disease Signs and symptoms due to the cryoglobulins of type I disease reflect the hyperviscosity and deposition of cryoglobulins within the blood vessels which reduce or stop blood perfusion to tissues. These events occur particularly in cases where blood cryoglobulin levels of monoclonal IgM are high in patients with IgM MGUS, smoldering Waldenströms macroglobulinemia, or Waldenströms macroglobulinemia and in uncommon cases where the levels of monoclonal IgA, IgG, free κ light chains, or free λ light chains are extremely high in patients with non-IgM MGUS, non-IgM smoldering multiple myeloma, or multiple myeloma. The interruption of blood flow to neurological tissues can cause symptoms of confusion, headache, hearing loss, and peripheral neuropathy. Interruption of blood flow to other tissues in type I disease can cause cutaneous manifestations of purpura, blue discoloration of the arms or legs (acrocyanosis), necrosis, ulcers, and livedo reticularis; spontaneous nose bleeds, joint pain, membranoproliferative glomerulonephritis; and cardiovascular disturbances such as shortness of breath, inadequate levels of oxygen in the blood (hypoxemia), and congestive heart failure. Types II and III cryoglobulinemic disease Types II and III (or mixed or variant) cryoglobulinemic disease may also present with symptoms and signs of blood hyperviscosity syndrome and deposition of cryoglobulins within blood vessels but also include those attributable to cryoglobulinemic vasculitis. "Meltzers triad" of palpable purpura, joint pain, and generalized weakness occurs in ≈33% of patients presenting with type II or type III disease. One or more skin lesions including palpable purpura, ulcers, digital gangrene, and areas of necrosis occur in 69-89% of these mixed disease cases (see attached photograph); less common findings include painful peripheral neuropathy (often manifesting as mononeuritis multiplex in 19-44% of cases), kidney disease (primarily membranoproliferative glomerulonephritis (30%), joint pain (28%), and, less commonly, dry eye syndrome, Raynaud phenomenon (i.e., episodic painful reductions in blood flow to the fingers and toes). While the glomerulonephritis occurring in mixed disease appears to be due to inflammatory vasculitis, the glomerulonephritis occurring in type I disease appears due to the interruption of blood flow. The hematological, infectious, and autoimmune diseases underlying type II cryoglobulinemic disease and the infectious and autoimmune diseases underlying type III cryoglobulinemic disease are also critical parts of the diseases clinical findings. Mechanism Cryoglobulins Cryoglobulins consists of one or more of the following components: monoclonal or polyclonal IgM, IgG, IgA antibodies, monoclonal κ, or λ free light chain portions of these antibodies, and proteins of the blood complement system, particularly complement component 4 (C4). The particular components involved are a reflection of the disorders which are associated with, and considered to be the cause of, the cryoglobulinemic disease. The cryoglobulin compositions and disorder associations in cryoglobulinemic disease are as follows: Monoclonal IgM-based cryoglobulin occurs in cases of Waldenströms macroglobulinemia and the pre-malignant precursors to this cancer, IgM monoclonal gammopathy of undetermined significance and smoldering Waldenstroms macroglobulinemia. Monoclonal IgG or, rarely, IgA, κ light chain, or λ light chain cryoglobulins occur in cases of multiple myeloma and the pre-malignant precursors to this cancer, non-IgM monoclonal gammopathy of undetermined significance and non-IgM smoldering multiple myeloma. Non-IgM monoclonal immunoglobulin-based cases of cryoglobulinemic disease are less commonly associated with other B-cell lymphocytic diseases viz., Non-Hodgkin lymphoma, Hodgkin lymphoma, B-cell chronic lymphocytic leukemia, and Castleman disease; they occur rarely in non-B cell hematological disorders such as myelodysplastic syndromes and chronic myelogenous leukemia. Among these purely monoclonal immunoglobulin causes of cryoglobulinemic disease, Waldenström macroglobulinemia and multiple myeloma together account for ≈40% of cases; their pre-malignant precursors account for ≈44% of cases; and the other cited hematological diseases account for ≈16% of cases. Mixtures of monoclonal or polyclonal IgM, IgG, and/or IgA along with blood complement proteins such as C4 are the cryoglobulins associated with cases of infectious diseases, particularly hepatitis C infection, HIV infection, and Hepatitis C and HIV coinfection, and, less commonly or rarely, with cases of other infectious diseases such as hepatitis B infection, hepatitis A infection, cytomegalovirus infection, Epstein–Barr virus infection, Lyme disease, syphilis, lepromatous leprosy, Q fever, poststreptococcal nephritis, subacute bacterial endocarditis, coccidioidomycosis, malaria, schistosomiasis, echinococcosis, toxoplasmosis, and Kala-azar. These mixed-protein cryoglobulins are also associated with autoimmune diseases, particularly Sjögren syndrome, less commonly systemic lupus erythematosus and rheumatoid arthritis, and rarely polyarteritis nodosa, systemic sclerosis, temporal arteritis, polymyositis, Henoch–Schönlein purpura, pemphigus vulgaris, sarcoidosis, inflammatory bowel diseases, and others. In these mixed-protein depositions, the monoclonal or polyclonal IgM typically possesses rheumatoid factor activity and therefore binds to the Fc region of polyclonal IgG antibodies, activates the blood complement system, and complexes with complement components to form precipitates composed of IgM, IgG or IgG, and complement components, particularly complement component 4 (C4). Diagnosis Cryoglobulinemia and cryoglobulinemic disease must be distinguished from cryofibrinogenemia or cryofibrinogenemic disease, conditions which involve the cold-induced intravascular deposition of circulating native fibrinogens. These molecules precipitate at lower temperatures (e.g., 4 °C). Since cryofibrinogens are present in plasma but greatly depleted in serum, precipitation tests for them are positive in plasma but negative in serum. Cryofibrinogenemia is occasionally found in cases of cryoglobulinemic disease. Cryoglobulinemic disease must also be distinguished from frostbite as well as numerous other conditions that have a clinical (particularly cutaneous) presentation similar to cryoglobulinemic disease but are not exacerbated by cold temperature, e.g., dysfibrinogenemia and dysfibrinogenemic disease (conditions involving the intravascular deposition of genetically abnormal circulating fibrinogens), purpura fulminans, cholesterol emboli, warfarin necrosis, ecthyma gangrenosum, and various hypercoagulable states.Rheumatoid factor is a sensitive test for cryoglobulinemia. The precipitated cryoglobulins are examined by immunoelectrophoresis and immunofixation to detect and quantify the presence of monoclonal IgG, IgM, IgA, κ light chain, or λ light chain immunoglobins. Other routine tests include measuring blood levels of rheumatoid factor activity, complement C4, other complement components, and hepatitic C antigen. Biopsies of skin lesions and, where indicated, kidney or other tissues can help in determining the nature of the vascular disease (immunoglobulin deposition, cryoglobulinemic vasculitis, or, in cases showing the presence of cryfibrinogenemia, fibrinogen deposition. In all events, further studies to determine the presence of hematological, infections, and autoimmune disorders are conducted on the basis of these findings as well as each cases clinical findings. Treatment All patients with symptomatic cryoglobulinemia are advised to avoid, or protect their extremities, from exposure to cold temperatures. Refrigerators, freezers, and air-conditioning represent dangers of such exposure. Asymptomatic cryoglobulinemia Individuals found to have circulating cryoglobulins but no signs or symptoms of cryoglobulinemic diseases should be evaluated for the possibility that their cryoglobulinemia is a transient response to a recent or resolving infection. Those with a history of recent infection that also have a spontaneous and full resolution of their cryoglobulinemia need no further treatment. Individuals without a history of infection and not showing resolution of their cryoglobulinemia need to be further evaluated. Their cryoglobulins should be analyzed for their composition of immunoglobulin type(s) and complement component(s) and examined for the presence of the premalignant and malignant diseases associated with Type I disease as well as the infectious and autoimmune diseases associated with type II and type III disease. A study conducted in Italy on >140 asymptomatic individuals found five cases of hepatitis C-related and one case of hepatitis b-related cryoglobulinemia indicating that a complete clinical examination of asymptomatic individuals with cryoglobulinemia offers a means for finding people with serious but potentially treatable and even curable diseases. Individuals who show no evidence of a disease underlying their cryoglobulinemia and who remain asymptomatic should be followed closely for any changes that may indicate development of cryoglobulinemic disease. Severely symptomatic cryoglobulinemic disease People affected by the severest, often life-threatening, complications of cryoglobulinemic disease require urgent plasmapharesis and/or plasma exchange in order to rapidly reduce the circulating levels of their cryoglobulins. Complications commonly requiring this intervention include: hyperviscosity disease with severe symptoms of neurological (e.g., stroke, mental impairment, and myelitis) and/or cardiovascular (e.g., congestive heart failure, myocardial infarction) disturbances; vasculitis-driven intestinal ischemia, intestinal perforation, cholecystitis, or pancreatitis, causing acute abdominal pain, general malaise, fever, and/or bloody bowel movements; vasculitis-driven pulmonary disturbances (e.g., coughing up blood, acute respiratory failure, X-ray evidence of diffuse pulmonary infiltrates caused by diffuse alveolar hemorrhage); and severe kidney dysfunction due to intravascular deposition of immunoglobulins or vasculitis. Along with this urgent treatment, severely symptomatic patients are commonly started on therapy to treat any underlying disease; this treatment is often supplemented with anti-inflammatory drugs such as corticosteroids (e.g., dexamethasone) and/or immunosuppressive drugs. Cases where no underlying disease is known are also often treated with the latter corticosteroid and immunosuppressive medications. Type I cryoglobulinemic disease Treatment of Type I disease is generally directed towards treating the underlying pre-malignant or malignant disorder (see plasma cell dyscrasia, Waldenströms macroglobulinemia, and chronic lymphocytic leukemia). This involves appropriate chemotherapy regimens which may include bortezomib (promotes cell death by apoptosis in cells accumulating immunoglobulins) in patients with monoclonal immunoglobulin-induced kidney failure and rituximab (antibody directed against CD20 surface antigen-bearing lymphocytes) in patients with Waldenstroms macroglobulonemia). Type II and III cryoglobulinemic disease Treatment of mixed cryoglobulinemic disease is, similar to type I disease, directed toward treating any underlying disorder. This includes malignant (particularly Waldenströms macroglobulinemia in type II disease), infectious, or autoimmune diseases in type II and III disease. Recently, evidence of hepatitis C infection has been reported in the majority of mixed disease cases with rates being 70-90% in areas with high incidences of hepatitis C. The most effective therapy for hepatitis C-associated cryoglobulinemic disease consists of a combination of anti-viral drugs, pegylated INFα and ribavirin; depletion of B cells using rituximab in combination with antiviral therapy or used alone in patients refractory to antiviral therapy has also proven successful in treating the hepatitis C-associated disease. Data on the treatment of infectious causes other than hepatitis C for the mixed disease are limited. A current recommendation treats the underlying disease with appropriate antiviral, anti-bacterial, or anti-fungal agents, if available; in cases refractory to an appropriate drug, the addition of immunosuppressive drugs to the therapeutic regimen may improve results. Mixed cryoglobulinemic disease associated with autoimmune disorders is treated with immunosuppressive drugs: combination of a corticosteroid with either cyclophosphamide, azathioprine, or mycophenolate or combination of a corticosteroid with rituximab have been used successfully to treated mixed disease associated with autoimmune disorders. See also Cryofibrinogenemia Cryoglobulinemic purpura Cryoglobulinemic vasculitis Dysfibrinogenemia Hematopoietic ulcer Hyperviscosity syndrome Paraproteinemia Plasma cell dyscrasias References == External links ==

Lyme disease

Lyme disease, also known as Lyme borreliosis, is a vector-borne disease caused by the Borrelia bacterium, which is spread by ticks in the genus Ixodes. The most common sign of infection is an expanding red rash, known as erythema migrans, which appears at the site of the tick bite about a week afterwards. The rash is typically neither itchy nor painful. Approximately 70–80% of infected people develop a rash. Early diagnosis can be difficult. Other early symptoms may include fever, headaches and tiredness. If untreated, symptoms may include loss of the ability to move one or both sides of the face, joint pains, severe headaches with neck stiffness or heart palpitations. Months to years later repeated episodes of joint pain and swelling may occur. Occasionally shooting pains or tingling in the arms and legs may develop. Despite appropriate treatment about 10 to 20% of those affected develop joint pains, memory problems and tiredness for at least six months.Lyme disease is transmitted to humans by the bites of infected ticks of the genus Ixodes. In the United States ticks of concern are usually of the Ixodes scapularis type and must be attached for at least 36 hours before the bacteria can spread. In Europe Ixodes ricinus ticks may spread the bacteria more quickly. In North America the bacteria Borrelia burgdorferi and B. mayonii cause Lyme disease. In Europe and Asia Borrelia afzelii, Borrelia garinii, B. spielmanii and four other species also cause the disease. The disease does not appear to be transmissible between people, by other animals nor through food. Diagnosis is based on a combination of symptoms, history of tick exposure and possibly testing for specific antibodies in the blood. Blood tests are often negative in the early stages of the disease. Testing of individual ticks is not typically useful.Prevention includes efforts to prevent tick bites by wearing clothing to cover the arms and legs and using DEET or picaridin-based insect repellents. Using pesticides to reduce tick numbers may also be effective. Ticks can be removed using tweezers. If the removed tick is full of blood a single dose of doxycycline may be used to prevent the development of infection but is not generally recommended since the development of infection is rare. If an infection develops, a number of antibiotics are effective, including doxycycline, amoxicillin and cefuroxime. Standard treatment usually lasts for two or three weeks. Some people develop a fever and muscle and joint pains from treatment, which may last for one or two days. In those who develop persistent symptoms, long-term antibiotic therapy has not been found to be useful.Lyme disease is the most common disease spread by ticks in the Northern Hemisphere. An estimated 476,000 people a year are diagnosed and treated for the disease in the United States, and over 200,000 people a year in Western Europe. Infections are most common in the spring and early summer. Lyme disease was diagnosed as a separate condition for the first time in 1975 in Lyme, Connecticut. It was originally mistaken for juvenile rheumatoid arthritis. The bacterium involved was first described in 1981 by Willy Burgdorfer. Chronic symptoms following treatment are known as "post-treatment Lyme disease syndrome" (PTLDS). PTLDS is different from chronic Lyme disease, a term no longer supported by scientists and used in different ways by different groups. Some healthcare providers claim that PTLDS is caused by persistent infection but this is not believed to be true because no evidence of persistent infection can be found after standard treatment.No human vaccines for Lyme disease are currently available, although research is ongoing. Multiple vaccines are available for the prevention of Lyme disease in dogs. Signs and symptoms Lyme disease can affect several body systems and produce a broad range of symptoms. Not everyone with Lyme disease has all of the symptoms and many of the symptoms are not specific to Lyme disease but can occur with other diseases as well.The incubation period from infection to the onset of symptoms is usually one to two weeks but can be much shorter (days) or much longer (months to years). Lyme symptoms most often occur from May to September in the northern hemisphere because the nymphal stage of the tick is responsible for most cases. Asymptomatic infection exists but occurs in less than 7% of infected individuals in the United States. Asymptomatic infection may be much more common among those infected in Europe. Early localized infection Early localized infection can occur when the infection has not yet spread throughout the body. Only the site where the infection has first come into contact with the skin is affected. The initial sign of about 80% of Lyme infections is an erythema migrans (EM) rash at the site of a tick bite, often near skin folds such as the armpit, groin or back of the knee, on the trunk, under clothing straps, or in childrens hair, ears or neck. Most people who get infected do not remember seeing a tick or a bite. The rash appears typically one or two weeks (range 3–32 days) after the bite and expands 2–3 cm per day up to a diameter of 5–70 cm (median 16 cm). The rash is usually circular or oval, red or bluish, and may have an elevated or darker center. In about 79% of cases in Europe but only 19% of cases in endemic areas of the U.S. the rash gradually clears from the center toward the edges, possibly forming a "bulls eye" pattern. The rash may feel warm but usually is not itchy, is rarely tender or painful and takes up to four weeks to resolve if untreated.The EM rash is often accompanied by symptoms of a viral-like illness, including fatigue, headache, body aches, fever and chills but usually not nausea or upper-respiratory problems. These symptoms may also appear without a rash or linger after the rash has disappeared. Lyme can progress to later stages without these symptoms or a rash.People with high fever for more than two days or whose other symptoms of viral-like illness do not improve despite antibiotic treatment for Lyme disease, or who have abnormally low levels of white or red cells or platelets in the blood, should be investigated for possible coinfection with other tick-borne diseases such as ehrlichiosis and babesiosis. Early disseminated infection Within days to weeks after the onset of local infection the Borrelia bacteria may spread through the lymphatic system or bloodstream. In 10–20% of untreated cases EM rashes develop at sites across the body that bear no relation to the original tick bite. Transient muscle pains and joint pains are also common.In about 10–15% of untreated people Lyme causes neurological problems known as neuroborreliosis. Early neuroborreliosis typically appears 4–6 weeks (range 1–12 weeks) after the tick bite and involves some combination of lymphocytic meningitis, cranial neuritis, radiculopathy and/or mononeuritis multiplex. Lymphocytic meningitis causes characteristic changes in the cerebrospinal fluid (CSF) and may be accompanied for several weeks by variable headache and, less commonly, usually mild meningitis signs such as inability to flex the neck fully and intolerance to bright lights but typically no or only very low fever. After several months neuroborreliosis can also present otolaryngological symptoms. Up to 76.5% of these otolaryngological present as tinnitus, the most common symptom. Vertigo and dizziness (53.7%) and hearing loss (16.7%) were the next most common symptoms. In children partial loss of vision may also occur. Cranial neuritis is an inflammation of cranial nerves. When due to Lyme it most typically causes facial palsy, impairing blinking, smiling and chewing on one or both sides of the face. It may also cause intermittent double vision. Lyme radiculopathy is an inflammation of spinal nerve roots that often causes pain and less often weakness, numbness, or altered sensation in the areas of the body served by nerves connected to the affected roots, e.g. limb(s) or part(s) of trunk. The pain is often described as unlike any other previously felt, excruciating, migrating, worse at night, rarely symmetrical, and often accompanied by extreme sleep disturbance. Mononeuritis multiplex is an inflammation causing similar symptoms in one or more unrelated peripheral nerves. Rarely, early neuroborreliosis may involve inflammation of the brain or spinal cord, with symptoms such as confusion, abnormal gait, ocular movements, or speech, impaired movement, impaired motor planning, or shaking.In North America, facial palsy is the typical early neuroborreliosis presentation, occurring in 5–10% of untreated people, in about 75% of cases accompanied by lymphocytic meningitis. Lyme radiculopathy is reported half as frequently, but many cases may be unrecognized. In European adults, the most common presentation is a combination of lymphocytic meningitis and radiculopathy known as Bannwarth syndrome, accompanied in 36-89% of cases by facial palsy. In this syndrome, radicular pain tends to start in the same body region as the initial erythema migrans rash, if there was one, and precedes possible facial palsy and other impaired movement. In extreme cases, permanent impairment of motor or sensory function of the lower limbs may occur. In European children, the most common manifestations are facial palsy (in 55%), other cranial neuritis, and lymphocytic meningitis (in 27%).In about 4–10% of untreated cases in the U.S. and 0.3–4% of untreated cases in Europe, typically between June and December, about one month (range 4 days-7 months) after the tick bite, the infection may cause heart complications known as Lyme carditis. Symptoms may include heart palpitations (in 69% of people), dizziness, fainting, shortness of breath, and chest pain. Other symptoms of Lyme disease may also be present, such as EM rash, joint aches, facial palsy, headaches, or radicular pain. In some people, however, carditis may be the first manifestation of Lyme disease. Lyme carditis in 19–87% of people adversely impacts the hearts electrical conduction system, causing atrioventricular block that often manifests as heart rhythms that alternate within minutes between abnormally slow and abnormally fast. In 10–15% of people, Lyme causes myocardial complications such as cardiomegaly, left ventricular dysfunction, or congestive heart failure.Another skin condition, found in Europe but not in North America, is borrelial lymphocytoma, a purplish lump that develops on the ear lobe, nipple, or scrotum. Late disseminated infection Lyme arthritis occurs in up to 60% of untreated people, typically starting about six months after infection. It usually affects only one or a few joints, often a knee or possibly the hip, other large joints, or the temporomandibular joint. There is usually large joint effusion and swelling, but only mild or moderate pain. Without treatment, swelling and pain typically resolve over time but periodically return. Bakers cysts may form and rupture. In early US studies of Lyme disease, a rare peripheral neuropathy was described that included numbness, tingling or burning starting at the feet or hands and over time possibly moving up the limbs. In a later analysis that discovered poor documentation of this manifestation, experts wondered if it exists at all in the US or is merely very rare.A neurologic syndrome called Lyme encephalopathy is associated with subtle memory and cognitive difficulties, insomnia, a general sense of feeling unwell, and changes in personality. However, problems such as depression and fibromyalgia are as common in people with Lyme disease as in the general population.Acrodermatitis chronica atrophicans (ACA) is a chronic skin disorder observed primarily in Europe among the elderly. ACA begins as a reddish-blue patch of discolored skin, often on the backs of the hands or feet. The lesion slowly atrophies over several weeks or months, with the skin becoming first thin and wrinkled and then, if untreated, completely dry and hairless. ACA is also associated with peripheral neuropathy. Cause Lyme disease is caused by spirochetes, spiral bacteria from the genus Borrelia. Spirochetes are surrounded by peptidoglycan and flagella, along with an outer membrane similar to Gram-negative bacteria. Because of their double-membrane envelope, Borrelia bacteria are often mistakenly described as Gram negative despite the considerable differences in their envelope components from Gram-negative bacteria. The Lyme-related Borrelia species are collectively known as Borrelia burgdorferi sensu lato, and show a great deal of genetic diversity.B. burgdorferi sensu lato is a species complex made up of 20 accepted and three proposed genospecies. Eight species are known to cause Lyme disease: B. mayonii (found in North America), B. burgdorferi sensu stricto, (found in North America and Europe), B. afzelii, B. garinii, B. spielmanii, and B. lusitaniae (all found in Eurasia). Some studies have also proposed that B. valaisiana may sometimes infect humans, but this species does not seem to be important causes of disease. Tick life cycle There are three stages in the life cycle of a tick. Larva, nymph, and adult. During the nymph stage, ticks most frequently transmit Lyme disease and are usually most active in late spring and early summer in regions where the climate is mild. During the adult stage, Lyme disease transmission is less common due to the fact that it is less possible for adult ticks to bite humans and because they tend to be larger in size and therefore can be easily seen and removed. Transmission Lyme disease is classified as a zoonosis, as it is transmitted to humans from a natural reservoir among small mammals and birds by ticks that feed on both sets of hosts. Hard-bodied ticks of the genus Ixodes are the vectors of Lyme disease (also the vector for Babesia). Most infections are caused by ticks in the nymphal stage, because they are very small and thus may feed for long periods of time undetected. Nymphal ticks are generally the size of a poppy seed and sometimes with a dark head and a translucent body. Or, the nymphal ticks can be darker. (The younger larval ticks are very rarely infected.) Although deer are the preferred hosts of adult deer ticks, and tick populations are much lower in the absence of deer, ticks generally do not acquire Borrelia from deer, instead they obtain them from infected small mammals such as the white-footed mouse, and occasionally birds. Areas where Lyme is common are expanding.Within the tick midgut, the Borrelias outer surface protein A (OspA) binds to the tick receptor for OspA, known as TROSPA. When the tick feeds, the Borrelia downregulates OspA and upregulates OspC, another surface protein. After the bacteria migrate from the midgut to the salivary glands, OspC binds to Salp15, a tick salivary protein that appears to have immunosuppressive effects that enhance infection. Successful infection of the mammalian host depends on bacterial expression of OspC.Tick bites often go unnoticed because of the small size of the tick in its nymphal stage, as well as tick secretions that prevent the host from feeling any itch or pain from the bite. However, transmission is quite rare, with only about 1.2 to 1.4 percent of recognized tick bites resulting in Lyme disease. In Europe, the main vector is Ixodes ricinus, which is also called the sheep tick or castor bean tick. In China, Ixodes persulcatus (the taiga tick) is probably the most important vector. In North America, the black-legged tick or deer tick (Ixodes scapularis) is the main vector on the East Coast.The lone star tick (Amblyomma americanum), which is found throughout the Southeastern United States as far west as Texas, is unlikely to transmit the Lyme disease spirochetes, though it may be implicated in a related syndrome called southern tick-associated rash illness, which resembles a mild form of Lyme disease.On the West Coast of the United States, the main vector is the western black-legged tick (Ixodes pacificus). The tendency of this tick species to feed predominantly on host species such as the Western Fence Lizard that are resistant to Borrelia infection appears to diminish transmission of Lyme disease in the West.Transmission can occur across the placenta during pregnancy and as with a number of other spirochetal diseases, adverse pregnancy outcomes are possible with untreated infection; prompt treatment with antibiotics reduces or eliminates this risk.There is no scientific evidence to support Lyme disease transmission via blood transfusion, sexual contact, or breast milk. Tick-borne coinfections Ticks that transmit B. burgdorferi to humans can also carry and transmit several other parasites, such as Babesia microti and Anaplasma phagocytophilum, which cause the diseases babesiosis and human granulocytic anaplasmosis (HGA), respectively. Among people with early Lyme disease, depending on their location, 2–12% will also have HGA and 2–40% will have babesiosis. Ticks in certain regions, including the lands along the eastern Baltic Sea, also transmit viruses that cause tick-borne encephalitis.Coinfections complicate Lyme symptoms, especially diagnosis and treatment. It is possible for a tick to carry and transmit one of the coinfections and not Borrelia, making diagnosis difficult and often elusive. The Centers for Disease Control and Prevention studied 100 ticks in rural New Jersey and detected two pathogens in 10% of the ticks. Pathophysiology B. burgdorferi can spread throughout the body during the course of the disease, and has been found in the skin, heart, joints, peripheral nervous system, and central nervous system. B. Burgdorferi does not produce toxins. Therefore, many of the signs and symptoms of Lyme disease are a consequence of the immune response to spirochete in those tissues.B. burgdorferi is injected into the skin by the bite of an infected Ixodes tick. Tick saliva, which accompanies the spirochete into the skin during the feeding process, contains substances that disrupt the immune response at the site of the bite. This provides a protective environment where the spirochete can establish infection. The spirochetes multiply and migrate outward within the dermis. The host inflammatory response to the bacteria in the skin causes the characteristic circular EM lesion. Neutrophils, however, which are necessary to eliminate the spirochetes from the skin, fail to appear in necessary numbers in the developing EM lesion because tick saliva inhibits neutrophil function. This allows the bacteria to survive and eventually spread throughout the body.Days to weeks following the tick bite, the spirochetes spread via the bloodstream to joints, heart, nervous system, and distant skin sites, where their presence gives rise to the variety of symptoms of the disseminated disease. The spread of B. burgdorferi is aided by the attachment of the host protease plasmin to the surface of the spirochete.If untreated, the bacteria may persist in the body for months or even years, despite the production of B. burgdorferi antibodies by the immune system. The spirochetes may avoid the immune response by decreasing expression of surface proteins that are targeted by antibodies, antigenic variation of the VlsE surface protein, inactivating key immune components such as complement, and hiding in the extracellular matrix, which may interfere with the function of immune factors.In the brain, B. burgdorferi may induce astrocytes to undergo astrogliosis (proliferation followed by apoptosis), which may contribute to neurodysfunction. The spirochetes may also induce host cells to secrete quinolinic acid, which stimulates the NMDA receptor on nerve cells, which may account for the fatigue and malaise observed with Lyme encephalopathy. In addition, diffuse white matter pathology during Lyme encephalopathy may disrupt gray matter connections, and could account for deficits in attention, memory, visuospatial ability, complex cognition, and emotional status. White matter disease may have a greater potential for recovery than gray matter disease, perhaps because neuronal loss is less common. Resolution of MRI white matter hyperintensities after antibiotic treatment has been observed.Tryptophan, a precursor to serotonin, appears to be reduced within the central nervous system in a number of infectious diseases that affect the brain, including Lyme. Researchers are investigating if this neurohormone secretion is the cause of neuropsychiatric disorders developing in some people with borreliosis. Immunological studies Exposure to the Borrelia bacterium during Lyme disease possibly causes a long-lived and damaging inflammatory response, a form of pathogen-induced autoimmune disease. The production of this reaction might be due to a form of molecular mimicry, where Borrelia avoids being killed by the immune system by resembling normal parts of the bodys tissues.Chronic symptoms from an autoimmune reaction could explain why some symptoms persist even after the spirochetes have been eliminated from the body. This hypothesis may explain why chronic arthritis persists after antibiotic therapy, similar to rheumatic fever, but its wider application is controversial. Diagnosis Lyme disease is diagnosed based on symptoms, objective physical findings (such as erythema migrans (EM) rash, facial palsy, or arthritis), history of possible exposure to infected ticks, and possibly laboratory tests. People with symptoms of early Lyme disease should have a total body skin examination for EM rashes and asked whether EM-type rashes had manifested within the last 1–2 months. Presence of an EM rash and recent tick exposure (i.e., being outdoors in a likely tick habitat where Lyme is common, within 30 days of the appearance of the rash) are sufficient for Lyme diagnosis; no laboratory confirmation is needed or recommended. Most people who get infected do not remember a tick or a bite, and the EM rash need not look like a bulls eye (most EM rashes in the U.S. do not) or be accompanied by any other symptoms. In the U.S., Lyme is most common in the New England and Mid-Atlantic states and parts of Wisconsin and Minnesota, but it is expanding into other areas. Several bordering areas of Canada also have high Lyme risk.In the absence of an EM rash or history of tick exposure, Lyme diagnosis depends on laboratory confirmation. The bacteria that cause Lyme disease are difficult to observe directly in body tissues and also difficult and too time-consuming to grow in the laboratory. The most widely used tests look instead for presence of antibodies against those bacteria in the blood. A positive antibody test result does not by itself prove active infection but can confirm an infection that is suspected because of symptoms, objective findings, and history of tick exposure in a person. Because as many as 5–20% of the normal population have antibodies against Lyme, people without history and symptoms suggestive of Lyme disease should not be tested for Lyme antibodies: a positive result would likely be false, possibly causing unnecessary treatment.In some cases, when history, signs, and symptoms are strongly suggestive of early disseminated Lyme disease, empiric treatment may be started and reevaluated as laboratory test results become available. Laboratory testing Tests for antibodies in the blood by ELISA and Western blot is the most widely used method for Lyme diagnosis. A two-tiered protocol is recommended by the Centers for Disease Control and Prevention (CDC): the sensitive ELISA test is performed first, and if it is positive or equivocal, then the more specific Western blot is run. The immune system takes some time to produce antibodies in quantity. After Lyme infection onset, antibodies of types IgM and IgG usually can first be detected respectively at 2–4 weeks and 4–6 weeks, and peak at 6–8 weeks. When an EM rash first appears, detectable antibodies may not be present. Therefore, it is recommended that testing not be performed and diagnosis be based on the presence of the EM rash. Up to 30 days after suspected Lyme infection onset, infection can be confirmed by detection of IgM or IgG antibodies; after that, it is recommended that only IgG antibodies be considered. A positive IgM and negative IgG test result after the first month of infection is generally indicative of a false-positive result. The number of IgM antibodies usually collapses 4–6 months after infection, while IgG antibodies can remain detectable for years.Other tests may be used in neuroborreliosis cases. In Europe, neuroborreliosis is usually caused by Borrelia garinii and almost always involves lymphocytic pleocytosis, i.e. the densities of lymphocytes (infection-fighting cells) and protein in the cerebrospinal fluid (CSF) typically rise to characteristically abnormal levels, while glucose level remains normal. Additionally, the immune system produces antibodies against Lyme inside the intrathecal space, which contains the CSF. Demonstration by lumbar puncture and CSF analysis of pleocytosis and intrathecal antibody production are required for definite diagnosis of neuroborreliosis in Europe (except in cases of peripheral neuropathy associated with acrodermatitis chronica atrophicans, which usually is caused by Borrelia afzelii and confirmed by blood antibody tests). In North America, neuroborreliosis is caused by Borrelia burgdorferi and may not be accompanied by the same CSF signs; they confirm a diagnosis of central nervous system (CNS) neuroborreliosis if positive, but do not exclude it if negative. American guidelines consider CSF analysis optional when symptoms appear to be confined to the peripheral nervous system (PNS), e.g. facial palsy without overt meningitis symptoms. Unlike blood and intrathecal antibody tests, CSF pleocytosis tests revert to normal after infection ends and therefore can be used as objective markers of treatment success and inform decisions on whether to retreat. In infection involving the PNS, electromyography and nerve conduction studies can be used to monitor objectively the response to treatment.In Lyme carditis, electrocardiograms are used to evidence heart conduction abnormalities, while echocardiography may show myocardial dysfunction. Biopsy and confirmation of Borrelia cells in myocardial tissue may be used in specific cases but are usually not done because of risk of the procedure.Polymerase chain reaction (PCR) tests for Lyme disease have also been developed to detect the genetic material (DNA) of the Lyme disease spirochete. Culture or PCR are the current means for detecting the presence of the organism, as serologic studies only test for antibodies of Borrelia. PCR has the advantage of being much faster than culture. However, PCR tests are susceptible to false positive results, e.g. by detection of debris of dead Borrelia cells or specimen contamination. Even when properly performed, PCR often shows false-negative results because few Borrelia cells can be found in blood and cerebrospinal fluid (CSF) during infection. Hence, PCR tests are recommended only in special cases, e.g. diagnosis of Lyme arthritis, because it is a highly sensitive way of detecting ospA DNA in synovial fluid. Although sensitivity of PCR in CSF is low, its use may be considered when intrathecal antibody production test results are suspected of being falsely negative, e.g. in very early (< 6 weeks) neuroborreliosis or in immunosuppressed people.Several other forms of laboratory testing for Lyme disease are available, some of which have not been adequately validated. OspA antigens, shed by live Borrelia bacteria into urine, are a promising technique being studied. The use of nanotrap particles for their detection is being looked at and the OspA has been linked to active symptoms of Lyme. High titers of either immunoglobulin G (IgG) or immunoglobulin M (IgM) antibodies to Borrelia antigens indicate disease, but lower titers can be misleading, because the IgM antibodies may remain after the initial infection, and IgG antibodies may remain for years.The CDC does not recommend urine antigen tests, PCR tests on urine, immunofluorescent staining for cell-wall-deficient forms of B. burgdorferi, and lymphocyte transformation tests. Imaging Neuroimaging is controversial in whether it provides specific patterns unique to neuroborreliosis, but may aid in differential diagnosis and in understanding the pathophysiology of the disease. Though controversial, some evidence shows certain neuroimaging tests can provide data that are helpful in the diagnosis of a person. Magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) are two of the tests that can identify abnormalities in the brain of a person affected with this disease. Neuroimaging findings in an MRI include lesions in the periventricular white matter, as well as enlarged ventricles and cortical atrophy. The findings are considered somewhat unexceptional because the lesions have been found to be reversible following antibiotic treatment. Images produced using SPECT show numerous areas where an insufficient amount of blood is being delivered to the cortex and subcortical white matter. However, SPECT images are known to be nonspecific because they show a heterogeneous pattern in the imaging. The abnormalities seen in the SPECT images are very similar to those seen in people with cerebral vacuities and Creutzfeldt–Jakob disease, which makes them questionable. Differential diagnosis Community clinics have been reported to misdiagnose 23–28% of Erythema migrans (EM) rashes and 83% of other objective manifestations of early Lyme disease. EM rashes are often misdiagnosed as spider bites, cellulitis, or shingles. Many misdiagnoses are credited to the widespread misconception that EM rashes should look like a bulls eye. Actually, the key distinguishing features of the EM rash are the speed and extent to which it expands, respectively up to 2–3 cm/day and a diameter of at least 5 cm, and in 50% of cases more than 16 cm. The rash expands away from its center, which may or may not look different or be separated by ring-like clearing from the rest of the rash. Compared to EM rashes, spider bites are more common in the limbs, tend to be more painful and itchy or become swollen, and some may cause necrosis (sinking dark blue patch of dead skin). Cellulitis most commonly develops around a wound or ulcer, is rarely circular, and is more likely to become swollen and tender. EM rashes often appear at sites that are unusual for cellulitis, such as the armpit, groin, abdomen, or back of knee. Like Lyme, shingles often begins with headache, fever, and fatigue, which are followed by pain or numbness. However, unlike Lyme, in shingles these symptoms are usually followed by appearance of rashes composed of multiple small blisters along with a nerves dermatome, and shingles can also be confirmed by quick laboratory tests.Facial palsy caused by Lyme disease (LDFP) is often misdiagnosed as Bells palsy. Although Bells palsy is the most common type of one-sided facial palsy (about 70% of cases), LDFP can account for about 25% of cases of facial palsy in areas where Lyme disease is common. Compared to LDFP, Bells palsy much less frequently affects both sides of the face. Even though LDFP and Bells palsy have similar symptoms and evolve similarly if untreated, corticosteroid treatment is beneficial for Bells Palsy, while being detrimental for LDFP. Recent history of exposure to a likely tick habitat during warmer months, EM rash, viral-like symptoms such as headache and fever, and/or palsy in both sides of the face should be evaluated for the likelihood of LDFP; if it is more than minimal, empiric therapy with antibiotics should be initiated, without corticosteroids, and reevaluated upon completion of laboratory tests for Lyme disease.Unlike viral meningitis, Lyme lymphocytic meningitis tends to not cause fever, last longer, and recur. Lymphocytic meningitis is also characterized by possibly co-occurring with EM rash, facial palsy, or partial vision obstruction and having much lower percentage of polymorphonuclear leukocytes in CSF.Lyme radiculopathy affecting the limbs is often misdiagnosed as a radiculopathy caused by nerve root compression, such as sciatica. Although most cases of radiculopathy are compressive and resolve with conservative treatment (e.g., rest) within 4–6 weeks, guidelines for managing radiculopathy recommend first evaluating risks of other possible causes that, although less frequent, require immediate diagnosis and treatment, including infections such as Lyme and shingles. A history of outdoor activities in likely tick habitats in the last 3 months possibly followed by a rash or viral-like symptoms, and current headache, other symptoms of lymphocytic meningitis, or facial palsy would lead to suspicion of Lyme disease and recommendation of serological and lumbar puncture tests for confirmation.Lyme radiculopathy affecting the trunk can be misdiagnosed as myriad other conditions, such as diverticulitis and acute coronary syndrome. Diagnosis of late-stage Lyme disease is often complicated by a multifaceted appearance and nonspecific symptoms, prompting one reviewer to call Lyme the new "great imitator". As all people with later-stage infection will have a positive antibody test, simple blood tests can exclude Lyme disease as a possible cause of a persons symptoms. Prevention Tick bites may be prevented by avoiding or reducing time in likely tick habitats and taking precautions while in and when getting out of one.Most Lyme human infections are caused by Ixodes nymph bites between April and September. Ticks prefer moist, shaded locations in woodlands, shrubs, tall grasses and leaf litter or wood piles. Tick densities tend to be highest in woodlands, followed by unmaintained edges between woods and lawns (about half as high), ornamental plants and perennial groundcover (about a quarter), and lawns (about 30 times less). Ixodes larvae and nymphs tend to be abundant also where mice nest, such as stone walls and wood logs. Ixodes larvae and nymphs typically wait for potential hosts ("quest") on leaves or grasses close to the ground with forelegs outstretched; when a host brushes against its limbs, the tick rapidly clings and climbs on the host looking for a skin location to bite. In Northeastern United States, 69% of tick bites are estimated to happen in residences, 11% in schools or camps, 9% in parks or recreational areas, 4% at work, 3% while hunting, and 4% in other areas. Activities associated with tick bites around residences include yard work, brush clearing, gardening, playing in the yard, and letting into the house dogs or cats that roam outside in woody or grassy areas. In parks, tick bites often happen while hiking or camping. Walking on a mowed lawn or center of a trail without touching adjacent vegetation is less risky than crawling or sitting on a log or stone wall. Pets should not be allowed to roam freely in likely tick habitats.As a precaution, CDC recommends soaking or spraying clothes, shoes, and camping gear such as tents, backpacks and sleeping bags with 0.5% permethrin solution and hanging them to dry before use. Permethrin is odorless and safe for humans but highly toxic to ticks. After crawling on permethrin-treated fabric for as few as 10–20 seconds, tick nymphs become irritated and fall off or die. Permethrin-treated closed-toed shoes and socks reduce by 74 times the number of bites from nymphs that make first contact with a shoe of a person also wearing treated shorts (because nymphs usually quest near the ground, this is a typical contact scenario). Better protection can be achieved by tucking permethrin-treated trousers (pants) into treated socks and a treated long-sleeve shirt into the trousers so as to minimize gaps through which a tick might reach the wearers skin. Light-colored clothing may make it easier to see ticks and remove them before they bite. Military and outdoor workers uniforms treated with permethrin have been found to reduce the number of bite cases by 80–95%. Permethrin protection lasts several weeks of wear and washings in customer-treated items and up to 70 washings for factory-treated items. Permethrin should not be used on human skin, underwear or cats.The EPA recommends several tick repellents for use on exposed skin, including DEET, picaridin, IR3535 (a derivative of amino acid beta-alanine), oil of lemon eucalyptus (OLE, a natural compound) and OLEs active ingredient para-menthane-diol (PMD). Unlike permethrin, repellents repel but do not kill ticks, protect for only several hours after application, and may be washed off by sweat or water. The most popular repellent is DEET in the U.S. and picaridin in Europe. Unlike DEET, picaridin is odorless and is less likely to irritate the skin or harm fabric or plastics. Repellents with higher concentration may last longer but are not more effective; against ticks, 20% picaridin may work for 8 hours vs. 55–98.11% DEET for 5–6 hours or 30–40% OLE for 6 hours. Repellents should not be used under clothes, on eyes, mouth, wounds or cuts, or on babies younger than 2 months (3 years for OLE or PMD). If sunscreen is used, repellent should be applied on top of it. Repellents should not be sprayed directly on a face, but should instead be sprayed on a hand and then rubbed on the face.After coming indoors, clothes, gear and pets should be checked for ticks. Clothes can be put into a hot dryer for 10 minutes to kill ticks (just washing or warm dryer are not enough). Showering as soon as possible, looking for ticks over the entire body, and removing them reduce risk of infection. Unfed tick nymphs are the size of a poppy seed, but a day or two after biting and attaching themselves to a person, they look like a small blood blister. The following areas should be checked especially carefully: armpits, between legs, back of knee, bellybutton, trunk, and in children ears, neck and hair. Tick removal Attached ticks should be removed promptly. Risk of infection increases with time of attachment, but in North America risk of Lyme disease is small if the tick is removed within 36 hours. CDC recommends inserting a fine-tipped tweezer between the skin and the tick, grasping very firmly, and pulling the closed tweezer straight away from the skin without twisting, jerking, squeezing or crushing the tick. After tick removal, any tick parts remaining in the skin should be removed with a clean tweezer, if possible. The wound and hands should then be cleaned with alcohol or soap and water. The tick may be disposed by placing it in a container with alcohol, sealed bag, tape or flushed down the toilet. The bitten person should write down where and when the bite happened so that this can be informed to a doctor if the person gets a rash or flu-like symptoms in the following several weeks. CDC recommends not using fingers, nail polish, petroleum jelly or heat on the tick to try to remove it.In Australia, where the Australian paralysis tick is prevalent, the Australasian Society of Clinical Immunology and Allergy recommends not using tweezers to remove ticks, because if the person is allergic, anaphylaxis could result. Instead, a product should be sprayed on the tick to cause it to freeze and then drop off. A doctor would use liquid nitrogen, but products available from chemists for freezing warts can be used instead. Another method originating from Australia consists in using about 20 cm of dental floss or fishing line for slowly tying an overhand knot between the skin and the tick and then pulling it away from the skin. Preventive antibiotics The risk of infectious transmission increases with the duration of tick attachment. It requires between 36 and 48 hours of attachment for the bacteria that causes Lyme to travel from within the tick into its saliva. If a deer tick that is sufficiently likely to be carrying Borrelia is found attached to a person and removed, and if the tick has been attached for 36 hours or is engorged, a single dose of doxycycline administered within the 72 hours after removal may reduce the risk of Lyme disease. It is not generally recommended for all people bitten, as development of infection is rare: about 50 bitten people would have to be treated this way to prevent one case of erythema migrans (i.e. the typical rash found in about 70–80% of people infected). Garden landscaping Several landscaping practices may reduce risk of tick bites in residential yards. The lawn should be kept mowed, leaf litter and weeds removed and groundcover use avoided. Woodlands, shrubs, stone walls and wood piles should be separated from the lawn by a 3-ft-wide rock or woodchip barrier. Without vegetation on the barrier, ticks will tend not to cross it; acaricides may also be sprayed on it to kill ticks. A sun-exposed tick-safe zone at least 9 ft from the barrier should concentrate human activity on the yard, including any patios, playgrounds and gardening. Materials such as wood decking, concrete, bricks, gravel or woodchips may be used on the ground under patios and playgrounds so as to discourage ticks there. An 8-ft-high fence may be added to keep deer away from the tick-safe zone. Occupational exposure Outdoor workers are at risk of Lyme disease if they work at sites with infected ticks. This includes construction, landscaping, forestry, brush clearing, land surveying, farming, railroad work, oil field work, utility line work, park or wildlife management. U.S. workers in the northeastern and north-central states are at highest risk of exposure to infected ticks. Ticks may also transmit other tick-borne diseases to workers in these and other regions of the country. Worksites with woods, bushes, high grass or leaf litter are likely to have more ticks. Outdoor workers should be most careful to protect themselves in the late spring and summer when young ticks are most active. Host animals Ticks can feed upon the blood of a wide array of possible host species, including lizards, birds, mice, cats, dogs, deer, cattle and humans. The extent to which a tick can feed, reproduce, and spread will depend on the type and availability of its hosts. Whether it will spread disease is also affected by its available hosts. Some species, such as lizards, are referred to as "dilution hosts" because they dont tend to support Lyme disease pathogens and so decrease the likelihood that the disease will be passed on by ticks feeding on them. White-tailed deer are both a food source and a "reproductive host", where ticks tend to mate. The white-footed mouse is a reservoir host in which the pathogen for Lyme disease can survive. Availability of hosts can have significant impacts on the transmission of Lyme disease. A greater diversity of hosts, or of those that dont support the pathogen, tends to decrease the likelihood that the disease will be transmitted.In the United States, one approach to reducing the incidence of Lyme and other deer tick-borne diseases has been to greatly reduce the deer population on which the adult ticks depend for feeding and reproduction. Lyme disease cases fell following deer eradication on an island, Monhegan, Maine, and following deer control in Mumford Cove, Connecticut. Advocates have suggested reducing the deer population to levels of 8 to 10 deer per square mile, compared to levels of 60 or more deer per square mile in the areas of the country with the highest Lyme disease rates.Others have noted that while deer are reproductive hosts, they are not Borrelia burgdorferi reservoirs. Researchers have suggested that smaller, less obviously visible Lyme reservoirs, like white-footed mice and Eastern chipmunks, may more strongly impact Lyme disease occurrence. Ecosystem studies in New York state suggest that white-footed mice thrive when forests are broken into smaller isolated chunks of woodland with fewer rodent predators. With more rodents harboring the disease, the odds increase that a tick will feed on a disease-harboring rodent and that someone will pick up a disease-carrying tick in their garden or walking in the woods. Data indicates that the smaller the wooded area, the more ticks it will contain and the likely they are to carry Lyme disease, supporting the idea that deforestation and habitat fragmentation affect ticks, hosts and disease transmission.Tick-borne diseases are estimated to affect ~80 % of cattle worldwide. They also affect cats, dogs, and other pets. Routine veterinary control of ticks of domestic animals through the use of acaricides has been suggested as a way to reduce exposure of humans to ticks. However, chemical control with acaricides is now criticized on a number of grounds. Ticks appear to develop resistance to acaricides; acaricides are costly; and there are concerns over their toxicity and the potential for chemical residues to affect food and the environment.In Europe, known reservoirs of Borrelia burgdorferi were 9 small mammals, 7 medium-sized mammals and 16 species of birds (including passerines, sea-birds and pheasants). These animals seem to transmit spirochetes to ticks and thus participate in the natural circulation of B. burgdorferi in Europe. The house mouse is also suspected as well as other species of small rodents, particularly in Eastern Europe and Russia. "The reservoir species that contain the most pathogens are the European roe deer Capreolus capreolus; "it does not appear to serve as a major reservoir of B. burgdorferi" thought Jaenson & al. (1992) (incompetent host for B. burgdorferi and TBE virus) but it is important for feeding the ticks, as red deer and wild boars (Sus scrofa), in which one Rickettsia and three Borrelia species were identified", with high risks of coinfection in roe deer. Nevertheless, in the 2000s, in roe deer in Europe "two species of Rickettsia and two species of Borrelia were identified". Vaccination No human vaccines for Lyme disease are currently available. The only human vaccine to advance to market was LYMErix, which was available briefly before being pulled from the market in 2002. The vaccine candidate VLA15 is scheduled to start a phase 3 trial in the third quarter of 2022, and other research is ongoing. Multiple vaccines are available for the prevention of Lyme disease in dogs. LYMErix The vaccine LYMErix was available from 1998 to 2002. The recombinant vaccine against Lyme disease, based on the outer surface protein A (OspA) of B. burgdorferi with aluminum hydroxide as adjuvant, was developed by SmithKline Beecham. In clinical trials involving more than 10,000 people, the vaccine was found to confer protective immunity to Lyme disease in 76% of adults after three doses with only mild or moderate and transient adverse effects. On 21 December 1998, the Food and Drug Administration (FDA) approved LYMErix on the basis of these trials for persons of ages 15 through 70.Following approval of the vaccine, its entry into clinical practice was slow for a variety of reasons, including its cost, which was often not reimbursed by insurance companies. Subsequently, hundreds of vaccine recipients reported they had developed autoimmune and other side effects. Supported by some advocacy groups, a number of class-action lawsuits were filed against GlaxoSmithKline, alleging the vaccine had caused these health problems. These claims were investigated by the FDA and the Centers for Disease Control, which found no connection between the vaccine and the autoimmune complaints.Despite the lack of evidence that the complaints were caused by the vaccine, sales plummeted and LYMErix was withdrawn from the U.S. market by GlaxoSmithKline in February 2002, in the setting of negative media coverage and fears of vaccine side effects. The fate of LYMErix was described in the medical literature as a "cautionary tale"; an editorial in Nature cited the withdrawal of LYMErix as an instance in which "unfounded public fears place pressures on vaccine developers that go beyond reasonable safety considerations." The original developer of the OspA vaccine at the Max Planck Institute told Nature: "This just shows how irrational the world can be ... There was no scientific justification for the first OspA vaccine LYMErix being pulled." VLA15 The hexavalent (OspA) protein subunit-based vaccine candidate VLA15 was developed by Valneva. It was granted fast track designation by the U.S. Food and Drug Administration in July 2017. In April 2020 Pfizer paid $130 million for the rights to the vaccine, and the companies are developing it together, performing multiple phase 2 trials.A phase 3 trial of VLA15 was scheduled for late 2022, recruiting volunteers at test sites located across the northeastern United States and in Europe. Participants were scheduled to receive an initial three-dose series of vaccines over the course of five to nine months, followed by a booster dose after twelve months, with both the initial series and the booster dose scheduled to be complete before the years peak Lyme disease season. Other research An mRNA vaccine designed to cause a strong fast immune response to tick saliva allowed the immune system to detect and remove the ticks from test animals before they were able to transmit the infectious bacteria. The vaccine contains mRNAs for the body to build 19 proteins in tick saliva which, by enabling quick development of erythema (itchy redness) at the bite site, protects guinea pigs against Lyme disease. It also protected the test animals if the tick is not removed if only one tick, but not three, remain attached. Canine vaccines Canine vaccines have been formulated and approved for the prevention of Lyme disease in dogs. Currently, three Lyme disease vaccines are available. LymeVax, formulated by Fort Dodge Laboratories, contains intact dead spirochetes which expose the host to the organism. Galaxy Lyme, Intervet-Schering-Ploughs vaccine, targets proteins OspC and OspA. The OspC antibodies kill any of the bacteria that have not been killed by the OspA antibodies. Canine Recombinant Lyme, formulated by Merial, generates antibodies against the OspA protein so a tick feeding on a vaccinated dog draws in blood full of anti-OspA antibodies, which kill the spirochetes in the ticks gut before they are transmitted to the dog. Treatment Antibiotics are the primary treatment. The specific approach to their use is dependent on the individual affected and the stage of the disease. For most people with early localized infection, oral administration of doxycycline is widely recommended as the first choice, as it is effective against not only Borrelia bacteria but also a variety of other illnesses carried by ticks. People taking doxycycline should avoid sun exposure because of higher risk of sunburns. Doxycycline is contraindicated in children younger than eight years of age and women who are pregnant or breastfeeding; alternatives to doxycycline are amoxicillin, cefuroxime axetil, and azithromycin. Azithromycin is recommended only in case of intolerance to the other antibiotics. The standard treatment for cellulitis, cephalexin, is not useful for Lyme disease. When it is unclear if a rash is caused by Lyme or cellulitis, the IDSA recommends treatment with cefuroxime or amoxicillin/clavulanic acid, as these are effective against both infections. Individuals with early disseminated or late Lyme infection may have symptomatic cardiac disease, Lyme arthritis, or neurologic symptoms like facial palsy, radiculopathy, meningitis, or peripheral neuropathy. Intravenous administration of ceftriaxone is recommended as the first choice in these cases; cefotaxime and doxycycline are available as alternatives.Treatment regimens for Lyme disease range from 14 days in early localized disease, to 14–21 days in early disseminated disease to 14–28 days in late disseminated disease. Neurologic complications of Lyme disease may be treated with doxycycline as it can be taken by mouth and has a lower cost, although in North America evidence of efficacy is only indirect. In case of failure, guidelines recommend retreatment with injectable ceftriaxone. Several months after treatment for Lyme arthritis, if joint swelling persists or returns, a second round of antibiotics may be considered; intravenous antibiotics are preferred for retreatment in case of poor response to oral antibiotics. Outside of that, a prolonged antibiotic regimen lasting more than 28 days is not recommended as no evidence shows it to be effective. IgM and IgG antibody levels may be elevated for years even after successful treatment with antibiotics. As antibody levels are not indicative of treatment success, testing for them is not recommended.Facial palsy may resolve without treatment; however, antibiotic treatment is recommended to stop other Lyme complications. Corticosteroids are not recommended when facial palsy is caused by Lyme disease. In those with facial palsy, frequent use of artificial tears while awake is recommended, along with ointment and a patch or taping the eye closed when sleeping.About a third of people with Lyme carditis need a temporary pacemaker until their heart conduction abnormality resolves, and 21% need to be hospitalized. Lyme carditis should not be treated with corticosteroids.People with Lyme arthritis should limit their level of physical activity to avoid damaging affected joints, and in case of limping should use crutches. Pain associated with Lyme disease may be treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Corticosteroid joint injections are not recommended for Lyme arthritis that is being treated with antibiotics. People with Lyme arthritis treated with intravenous antibiotics or two months of oral antibiotics who continue to have joint swelling two months after treatment and have negative PCR test for Borrelia DNA in the synovial fluid are said to have antibiotic-refractory Lyme arthritis; this is more common after infection by certain Borrelia strains in people with certain genetic and immunologic characteristics. Antibiotic-refractory Lyme arthritis may be symptomatically treated with NSAIDs, disease-modifying antirheumatic drugs (DMARDs), or arthroscopic synovectomy. Physical therapy is recommended for adults after resolution of Lyme arthritis.People receiving treatment should be advised that reinfection is possible and how to prevent it. Prognosis Lyme diseases typical first sign, the erythema migrans (EM) rash, resolves within several weeks even without treatment. However, in untreated people, the infection often disseminates to the nervous system, heart, or joints, possibly causing permanent damage to body tissues.People who receive recommended antibiotic treatment within several days of appearance of an initial EM rash have the best prospects. Recovery may not be total or immediate. The percentage of people achieving full recovery in the United States increases from about 64–71% at end of treatment for EM rash to about 84–90% after 30 months; higher percentages are reported in Europe. Treatment failure, i.e. persistence of original or appearance of new signs of the disease, occurs only in a few people. Remaining people are considered cured but continue to experience subjective symptoms, e.g. joint or muscle pains or fatigue. These symptoms usually are mild and nondisabling.People treated only after nervous system manifestations of the disease may end up with objective neurological deficits, in addition to subjective symptoms. In Europe, an average of 32–33 months after initial Lyme symptoms in people treated mostly with doxycycline 200 mg for 14–21 days, the percentage of people with lingering symptoms was much higher among those diagnosed with neuroborreliosis (50%) than among those with only an EM rash (16%). In another European study, 5 years after treatment for neuroborreliosis, lingering symptoms were less common among children (15%) than adults (30%), and in the latter was less common among those treated within 30 days of the first symptom (16%) than among those treated later (39%); among those with lingering symptoms, 54% had daily activities restricted and 19% were on sick leave or incapacitated.Some data suggest that about 90% of Lyme facial palsies treated with antibiotics recover fully a median of 24 days after appearing and most of the rest recover with only mild abnormality. However, in Europe 41% of people treated for facial palsy had other lingering symptoms at followup up to 6 months later, including 28% with numbness or altered sensation and 14% with fatigue or concentration problems. Palsies in both sides of the face are associated with worse and longer time to recovery. Historical data suggests that untreated people with facial palsies recover at nearly the same rate, but 88% subsequently have Lyme arthritis. Other research shows that synkinesis (involuntary movement of a facial muscle when another one is voluntarily moved) can become evident only 6–12 months after facial palsy appears to be resolved, as damaged nerves regrow and sometimes connect to incorrect muscles. Synkinesis is associated with corticosteroid use. In longer-term follow-up, 16–23% of Lyme facial palsies do not fully recover.In Europe, about a quarter of people with Bannwarth syndrome (Lyme radiculopathy and lymphocytic meningitis) treated with intravenous ceftriaxone for 14 days an average of 30 days after first symptoms had to be retreated 3–6 months later because of unsatisfactory clinical response or continued objective markers of infection in cerebrospinal fluid; after 12 months, 64% recovered fully, 31% had nondisabling mild or infrequent symptoms that did not require regular use of analgesics, and 5% had symptoms that were disabling or required substantial use of analgesics. The most common lingering nondisabling symptoms were headache, fatigue, altered sensation, joint pains, memory disturbances, malaise, radicular pain, sleep disturbances, muscle pains, and concentration disturbances. Lingering disabling symptoms included facial palsy and other impaired movement.Recovery from late neuroborreliosis tends to take longer and be less complete than from early neuroborreliosis, probably because of irreversible neurologic damage.About half the people with Lyme carditis progress to complete heart block, but it usually resolves in a week. Other Lyme heart conduction abnormalities resolve typically within 6 weeks. About 94% of people have full recovery, but 5% need a permanent pacemaker and 1% end up with persistent heart block (the actual percentage may be higher because of unrecognized cases). Lyme myocardial complications usually are mild and self-limiting. However, in some cases Lyme carditis can be fatal.Recommended antibiotic treatments are effective in about 90% of Lyme arthritis cases, although it can take several months for inflammation to resolve and a second round of antibiotics is often necessary. Antibiotic-refractory Lyme arthritis also eventually resolves, typically within 9–14 months (range 4 months – 4 years); DMARDs or synovectomy can accelerate recovery.Reinfection is not uncommon. In a U.S. study, 6–11% of people treated for an EM rash had another EM rash within 30 months. The second rash typically is due to infection by a different Borrelia strain.People who have nonspecific, subjective symptoms such as fatigue, joint and muscle aches, or cognitive difficulties for more than six months after recommended treatment for Lyme disease are said to have post-treatment Lyme disease syndrome (PTLDS). As of 2016 the reason for the lingering symptoms was not known; the condition is generally managed similarly to fibromyalgia or chronic fatigue syndrome. Epidemiology Lyme disease occurs regularly in Northern Hemisphere temperate regions. There is evidence that tick populations and Lyme disease occurrence are increasing and spreading into new areas, due in part to the warming temperatures of climate change. Africa In northern Africa, B. burgdorferi sensu lato has been identified in Morocco, Algeria, Egypt and Tunisia.Lyme disease in sub-Saharan Africa is presently unknown, but evidence indicates it may occur in humans in this region. The abundance of hosts and tick vectors would favor the establishment of Lyme infection in Africa. In East Africa, two cases of Lyme disease have been reported in Kenya. Asia B. burgdorferi sensu lato-infested ticks are being found more frequently in Japan, as well as in northwest China, Nepal, Thailand and far eastern Russia. Borrelia has also been isolated in Mongolia. Europe In Europe, Lyme disease is caused by infection with one or more pathogenic European genospecies of the spirochaete B. burgdorferi sensu lato, mainly transmitted by the tick Ixodes ricinus. Cases of B. burgdorferi sensu lato-infected ticks are found predominantly in central Europe, particularly in Slovenia and Austria, but have been isolated in almost every country on the continent. Number of cases in southern Europe, such as Italy and Portugal, is much lower. Diagnosed cases in some Western countries, such as Iceland, are rising. United Kingdom In the United Kingdom the number of laboratory confirmed cases of Lyme disease has been rising steadily since voluntary reporting was introduced in 1986 when 68 cases were recorded in the UK and Ireland combined. In the UK there were 23 confirmed cases in 1988 and 19 in 1990, but 973 in 2009 and 953 in 2010. Provisional figures for the first 3 quarters of 2011 show a 26% increase on the same period in 2010.It is thought, however, that the actual number of cases is significantly higher than suggested by the above figures, with the UKs Health Protection Agency estimating that there are between 2,000 and 3,000 cases per year, (with an average of around 15% of the infections acquired overseas), while Dr Darrel Ho-Yen, Director of the Scottish Toxoplasma Reference Laboratory and National Lyme Disease Testing Service, believes that the number of confirmed cases should be multiplied by 10 "to take account of wrongly diagnosed cases, tests giving false results, sufferers who werent tested, people who are infected but not showing symptoms, failures to notify and infected individuals who dont consult a doctor."Despite Lyme disease (Borrelia burgdorferi infection) being a notifiable disease in Scotland since January 1990 which should therefore be reported on the basis of clinical suspicion, it is believed that many GPs are unaware of the requirement. Mandatory reporting, limited to laboratory test results only, was introduced throughout the UK in October 2010, under the Health Protection (Notification) Regulations 2010.Although there is a greater number of cases of Lyme disease in the New Forest, Salisbury Plain, Exmoor, the South Downs, parts of Wiltshire and Berkshire, Thetford Forest and the West coast and islands of Scotland, infected ticks are widespread, and can even be found in the parks of London. A 1989 report found that 25% of forestry workers in the New Forest were seropositive, as were between 2% and 4–5% of the general local population of the area.Tests on pet dogs carried out throughout the country in 2009 indicated that around 2.5% of ticks in the UK may be infected, considerably higher than previously thought. It is thought that global warming may lead to an increase in tick activity in the future, as well as an increase in the amount of time that people spend in public parks, thus increasing the risk of infection. North America Many studies in North America have examined ecological and environmental correlates of the number of people affected by Lyme disease. A 2005 study using climate suitability modelling of I. scapularis projected that climate change would cause an overall 213% increase in suitable vector habitat by 2080, with northward expansions in Canada, increased suitability in the central U.S., and decreased suitable habitat and vector retraction in the southern U.S. A 2008 review of published studies concluded that the presence of forests or forested areas was the only variable that consistently elevated the risk of Lyme disease whereas other environmental variables showed little or no concordance between studies. The authors argued that the factors influencing tick density and human risk between sites are still poorly understood, and that future studies should be conducted over longer time periods, become more standardized across regions, and incorporate existing knowledge of regional Lyme disease ecology. Canada The range of ticks able to carry Lyme disease has expanded from a limited area of Ontario to include areas of southern Quebec, Manitoba, northern Ontario, southern New Brunswick, southwest Nova Scotia and limited parts of Saskatchewan and Alberta, as well as British Columbia. Cases have been reported as far east as the island of Newfoundland. A model-based prediction by Leighton et al. (2012) suggests that the range of the I. scapularis tick will expand into Canada by 46 km/year over the next decade, with warming climatic temperatures as the main driver of increased speed of spread. Mexico A 2007 study suggests Borrelia burgdorferi infections are endemic to Mexico, from four cases reported between 1999 and 2000. United States In 2019, according to the CDC, there were approximately 35,000 confirmed and probable cases in the U.S. with incidences occurring in almost every state. The CDC is currently conducting research on evaluation and diagnostics of the disease and preliminary results suggest the number of new cases to be around 300,000.Lyme disease is the most common tick-borne disease in North America and Europe, and one of the fastest-growing infectious diseases in the United States. Of cases reported to the United States CDC, the ratio of Lyme disease infection is 7.9 cases for every 100,000 persons. In the ten states where Lyme disease is most common, the average was 31.6 cases for every 100,000 persons for the year 2005.Although Lyme disease has been reported in all states about 99% of all reported cases are confined to just five geographic areas (New England, Mid-Atlantic, East-North Central, South Atlantic, and West North-Central). New 2011 CDC Lyme case definition guidelines are used to determine confirmed CDC surveillance cases.Effective January 2008, the CDC gives equal weight to laboratory evidence from 1 a positive culture for B. burgdorferi; 2) two-tier testing (ELISA screening and Western blot confirming); or 3) single-tier IgG (old infection) Western blot. Previously, the CDC only included laboratory evidence based on (1) and (2) in their surveillance case definition. The case definition now includes the use of Western blot without prior ELISA screen.The number of reported cases of the disease has been increasing, as are endemic regions in North America. For example, B. burgdorferi sensu lato was previously thought to be hindered in its ability to be maintained in an enzootic cycle in California, because it was assumed the large lizard population would dilute the number of people affected by B. burgdorferi in local tick populations; this has since been brought into question, as some evidence has suggested lizards can become infected.Except for one study in Europe, much of the data implicating lizards is based on DNA detection of the spirochete and has not demonstrated that lizards are able to infect ticks feeding upon them. As some experiments suggest lizards are refractory to infection with Borrelia, it appears likely their involvement in the enzootic cycle is more complex and species-specific.While B. burgdorferi is most associated with ticks hosted by white-tailed deer and white-footed mice, Borrelia afzelii is most frequently detected in rodent-feeding vector ticks, and Borrelia garinii and Borrelia valaisiana appear to be associated with birds. Both rodents and birds are competent reservoir hosts for B. burgdorferi sensu stricto. The resistance of a genospecies of Lyme disease spirochetes to the bacteriolytic activities of the alternative complement pathway of various host species may determine its reservoir host association.Several similar but apparently distinct conditions may exist, caused by various species or subspecies of Borrelia in North America. A regionally restricted condition that may be related to Borrelia infection is southern tick-associated rash illness (STARI), also known as Masters disease. Amblyomma americanum, known commonly as the lone-star tick, is recognized as the primary vector for STARI. In some parts of the geographical distribution of STARI, Lyme disease is quite rare (e.g., Arkansas), so people in these regions experiencing Lyme-like symptoms—especially if they follow a bite from a lone-star tick—should consider STARI as a possibility. It is generally a milder condition than Lyme and typically responds well to antibiotic treatment.In recent years there have been 5 to 10 cases a year of a disease similar to Lyme occurring in Montana. It occurs primarily in pockets along the Yellowstone River in central Montana. People have developed a red bulls-eye rash around a tick bite followed by weeks of fatigue and a fever.Lyme disease effects are comparable among males and females. A wide range of age groups is affected, though the number of cases is highest among 10- to 19-year-olds. For unknown reasons, Lyme disease is seven times more common among Asians. South America In South America, tick-borne disease recognition and occurrence is rising. In Brazil, a Lyme-like disease known as Baggio–Yoshinari syndrome was identified, caused by microorganisms that do not belong to the B. burgdorferi sensu lato complex and transmitted by ticks of the Amblyomma and Rhipicephalus genera. The first reported case of BYS in Brazil was made in 1992 in Cotia, São Paulo. History The evolutionary history of Borrelia burgdorferi genetics has been the subject of recent studies. One study has found that prior to the reforestation that accompanied post-colonial farm abandonment in New England and the wholesale migration into the mid-west that occurred during the early 19th century, Lyme disease was present for thousands of years in America and had spread along with its tick hosts from the Northeast to the Midwest.John Josselyn, who visited New England in 1638 and again from 1663 to 1670, wrote "there be infinite numbers of ticks hanging upon the bushes in summertime that will cleave to mans garments and creep into his breeches, eating themselves in a short time into the very flesh of a man. I have seen the stockings of those that have gone through the woods covered with them."This is also confirmed by the writings of Peter Kalm, a Swedish botanist who was sent to America by Linnaeus, and who found the forests of New York "abound" with ticks when he visited in 1749. When Kalms journey was retraced 100 years later, the forests were gone and the Lyme bacterium had probably become isolated to a few pockets along the northeast coast, Wisconsin, and Minnesota.Perhaps the first detailed description of what is now known as Lyme disease appeared in the writings of John Walker after a visit to the island of Jura (Deer Island) off the west coast of Scotland in 1764. He gives a good description both of the symptoms of Lyme disease (with "exquisite pain [in] the interior parts of the limbs") and of the tick vector itself, which he describes as a "worm" with a body which is "of a reddish color and of a compressed shape with a row of feet on each side" that "penetrates the skin". Many people from this area of Great Britain emigrated to North America between 1717 and the end of the 18th century.The examination of preserved museum specimens has found Borrelia DNA in an infected Ixodes ricinus tick from Germany that dates back to 1884, and from an infected mouse from Cape Cod that died in 1894. The 2010 autopsy of Ötzi the Iceman, a 5,300-year-old mummy, revealed the presence of the DNA sequence of Borrelia burgdorferi making him the earliest known human with Lyme disease.The early European studies of what is now known as Lyme disease described its skin manifestations. The first study dates to 1883 in Breslau, Germany (now Wrocław, Poland), where physician Alfred Buchwald described a man who for 16 years had had a degenerative skin disorder now known as acrodermatitis chronica atrophicans.At a 1909 research conference, Swedish dermatologist Arvid Afzelius presented a study about an expanding, ring-like lesion he had observed in an older woman following the bite of a sheep tick. He named the lesion erythema migrans. The skin condition now known as borrelial lymphocytoma was first described in 1911.The modern history of medical understanding of the disease, including its cause, diagnosis, and treatment, has been difficult.Neurological problems following tick bites were recognized starting in the 1920s. French physicians Garin and Bujadoux described a farmer with a painful sensory radiculitis accompanied by mild meningitis following a tick bite. A large, ring-shaped rash was also noted, although the doctors did not relate it to the meningoradiculitis. In 1930, the Swedish dermatologist Sven Hellerström was the first to propose EM and neurological symptoms following a tick bite were related. In the 1940s, German neurologist Alfred Bannwarth described several cases of chronic lymphocytic meningitis and polyradiculoneuritis, some of which were accompanied by erythematous skin lesions. Carl Lennhoff, who worked at the Karolinska Institute in Sweden, believed many skin conditions were caused by spirochetes. In 1948, he used a special stain to microscopically observe what he believed were spirochetes in various types of skin lesions, including EM. Although his conclusions were later shown to be erroneous, interest in the study of spirochetes was sparked. In 1949, Nils Thyresson, who also worked at the Karolinska Institute, was the first to treat ACA with penicillin. In the 1950s, the relationship among tick bite, lymphocytoma, EM and Bannwarths syndrome was recognized throughout Europe leading to the widespread use of penicillin for treatment in Europe.In 1970, a dermatologist in Wisconsin named Rudolph Scrimenti recognized an EM lesion in a person after recalling a paper by Hellerström that had been reprinted in an American science journal in 1950. This was the first documented case of EM in the United States. Based on the European literature, he treated the person with penicillin.The full syndrome now known as Lyme disease was not recognized until a cluster of cases originally thought to be juvenile rheumatoid arthritis was identified in three towns in southeastern Connecticut in 1975, including the towns Lyme and Old Lyme, which gave the disease its popular name. This was investigated by physicians David Snydman and Allen Steere of the Epidemic Intelligence Service, and by others from Yale University, including Stephen Malawista, who is credited as a co-discover of the disease. The recognition that the people in the United States had EM led to the recognition that "Lyme arthritis" was one manifestation of the same tick-borne condition known in Europe.Before 1976, the elements of B. burgdorferi sensu lato infection were called or known as tick-borne meningopolyneuritis, Garin-Bujadoux syndrome, Bannwarth syndrome, Afzeliuss disease, Montauk Knee or sheep tick fever. Since 1976 the disease is most often referred to as Lyme disease, Lyme borreliosis or simply borreliosis.In 1980, Steere, et al., began to test antibiotic regimens in adults with Lyme disease. In the same year, New York State Health Dept. epidemiologist Jorge Benach provided Willy Burgdorfer, a researcher at the Rocky Mountain Biological Laboratory, with collections of I. dammini [scapularis] from Shelter Island, New York, a known Lyme-endemic area as part of an ongoing investigation of Rocky Mountain spotted fever. In examining the ticks for rickettsiae, Burgdorfer noticed "poorly stained, rather long, irregularly coiled spirochetes." Further examination revealed spirochetes in 60% of the ticks. Burgdorfer credited his familiarity with the European literature for his realization that the spirochetes might be the "long-sought cause of ECM and Lyme disease." Benach supplied him with more ticks from Shelter Island and sera from people diagnosed with Lyme disease. University of Texas Health Science Center researcher Alan Barbour "offered his expertise to culture and immunochemically characterize the organism." Burgdorfer subsequently confirmed his discovery by isolating, from people with Lyme disease, spirochetes identical to those found in ticks. In June 1982, he published his findings in Science, and the spirochete was named Borrelia burgdorferi in his honor.After the identification of B. burgdorferi as the causative agent of Lyme disease, antibiotics were selected for testing, guided by in vitro antibiotic sensitivities, including tetracycline antibiotics, amoxicillin, cefuroxime axetil, intravenous and intramuscular penicillin and intravenous ceftriaxone. The mechanism of tick transmission was also the subject of much discussion. B. burgdorferi spirochetes were identified in tick saliva in 1987, confirming the hypothesis that transmission occurred via tick salivary glands. Society and culture Urbanization and other anthropogenic factors can be implicated in the spread of Lyme disease to humans. In many areas, expansion of suburban neighborhoods has led to gradual deforestation of surrounding wooded areas and increased border contact between humans and tick-dense areas. Human expansion has also resulted in a reduction of predators that hunt deer as well as mice, chipmunks and other small rodents—the primary reservoirs for Lyme disease. As a consequence of increased human contact with host and vector, the likelihood of transmission of the disease has greatly increased. Researchers are investigating possible links between global warming and the spread of vector-borne diseases, including Lyme disease. Controversy The term "chronic Lyme disease" is controversial and not recognized in the medical literature, and most medical authorities advise against long-term antibiotic treatment for Lyme disease. Studies have shown that most people diagnosed with "chronic Lyme disease" either have no objective evidence of previous or current infection with B. burgdorferi or are people who should be classified as having post-treatment Lyme disease syndrome (PTLDS), which is defined as continuing or relapsing non-specific symptoms (such as fatigue, musculoskeletal pain, and cognitive complaints) in a person previously treated for Lyme disease.The 2008 documentary Under Our Skin is known for promoting conspiracy theories about "chronic Lyme disease". Other animals Pets Prevention of Lyme disease is an important step in keeping dogs safe in endemic areas. Prevention education and a number of preventive measures are available. First, for dog owners who live near or who often frequent tick-infested areas, routine vaccinations of their dogs is an important step.Another crucial preventive measure is the use of persistent acaricides, such as topical repellents or pesticides that contain triazapentadienes (Amitraz), phenylpyrazoles (Fipronil), or permethrin (pyrethroids). These acaricides target primarily the adult stages of Lyme-carrying ticks and reduce the number of reproductively active ticks in the environment. Formulations of these ingredients are available in a variety of topical forms, including spot-ons, sprays, powders, impregnated collars, solutions, and shampoos.Examination of a dog for ticks after being in a tick-infested area is an important precautionary measure to take in the prevention of Lyme disease. Key spots to examine include the head, neck, and ears.In dogs, a serious long-term prognosis may result in glomerular disease, which is a category of kidney damage that may cause chronic kidney disease. Dogs may also experience chronic joint disease if the disease is left untreated. However, the majority of cases of Lyme disease in dogs result in complete recovery with, and sometimes without, treatment with antibiotics. In rare cases, Lyme disease can be fatal to both humans and dogs. References This article incorporates public domain material from the Centers for Disease Control and Prevention document: "Post-Treatment Lyme Disease Syndrome". Further reading Ostfeld R (2012). Lyme Disease: The Ecology of a Complex System. New York: Oxford University Press. ISBN 978-0-19-992847-7. Barbour AG (2015). Lyme disease: why its spreading, how it makes you sick, and what to do about it. Baltimore. ISBN 978-1-4214-1721-9. Halperin JJ, ed. (2018). Lyme disease: an evidence-based approach (2nd ed.). Wallingford, Oxfordshire, UK: CABI. ISBN 978-1-78639-207-7. Radolf JD, Samuels DS, eds. (2021). Lyme disease and relapsing fever spirochetes: genomics, molecular biology, host interactions and disease pathogenesis. Poole, UK: Caister. ISBN 978-1-913652-61-6. Oaklander M (17 June 2021). "We Used to Have a Lyme Disease Vaccine. Are We Ready to Bring One Back?". Time. External links Lyme disease organizations at Curlie CDC - Lyme Disease Lyme Disease Tests – Lab Tests Online NIH – Lyme Disease NICE Guidelines – Lyme Disease

Cholecystitis

Cholecystitis is inflammation of the gallbladder. Symptoms include right upper abdominal pain, pain in the right shoulder, nausea, vomiting, and occasionally fever. Often gallbladder attacks (biliary colic) precede acute cholecystitis. The pain lasts longer in cholecystitis than in a typical gallbladder attack. Without appropriate treatment, recurrent episodes of cholecystitis are common. Complications of acute cholecystitis include gallstone pancreatitis, common bile duct stones, or inflammation of the common bile duct.More than 90% of the time acute cholecystitis is caused from blockage of the cystic duct by a gallstone. Risk factors for gallstones include birth control pills, pregnancy, a family history of gallstones, obesity, diabetes, liver disease, or rapid weight loss. Occasionally, acute cholecystitis occurs as a result of vasculitis or chemotherapy, or during recovery from major trauma or burns. Cholecystitis is suspected based on symptoms and laboratory testing. Abdominal ultrasound is then typically used to confirm the diagnosis.Treatment is usually with laparoscopic gallbladder removal, within 24 hours if possible. Taking pictures of the bile ducts during the surgery is recommended. The routine use of antibiotics is controversial. They are recommended if surgery cannot occur in a timely manner or if the case is complicated. Stones in the common bile duct can be removed before surgery by endoscopic retrograde cholangiopancreatography (ERCP) or during surgery. Complications from surgery are rare. In people unable to have surgery, gallbladder drainage may be tried.About 10–15% of adults in the developed world have gallstones. Women more commonly have stones than men and they occur more commonly after age 40. Certain ethnic groups are more often affected; for example, 48% of American Indians have gallstones. Of all people with stones, 1–4% have biliary colic each year. If untreated, about 20% of people with biliary colic develop acute cholecystitis. Once the gallbladder is removed outcomes are generally good. Without treatment, chronic cholecystitis may occur. The word is from Greek, cholecyst- meaning "gallbladder" and -itis meaning "inflammation". Signs and symptoms Most people with gallstones do not have symptoms. However, when a gallstone temporarily lodges in the cystic duct, they experience biliary colic. Biliary colic is abdominal pain in the right upper quadrant or epigastric region. It is episodic, occurring after eating greasy or fatty foods, and leads to nausea and/or vomiting. People with cholecystitis most commonly have symptoms of biliary colic before developing cholecystitis. The pain becomes severe and constant in cholecystitis. Nausea is common and vomiting occurs in 75% of people with cholecystitis. In addition to abdominal pain, right shoulder pain can be present.On physical examination, an inflamed gallbladder is almost always tender to the touch and palpable (~25-50% of cases) in the midclavicular right lower rib margin. Additionally, a fever is common. A gallbladder with cholecystitis is almost always tender to touch. Because of the inflammation, its size can be felt from the outside of the body in 25–50% of people with cholecystitis. Pain with deep inspiration leading to termination of the breath while pressing on the right upper quadrant of the abdomen usually causes severe pain (Murphys sign). Yellowing of the skin (jaundice) may occur but is often mild. Severe jaundice suggests another cause of symptoms such as choledocholithiasis. People who are old, have diabetes, chronic illness, or who are immunocompromised may have vague symptoms that may not include fever or localized tenderness. Complications A number of complications may occur from cholecystitis if not detected early or properly treated. Signs of complications include high fever, shock and jaundice. Complications include the following: Gangrene Gallbladder rupture Empyema Fistula formation and gallstone ileus Rokitansky-Aschoff sinuses Gangrene and gallbladder rupture Cholecystitis causes the gallbladder to become distended and firm. Distension can lead to decreased blood flow to the gallbladder, causing tissue death and eventually gangrene. Once tissue has died, the gallbladder is at greatly increased risk of rupture (perforation), which can cause sharp pain. Rupture can also occur in cases of chronic cholecystitis. Rupture is a rare but serious complication that leads to abscess formation or peritonitis. Massive rupture of the gallbladder has a mortality rate of 30%. Empyema Untreated cholecystitis can lead to worsened inflammation and infected bile that can lead to a collection of pus inside the gallbladder, also known as empyema. The symptoms of empyema are similar to uncomplicated cholecystitis but greater severity: high fever, severe abdominal pain, more severely elevated white blood count. Fistula formation and gallstone ileus The inflammation of cholecystitis can lead to adhesions between the gallbladder and other parts of the gastrointestinal tract, most commonly the duodenum. These adhesions can lead to the formation of direct connections between the gallbladder and gastrointestinal tract, called fistulas. With these direct connections, gallstones can pass from the gallbladder to the intestines. Gallstones can get trapped in the gastrointestinal tract, most commonly at the connection between the small and large intestines (ileocecal valve). When a gallstone gets trapped, it can lead to an intestinal obstruction, called gallstone ileus, leading to abdominal pain, vomiting, constipation, and abdominal distension. Causes Cholecystitis occurs when the gallbladder becomes inflamed. Gallstones are the most common cause of gallbladder inflammation but it can also occur due to blockage from a tumor or scarring of the bile duct. The greatest risk factor for cholecystitis is gallstones. Risk factors for gallstones include female sex, increasing age, pregnancy, oral contraceptives, obesity, diabetes mellitus, ethnicity (Native North American), rapid weight loss. Acute calculous cholecystitis Gallstones blocking the flow of bile account for 90% of cases of cholecystitis (acute calculous cholecystitis). Blockage of bile flow leads to thickening and buildup of bile causing an enlarged, red, and tense gallbladder. The gallbladder is initially sterile but often becomes infected by bacteria, predominantly E. coli, Klebsiella, Streptococcus, and Clostridium species. Inflammation can spread to the outer covering of the gallbladder and surrounding structures such as the diaphragm, causing referred right shoulder pain. Acalculous cholecystitis In acalculous cholecystitis, no stone is in the biliary ducts. It accounts for 5–10% of all cases of cholecystitis and is associated with high morbidity and mortality rates. Acalculous cholecystitis is typically seen in people who are hospitalized and critically ill. Males are more likely to develop acute cholecystitis following surgery in the absence of trauma. It is associated with many causes including vasculitis, chemotherapy, major trauma or burns.The presentation of acalculous cholecystitis is similar to calculous cholecystitis. Patients are more likely to have yellowing of the skin (jaundice) than in calculous cholecystitis. Ultrasonography or computed tomography often shows an immobile, enlarged gallbladder. Treatment involves immediate antibiotics and cholecystectomy within 24–72 hours. Chronic cholecystitis Chronic cholecystitis occurs after repeated episodes of acute cholecystitis and is almost always due to gallstones. Chronic cholecystitis may be asymptomatic, may present as a more severe case of acute cholecystitis, or may lead to a number of complications such as gangrene, perforation, or fistula formation.Xanthogranulomatous cholecystitis (XGC) is a rare form of chronic cholecystitis which mimics gallbladder cancer although it is not cancerous. It was first reported in the medical literature in 1976 by McCoy and colleagues. Mechanism Blockage of the cystic duct by a gallstone causes a buildup of bile in the gallbladder and increased pressure within the gallbladder. Concentrated bile, pressure, and sometimes bacterial infection irritate and damage the gallbladder wall, causing inflammation and swelling of the gallbladder. Inflammation and swelling of the gallbladder can reduce normal blood flow to areas of the gallbladder, which can lead to cell death due to inadequate oxygen. Diagnosis The diagnosis of cholecystitis is suggested by the history (abdominal pain, nausea, vomiting, fever) and physical examinations in addition to laboratory and ultrasonographic testing. Boass sign, which is pain in the area below the right scapula, can be a symptom of acute cholecystitis. Blood tests In someone suspected of having cholecystitis, blood tests are performed for markers of inflammation (e.g. complete blood count, C-reactive protein), as well as bilirubin levels in order to assess for bile duct blockage. Complete blood count typically shows an increased white blood count (12,000–15,000/mcL). C-reactive protein is usually elevated although not commonly measured in the United States. Bilirubin levels are often mildly elevated (1–4 mg/dL). If bilirubin levels are more significantly elevated, alternate or additional diagnoses should be considered such as gallstone blocking the common bile duct (common bile duct stone). Less commonly, blood aminotransferases are elevated. The degree of elevation of these laboratory values may depend on the degree of inflammation of the gallbladder. Imaging Right upper quadrant abdominal ultrasound is most commonly used to diagnose cholecystitis. Ultrasound findings suggestive of acute cholecystitis include gallstones, pericholecystic fluid (fluid surrounding the gallbladder), gallbladder wall thickening (wall thickness over 3 mm), dilation of the bile duct, and sonographic Murphys sign. Given its higher sensitivity, hepatic iminodiacetic acid (HIDA) scan can be used if ultrasound is not diagnostic. CT scan may also be used if complications such as perforation or gangrene are suspected. Histopathology Histopathology is indicated if preoperative imaging and/or gross examination gives a suspicion of gallbladder cancer. Differential diagnosis Many other diagnoses can have similar symptoms as cholecystitis. Additionally the symptoms of chronic cholecystitis are commonly vague and can be mistaken for other diseases. These alternative diagnoses include but are not limited to: Perforated peptic ulcer Acute pancreatitis Liver abscess Pneumonia Myocardial ischemia Hiatal hernia Biliary colic Choledocholithiasis Cholangitis Appendicitis Colitis Acute peptic ulcer exacerbation Amoebic liver abscess Acute intestinal obstruction Kidney stone Biliary ascariasis Treatment Surgery For most people with acute cholecystitis, the treatment of choice is surgical removal of the gallbladder, laparoscopic cholecystectomy. Laparoscopic cholecystectomy is performed using several small incisions located at various points across the abdomen. Several studies have demonstrated the superiority of laparoscopic cholecystectomy when compared to open cholecystectomy (using a large incision in the right upper abdomen under the rib cage). People undergoing laparoscopic surgery report less incisional pain postoperatively as well as having fewer long-term complications and less disability following the surgery. Additionally, laparoscopic surgery is associated with a lower rate of surgical site infection.During the days prior to laparoscopic surgery, studies showed that outcomes were better following early removal of the gallbladder, preferably within the first week. Early laparoscopic cholecystectomy (within 7 days of visiting a doctor with symptoms) as compared to delayed treatment (more than 6 weeks) may result in shorter hospital stays and a decreased risk of requiring an emergency procedure. There is no difference in terms of negative outcomes including bile duct injury or conversion to open cholecystectomy. For early cholecystectomy, the most common reason for conversion to open surgery is inflammation that hides Calots triangle. For delayed surgery, the most common reason was fibrotic adhesions. Other Supportive measures may be instituted prior to surgery. These measures include fluid resuscitation. Intravenous opioids can be used for pain control.Antibiotics are often not needed. If used they should target enteric organisms (e.g. Enterobacteriaceae), such as E. coli and Bacteroides. This may consist of a broad spectrum antibiotic; such as piperacillin-tazobactam, ampicillin-sulbactam, ticarcillin-clavulanate (Timentin), a third generation cephalosporin (e.g.ceftriaxone) or a quinolone antibiotic (such as ciprofloxacin) and anaerobic bacteria coverage, such as metronidazole. For penicillin allergic people, aztreonam or a quinolone with metronidazole may be used.In cases of severe inflammation, shock, or if the person has higher risk for general anesthesia (required for cholecystectomy), an interventional radiologist may insert a percutaneous drainage catheter into the gallbladder (percutaneous cholecystostomy tube) and treat the person with antibiotics until the acute inflammation resolves. A cholecystectomy may then be warranted if the persons condition improves.Homeopathic approaches to treating cholecystitis have not been validated by evidence and should not be used in place of surgery. Epidemiology Cholecystitis accounts for 3–10% of cases of abdominal pain worldwide. Cholecystitis caused an estimated 651,829 emergency department visits and 389,180 hospital admissions in the US in 2012. The 2012 US mortality rate was 0.7 per 100,000 people. The frequency of cholecystitis is highest in people age 50–69 years old. References == External links ==

Anemia of chronic disease

Anemia of chronic disease (ACD) or anemia of chronic inflammation is a form of anemia seen in chronic infection, chronic immune activation, and malignancy. These conditions all produce elevation of interleukin-6, which stimulates hepcidin production and release from the liver, which in turn shuts down ferroportin, a protein that controls export of iron from the gut and from iron storing cells (e.g. macrophages). As a consequence, circulating iron levels are reduced. Other mechanisms may also play a role, such as reduced erythropoiesis. It is also known as anemia of inflammation, or anemia of inflammatory response. Classification Anemia of chronic disease is usually mild but can be severe. It is usually normocytic, but can be microcytic. The presence of both anemia of chronic disease and dietary iron deficiency results in a more severe anemia. Pathophysiology Anemia is defined by hemoglobin (Hb) concentration < 13.0 g/dL (130 g/L) in males < 11.5 g/dL (115 g/L) in femalesIn response to inflammatory cytokines, increasingly IL-6, the liver produces increased amounts of hepcidin. Hepcidin in turn causes increased internalisation of ferroportin molecules on cell membranes which prevents release from iron stores. Inflammatory cytokines also appear to affect other important elements of iron metabolism, including decreasing ferroportin expression, and probably directly blunting erythropoiesis by decreasing the ability of the bone marrow to respond to erythropoietin. Before the recent discovery of hepcidin and its function in iron metabolism, anemia of chronic disease was seen as the result of a complex web of inflammatory changes. Over the last few years, however, many investigators have come to feel that hepcidin is the central actor in producing anemia of chronic inflammation. Hepcidin provides a unifying explanation for the condition, and more recent descriptions of human iron metabolism and hepcidin function reflect this view.In addition to effects of iron sequestration, inflammatory cytokines promote the production of white blood cells. Bone marrow produces both white blood cells and red blood cells from the same precursor stem cells. Therefore, the upregulation of white blood cells causes fewer stem cells to differentiate into red blood cells. This effect may be an important additional cause for the decreased erythropoiesis and red blood cell production seen in anemia of inflammation, even when erythropoietin levels are normal, and even aside from the effects of hepcidin. Nonetheless, there are other mechanisms that also contribute to the lowering of hemoglobin levels during inflammation: (i) Inflammatory cytokines suppress the proliferation of erythroid precursors in the bone marrow.; (ii) inflammatory cytokines inhibit the release of erythropoietin (EPO) from the kidney; and (iii) the survival time of circulating red cells is shortened.In the short term, the overall effect of these changes is likely positive: it allows the body to keep more iron away from bacterial pathogens in the body, while producing more immune cells to fight off infection. Almost all bacteria depend on iron to live and multiply. However, if inflammation continues, the effect of locking up iron stores is to reduce the ability of the bone marrow to produce red blood cells. These cells require iron for their massive amounts of hemoglobin which allow them to transport oxygen.Because anemia of chronic disease can be the result of non-infective causes of inflammation, future research is likely to investigate whether hepcidin antagonists might be able to treat this problem. Anemia of chronic disease may also be due to neoplastic disorders and non-infectious inflammatory diseases. Neoplastic disorders include Hodgkin disease and lung and breast carcinoma, while non-infectious inflammatory diseases include celiac disease, rheumatoid arthritis, systemic lupus erythematosus, scleroderma and dermatomyositis. Anemia of chronic disease, as it is now understood, is to at least some degree separate from the anemia seen in kidney failure in which anemia results from reduced production of erythropoietin, or the anemia caused by some drugs (like AZT, used to treat HIV infection) that have the side effect of inhibiting erythropoiesis. In other words, not all anemia seen in people with chronic disease should be diagnosed as anemia of chronic disease. On the other hand, both of these examples show the complexity of this diagnosis: HIV infection itself can produce anemia of chronic disease, and kidney failure can lead to inflammatory changes that also can produce anemia of chronic disease. Diagnosis While no single test is reliable to distinguish iron deficiency anemia from the anemia of chronic inflammation, there are sometimes some suggestive data: In anemia of chronic inflammation without iron deficiency, ferritin is normal or high, reflecting the fact that iron is sequestered within cells, and ferritin is being produced as an acute phase reactant. In iron deficiency anemia ferritin is low. Total iron-binding capacity (TIBC) is high in iron deficiency, reflecting production of more transferrin to increase iron binding; TIBC is low or normal in anemia of chronic inflammation. Treatment The ideal treatment for anemia of chronic disease is to treat the chronic disease successfully, but this is rarely possible. Parenteral iron is increasingly used for anemia in chronic renal disease and inflammatory bowel disease.Erythropoietin can be helpful, but this is costly and may be dangerous. Erythropoietin is advised either in conjunction with adequate iron replacement which in practice is intravenous, or when IV iron has proved ineffective.Limiting some microbes access to iron can reduce their virulence, thereby potentially reducing the severity of infection. Blood transfusion to patients with anemia of chronic disease is associated with a higher mortality, supporting the concept. See also List of circulatory system conditions List of hematologic conditions References External links National Anemia Action Council

Primary polydipsia

Primary polydipsia and psychogenic polydipsia are forms of polydipsia characterised by excessive fluid intake in the absence of physiological stimuli to drink. Psychogenic polydipsia which is caused by psychiatric disorders, often schizophrenia, is often accompanied by the sensation of dry mouth. Some forms of polydipsia are explicitly non-psychogenic. Primary polydipsia is a diagnosis of exclusion. Signs and symptoms Signs and symptoms of psychogenic polydipsia include: Excessive thirst and xerostomia, leading to overconsumption of water Hyponatraemia, causing headache, muscular weakness, twitching, confusion, vomiting, irritability etc., although this is only seen in 20% – 30% of cases. Hypervolemia, leading to oedema, hypertension and weight gain (due to the kidneys being unable to filter the excess blood) in extreme episodes Tonic-clonic seizure Behavioural changes, including fluid-seeking behaviour; patients have been known to seek fluids from any available source, such as toilets and shower rooms.The most common presenting symptom is tonic-clonic seizure, found in 80% of patients. Psychogenic polydipsia should be considered a life-threatening condition, since it has been known to cause severe hyponatraemia, leading to cardiac arrest, coma and cerebral oedema. Brain differences Psychogenic polydipsia in individuals with schizophrenia is associated with differences seen in neuroimaging. MRI scans may be used to help with differentiating between PPD and diabetes insipidus, such as by examining the signal of the posterior pituitary (weakened or absent in central DI). Some patients, most often with a history of mental illness, show a shrunken cortex and enlarged ventricles on an MRI scan, which makes differentiation between psychogenic and physiological cause difficult. However, these changes will likely only develop after chronic PPD associated with severe mental illness, as opposed to less severe forms of the disorder as seen in those with anxiety and affective disorders. PPD is also linked with significant reductions in insular cortex volume, although this may be caused by the secondary hyponatraemia. It has been suggested that these deficits lead to moderate to severe cognitive impairments, especially affecting working memory, verbal memory, executive function, attention and motor speed.Other areas with volume reductions (both white and grey matter) include: Right posterior lobe Right inferior temporal gyrus Parahippocampal gyrus Both left and right superior temporal gyri Right cuneus Left medial frontal gyryus and inferior frontal gyrus Right lingual gyrus Diagnosis As a diagnosis of exclusion, a diagnosis of primary polydipsia may be the result of elimination of the possibility of diseases causing similar signs and symptoms, such as diabetes insipidus. Diagnosis may be complicated by the fact that chronic and extreme compulsive drinking may impair the response of the kidneys to vasopressin, thus reducing the kidneys ability to concentrate the urine. This means that psychogenic polydipsia may lead to test results (e.g. in a water restriction test) consistent with diabetes insipidus or SIADH, leading to misdiagnosis.Dry mouth is often a side effect of medications used in the treatment of some mental disorders, rather than being caused by the underlying condition. Such medications include antipsychotics, antidepressants, anticonvulsants, alpha agonists and anticholinergics. It should also be ensured that the thirst isnt caused by diuretic use (particularly thiazide diuretics), MDMA use, excessive solute intake or chronic alcoholism. Alcoholism may cause physiological thirst since ethanol inhibits vasopressin, the hormone primarily responsible for water retention in osmoregulation. The following conditions should also be excluded: DI, cerebral salt wasting, pseudohyponatraemia caused by hyperlipidemia or hyperparaproteinemia, SIADH, mineralcorticoid deficiency, salt-wasting nephropathy, nephrotic syndrome, chronic heart failure and cirrhosis.Tobacco smoking is an often overlooked factor linked to hyponatremia, due to the ADH-releasing effect of nicotine, although this is usually limited to heavy smokers. One study suggested that around 70% of patients with self-induced polydipsia were tobacco smokers. Diagnostic tests for primary polydipsia usually involves the fluid deprivation test to exclude ADH problems. The desmopressin test is also used, in which the synthetic hormone is used as a diagnostic workup to test for inappropriate secretion of vasopressin, as seen in DI and SIADH. Patient profiles Psychogenic polydipsia is found in patients with mental illnesses, most commonly schizophrenia, but also anxiety disorders and rarely affective disorders, anorexia nervosa and personality disorders. PPD occurs in between 6% and 20% of psychiatric inpatients. It may also be found in people with developmental disorders, such as those with autism. While psychogenic polydipsia is usually not seen outside the population of those with serious mental disorders, it may occasionally be found among others in the absence of psychosis, although there is no existent research to document this other than anecdotal observations. Such persons typically prefer to possess bottled water that is ice-cold, consume water and other fluids at excessive levels. However, a preference for ice-cold water is also seen in diabetes insipidus. Treatment Treatment for psychogenic polydipsia depends on severity and may involve behavioural and pharmacological modalities. Acute hyponatraemia If the patient presents with acute hyponatraemia (overhydration) caused by psychogenic polydipsia, treatment usually involves administration of intravenous hypertonic (3%) saline until the serum sodium levels stabilise to within a normal range, even if the patient becomes asymptomatic. Fluid restriction If the patient is institutionalised, monitoring of behaviour and serum sodium levels is necessary. In treatment-resistant polydipsic psychiatric patients, regulation in the inpatient setting can be accomplished by use of a weight-water protocol. First, base-line weights must be established and correlated to serum sodium levels. Weight will normally fluctuate during the day, but as the water intake of the polydipsic goes up, the weight will naturally rise. The physician can order a stepped series of interventions as the weight rises. The correlation must be individualized with attention paid to the patients normal weight and fluctuations, diet, comorbid disorders (such as a seizure disorder) and urinary system functioning. Progressive steps might include redirection, room restriction, and increasing levels of physical restraint with monitoring. Such plans should also include progressive increases in monitoring, as well as a level at which a serum sodium level is drawn. Behavioural Behavioural treatments may involve the use of a token economy to provide positive reinforcement to desirable behaviour. Furthermore, cognitive therapy techniques can be used to address the thought patterns that lead to compulsive drinking behaviour. Success has been seen in trials of this technique, with emphasis on the development of coping techniques (e.g. taking small sips of water, having ice cubes instead of drinks) in addition to challenging delusions leading to excessive drinking.Psychogenic polydipsia often leads to institutionalisation of mentally ill patients, since it is difficult to manage in the community. Most studies of behavioural treatments occur in institutional settings and require close monitoring of the patient and a large degree of time commitment from staff. Pharmaceutical A number of pharmaceuticals may be used in an attempt to bring the polydipsia under control, including: Atypical antipsychotics, such as clozapine, olanzapine and risperidone Demeclocycline, a tetracycline antibiotic, which is effective due to the side effect of inducing nephrogenic diabetes insipidus. Demeclocycline is used for cases of psychogenic polydipsia, including those with nocturnal enuresis (bed-wetting). Its mechanism of action involves direct inhibition of vasopressin at the DCTs, thus reducing urine concentration.There are a number of emerging pharmaceutical treatments for psychogenic polydipsia, although these need further investigation: ACE Inhibitors, such as enalapril Clonidine, an alpha-2 adrenergic agonist Irbesartan, an angiotensin II receptor antagonist Propranolol, a sympatholytic beta blocker Vasopressin receptor antagonists, such as conivaptan Acetazolamide, a carbonic anhydrase inhibitorLithium was previously used for treatment of PPD as a direct competitive ADH antagonist, but is now generally avoided due to its toxic effects on the thyroid and kidneys.It is important to note that the majority of psychotropic drugs (and a good many of other classes) can cause dry mouth as a side effect, but this is not to be confused with true polydipsia in which a dangerous drop in serum sodium will be seen. Terminology In diagnosis, primary polydipsia is usually categorised as: Psychogenic (PPD) – caused by underlying psychiatric symptoms, including those caused by psychoses and rarely by affective disorders Non-psychogenic – another non-psychological cause, including idiopathic (unknown cause)The terms primary polydipsia and psychogenic polydipsia are sometimes incorrectly used interchangeably – to be considered psychogenic, the patient needs to have some other psychiatric symptoms, such as delusions involving fluid intake or other unusual behaviours. Primary polydipsia may have physiological causes, such as autoimmune hepatitis. Since primary polydipsia is a diagnosis of exclusion, the diagnosis may be made for patients who have medically unexplained excessive thirst, and this is sometimes incorrectly referred to as psychogenic rather than primary polydipsia. Non-psychogenic Although primary polydipsia is usually categorised as psychogenic, there are some rare non-psychogenic causes. An example is polydipsia found in patients with autoimmune chronic hepatitis with severely elevated globulin levels. Evidence for the thirst being non-psychogenic is gained from the fact that it disappears after treatment of the underlying disease. Non-human animals Psychogenic polydipsia is also observed in some non-human patients, such as in rats and cats. See also Water intoxication Fluid deprivation test References Further reading Siegler EL, Tamres D, Berlin JA, Allen-Taylor L, Strom BL (May 1995). "Risk factors for the development of hyponatremia in psychiatric inpatients". Archives of Internal Medicine. 155 (9): 953–957. doi:10.1001/archinte.1995.00430090099011. PMID 7726704. Mauri MC, Volonteri LS, Fiorentini A, Dieci M, Righini A, Vita A (July 2002). "Efficacy of clozapine in a non-schizophrenic patient with psychogenic polydipsia and central pontine myelinolysis". Human Psychopharmacology. 17 (5): 253–255. doi:10.1002/hup.407. PMID 12404683. S2CID 21589725. External links Psychogenic Polydipsia (Excessive Fluid seeking Behaviour) by Donald "Don" Hutcheon on the APAs website

Urinary tract infection

A urinary tract infection (UTI) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidney infection (pyelonephritis). Symptoms from a lower urinary tract infection include pain with urination, frequent urination, and feeling the need to urinate despite having an empty bladder. Symptoms of a kidney infection include fever and flank pain usually in addition to the symptoms of a lower UTI. Rarely the urine may appear bloody. In the very old and the very young, symptoms may be vague or non-specific.The most common cause of infection is Escherichia coli, though other bacteria or fungi may sometimes be the cause. Risk factors include female anatomy, sexual intercourse, diabetes, obesity, and family history. Although sexual intercourse is a risk factor, UTIs are not classified as sexually transmitted infections (STIs). Kidney infection, if it occurs, usually follows a bladder infection but may also result from a blood-borne infection. Diagnosis in young healthy women can be based on symptoms alone. In those with vague symptoms, diagnosis can be difficult because bacteria may be present without there being an infection. In complicated cases or if treatment fails, a urine culture may be useful.In uncomplicated cases, UTIs are treated with a short course of antibiotics such as nitrofurantoin or trimethoprim/sulfamethoxazole. Resistance to many of the antibiotics used to treat this condition is increasing. In complicated cases, a longer course or intravenous antibiotics may be needed. If symptoms do not improve in two or three days, further diagnostic testing may be needed. Phenazopyridine may help with symptoms. In those who have bacteria or white blood cells in their urine but have no symptoms, antibiotics are generally not needed, although during pregnancy is an exception. In those with frequent infections, a short course of antibiotics may be taken as soon as symptoms begin or long-term antibiotics may be used as a preventive measure.About 150 million people develop a urinary tract infection in a given year. They are more common in women than men. In women, they are the most common form of bacterial infection. Up to 10% of women have a urinary tract infection in a given year, and half of women have at least one infection at some point in their lifetime. They occur most frequently between the ages of 16 and 35 years. Recurrences are common. Urinary tract infections have been described since ancient times with the first documented description in the Ebers Papyrus dated to c. 1550 BC. Signs and symptoms Lower urinary tract infection is also referred to as a bladder infection. The most common symptoms are burning with urination and having to urinate frequently (or an urge to urinate) in the absence of vaginal discharge and significant pain. These symptoms may vary from mild to severe and in healthy women last an average of six days. Some pain above the pubic bone or in the lower back may be present. People experiencing an upper urinary tract infection, or pyelonephritis, may experience flank pain, fever, or nausea and vomiting in addition to the classic symptoms of a lower urinary tract infection. Rarely, the urine may appear bloody or contain visible pus in the urine.UTIs have been associated with onset or worsening of delirium, dementia, and neuropsychiatric disorders such as depression and psychosis. The reasons for this are unknown, but may involve a UTI-mediated systemic inflammatory response which affects the brain. Cytokines produced as part of the inflammatory response may produce neuroinflammation, in turn affecting dopaminergic and/or glutamatergic neurotransmission as well as brain glucose metabolism. Children In young children, the only symptom of a urinary tract infection (UTI) may be a fever. Because of the lack of more obvious symptoms, when females under the age of two or uncircumcised males less than a year exhibit a fever, a culture of the urine is recommended by many medical associations. Infants may feed poorly, vomit, sleep more, or show signs of jaundice. In older children, new onset urinary incontinence (loss of bladder control) may occur. About 1 in 400 infants of 1 to 3 months of age with a UTI also have bacterial meningitis. Elderly Urinary tract symptoms are frequently lacking in the elderly. The presentations may be vague with incontinence, a change in mental status, or fatigue as the only symptoms, while some present to a health care provider with sepsis, an infection of the blood, as the first symptoms. Diagnosis can be complicated by the fact that many elderly people have preexisting incontinence or dementia.It is reasonable to obtain a urine culture in those with signs of systemic infection that may be unable to report urinary symptoms, such as when advanced dementia is present. Systemic signs of infection include a fever or increase in temperature of more than 1.1 °C (2.0 °F) from usual, chills, and an increased white blood cell count. Cause Uropathogenic E. coli from the gut is the cause of 80–85% of community-acquired urinary tract infections, with Staphylococcus saprophyticus being the cause in 5–10%. Rarely they may be due to viral or fungal infections. Healthcare-associated urinary tract infections (mostly related to urinary catheterization) involve a much broader range of pathogens including: E. coli (27%), Klebsiella (11%), Pseudomonas (11%), the fungal pathogen Candida albicans (9%), and Enterococcus (7%) among others. Urinary tract infections due to Staphylococcus aureus typically occur secondary to blood-borne infections. Chlamydia trachomatis and Mycoplasma genitalium can infect the urethra but not the bladder. These infections are usually classified as a urethritis rather than urinary tract infection. Intercourse In young sexually active women, sexual activity is the cause of 75–90% of bladder infections, with the risk of infection related to the frequency of sex. The term "honeymoon cystitis" has been applied to this phenomenon of frequent UTIs during early marriage. In post-menopausal women, sexual activity does not affect the risk of developing a UTI. Spermicide use, independent of sexual frequency, increases the risk of UTIs. Diaphragm use is also associated. Condom use without spermicide or use of birth control pills does not increase the risk of uncomplicated urinary tract infection. Sex Women are more prone to UTIs than men because, in females, the urethra is much shorter and closer to the anus. As a womans estrogen levels decrease with menopause, her risk of urinary tract infections increases due to the loss of protective vaginal flora. Additionally, vaginal atrophy that can sometimes occur after menopause is associated with recurrent urinary tract infections.Chronic prostatitis in the forms of chronic prostatitis/chronic pelvic pain syndrome and chronic bacterial prostatitis (not acute bacterial prostatitis or asymptomatic inflammatory prostatitis) may cause recurrent urinary tract infections in males. Risk of infections increases as males age. While bacteria is commonly present in the urine of older males this does not appear to affect the risk of urinary tract infections. Urinary catheters Urinary catheterization increases the risk for urinary tract infections. The risk of bacteriuria (bacteria in the urine) is between three and six percent per day and prophylactic antibiotics are not effective in decreasing symptomatic infections. The risk of an associated infection can be decreased by catheterizing only when necessary, using aseptic technique for insertion, and maintaining unobstructed closed drainage of the catheter.Male scuba divers using condom catheters and female divers using external catching devices for their dry suits are also susceptible to urinary tract infections. Others A predisposition for bladder infections may run in families. This is believed to be related to genetics. Other risk factors include diabetes, being uncircumcised, and having a large prostate. In children UTIs are associated with vesicoureteral reflux (an abnormal movement of urine from the bladder into ureters or kidneys) and constipation.Persons with spinal cord injury are at increased risk for urinary tract infection in part because of chronic use of catheter, and in part because of voiding dysfunction. It is the most common cause of infection in this population, as well as the most common cause of hospitalization. Pathogenesis The bacteria that cause urinary tract infections typically enter the bladder via the urethra. However, infection may also occur via the blood or lymph. It is believed that the bacteria are usually transmitted to the urethra from the bowel, with females at greater risk due to their anatomy. After gaining entry to the bladder, E. Coli are able to attach to the bladder wall and form a biofilm that resists the bodys immune response.Escherichia coli is the single most common microorganism, followed by Klebsiella and Proteus spp., to cause urinary tract infection. Klebsiella and Proteus spp., are frequently associated with stone disease. The presence of Gram positive bacteria such as Enterococcus and Staphylococcus increased.The increased resistance of urinary pathogens to quinolone antibiotics has been reported worldwide and might be the consequence of overuse and misuse of quinolones. Diagnosis In straightforward cases, a diagnosis may be made and treatment given based on symptoms alone without further laboratory confirmation. In complicated or questionable cases, it may be useful to confirm the diagnosis via urinalysis, looking for the presence of urinary nitrites, white blood cells (leukocytes), or leukocyte esterase. Another test, urine microscopy, looks for the presence of red blood cells, white blood cells, or bacteria. Urine culture is deemed positive if it shows a bacterial colony count of greater than or equal to 103 colony-forming units per mL of a typical urinary tract organism. Antibiotic sensitivity can also be tested with these cultures, making them useful in the selection of antibiotic treatment. However, women with negative cultures may still improve with antibiotic treatment. As symptoms can be vague and without reliable tests for urinary tract infections, diagnosis can be difficult in the elderly. Based on pH Normal urine pH is slightly acidic, with usual values of 6.0 to 7.5, but the normal range is 4.5 to 8.0. A urine pH of 8.5 or 9.0 is indicative of a urea-splitting organism, such as Proteus, Klebsiella, or Ureaplasma urealyticum; therefore, an asymptomatic patient with a high pH means UTI regardless of the other urine test results. Alkaline pH also can signify struvite kidney stones, which are also known as “infection stones.” Classification A urinary tract infection may involve only the lower urinary tract, in which case it is known as a bladder infection. Alternatively, it may involve the upper urinary tract, in which case it is known as pyelonephritis. If the urine contains significant bacteria but there are no symptoms, the condition is known as asymptomatic bacteriuria. If a urinary tract infection involves the upper tract, and the person has diabetes mellitus, is pregnant, is male, or immunocompromised, it is considered complicated. Otherwise if a woman is healthy and premenopausal it is considered uncomplicated. In children when a urinary tract infection is associated with a fever, it is deemed to be an upper urinary tract infection. Children To make the diagnosis of a urinary tract infection in children, a positive urinary culture is required. Contamination poses a frequent challenge depending on the method of collection used, thus a cutoff of 105 CFU/mL is used for a "clean-catch" mid stream sample, 104 CFU/mL is used for catheter-obtained specimens, and 102 CFU/mL is used for suprapubic aspirations (a sample drawn directly from the bladder with a needle). The use of "urine bags" to collect samples is discouraged by the World Health Organization due to the high rate of contamination when cultured, and catheterization is preferred in those not toilet trained. Some, such as the American Academy of Pediatrics recommends renal ultrasound and voiding cystourethrogram (watching a persons urethra and urinary bladder with real time x-rays while they urinate) in all children less than two years old who have had a urinary tract infection. However, because there is a lack of effective treatment if problems are found, others such as the National Institute for Health and Care Excellence only recommends routine imaging in those less than six months old or who have unusual findings. Differential diagnosis In women with cervicitis (inflammation of the cervix) or vaginitis (inflammation of the vagina) and in young men with UTI symptoms, a Chlamydia trachomatis or Neisseria gonorrhoeae infection may be the cause. These infections are typically classified as a urethritis rather than a urinary tract infection. Vaginitis may also be due to a yeast infection. Interstitial cystitis (chronic pain in the bladder) may be considered for people who experience multiple episodes of UTI symptoms but urine cultures remain negative and not improved with antibiotics. Prostatitis (inflammation of the prostate) may also be considered in the differential diagnosis.Hemorrhagic cystitis, characterized by blood in the urine, can occur secondary to a number of causes including: infections, radiation therapy, underlying cancer, medications and toxins. Medications that commonly cause this problem include the chemotherapeutic agent cyclophosphamide with rates of 2 to 40%. Eosinophilic cystitis is a rare condition where eosinophiles are present in the bladder wall. Signs and symptoms are similar to a bladder infection. Its cause is not entirely clear; however, it may be linked to food allergies, infections, and medications among others. Prevention A number of measures have not been confirmed to affect UTI frequency including: urinating immediately after intercourse, the type of underwear used, personal hygiene methods used after urinating or defecating, or whether a person typically bathes or showers. There is similarly a lack of evidence surrounding the effect of holding ones urine, tampon use, and douching. In those with frequent urinary tract infections who use spermicide or a diaphragm as a method of contraception, they are advised to use alternative methods. In those with benign prostatic hyperplasia urinating in a sitting position appears to improve bladder emptying which might decrease urinary tract infections in this group.Using urinary catheters as little and as short of time as possible and appropriate care of the catheter when used prevents catheter-associated urinary tract infections. They should be inserted using sterile technique in hospital however non-sterile technique may be appropriate in those who self catheterize. The urinary catheter set up should also be kept sealed. Evidence does not support a significant decrease in risk when silver-alloy catheters are used. Medications For those with recurrent infections, taking a short course of antibiotics when each infection occurs is associated with the lowest antibiotic use. A prolonged course of daily antibiotics is also effective. Medications frequently used include nitrofurantoin and trimethoprim/sulfamethoxazole. Methenamine is another agent used for this purpose as in the bladder where the acidity is low it produces formaldehyde to which resistance does not develop. Some recommend against prolonged use due to concerns of antibiotic resistance.In cases where infections are related to intercourse, taking antibiotics afterwards may be useful. In post-menopausal women, topical vaginal estrogen has been found to reduce recurrence. As opposed to topical creams, the use of vaginal estrogen from pessaries has not been as useful as low dose antibiotics. Antibiotics following short term urinary catheterization decreases the subsequent risk of a bladder infection. A number of vaccines are in development as of 2018. Children The evidence that preventive antibiotics decrease urinary tract infections in children is poor. However recurrent UTIs are a rare cause of further kidney problems if there are no underlying abnormalities of the kidneys, resulting in less than a third of a percent (0.33%) of chronic kidney disease in adults. Whether routine circumcision prevents UTIs has not been well studied as of 2011. Alternative medicine Some research suggests that cranberry (juice or capsules) may decrease the number of UTIs in those with frequent infections. A Cochrane review concluded that the benefit, if it exists, is small; so did a randomized controlled trial in 2016. Long-term tolerance is also an issue with gastrointestinal upset occurring in more than 30%. Cranberry juice is thus not currently recommended for this indication. As of 2015, probiotics require further study to determine if they are beneficial. The role of the urinary microbiome in maintaining urinary tract health is not well understood as of 2015. There is some evidence that mannose can be an effective treatment and prophylaxis of recurrent UTIs in adult women. Treatment The mainstay of treatment is antibiotics. Phenazopyridine is occasionally prescribed during the first few days in addition to antibiotics to help with the burning and urgency sometimes felt during a bladder infection. However, it is not routinely recommended due to safety concerns with its use, specifically an elevated risk of methemoglobinemia (higher than normal level of methemoglobin in the blood). Paracetamol may be used for fevers. There is no good evidence for the use of cranberry products for treating current infections.Fosfomycin can be used as an efficacious treatment for both UTIs and complicated UTIs including acute pyelonephritis. The standard regimen for complicated UTIs is an oral 3g dose administered once every 48 or 72 hours for a total of 3 doses or a 6 grams every 8 hours for 7 days to 14 days when fosfomycin is given in IV form. Asymptomatic bacteriuria Those who have bacteria in the urine but no symptoms should not generally be treated with antibiotics. This includes those who are old, those with spinal cord injuries, and those who have urinary catheters. Pregnancy is an exception and it is recommended that women take 7 days of antibiotics. If not treated it causes up to 30% of mothers to develop pyelonephritis and increases risk of low birth weight and preterm birth. Some also support treatment of those with diabetes mellitus and treatment before urinary tract procedures which will likely cause bleeding. Uncomplicated Uncomplicated infections can be diagnosed and treated based on symptoms alone. Antibiotics taken by mouth such as trimethoprim/sulfamethoxazole, nitrofurantoin, or fosfomycin are typically first line. Cephalosporins, amoxicillin/clavulanic acid, or a fluoroquinolone may also be used. However, antibiotic resistance to fluoroquinolones among the bacteria that cause urinary infections has been increasing. The Food and Drug Administration (FDA) recommends against the use of fluoroquinolones, including a Boxed Warning, when other options are available due to higher risks of serious side effects, such as tendinitis, tendon rupture and worsening of myasthenia gravis. These medications substantially shorten the time to recovery with all being equally effective. A three-day treatment with trimethoprim/sulfamethoxazole, or a fluoroquinolone is usually sufficient, whereas nitrofurantoin requires 5–7 days. Fosfomycin may be used as a single dose but is not as effective.Fluoroquinolones are not recommended as a first treatment. The Infectious Diseases Society of America states this due to the concern of generating resistance to this class of medication. Amoxicillin-clavulanate appears less effective than other options. Despite this precaution, some resistance has developed to all of these medications related to their widespread use. Trimethoprim alone is deemed to be equivalent to trimethoprim/sulfamethoxazole in some countries. For simple UTIs, children often respond to a three-day course of antibiotics. Women with recurrent simple UTIs are over 90% accurate in identifying new infections. They may benefit from self-treatment upon occurrence of symptoms with medical follow-up only if the initial treatment fails. Complicated Complicated UTIs are more difficult to treat and usually requires more aggressive evaluation, treatment and follow-up. It may require identifying and addressing the underlying complication. Increasing antibiotic resistance is causing concern about the future of treating those with complicated and recurrent UTI. Pyelonephritis Pyelonephritis is treated more aggressively than a simple bladder infection using either a longer course of oral antibiotics or intravenous antibiotics. Seven days of the oral fluoroquinolone ciprofloxacin is typically used in areas where the resistance rate is less than 10%. If the local resistance rates are greater than 10%, a dose of intravenous ceftriaxone is often prescribed. Trimethoprim/sulfamethoxazole or amoxicillin/clavulanate orally for 14 days is another reasonable option. In those who exhibit more severe symptoms, admission to a hospital for ongoing antibiotics may be needed. Complications such as ureteral obstruction from a kidney stone may be considered if symptoms do not improve following two or three days of treatment. Prognosis With treatment, symptoms generally improve within 36 hours. Up to 42% of uncomplicated infections may resolve on their own within a few days or weeks.Some children will develop recurrent urinary tract infection. When urinary tract infection involves the lower urinary tract, it develop cystitis, if urinary tract infection involves the upper tract, pyelonephritis develops. About 10 to 20% of pyelonephritis will go on and develop scarring of the affected kidney. Then, 10 to 20% of those develop scarring will have increased risk of hypertension in later life. Epidemiology Urinary tract infections are the most frequent bacterial infection in women. They occur most frequently between the ages of 16 and 35 years, with 10% of women getting an infection yearly and more than 40–60% having an infection at some point in their lives. Recurrences are common, with nearly half of people getting a second infection within a year. Urinary tract infections occur four times more frequently in females than males. Pyelonephritis occurs between 20 and 30 times less frequently. They are the most common cause of hospital-acquired infections accounting for approximately 40%. Rates of asymptomatic bacteria in the urine increase with age from two to seven percent in women of child-bearing age to as high as 50% in elderly women in care homes. Rates of asymptomatic bacteria in the urine among men over 75 are between 7–10%. Asymptomatic bacteria in the urine occurs in 2% to 10% of pregnancies.Urinary tract infections may affect 10% of people during childhood. Among children, urinary tract infections are most common in uncircumcised males less than three months of age, followed by females less than one year. Estimates of frequency among children, however, vary widely. In a group of children with a fever, ranging in age between birth and two years, two to 20% were diagnosed with a UTI. History Urinary tract infections have been described since ancient times with the first documented description in the Ebers Papyrus dated to c. 1550 BC. It was described by the Egyptians as "sending forth heat from the bladder". Effective treatment did not occur until the development and availability of antibiotics in the 1930s before which time herbs, bloodletting and rest were recommended. Pregnancy Urinary tract infections are more concerning in pregnancy due to the increased risk of kidney infections. During pregnancy, high progesterone levels elevate the risk of decreased muscle tone of the ureters and bladder, which leads to a greater likelihood of reflux, where urine flows back up the ureters and towards the kidneys. While pregnant women do not have an increased risk of asymptomatic bacteriuria, if bacteriuria is present they do have a 25–40% risk of a kidney infection. Thus if urine testing shows signs of an infection—even in the absence of symptoms—treatment is recommended. Cephalexin or nitrofurantoin are typically used because they are generally considered safe in pregnancy. A kidney infection during pregnancy may result in preterm birth or pre-eclampsia (a state of high blood pressure and kidney dysfunction during pregnancy that can lead to seizures). Some women have UTIs that keep coming back in pregnancy. Currently, there is insufficient research on how to best treat these recurrent infections. References == External links ==

Cerebral palsy

Cerebral palsy (CP) is a group of movement disorders that appear in early childhood. Signs and symptoms vary among people and over time, but include poor coordination, stiff muscles, weak muscles, and tremors. There may be problems with sensation, vision, hearing, and speaking. Often, babies with cerebral palsy do not roll over, sit, crawl or walk as early as other children of their age. Other symptoms include seizures and problems with thinking or reasoning, which each occur in about one-third of people with CP. While symptoms may get more noticeable over the first few years of life, underlying problems do not worsen over time.Cerebral palsy is caused by abnormal development or damage to the parts of the brain that control movement, balance, and posture. Most often, the problems occur during pregnancy, but they may also occur during childbirth or shortly after birth. Often, the cause is unknown. Risk factors include preterm birth, being a twin, certain infections during pregnancy, such as toxoplasmosis or rubella, exposure to methylmercury during pregnancy, a difficult delivery, and head trauma during the first few years of life, among others. About 2% of cases are believed to be due to an inherited genetic cause. A number of sub-types are classified, based on the specific problems present. For example, those with stiff muscles have spastic cerebral palsy, those with poor coordination in locomotion have ataxic cerebral palsy, and those with writhing movements have dyskinetic cerebral palsy. Diagnosis is based on the childs development over time. Blood tests and medical imaging may be used to rule out other possible causes.CP is partly preventable through immunization of the mother, and efforts to prevent head injuries in children such as through improved safety. There is no known cure for CP, but supportive treatments, medication and surgery may help many individuals. This may include physical therapy, occupational therapy and speech therapy. Medications such as diazepam, baclofen and botulinum toxin may help relax stiff muscles. Surgery may include lengthening muscles and cutting overly active nerves. Often, external braces and other assistive technology are helpful. Some affected children can achieve near normal adult lives with appropriate treatment. While alternative medicines are frequently used, there is no evidence to support their use.Cerebral palsy is the most common movement disorder in children. It occurs in about 2.1 per 1,000 live births. Cerebral palsy has been documented throughout history, with the first known descriptions occurring in the work of Hippocrates in the 5th century BCE. Extensive study of the condition began in the 19th century by William John Little, after whom spastic diplegia was called "Littles disease". William Osler first named it "cerebral palsy" from the German zerebrale Kinderlähmung (cerebral child-paralysis). A number of potential treatments are being examined, including stem cell therapy. However, more research is required to determine if it is effective and safe. Signs and symptoms Cerebral palsy is defined as "a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain." While movement problems are the central feature of CP, difficulties with thinking, learning, feeling, communication and behavior often co-occur, with 28% having epilepsy, 58% having difficulties with communication, at least 42% having problems with their vision, and 23–56% having learning disabilities. Muscle contractions in people with cerebral palsy are commonly thought to arise from overactivation.Cerebral palsy is characterized by abnormal muscle tone, reflexes, or motor development and coordination. The neurological lesion is primary and permanent while orthopedic manifestations are secondary and progressive. In cerebral palsy unequal growth between muscle-tendon units and bone eventually leads to bone and joint deformities. At first, deformities are dynamic. Over time, deformities tend to become static, and joint contractures develop. Deformities in general and static deformities in specific (joint contractures) cause increasing gait difficulties in the form of tip-toeing gait, due to tightness of the Achilles tendon, and scissoring gait, due to tightness of the hip adductors. These gait patterns are among the most common gait abnormalities in children with cerebral palsy. However, orthopaedic manifestations of cerebral palsy are diverse. Additionally, crouch gait (excessive knee flexion gait) is prevalent among children who possess the ability to walk. The effects of cerebral palsy fall on a continuum of motor dysfunction, which may range from slight clumsiness at the mild end of the spectrum to impairments so severe that they render coordinated movement virtually impossible at the other end of the spectrum. Although most people with CP have problems with increased muscle tone, some have normal or low muscle tone. High muscle tone can either be due to spasticity or dystonia.Babies born with severe cerebral palsy often have irregular posture; their bodies may be either very floppy or very stiff. Birth defects, such as spinal curvature, a small jawbone, or a small head sometimes occur along with CP. Symptoms may appear or change as a child gets older. Babies born with cerebral palsy do not immediately present with symptoms. Classically, CP becomes evident when the baby reaches the developmental stage at 6 to 9 months and is starting to mobilise, where preferential use of limbs, asymmetry, or gross motor developmental delay is seen.Drooling is common among children with cerebral palsy, which can have a variety of impacts including social rejection, impaired speaking, damage to clothing and books, and mouth infections. It can additionally cause choking.An average of 55.5% of people with cerebral palsy experience lower urinary tract symptoms, more commonly excessive storage issues than voiding issues. Those with voiding issues and pelvic floor overactivity can deteriorate as adults and experience upper urinary tract dysfunction.Children with CP may also have sensory processing issues. Adults with cerebral palsy have a higher risk of respiratory failure. Skeleton For bones to attain their normal shape and size, they require the stresses from normal musculature. People with cerebral palsy are at risk of low bone mineral density. The shafts of the bones are often thin (gracile), and become thinner during growth. When compared to these thin shafts (diaphyses), the centres (metaphyses) often appear quite enlarged (ballooning). Due to more than normal joint compression caused by muscular imbalances, articular cartilage may atrophy,: 46  leading to narrowed joint spaces. Depending on the degree of spasticity, a person with CP may exhibit a variety of angular joint deformities. Because vertebral bodies need vertical gravitational loading forces to develop properly, spasticity and an abnormal gait can hinder proper or full bone and skeletal development. People with CP tend to be shorter in height than the average person because their bones are not allowed to grow to their full potential. Sometimes bones grow to different lengths, so the person may have one leg longer than the other.Children with CP are prone to low trauma fractures, particularly children with higher Gross Motor Function Classification System (GMFCS) levels who cannot walk. This further affects a childs mobility, strength, and experience of pain, and can lead to missed schooling or child abuse suspicions. These children generally have fractures in the legs, whereas non-affected children mostly fracture their arms in the context of sporting activities.Hip dislocation and ankle equinus or plantar flexion deformity are the two most common deformities among children with cerebral palsy. Additionally, flexion deformity of the hip and knee can occur. Torsional deformities of long bones such as the femur and tibia are also encountered, among others. Children may develop scoliosis before the age of 10 – estimated prevalence of scoliosis in children with CP is between 21% and 64%. Higher levels of impairment on the GMFCS are associated with scoliosis and hip dislocation. Scoliosis can be corrected with surgery, but CP makes surgical complications more likely, even with improved techniques. Hip migration can be managed by soft tissue procedures such as adductor musculature release. Advanced degrees of hip migration or dislocation can be managed by more extensive procedures such as femoral and pelvic corrective osteotomies. Both soft tissue and bony procedures aim at prevention of hip dislocation in the early phases or aim at hip containment and restoration of anatomy in the late phases of disease. Equinus deformity is managed by conservative methods especially when dynamic. If fixed/static deformity ensues surgery may become mandatory.Growth spurts during puberty can make walking more difficult for people with CP. Eating Due to sensory and motor impairments, those with CP may have difficulty preparing food, holding utensils, or chewing and swallowing. An infant with CP may not be able to suck, swallow or chew. Gastro-oesophageal reflux is common in children with CP. Children with CP may have too little or too much sensitivity around and in the mouth. Poor balance when sitting, lack of control of the head, mouth, and trunk, not being able to bend the hips enough to allow the arms to stretch forward to reach and grasp food or utensils, and lack of hand-eye coordination can make self-feeding difficult. Feeding difficulties are related to higher GMFCS levels. Dental problems can also contribute to difficulties with eating. Pneumonia is also common where eating difficulties exist, caused by undetected aspiration of food or liquids. Fine finger dexterity, like that needed for picking up a utensil, is more frequently impaired than gross manual dexterity, like that needed for spooning food onto a plate. Grip strength impairments are less common.Children with severe cerebral palsy, particularly with oropharyngeal issues, are at risk of undernutrition. Triceps skin fold tests have been found to be a very reliable indicator of malnutrition in children with cerebral palsy. Language Speech and language disorders are common in people with cerebral palsy. The incidence of dysarthria is estimated to range from 31% to 88%, and around a quarter of people with CP are non-verbal. Speech problems are associated with poor respiratory control, laryngeal and velopharyngeal dysfunction, and oral articulation disorders that are due to restricted movement in the oral-facial muscles. There are three major types of dysarthria in cerebral palsy: spastic, dyskinetic (athetotic), and ataxic.Early use of augmentative and alternative communication systems may assist the child in developing spoken language skills. Overall language delay is associated with problems of cognition, deafness, and learned helplessness. Children with cerebral palsy are at risk of learned helplessness and becoming passive communicators, initiating little communication. Early intervention with this clientele, and their parents, often targets situations in which children communicate with others so that they learn that they can control people and objects in their environment through this communication, including making choices, decisions, and mistakes. Pain and sleep Pain is common and may result from the inherent deficits associated with the condition, along with the numerous procedures children typically face. When children with cerebral palsy are in pain, they experience worse muscle spasms. Pain is associated with tight or shortened muscles, abnormal posture, stiff joints, unsuitable orthosis, etc. Hip migration or dislocation is a recognizable source of pain in CP children and especially in the adolescent population. Nevertheless, the adequate scoring and scaling of pain in CP children remains challenging. Pain in CP has a number of different causes, and different pains respond to different treatments.There is also a high likelihood of chronic sleep disorders secondary to both physical and environmental factors. Children with cerebral palsy have significantly higher rates of sleep disturbance than typically developing children. Babies with cerebral palsy who have stiffness issues might cry more and be harder to put to sleep than non-disabled babies, or "floppy" babies might be lethargic. Chronic pain is under-recognized in children with cerebral palsy, even though three out of four children with cerebral palsy experience pain. Adults with CP also experience more pain than the general population. Associated disorders Associated disorders include intellectual disabilities, seizures, muscle contractures, abnormal gait, osteoporosis, communication disorders, malnutrition, sleep disorders, and mental health disorders, such as depression and anxiety. In addition to these, functional gastrointestinal abnormalities contributing to bowel obstruction, vomiting, and constipation may also arise. Adults with cerebral palsy may have ischemic heart disease, cerebrovascular disease, cancer, and trauma more often. Obesity in people with cerebral palsy or a more severe Gross Motor Function Classification System assessment in particular are considered risk factors for multimorbidity. Other medical issues can be mistaken for being symptoms of cerebral palsy, and so may not be treated correctly.Related conditions can include apraxia, sensory impairments, urinary incontinence, fecal incontinence, or behavioural disorders.Seizure management is more difficult in people with CP as seizures often last longer. Epilepsy and asthma are common co-occurring diseases in adults with CP. The associated disorders that co-occur with cerebral palsy may be more disabling than the motor function problems. Causes Cerebral palsy is due to abnormal development or damage occurring to the developing brain. This damage can occur during pregnancy, delivery, the first month of life, or less commonly in early childhood. Structural problems in the brain are seen in 80% of cases, most commonly within the white matter. More than three-quarters of cases are believed to result from issues that occur during pregnancy. Most children who are born with cerebral palsy have more than one risk factor associated with CP.While in certain cases there is no identifiable cause, typical causes include problems in intrauterine development (e.g. exposure to radiation, infection, fetal growth restriction), hypoxia of the brain (thrombotic events, placental insufficiency, umbilical cord prolapse), birth trauma during labor and delivery, and complications around birth or during childhood.In Africa birth asphyxia, high bilirubin levels, and infections in newborns of the central nervous system are main cause. Many cases of CP in Africa could be prevented with better resources available. Preterm birth Between 40% and 50% of all children who develop cerebral palsy were born prematurely. Most of these cases (75–90%) are believed to be due to issues that occur around the time of birth, often just after birth. Multiple-birth infants are also more likely than single-birth infants to have CP. They are also more likely to be born with a low birth weight.In those who are born with a weight between 1 kg and 1.5 kg CP occurs in 6%. Among those born before 28 weeks of gestation it occurs in 8%. Genetic factors are believed to play an important role in prematurity and cerebral palsy generally. While in those who are born between 34 and 37 weeks the risk is 0.4% (three times normal). Term infants In babies that are born at term risk factors include problems with the placenta, birth defects, low birth weight, breathing meconium into the lungs, a delivery requiring either the use of instruments or an emergency Caesarean section, birth asphyxia, seizures just after birth, respiratory distress syndrome, low blood sugar, and infections in the baby.As of 2013, it was unclear how much of a role birth asphyxia plays as a cause. It is unclear if the size of the placenta plays a role. As of 2015 it is evident that in advanced countries, most cases of cerebral palsy in term or near-term neonates have explanations other than asphyxia. Genetics Cerebral palsy is not commonly considered a genetic disease. About 2% of all CP cases are expected to be inherited, with glutamate decarboxylase-1 being one of the possible enzymes involved. Most inherited cases are autosomal recessive. However, the vast majority of CP cases are connected to brain damage during birth and in infancy. There is a small percentage of CP cases caused by brain damage that stemmed from the prenatal period, which is estimated to be less than 5% of CP cases overall. Moreover, there is no one reason why some CP cases come from prenatal brain damage, and its not known if those cases have a genetic basis. Early childhood After birth, other causes include toxins, severe jaundice, lead poisoning, physical brain injury, stroke, abusive head trauma, incidents involving hypoxia to the brain (such as near drowning), and encephalitis or meningitis. Others Infections in the mother, even those not easily detected, can triple the risk of the child developing cerebral palsy. Infections of the fetal membranes known as chorioamnionitis increases the risk.Intrauterine and neonatal insults (many of which are infectious) increase the risk.Rh blood type incompatibility can cause the mothers immune system to attack the babys red blood cells.It has been hypothesised that some cases of cerebral palsy are caused by the death in very early pregnancy of an identical twin. Diagnosis The diagnosis of cerebral palsy has historically rested on the persons history and physical examination and is generally assessed at a young age. A general movements assessment, which involves measuring movements that occur spontaneously among those less than four months of age, appears most accurate. Children who are more severely affected are more likely to be noticed and diagnosed earlier. Abnormal muscle tone, delayed motor development and persistence of primitive reflexes are the main early symptoms of CP. Symptoms and diagnosis typically occur by the age of two, although depending on factors like malformations and congenital issues, persons with milder forms of cerebral palsy may be over the age of five, if not in adulthood, when finally diagnosed. Cognitive assessments and medical observations are also useful to help confirm a diagnosis. Additionally, evaluations of the childs mobility, speech and language, hearing, vision, gait, feeding and digestion are also useful to determine the extent of the disorder. Early diagnosis and intervention are seen as being a key part of managing cerebral palsy. Machine learning algorithms facilitate automatic early diagnosis, with methods such as deep neural network and geometric feature fusion producing high accuracy in predicting cerebral palsy from short videos. It is a developmental disability.Once a person is diagnosed with cerebral palsy, further diagnostic tests are optional. Neuroimaging with CT or MRI is warranted when the cause of a persons cerebral palsy has not been established. An MRI is preferred over CT, due to diagnostic yield and safety. When abnormal, the neuroimaging study can suggest the timing of the initial damage. The CT or MRI is also capable of revealing treatable conditions, such as hydrocephalus, porencephaly, arteriovenous malformation, subdural hematomas and hygromas, and a vermian tumour (which a few studies suggest are present 5–22% of the time). Furthermore, an abnormal neuroimaging study indicates a high likelihood of associated conditions, such as epilepsy and intellectual disability. There is a small risk associated with sedating children to facilitate a clear MRI.The age when CP is diagnosed is important, but medical professionals disagree over the best age to make the diagnosis. The earlier CP is diagnosed correctly, the better the opportunities are to provide the child with physical and educational help, but there might be a greater chance of confusing CP with another problem, especially if the child is 18 months of age or younger. Infants may have temporary problems with muscle tone or control that can be confused with CP, which is permanent. A metabolism disorder or tumors in the nervous system may appear to be CP; metabolic disorders, in particular, can produce brain problems that look like CP on an MRI. Disorders that deteriorate the white matter in the brain and problems that cause spasms and weakness in the legs, may be mistaken for CP if they first appear early in life. However, these disorders get worse over time, and CP does not (although it may change in character). In infancy it may not be possible to tell the difference between them. In the UK, not being able to sit independently by the age of 8 months is regarded as a clinical sign for further monitoring. Fragile X syndrome (a cause of autism and intellectual disability) and general intellectual disability must also be ruled out. Cerebral palsy specialist John McLaughlin recommends waiting until the child is 36 months of age before making a diagnosis because, by that age, motor capacity is easier to assess. Classification CP is classified by the types of motor impairment of the limbs or organs, and by restrictions to the activities an affected person may perform. The Gross Motor Function Classification System-Expanded and Revised and the Manual Ability Classification System are used to describe mobility and manual dexterity in people with cerebral palsy, and recently the Communication Function Classification System, and the Eating and Drinking Ability Classification System have been proposed to describe those functions. There are three main CP classifications by motor impairment: spastic, ataxic, and dyskinetic. Additionally, there is a mixed type that shows a combination of features of the other types. These classifications reflect the areas of the brain that are damaged.Cerebral palsy is also classified according to the topographic distribution of muscle spasticity. This method classifies children as diplegic, (bilateral involvement with leg involvement greater than arm involvement), hemiplegic (unilateral involvement), or quadriplegic (bilateral involvement with arm involvement equal to or greater than leg involvement). Spastic Spastic cerebral palsy is the type of cerebral palsy characterized by spasticity or high muscle tone often resulting in stiff, jerky movements. Itself an umbrella term encompassing spastic hemiplegia, spastic diplegia, spastic quadriplegia and – where solely one limb or one specific area of the body is affected – spastic monoplegia. Spastic cerebral palsy affects the motor cortex of the brain, a specific portion of the cerebral cortex responsible for the planning and completion of voluntary movement. Spastic CP is the most common type of overall cerebral palsy, representing about 80% of cases. Botulinum toxin is effective in decreasing spasticity. It can help increase range of motion which could help mitigate CPs effects on the growing bones of children. There may be an improvement in motor functions in the children and ability to walk. however, the main benefit derived from botulinum toxin A comes from its ability to reduce muscle tone and spasticity and thus prevent or delay the development of fixed muscle contractures. Ataxic Ataxic cerebral palsy is observed in approximately 5–10% of all cases of cerebral palsy, making it the least frequent form of cerebral palsy. Ataxic cerebral palsy is caused by damage to cerebellar structures. Because of the damage to the cerebellum, which is essential for coordinating muscle movements and balance, patients with ataxic cerebral palsy experience problems in coordination, specifically in their arms, legs, and trunk. Ataxic cerebral palsy is known to decrease muscle tone. The most common manifestation of ataxic cerebral palsy is intention (action) tremor, which is especially apparent when carrying out precise movements, such as tying shoe laces or writing with a pencil. This symptom gets progressively worse as the movement persists, making the hand shake. As the hand gets closer to accomplishing the intended task, the trembling intensifies, which makes it even more difficult to complete. Dyskinetic Dyskinetic cerebral palsy (sometimes abbreviated DCP) is primarily associated with damage to the basal ganglia and the substantia nigra in the form of lesions that occur during brain development due to bilirubin encephalopathy and hypoxic-ischemic brain injury. DCP is characterized by both hypertonia and hypotonia, due to the affected individuals inability to control muscle tone. Clinical diagnosis of DCP typically occurs within 18 months of birth and is primarily based upon motor function and neuroimaging techniques. Dyskinetic cerebral palsy is an extrapyramidal form of cerebral palsy. Dyskinetic cerebral palsy can be divided into two different groups; choreoathetosis and dystonia. Choreo-athetotic CP is characterized by involuntary movements, whereas dystonic CP is characterized by slow, strong contractions, which may occur locally or encompass the whole body. Mixed Mixed cerebral palsy has symptoms of dyskinetic, ataxic and spastic CP appearing simultaneously, each to varying degrees, and both with and without symptoms of each. Mixed CP is the most difficult to treat as it is extremely heterogeneous and sometimes unpredictable in its symptoms and development over the lifespan. Gait Classification In patients with spastic hemiplegia or diplegia, various gait patterns can be observed, the exact form of which can only be described with the help of complex gait analysis systems. In order to facilitate interdisciplinary communication in the interdisciplinary team between those affected, doctors, physiotherapists and orthotists, a simple description of the gait pattern is useful. J. Rodda and H. K. Graham already described in 2001 how gait patterns of CP patients can be more easily recognized and defined gait types which they compared in a classification. They also described that gait patterns can vary with age. Building on this, the Amsterdam Gait Classification was developed at the free university in Amsterdam, the VU medisch centrum. A special feature of this classification is that it makes different gait patterns very easy to recognize and can be used in CP patients in whom only one leg and both legs are affected. According to the Amsterdam Gait Classification, five gait types are described. To assess the gait pattern, the patient is viewed visually or via a video recording from the side of the leg to be assessed. At the point in time at which the leg to be viewed is in mid stance and the leg not to be viewed is in mid swing, the knee angle and the contact of the foot with the ground are assessed on the one hand.Classification of the gait pattern according to the Amsterdam Gait Classification: In gait type 1, the knee angle is normal and the foot contact is complete. In gait type 2, the knee angle is hyperextended and the foot contact is complete. In gait type 3, the knee angle is hyperextended and foot contact is incomplete (only on the forefoot). In gait type 4, the knee angle is bent and foot contact is incomplete (only on the forefoot). With gait type 5, the knee angle is bent and the foot contact is complete.Gait types 5 is also known as crouch gait. Prevention Because the causes of CP are varied, a broad range of preventive interventions have been investigated.Electronic fetal monitoring has not helped to prevent CP, and in 2014 the American College of Obstetricians and Gynecologists, the Royal Australian and New Zealand College of Obstetricians and Gynaecologists, and the Society of Obstetricians and Gynaecologists of Canada have acknowledged that there are no long-term benefits of electronic fetal monitoring. Before this, electronic fetal monitoring was widely used to prop up obstetric litigation.In those at risk of an early delivery, magnesium sulphate appears to decrease the risk of cerebral palsy. It is unclear if it helps those who are born at term. In those at high risk of preterm labor a review found that moderate to severe CP was reduced by the administration of magnesium sulphate, and that adverse effects on the babies from the magnesium sulphate were not significant. Mothers who received magnesium sulphate could experience side effects such as respiratory depression and nausea. However, guidelines for the use of magnesium sulfate in mothers at risk of preterm labour are not strongly adhered to. Caffeine is used to treat apnea of prematurity and reduces the risk of cerebral palsy in premature babies, but there are also concerns of long term negative effects. A moderate quality level of evidence indicates that giving women antibiotics during preterm labor before her membranes have ruptured (water is not yet not broken) may increase the risk of cerebral palsy for the child. Additionally, for preterm babies for whom there is a chance of fetal compromise, allowing the birth to proceed rather than trying to delay the birth may lead to an increased risk of cerebral palsy in the child. Corticosteroids are sometimes taken by pregnant women expecting a preterm birth to provide neuroprotection to their baby. Taking corticosteroids during pregnancy is shown to have no significant correlation with developing cerebral palsy in preterm births.Cooling high-risk full-term babies shortly after birth may reduce disability, but this may only be useful for some forms of the brain damage that causes CP. Management Over time, the approach to CP management has shifted away from narrow attempts to fix individual physical problems – such as spasticity in a particular limb – to making such treatments part of a larger goal of maximizing the persons independence and community engagement.: 886  However, the evidence base for the effectiveness of intervention programs reflecting the philosophy of independence has not yet caught up: effective interventions for body structures and functions have a strong evidence base, but evidence is lacking for effective interventions targeted toward participation, environment, or personal factors. There is also no good evidence to show that an intervention that is effective at the body-specific level will result in an improvement at the activity level or vice versa. Although such cross-over benefit might happen, not enough high-quality studies have been done to demonstrate it.Because cerebral palsy has "varying severity and complexity" across the lifespan, it can be considered a collection of conditions for management purposes. A multidisciplinary approach for cerebral palsy management is recommended, focusing on "maximising individual function, choice and independence" in line with the International Classification of Functioning, Disability and Healths goals. The team may include a paediatrician, a health visitor, a social worker, a physiotherapist, an orthotist, a speech and language therapist, an occupational therapist, a teacher specialising in helping children with visual impairment, an educational psychologist, an orthopaedic surgeon, a neurologist and a neurosurgeon.Various forms of therapy are available to people living with cerebral palsy as well as caregivers and parents. Treatment may include one or more of the following: physical therapy; occupational therapy; speech therapy; water therapy; drugs to control seizures, alleviate pain, or relax muscle spasms (e.g. benzodiazepines); surgery to correct anatomical abnormalities or release tight muscles; braces and other orthotic devices; rolling walkers; and communication aids such as computers with attached voice synthesisers. A Cochrane review published in 2004 found a trend toward the benefit of speech and language therapy for children with cerebral palsy but noted the need for high-quality research. A 2013 systematic review found that many of the therapies used to treat CP have no good evidence base; the treatments with the best evidence are medications (anticonvulsants, botulinum toxin, bisphosphonates, diazepam), therapy (bimanual training, casting, constraint-induced movement therapy, context-focused therapy, fitness training, goal-directed training, hip surveillance, home programmes, occupational therapy after botulinum toxin, pressure care) and surgery. There is also research on whether the sleeping position might improve hip migration, but there are not yet high-quality evidence studies to support that theory. Research papers also call for an agreed consensus on outcome measures which will allow researchers to cross-reference research. Also, the terminology used to describe orthoses needs to be standardised to ensure studies can be reproduced and readily compared and evaluated. Surgical intervention in CP children mainly includes orthopaedic surgery and neurosurgery (selective dorsal rhizotomy). Orthotics in the concept of therapy To improve the gait pattern, orthotics can be included in the therapy concept. An orthosis can support physiotherapeutic treatment in setting the right motor impulses in order to create new cerebral connections. The orthosis must meet the requirements of the medical prescription. In addition, the orthosis must be designed by the orthotist in such a way that it achieves the effectiveness of the necessary levers, matching the gait pattern, in order to support the proprioceptive approaches of physiotherapy. The characteristics of the stiffness of the orthosis shells and the adjustable dynamics in the ankle joint are important elements of the orthosis to be considered. Due to these requirements, the development of orthoses has changed significantly in recent years, especially since around 2010. At about the same time, care concepts were developed that deal intensively with the orthotic treatment of the lower extremities in cerebral palsy. Modern materials and new functional elements enable the rigidity to be specifically adapted to the requirements that fits to the gait pattern of the CP patient. The adjustment of the stiffness has a decisive influence on the gait pattern and on the energy cost of walking. It is of great advantage if the stiffness of the orthosis can be adjusted separately from one another via resistances of the two functional elements in the two directions of movement, dorsiflexion and plantar flexion. Prognosis CP is not a progressive disorder (meaning the brain damage does not worsen), but the symptoms can become more severe over time. A person with the disorder may improve somewhat during childhood if he or she receives extensive care, but once bones and musculature become more established, orthopedic surgery may be required. People with CP can have varying degrees of cognitive impairment or none whatsoever. The full intellectual potential of a child born with CP is often not known until the child starts school. People with CP are more likely to have learning disorders but have normal intelligence. Intellectual level among people with CP varies from genius to intellectually disabled, as it does in the general population, and experts have stated that it is important not to underestimate the capabilities of a person with CP and to give them every opportunity to learn.The ability to live independently with CP varies widely, depending partly on the severity of each persons impairment and partly on the capability of each person to self-manage the logistics of life. Some individuals with CP require personal assistant services for all activities of daily living. Others only need assistance with certain activities, and still others do not require any physical assistance. But regardless of the severity of a persons physical impairment, a persons ability to live independently often depends primarily on the persons capacity to manage the physical realities of his or her life autonomously. In some cases, people with CP recruit, hire, and manage a staff of personal care assistants (PCAs). PCAs facilitate the independence of their employers by assisting them with their daily personal needs in a way that allows them to maintain control over their lives.Puberty in young adults with cerebral palsy may be precocious or delayed. Delayed puberty is thought to be a consequence of nutritional deficiencies. There is currently no evidence that CP affects fertility, although some of the secondary symptoms have been shown to affect sexual desire and performance. Adults with CP were less likely to get routine reproductive health screening as of 2005. Gynecological examinations may have to be performed under anesthesia due to spasticity, and equipment is often not accessible. Breast self-examination may be difficult, so partners or carers may have to perform it. Women with CP reported higher levels of spasticity and urinary incontinence during menstruation in a study. Men with CP have higher levels of cryptorchidism at the age of 21.CP can significantly reduce a persons life expectancy, depending on the severity of their condition and the quality of care they receive. 5–10% of children with CP die in childhood, particularly where seizures and intellectual disability also affect the child. The ability to ambulate, roll, and self-feed has been associated with increased life expectancy. While there is a lot of variation in how CP affects people, it has been found that "independent gross motor functional ability is a very strong determinant of life expectancy". According to the Australian Bureau of Statistics, in 2014, 104 Australians died of cerebral palsy. The most common causes of death in CP are related to respiratory causes, but in middle age cardiovascular issues and neoplastic disorders become more prominent. Self-care For many children with CP, parents are heavily involved in self-care activities. Self-care activities, such as bathing, dressing, and grooming, can be difficult for children with CP, as self-care depends primarily on the use of the upper limbs. For those living with CP, impaired upper limb function affects almost 50% of children and is considered the main factor contributing to decreased activity and participation. As the hands are used for many self-care tasks, sensory and motor impairments of the hands make daily self-care more difficult. Motor impairments cause more problems than sensory impairments. The most common impairment is that of finger dexterity, which is the ability to manipulate small objects with the fingers. Compared to other disabilities, people with cerebral palsy generally need more help in performing daily tasks. Occupational therapists are healthcare professionals that help individuals with disabilities gain or regain their independence through the use of meaningful activities. Productivity The effects of sensory, motor, and cognitive impairments affect self-care occupations in children with CP and productivity occupations. Productivity can include but is not limited to, school, work, household chores, or contributing to the community.Play is included as a productive occupation as it is often the primary activity for children. If play becomes difficult due to a disability, like CP, this can cause problems for the child. These difficulties can affect a childs self-esteem. In addition, the sensory and motor problems experienced by children with CP affect how the child interacts with their surroundings, including the environment and other people. Not only do physical limitations affect a childs ability to play, the limitations perceived by the childs caregivers and playmates also affect the childs play activities. Some children with disabilities spend more time playing by themselves. When a disability prevents a child from playing, there may be social, emotional and psychological problems, which can lead to increased dependence on others, less motivation, and poor social skills.In school, students are asked to complete many tasks and activities, many of which involve handwriting. Many children with CP have the capacity to learn and write in the school environment. However, students with CP may find it difficult to keep up with the handwriting demands of school and their writing may be difficult to read. In addition, writing may take longer and require greater effort on the students part. Factors linked to handwriting include postural stability, sensory and perceptual abilities of the hand, and writing tool pressure.Speech impairments may be seen in children with CP depending on the severity of brain damage. Communication in a school setting is important because communicating with peers and teachers is very much a part of the "school experience" and enhances social interaction. Problems with language or motor dysfunction can lead to underestimating a students intelligence. In summary, children with CP may experience difficulties in school, such as difficulty with handwriting, carrying out school activities, communicating verbally, and interacting socially. Leisure Leisure activities can have several positive effects on physical health, mental health, life satisfaction, and psychological growth for people with physical disabilities like CP. Common benefits identified are stress reduction, development of coping skills, companionship, enjoyment, relaxation and a positive effect on life satisfaction. In addition, for children with CP, leisure appears to enhance adjustment to living with a disability.Leisure can be divided into structured (formal) and unstructured (informal) activities. Children and teens with CP engage in less habitual physical activity than their peers. Children with CP primarily engage in physical activity through therapies aimed at managing their CP, or through organized sport for people with disabilities. It is difficult to sustain behavioural change in terms of increasing physical activity of children with CP. Gender, manual dexterity, the childs preferences, cognitive impairment and epilepsy were found to affect childrens leisure activities, with manual dexterity associated with more leisure activity. Although leisure is important for children with CP, they may have difficulties carrying out leisure activities due to social and physical barriers.Children with cerebral palsy may face challenges when it comes to participating in sports. This comes with being discouraged from physical activity because of these perceived limitations imposed by their medical condition. Participation and barriers Participation is involvement in life situations and everyday activities. Participation includes self-care, productivity, and leisure. In fact, communication, mobility, education, home life, leisure, and social relationships require participation, and indicate the extent to which children function in their environment. Barriers can exist on three levels: micro, meso, and macro. First, the barriers at the micro level involve the person. Barriers at the micro level include the childs physical limitations (motor, sensory and cognitive impairments) or their subjective feelings regarding their ability to participate. For example, the child may not participate in group activities due to lack of confidence. Second, barriers at the meso level include the family and community. These may include negative attitudes of people toward disability or lack of support within the family or in the community. One of the main reasons for this limited support appears to be the result of a lack of awareness and knowledge regarding the childs ability to engage in activities despite his or her disability. Third, barriers at the macro level incorporate the systems and policies that are not in place or hinder children with CP. These may be environmental barriers to participation such as architectural barriers, lack of relevant assistive technology, and transportation difficulties due to limited wheelchair access or public transit that can accommodate children with CP. For example, a building without an elevator can prevent the child from accessing higher floors.A 2013 review stated that outcomes for adults with cerebral palsy without intellectual disability in the 2000s were that "60–80% completed high school, 14–25% completed college, up to 61% were living independently in the community, 25–55% were competitively employed, and 14–28% were involved in long term relationships with partners or had established families". Adults with cerebral palsy may not seek physical therapy due to transport issues, financial restrictions and practitioners not feeling like they know enough about cerebral palsy to take people with CP on as clients.A study in young adults (18–34) on transitioning to adulthood found that their concerns were physical health care and understanding their bodies, being able to navigate and use services and supports successfully, and dealing with prejudices. A feeling of being "thrust into adulthood" was common in the study. Aging Children with CP may not successfully transition into using adult services because they are not referred to one upon turning 18, and may decrease their use of services. Quality of life outcomes tend to decline for adults with cerebral palsy. Because children with cerebral palsy are often told that it is a non-progressive disease, they may be unprepared for the greater effects of the aging process as they head into their 30s. Young adults with cerebral palsy experience problems with aging that non-disabled adults experience "much later in life".: 42  25% or more adults with cerebral palsy who can walk experience increasing difficulties walking with age. Hand function does not seem to have similar declines. Chronic disease risk, such as obesity, is also higher among adults with cerebral palsy than the general population. Common problems include increased pain, reduced flexibility, increased spasms and contractures, post-impairment syndrome and increasing problems with balance. Increased fatigue is also a problem. When adulthood and cerebral palsy is discussed, as of 2011, it is not discussed in terms of the different stages of adulthood.Like they did in childhood, adults with cerebral palsy experience psychosocial issues related to their CP, chiefly the need for social support, self-acceptance, and acceptance by others. Workplace accommodations may be needed to enhance continued employment for adults with CP as they age. Rehabilitation or social programs that include salutogenesis may improve the coping potential of adults with CP as they age. Epidemiology Cerebral palsy occurs in about 2.1 per 1000 live births. In those born at term rates are lower at 1 per 1000 live births. Within a population it may occur more often in poorer people. The rate is higher in males than in females; in Europe it is 1.3 times more common in males.There was a "moderate, but significant" rise in the prevalence of CP between the 1970s and 1990s. This is thought to be due to a rise in low birth weight of infants and the increased survival rate of these infants. The increased survival rate of infants with CP in the 1970s and 80s may be indirectly due to the disability rights movement challenging perspectives around the worth of infants with a disability, as well as the Baby Doe Law.As of 2005, advances in the care of pregnant mothers and their babies have not resulted in a noticeable decrease in CP. This is generally attributed to medical advances in areas related to the care of premature babies (which results in a greater survival rate). Only the introduction of quality medical care to locations with less-than-adequate medical care has shown any decreases. The incidence of CP increases with premature or very low-weight babies regardless of the quality of care. As of 2016, there is a suggestion that both incidence and severity are slightly decreasing – more research is needed to find out if this is significant, and if so, which interventions are effective. It has been found that high-income countries have lower rates of children born with cerebral palsy than low or middle-income countries.Prevalence of cerebral palsy is best calculated around the school entry age of about six years; the prevalence in the U.S. is estimated to be 2.4 out of 1000 children. History Cerebral palsy has affected humans since antiquity. A decorated grave marker dating from around the 15th to 14th century BCE shows a figure with one small leg and using a crutch, possibly due to cerebral palsy. The oldest likely physical evidence of the condition comes from the mummy of Siptah, an Egyptian Pharaoh who ruled from about 1196 to 1190 BCE and died at about 20 years of age. The presence of cerebral palsy has been suspected due to his deformed foot and hands.The medical literature of the ancient Greeks discusses paralysis and weakness of the arms and legs; the modern word palsy comes from the Ancient Greek words παράλυση or πάρεση, meaning paralysis or paresis respectively. The works of the school of Hippocrates (460–c. 370 BCE), and the manuscript On the Sacred Disease in particular, describe a group of problems that matches up very well with the modern understanding of cerebral palsy. The Roman Emperor Claudius (10 BCE–54 CE) is suspected of having CP, as historical records describe him as having several physical problems in line with the condition. Medical historians have begun to suspect and find depictions of CP in much later art. Several paintings from the 16th century and later show individuals with problems consistent with it, such as Jusepe de Riberas 1642 painting The Clubfoot.The modern understanding of CP as resulting from problems within the brain began in the early decades of the 1800s with a number of publications on brain abnormalities by Johann Christian Reil, Claude François Lallemand and Philippe Pinel. Later physicians used this research to connect problems in the brain with specific symptoms. The English surgeon William John Little (1810–1894) was the first person to study CP extensively. In his doctoral thesis he stated that CP was a result of a problem around the time of birth. He later identified a difficult delivery, a preterm birth and perinatal asphyxia in particular as risk factors. The spastic diplegia form of CP came to be known as Littles disease. At around this time, a German surgeon was also working on cerebral palsy, and distinguished it from polio. In the 1880s British neurologist William Gowers built on Littles work by linking paralysis in newborns to difficult births. He named the problem "birth palsy" and classified birth palsies into two types: peripheral and cerebral.Working in Pennsylvania in the 1880s, Canadian-born physician William Osler (1849–1919) reviewed dozens of CP cases to further classify the disorders by the site of the problems on the body and by the underlying cause. Osler made further observations tying problems around the time of delivery with CP, and concluded that problems causing bleeding inside the brain were likely the root cause. Osler also suspected polioencephalitis as an infectious cause. Through the 1890s, scientists commonly confused CP with polio.Before moving to psychiatry, Austrian neurologist Sigmund Freud (1856–1939) made further refinements to the classification of the disorder. He produced the system still being used today. Freuds system divides the causes of the disorder into problems present at birth, problems that develop during birth, and problems after birth. Freud also made a rough correlation between the location of the problem inside the brain and the location of the affected limbs on the body and documented the many kinds of movement disorders.In the early 20th century, the attention of the medical community generally turned away from CP until orthopedic surgeon Winthrop Phelps became the first physician to treat the disorder. He viewed CP from a musculoskeletal perspective instead of a neurological one. Phelps developed surgical techniques for operating on the muscles to address issues such as spasticity and muscle rigidity. Hungarian physical rehabilitation practitioner András Pető developed a system to teach children with CP how to walk and perform other basic movements. Petős system became the foundation for conductive education, widely used for children with CP today. Through the remaining decades, physical therapy for CP has evolved, and has become a core component of the CP management program.In 1997, Robert Palisano et al. introduced the Gross Motor Function Classification System (GMFCS) as an improvement over the previous rough assessment of limitation as either mild, moderate, or severe. The GMFCS grades limitation based on observed proficiency in specific basic mobility skills such as sitting, standing, and walking, and takes into account the level of dependency on aids such as wheelchairs or walkers. The GMFCS was further revised and expanded in 2007. Society and culture Economic impact It is difficult to directly compare the cost and cost-effectiveness of interventions to prevent cerebral palsy or the cost of interventions to manage CP. Access Economics has released a report on the economic impact of cerebral palsy in Australia. The report found that, in 2007, the financial cost of cerebral palsy (CP) in Australia was A$1.47 billion or 0.14% of GDP. Of this: A$1.03 billion (69.9%) was productivity lost due to lower employment, absenteeism, and premature death of Australians with CP A$141 million (9.6%) was the DWL from transfers including welfare payments and taxation forgone A$131 million (9.0%) was other indirect costs such as direct program services, aides and home modifications, and the bringing-forward of funeral costs A$129 million (8.8%) was the value of the informal care for people with CP A$40 million (2.8%) was direct health system expenditureThe value of lost well-being (disability and premature death) was a further A$2.4 billion.In per capita terms, this amounts to a financial cost of A$43,431 per person with CP per annum. Including the value of lost well-being, the cost is over $115,000 per person per annum.Individuals with CP bear 37% of the financial costs, and their families and friends bear a further 6%. The federal government bears around one-third (33%) of the financial costs (mainly through taxation revenues forgone and welfare payments). State governments bear under 1% of the costs, while employers bear 5% and the rest of society bears the remaining 19%. If the burden of disease (lost well-being) is included, individuals bear 76% of the costs.The average lifetime cost for people with CP in the US is US$921,000 per individual, including lost income.In the United States, many states allow Medicaid beneficiaries to use their Medicaid funds to hire their own PCAs, instead of forcing them to use institutional or managed care.In India, the government-sponsored program called "NIRAMAYA" for the medical care of children with neurological and muscular deformities has proved to be an ameliorating economic measure for persons with such disabilities. It has shown that persons with mental or physically debilitating congenital disabilities can lead better lives if they have financial independence. Use of the term "Cerebral" means "of, or pertaining to, the cerebrum or the brain" and "palsy" means "paralysis, generally partial, whereby a local body area is incapable of voluntary movement". It has been proposed to change the name to "cerebral palsy spectrum disorder" to reflect the diversity of presentations of CP.Many people would rather be referred to as a person with a disability (people-first language) instead of as "handicapped". "Cerebral Palsy: A Guide for Care" at the University of Delaware offers the following guidelines: Impairment is the correct term to use to define a deviation from normal, such as not being able to make a muscle move or not being able to control an unwanted movement. Disability is the term used to define a restriction in the ability to perform a normal activity of daily living which someone of the same age can perform. For example, a three-year-old child who is not able to walk has a disability because a normal three-year-old can walk independently. A handicapped child or adult is one who, because of the disability, is unable to achieve the normal role in society commensurate with his age and socio-cultural milieu. As an example, a sixteen-year-old who is unable to prepare his own meal or care for his own toilet or hygiene needs is handicapped. On the other hand, a sixteen-year-old who can walk only with the assistance of crutches but who attends a regular school and is fully independent in activities of daily living is disabled but not handicapped. All disabled people are impaired, and all handicapped people are disabled, but a person can be impaired and not necessarily be disabled, and a person can be disabled without being handicapped. The term "spastic" denotes the attribute of spasticity in types of spastic CP. In 1952 a UK charity called The Spastics Society was formed. The term "spastics" was used by the charity as a term for people with CP. The word "spastic" has since been used extensively as a general insult to disabled people, which some see as extremely offensive. They are also frequently used to insult non-disabled people when they seem overly uncoordinated, anxious, or unskilled in sports. The charity changed its name to Scope in 1994. In the United States the word spaz has the same usage as an insult but is not generally associated with CP. Media Maverick documentary filmmaker Kazuo Hara criticises the mores and customs of Japanese society in an unsentimental portrait of adults with cerebral palsy in his 1972 film Goodbye CP (Sayonara CP). Focusing on how people with cerebral palsy are generally ignored or disregarded in Japan, Hara challenges his societys taboos about physical handicaps. Using a deliberately harsh style, with grainy black-and-white photography and out-of-sync sound, Hara brings a stark realism to his subject.Spandan (2012), a film by Vegitha Reddy and Aman Tripathi, delves into the dilemma of parents whose child has cerebral palsy. While films made with children with special needs as central characters have been attempted before, the predicament of parents dealing with the stigma associated with the condition and beyond is dealt in Spandan. In one of the songs of Spandan "Chal chaal chaal tu bala" more than 50 CP kids have acted. The famous classical singer Devaki Pandit has given her voice to the song penned by Prof. Jayant Dhupkar and composed by National Film Awards winner Isaac Thomas Kottukapally.My Left Foot (1989) is a drama film directed by Jim Sheridan and starring Daniel Day-Lewis. It tells the true story of Christy Brown, an Irishman born with cerebral palsy, who could control only his left foot. Christy Brown grew up in a poor, working-class family, and became a writer and artist. It won the Academy Award for Best Actor (Daniel Day-Lewis) and Best Actress in a Supporting Role (Brenda Fricker). It was also nominated for Best Director, Best Picture and Best Writing, Screenplay Based on Material from Another Medium. It also won the New York Film Critics Circle Award for Best Film for 1989.Call the Midwife (2012–) has featured two episodes with actor Colin Young, who himself has cerebral palsy, playing a character with the same disability. His storylines have focused on the segregation of those with disabilities in the UK in the 1950s, and also romantic relationships between people with disabilities.Micah Fowler, an American actor with CP, stars in the ABC sitcom Speechless (2016–19), which explores both the serious and humorous challenges a family faces with a teenager with CP.9-1-1 (2018–) is a procedural drama series on Fox. From season 2 onwards, it features Gavin McHugh (who himself has cerebral palsy) in the recurring role as Christopher Diaz – a young child who has cerebral palsy. Special (2019) is a comedy series that premiered on Netflix on 12 April 2019. It was written, produced and stars Ryan OConnell as a young gay man with mild cerebral palsy. It is based on OConnells book Im Special: And Other Lies We Tell Ourselves.Australian drama serial The Heights (2019–) features a character with mild cerebral palsy, teenage girl Sabine Rosso, depicted by an actor who herself has mild cerebral palsy, Bridie McKim. Notable cases Christy Brown was the basis for the Academy Award-winning film, My Left Foot. Two sons of Canadian rock musician Neil Young, Zeke and Ben. In 1986, Young helped found the Bridge School, an educational organization for children with severe verbal and physical disabilities, and its annual supporting Bridge School Benefit concerts, together with his wife Pegi. Nicolas Hamilton, a British racing driver competing in BTCC. He is the half-brother of Formula 1 driver Lewis Hamilton. Geri Jewell, who had a regular role in the prime-time series The Facts of Life. Josh Blue, winner of the fourth season of NBCs Last Comic Standing, whose act revolves around his CP. Blue was also on the 2004 U.S. Paralympic soccer team. Jason Benetti, play-by-play broadcaster for ESPN, Fox Sports, Westwood One, and Time Warner covering football, baseball, lacrosse, hockey, and basketball. Since 2016, he is also the television play-by-play announcer for Chicago White Sox home games. Jack Carroll, British comedian and runner-up in the seventh season of Britains Got Talent. Abbey Curran, an American beauty queen who represented Iowa at Miss USA 2008 and was the first contestant with a disability to compete. Francesca Martinez, British stand-up comedian and actress. Evan OHanlon, Australian Paralympian, the fastest athlete with cerebral palsy in the world. Arun Shouries son Aditya, about whom he has written a book Does He Know a Mothers Heart Maysoon Zayid, the self-described "Palestinian Muslim virgin with cerebral palsy, from New Jersey", who is an actress, stand-up comedian, and activist. Zayid has been a resident of Cliffside Park, New Jersey. She is considered one of Americas first Muslim women comedians and the first person ever to perform standup in Palestine and Jordan. RJ Mitte, an American actor best known for his role as Walter White Jr. in Breaking Bad. He is also a celebrity ambassador for United Cerebral Palsy. Zach Anner, an American comedian, actor, and writer. He had a television series on Oprah Winfreys OWN called Rollin With Zach and is the author of If at Birth You Dont Succeed. Kaine, a member of the American hip-hop duo The Ying Yang Twins, has a mild form of cerebral palsy that causes him to limp. Hannah Cockroft, is a British wheelchair athlete specialising in sprint distances in the T34 classification. She holds the Paralympic and world records for the 100 metres, 200 metres and 400 metres in her classification. Keah Brown, American disability rights activist, author and journalist. Kuli Kohli, Indian-British writer, poet, activist. Simon James Stevens, a British disability issues consultant and activist, who starred in Im Spazticus and founded Wheelies virtual nightclub The Roman Emperor Claudius is hypothesized to have had cerebral palsy on the basis of his reported symptoms. Rosie Jones, a British comedian and actress, is incorporating her cerebral palsy into her comedic style. Litigation Because of the false perception that cerebral palsy is mostly caused by trauma during birth, as of 2005, 60% of obstetric litigation was about cerebral palsy, which Alastair MacLennan, Professor of Obstetrics and Gynaecology at the University of Adelaide, regards as causing an exodus from the profession. In the latter half of the 20th century, obstetric litigation about the cause of cerebral palsy became more common, leading to the practice of defensive medicine. See also Cerebral palsy sport classification – describes the disability sport classification for cerebral palsy. Inclusive recreation World Cerebral Palsy Day Notes References External links Cerebral palsy at Curlie Cerebral Palsy Information Page at NINDS

Pilonidal disease

Pilonidal disease is a type of skin infection which typically occurs as a cyst between the cheeks of the buttocks and often at the upper end. Symptoms may include pain, swelling, and redness. There may also be drainage of fluid, but rarely a fever.Risk factors include obesity, family history, prolonged sitting, greater amounts of hair, and not enough exercise. The underlying mechanism is believed to involve a mechanical process. The lesions may contain hair and skin debris. Diagnosis is based on symptoms and examination.If there is infection, treatment is generally by incision and drainage just off the midline. Shaving the area and laser hair removal may prevent recurrence. More extensive surgery may be required if the disease recurs. Antibiotics are usually not needed. Without treatment the condition may remain long term.About 3 per 10,000 people per year are affected, and it occurs more often in males than females. Young adults are most commonly affected. The term "pilonidal" means "nest of hair". The condition was first described in 1833. Signs and symptoms Pilonidal cysts are itchy and often very painful, and typically occur between the ages of 15 and 35. Although usually found near the coccyx, the condition can also affect the navel, armpit, the cheek, or the genital region, though these locations are much rarer. Signs and symptoms may include: Intermittent pain/discomfort or swelling above the anus or near the tailbone Opaque yellow (purulent) or bloody discharge from the tailbone area Unexpected moisture in the tailbone region Discomfort sitting on the tailbone, doing sit-ups or riding a bicycle—any activities that roll over the tailbone areaSome people with a pilonidal cyst will be asymptomatic. Pilonidal sinus Pilonidal sinus (PNS): is a sinus tract, or small channel, that may originate from the source of infection and open to the surface of the skin. Material from the cyst drains through the pilonidal sinus. A pilonidal cyst is usually painful, but with draining the patient might not feel pain. Causes One proposed cause of pilonidal cysts is ingrown hair, although hairs found in pilonidal sinus tracts may originate from the head. Excessive sitting is thought to predispose people to the condition, as sitting increases pressure on the coccygeal region. Trauma is not believed to cause a pilonidal cyst; however, such an event may result in inflammation of an existing cyst; there are cases where this can occur months after a localized injury to the area. Some researchers have proposed that pilonidal cysts may be caused by a congenital pilonidal dimple. Excessive sweating can also contribute to the formation of a pilonidal cyst: moisture can fill a stretched hair follicle, which helps create a low-oxygen environment that promotes the growth of anaerobic bacteria, often found in pilonidal cysts. The presence of bacteria and low oxygen levels hamper wound healing and exacerbate a forming pilonidal cyst. Differential diagnosis A pilonidal cyst can resemble a dermoid cyst, a kind of teratoma (germ cell tumor). In particular, a pilonidal cyst in the gluteal cleft can resemble a sacrococcygeal teratoma. Correct diagnosis is important because all teratomas require consultation with an oncologist and complete surgical excision, if possible without any spillage. Treatment If there is infection, treatment is generally by incision and drainage just off the midline. Following five simple rules has been known to prevent recurring inflammations for some people and avoid the surgery: 1. Avoiding chairs and car seats that put pressure on coccyx; 2. Being of normal weight, preferably with low BMI; 3. Keeping the area clean; 4. Keeping the area dry by wearing exclusively cotton garments; 5. Keeping the area completely hair free, for example by regularly using an IPL hair removal device.The evidence for elective treatment of pilonidal sinus disease is poor. The most commonly performed surgery is for the pilonidal sinus complex to be surgically excised with the wound often left open to heal. Post-surgical wound packing may be necessary, and packing typically must be replaced daily for 4 to 8 weeks. In some cases, two years may be required for complete granulation to occur. Sometimes the cyst is resolved via surgical marsupialization.Surgeons can also excise the sinus and repair with a reconstructive flap technique, such as a "cleft lift" procedure or Z-plasty, usually done under general anesthetic. This approach is especially useful for complicated or recurring pilonidal disease, leaves little scar tissue and flattens the region between the buttocks, reducing the risk of recurrence. This approach typically results in a more rapid recovery than the traditional surgery, however there are fewer surgeons trained in the cleft lift procedure and it consequently may not be as accessible to patients, depending on their location. Meta-analysis shows recurrence rates were lower in open healing than with primary closure (RR 0.60, 95% CI 0.42 to 0.87), at the expense of healing time. Pilonidal cysts can recur, and do so more frequently if the surgical wound is sutured in the midline, as opposed to away from the midline, which obliterates the natal cleft and removes the focus of shearing stress. An incision lateral to the intergluteal cleft is therefore preferred, especially given the poor healing of midline incisions in this region. Minimally invasive techniques with no wound and rapid return to full activities have been reported but await double blind randomised trials.Another technique is to treat pilonidal sinus with fibrin glue. This technique is of unclear benefit as of 2017 due to insufficient research. The evidence for any treatment is of low quality, and care must be taken not to over interpret any study in this field.In some cases wounds are left open after surgery to heal naturally instead of being closed with stiches. There are a lot of different dressings and topical agents (creams or lotions) that are available for helping these open wounds to heal. A 2022 systematic review brought together evidence from 11 studies that compared dressings and topical agents for treating open wounds after surgical treatment for pilonidal sinus of the buttocks. The authors concluded that: platelet rich plasma may help wounds to heal quicker compared to sterile gauze; Lietofax skin repair cream may help wounds to heal by 30 days compared to iodine (which helps to reduce bacteria in the wound); but it is not clear whether hydrogel dressings (designed to keep the wound moist) reduce the time it takes wounds to heal compared with cleaning the wound with iodine. Etymology Pilonidal means nest of hair and is derived from the Latin words for hair (pilus) and nest (nidus). The condition was first described by Herbert Mayo in 1833. R.M. Hodges was the first to use the phrase pilonidal cyst to describe the condition in 1880.The condition was widespread in the United States Army during World War II. The condition was termed "Jeep seat" or "Jeep riders disease", because a large portion of people who were being hospitalized for it rode in Jeeps, and prolonged rides in the bumpy vehicles were believed to have caused the condition due to irritation and pressure on the coccyx. References External links NHS Choices for pilonidal sinus treatment

Pterygium

Pterygium (plural pterygia or pterygiums) refers to any wing-like triangular membrane occurring in the neck, eyes, knees, elbows, ankles or digits.The term comes from the Greek word pterygion meaning "wing". Types Popliteal pterygium syndrome, a congenital condition affecting the face, limbs, or genitalia but named after the wing-like structural anomaly behind the knee Pterygium (eye) or surfers eye, a growth on the cornea of the eye Pterygium colli or webbed neck, a congenital skin fold of the neck down to the shoulders Pterygium inversum unguis or ventral pterygium, adherence of the distal portion of the nailbed to the ventral surface of the nail plate Pterygium unguis or dorsal pterygium, scarring between the proximal nail fold and matrix Pterygium of the eye A pterygium reduces the vision in several ways: Distortion of the corneal optics. This begins usually when the pterygium is greater than 2mm from the corneal edge (limbus). Disruption of the tear film. The tear film is the first lens in the eye. Pterygia are associated with eyelid inflammation, called Blepharitis. Growth over the corneal centre, which leads to dramatic reduction of vision. Induced anterior corneal scarring, which often remains after surgical removal.A pterygium of the eye grows very slowly. Usually it takes several years or decades to progress. Surgical removal Indications for surgery, in order of decreasing importance: Growth over the corneal centre. Reduced vision due to corneal distortion. Documented growth. Symptoms of discomfort. Cosmesis.Surgery is usually performed under local anaesthetic with light sedation as day surgery. The pterygium is stripped carefully off the surface of the eye. If this is all that is done, the pterygium regrows frequently. The technique with the lowest recurrence rate uses an auto graft of conjunctiva from under the eyelid. This is placed over the defect remaining from the removed pterygium. The graft can be stitched in place, which is time-consuming, and painful for the patient afterwards. An alternative is the use of tissue adhesive fibrin glue (Tisseel or Full Link or Beriplast P or Quixil). A Cochrane Review including 14 studies and last updated October 2016, found that using fibrin glue when doing conjunctival autografting was associated with a reduced likelihood of the pterygium recurring compared with sutures. The review found that operations may take less time but fibrin glue may be associated with more complications (for example, rupture, shrinking and inflammation (granuloma). A 3-year clinical study on the application of ologen collagen matrix as excision site grafts showed significantly improved surgery success rates.The mechanism of the collagen matrix graft (commercially available as ologen®) works by promoting healthy cell growth into the matrix, thus preventing conjunctiva overgrowth that can cover the iris. References == Further reading ==

Glaucoma

Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye remains open, with less common types including closed-angle (narrow angle, acute congestive) glaucoma and normal-tension glaucoma. Open-angle glaucoma develops slowly over time and there is no pain. Peripheral vision may begin to decrease, followed by central vision, resulting in blindness if not treated. Closed-angle glaucoma can present gradually or suddenly. The sudden presentation may involve severe eye pain, blurred vision, mid-dilated pupil, redness of the eye, and nausea. Vision loss from glaucoma, once it has occurred, is permanent. Eyes affected by glaucoma are referred to as being glaucomatous. Risk factors for glaucoma include increasing age, high pressure in the eye, a family history of glaucoma, and use of steroid medication. For eye pressures, a value of 21 mmHg or 2.8 kPa above atmospheric pressure (760 mmHg) is often used, with higher pressures leading to a greater risk. However, some may have high eye pressure for years and never develop damage. Conversely, optic nerve damage may occur with normal pressure, known as normal-tension glaucoma. The mechanism of open-angle glaucoma is believed to be the slow exit of aqueous humor through the trabecular meshwork, while in closed-angle glaucoma the iris blocks the trabecular meshwork. Diagnosis is achieved by performing a dilated eye examination. Often, the optic nerve shows an abnormal amount of cupping.If treated early, it is possible to slow or stop the progression of disease with medication, laser treatment, or surgery. The goal of these treatments is to decrease eye pressure. A number of different classes of glaucoma medication are available. Laser treatments may be effective in both open-angle and closed-angle glaucoma. A number of types of glaucoma surgeries may be used in people who do not respond sufficiently to other measures. Treatment of closed-angle glaucoma is a medical emergency.About 70 million people have glaucoma globally, with about two million patients in the United States. It is the leading cause of blindness in African Americans. It occurs more commonly among older people, and closed-angle glaucoma is more common in women. Glaucoma has been called the "silent thief of sight", because the loss of vision usually occurs slowly over a long period of time. Worldwide, glaucoma is the second-leading cause of blindness after cataracts. Cataracts caused 51% of blindness in 2010, while glaucoma caused 8%. The word "glaucoma" is from the Ancient Greek glaukos, which means "shimmering." In English, the word was used as early as 1587 but did not become commonly used until after 1850, when the development of the ophthalmoscope allowed doctors to see the optic nerve damage. Signs and symptoms As open-angle glaucoma is usually painless with no symptoms early in the disease process, screening through regular eye exams is important. The only signs are gradually progressive visual field loss and optic nerve changes (increased cup-to-disc ratio on fundoscopic examination). About 10% of people with closed angles present with acute angle closure characterized by sudden ocular pain, seeing halos around lights, red eye, very high intraocular pressure (>30 mmHg (4.0 kPa)), nausea and vomiting, suddenly decreased vision, and a fixed, mid-dilated pupil. It is also associated with an oval pupil in some cases. Acute angle closure is an emergency. Opaque specks may occur in the lens in glaucoma, known as glaukomflecken. Causes Ocular hypertension (increased pressure within the eye) is the most important risk factor for glaucoma, but only about 50% of people with primary open-angle glaucoma actually have elevated ocular pressure. Ocular hypertension—an intraocular pressure above the traditional threshold of 21 mmHg (2.8 kPa) or even above 24 mmHg (3.2 kPa)—is not necessarily a pathological condition, but it increases the risk of developing glaucoma. One study found a conversion rate of 18% within five years, meaning fewer than one in five people with elevated intraocular pressure will develop glaucomatous visual field loss over that period of time. It is a matter of debate whether every person with an elevated intraocular pressure should receive glaucoma therapy; currently, most ophthalmologists favor treatment of those with additional risk factors.Open-angle glaucoma accounts for 90% of glaucoma cases in the United States. Closed-angle glaucoma accounts for fewer than 10% of glaucoma cases in the United States, but as many as half of glaucoma cases in other nations (particularly East Asian countries). Dietary No clear evidence indicates that vitamin deficiencies cause glaucoma in humans. As such, oral vitamin supplementation is not a recommended treatment. Caffeine increases intraocular pressure in those with glaucoma, but does not appear to affect normal individuals. Ethnicity Many people of East Asian descent are prone to developing angle closure glaucoma because of shallower anterior chamber depths, with the majority of cases of glaucoma in this population consisting of some form of angle closure. Higher rates of glaucoma have also been reported for Inuit populations, compared to White populations, in Canada and Greenland. Genetics Positive family history is a risk factor for glaucoma. The relative risk of having primary open-angle glaucoma (POAG) is increased about two- to four-fold for people who have a sibling with glaucoma. Glaucoma, particularly primary open-angle glaucoma, is associated with mutations in several genes, including MYOC, ASB10, WDR36, NTF4, TBK1, and RPGRIP1, although most cases of glaucoma do not involve these genetic mutations. Normal-tension glaucoma, which comprises one-third of POAG, is also associated with genetic mutations (including OPA1 and OPTN genes).Various rare congenital/genetic eye malformations are associated with glaucoma. Occasionally, failure of the normal third-trimester gestational atrophy of the hyaloid canal and the tunica vasculosa lentis is associated with other anomalies. Angle closure-induced ocular hypertension and glaucomatous optic neuropathy may also occur with these anomalies and has been modelled in mice. Other Other factors can cause glaucoma, known as "secondary glaucoma", including prolonged use of steroids (steroid-induced glaucoma); conditions that severely restrict blood flow to the eye, such as severe diabetic retinopathy and central retinal vein occlusion (neovascular glaucoma); ocular trauma (angle-recession glaucoma); and inflammation of the middle layer of the pigmented vascular eye structure (uveitis), known as uveitic glaucoma. Pathophysiology The underlying cause of open-angle glaucoma remains unclear. Several theories exist on its exact etiology. However, the major risk factor for most glaucomas and the focus of treatment is increased intraocular pressure. Intraocular pressure is a function of production of liquid aqueous humor by the ciliary processes of the eye, and its drainage through the trabecular meshwork. Aqueous humor flows from the ciliary processes into the posterior chamber, bounded posteriorly by the lens and the zonules of Zinn, and anteriorly by the iris. It then flows through the pupil of the iris into the anterior chamber, bounded posteriorly by the iris and anteriorly by the cornea. From here, the trabecular meshwork drains aqueous humor via the scleral venous sinus (Schlemms canal) into scleral plexuses and general blood circulation.In open/wide-angle glaucoma, flow is reduced through the trabecular meshwork, due to the degeneration and obstruction of the trabecular meshwork, whose original function is to absorb the aqueous humor. Loss of aqueous humor absorption leads to increased resistance and thus a chronic, painless buildup of pressure in the eye.In close/narrow-angle, the iridocorneal angle is completely closed because of forward displacement of the final roll and root of the iris against the cornea, resulting in the inability of the aqueous fluid to flow from the posterior to the anterior chamber and then out of the trabecular network. This accumulation of aqueous humor causes an acute increase in pressure and pain. Degeneration of axons of the retinal ganglion cells (the optic nerve) is a hallmark of glaucoma. The inconsistent relationship of glaucomatous optic neuropathy with increased intraocular pressure has provoked hypotheses and studies on anatomic structure, eye development, nerve compression trauma, optic nerve blood flow, excitatory neurotransmitter, trophic factor, retinal ganglion cell/axon degeneration, glial support cell, immune system, aging mechanisms of neuron loss, and severing of the nerve fibers at the scleral edge. Diagnosis Screening for glaucoma is usually performed as part of a standard eye examination performed by optometrists and ophthalmologists. Testing for glaucoma includes measurements of the intraocular pressure using tonometry, anterior chamber angle examination or gonioscopy as well as examination of the optic nerve to discern visible damage, changes in the cup-to-disc ratio, rim appearance and vascular change. A formal visual field test is performed. The retinal nerve fiber layer can be assessed with imaging techniques such as optical coherence tomography, scanning laser polarimetry or scanning laser ophthalmoscopy (Heidelberg retinal tomogram). Visual field loss is the most specific sign of the condition, though it occurs later in the course of the disease.As all methods of tonometry are sensitive to corneal thickness, methods such as Goldmann tonometry may be augmented with pachymetry to measure the central corneal thickness (CCT). A thicker cornea can result in a pressure reading higher than the true pressure but a thinner cornea can produce a pressure reading lower than the true pressure.Because pressure-measurement error can be caused by more than just CCT (such as by corneal hydration or elastic properties), it is impossible to adjust pressure measurements based only on CCT measurements. The frequency-doubling illusion can also be used to detect glaucoma with the use of a frequency-doubling technology perimeter.Examination for glaucoma is assessed with attention given to gender, race, history of drug use, refraction, inheritance and family history. Glaucoma has been classified into specific types: Primary glaucoma and its variants Primary glaucoma (H40.1-H40.2) Primary open-angle glaucoma, also known as chronic open-angle glaucoma, chronic simple glaucoma, glaucoma simplexHigh-tension glaucoma Low-tension glaucomaPrimary angle closure glaucoma, also known as primary closed-angle glaucoma, narrow-angle glaucoma, pupil-block glaucoma, acute congestive glaucomaAcute angle closure glaucoma (aka AACG) Chronic angle closure glaucoma Intermittent angle closure glaucoma Superimposed on chronic open-angle closure glaucoma ("combined mechanism" – uncommon)Variants of primary glaucoma Pigmentary glaucoma Exfoliation glaucoma, also known as pseudoexfoliative glaucoma or glaucoma capsulare Primary juvenile glaucomaPrimary angle closure glaucoma is caused by contact between the iris and trabecular meshwork, which in turn obstructs outflow of the aqueous humor from the eye. This contact between iris and trabecular meshwork (TM) may gradually damage the function of the meshwork until it fails to keep pace with aqueous production, and the pressure rises. In over half of all cases, prolonged contact between iris and TM causes the formation of synechiae (effectively "scars"). These cause permanent obstruction of aqueous outflow. In some cases, pressure may rapidly build up in the eye, causing pain and redness (symptomatic, or so-called "acute" angle closure). In this situation, the vision may become blurred, and halos may be seen around bright lights. Accompanying symptoms may include a headache and vomiting. Diagnosis is made from physical signs and symptoms: pupils mid-dilated and unresponsive to light, cornea edematous (cloudy), reduced vision, redness, and pain. However, the majority of cases are asymptomatic. Prior to the very severe loss of vision, these cases can only be identified by examination, generally by an eye care professional. Once any symptoms have been controlled, the first line (and often definitive) treatment is laser iridotomy. This may be performed using either Nd:YAG or argon lasers, or in some cases by conventional incisional surgery. The goal of treatment is to reverse and prevent contact between the iris and trabecular meshwork. In early to moderately advanced cases, iridotomy is successful in opening the angle in around 75% of cases. In the other 25%, laser iridoplasty, medication (pilocarpine) or incisional surgery may be required. Primary open-angle glaucoma is when optic nerve damage results in a progressive loss of the visual field. This is associated with increased pressure in the eye. Not all people with primary open-angle glaucoma have eye pressure that is elevated beyond normal, but decreasing the eye pressure further has been shown to stop progression even in these cases. The increased pressure is caused by trabecular meshwork blockage. Because the microscopic passageways are blocked, the pressure builds up in the eye and causes imperceptible very gradual vision loss. Peripheral vision is affected first, but eventually the entire vision will be lost if not treated. Diagnosis is made by looking for cupping of the optic nerve. Prostaglandin agonists work by opening uveoscleral passageways. Beta-blockers, such as timolol, work by decreasing aqueous formation. Carbonic anhydrase inhibitors decrease bicarbonate formation from ciliary processes in the eye, thus decreasing the formation of aqueous humor. Parasympathetic analogs are drugs that work on the trabecular outflow by opening up the passageway and constricting the pupil. Alpha 2 agonists (brimonidine, apraclonidine) both decrease fluid production (via inhibition of AC) and increase drainage. Developmental glaucoma Developmental glaucoma (Q15.0) Primary congenital glaucoma Infantile glaucoma Glaucoma associated with hereditary or familial diseases Secondary glaucoma Secondary glaucoma (H40.3-H40.6) Inflammatory glaucomaUveitis of all types Fuchs heterochromic iridocyclitisPhacogenic glaucomaAngle-closure glaucoma with mature cataract Phacoanaphylactic glaucoma secondary to rupture of lens capsule Phacolytic glaucoma due to phacotoxic meshwork blockage Subluxation of lensGlaucoma secondary to intraocular hemorrhageHyphema Hemolytic glaucoma, also known as erythroclastic glaucomaTraumatic glaucomaAngle recession glaucoma: Traumatic recession on anterior chamber angle Postsurgical glaucomaAphakic pupillary block Ciliary block glaucomaNeovascular glaucoma (see below for more details) Drug-induced glaucomaCorticosteroid induced glaucoma Alpha-chymotrypsin glaucoma. Postoperative ocular hypertension from use of alpha chymotrypsin.Glaucoma of miscellaneous originAssociated with intraocular tumors Associated with retinal detachments Secondary to severe chemical burns of the eye Associated with essential iris atrophy Toxic glaucomaNeovascular glaucoma, an uncommon type of glaucoma, is difficult or nearly impossible to treat, and is often caused by proliferative diabetic retinopathy (PDR) or central retinal vein occlusion (CRVO). It may also be triggered by other conditions that result in ischemia of the retina or ciliary body. Individuals with poor blood flow to the eye are highly at risk for this condition. Neovascular glaucoma results when new, abnormal vessels begin developing in the angle of the eye that begin blocking the drainage. People with such condition begin to rapidly lose their eyesight. Sometimes, the disease appears very rapidly, especially after cataract surgery procedures. A new treatment for this disease, as first reported by Kahook and colleagues, involves the use of a novel group of medications known as anti-VEGF agents. These injectable medications can lead to a dramatic decrease in new vessel formation and, if injected early enough in the disease process, may lead to normalization of intraocular pressure. Currently, there are no high-quality controlled trials demonstrating a beneficial effect of anti-VEGF treatments in lowering IOP in people with neovascular glaucoma.Toxic glaucoma is open-angle glaucoma with an unexplained significant rise of intraocular pressure following unknown pathogenesis. Intraocular pressure can sometimes reach 80 mmHg (11 kPa). It characteristically manifests as ciliary body inflammation and massive trabecular oedema that sometimes extends to Schlemms canal. This condition is differentiated from malignant glaucoma by the presence of a deep and clear anterior chamber and a lack of aqueous misdirection. Also, the corneal appearance is not as hazy. A reduction in visual acuity can occur followed neuroretinal breakdown. Associated factors include inflammation, drugs, trauma and intraocular surgery, including cataract surgery and vitrectomy procedures. Gede Pardianto (2005) reported on four patients who had toxic glaucoma. One of them underwent phacoemulsification with small particle nucleus drops. Some cases can be resolved with some medication, vitrectomy procedures or trabeculectomy. Valving procedures can give some relief, but further research is required. Absolute glaucoma Absolute glaucoma (H44.5) is the end stage of all types of glaucoma. The eye has no vision, absence of pupillary light reflex and pupillary response, and has a stony appearance. Severe pain is present in the eye. The treatment of absolute glaucoma is a destructive procedure like cyclocryoapplication, cyclophotocoagulation, or injection of 99% alcohol. Types Glaucoma is an umbrella term for eye conditions that damage the optic nerve and that can lead to a loss of vision. The main cause of damage to the optic nerve is intraocular pressure (IOP), excessive fluid pressure within the eye, which can be caused by factors such as blockage of drainage ducts and narrowing or closure of the angle between the iris and cornea. Glaucoma is primarily categorized as either open-angle or closed-angle (or angle-closure). In open-angle glaucoma, the iris meets the cornea normally, allowing the fluid from inside the eye to drain, thus relieving the internal pressure. When this angle is narrowed or closed, pressure increases over time, causing damage to the optic nerve and leading to blindness. Primary open-angle glaucoma (also called primary or chronic glaucoma) involves the slow clogging of drainage canals resulting in increased eye pressure, which causes progressive optic nerve damage. This manifests as a gradual loss of the visual field, starting with a loss of peripheral vision, but eventually all vision will be lost if the condition is not treated. This is the most common type of glaucoma, accounting for 90% of cases in the United States, but is less prevalent in Asian countries. Onset is slow and painless, and loss of vision is gradual and irreversible. With narrow-angle glaucoma (also called closed-angle glaucoma), the iris bows forward, narrowing the angle that drains the eye, increasing pressure within the eye. If untreated, it can lead to the medical emergency of angle-closure glaucoma. With angle-closure glaucoma (also called closed-angle, primary angle-closure or acute glaucoma), the iris bows forward and causes physical contact between the iris and trabecular meshwork, which blocks the outflow of aqueous humor from within the eye. This contact may gradually damage the draining function of the meshwork until it fails to keep pace with aqueous production, and the intraocular pressure rises. The onset of symptoms is sudden and causes pain and other noticeable symptoms, and the condition is treated as a medical emergency. Unlike open-angle glaucoma, angle-closure glaucoma is a result of the closing of the angle between the iris and cornea. This tends to occur in the farsighted, who have smaller anterior chambers, making physical contact between the iris and trabecular meshwork more likely. A variety of tests may be performed to detect those at risk of angle-closure glaucoma.Normal-tension glaucoma (NTG, also called low-tension or normal-pressure glaucoma) is a condition in which the optic nerve is damaged although intraocular pressure (IOP) is in the normal range (12 to 22 mmHg (1.6 to 2.9 kPa)). Individuals with a family history of NTG, those of Japanese ancestry, those with a history of systemic heart disease and those with Flammer syndrome are at an elevated risk of developing NTG. The cause of NTG is unknown. Secondary glaucoma refers to any case in which another disease, trauma, drug or procedure causes increased eye pressure, resulting in optic nerve damage and vision loss, which may be mild or severe. This may be the result of an eye injury, inflammation, a tumor or advanced cases of cataracts or diabetes. It can also be caused by certain drugs such as steroids. Treatment depends on whether the condition is identified as open-angle or angle-closure glaucoma. With pseudoexfoliation glaucoma (also known as PEX or exfoliation glaucoma) the pressure results from the accumulation of microscopic granular protein fibers, which can block normal drainage of the aqueous humor. PEX is prevalent in Scandinavia, primarily in those over 70, and more commonly in women. Pigmentary glaucoma (also known as pigmentary dispersion syndrome) is caused by pigment cells sloughing off from the back of the iris and floating around in the aqueous humor. Over time, these pigment cells can accumulate in the anterior chamber and begin to clog the trabecular meshwork. It is a rare condition that occurs mostly among white males in their mid-20s to 40s, most of whom are nearsighted. Primary juvenile glaucoma is a neonate or juvenile abnormality in which ocular hypertension is evident at birth or shortly thereafter and is caused by abnormalities in the anterior chamber angle development that blocks the outflow of the aqueous humor. Uveitic glaucoma is caused by uveitis, the swelling and inflammation of the uvea, the middle layer of the eye. The uvea provides most of the blood supply to the retina. Increased eye pressure can result from the inflammation itself or from the steroids used to treat it. Visual field defects in glaucoma In glaucoma visual field defects result from damage to the retinal nerve fiber layer. Field defects are seen mainly in primary open angle glaucoma. Because of the unique anatomy of the RNFL, many noticeable patterns are seen in the visual field. Most of the early glaucomatous changes are seen within the central visual field, mainly in Bjerrums area, 10-20° from fixation.Following are the common glaucomatous field defects: Generalized depression: Generalized depression is seen in early stages of glaucoma and many other conditions. Mild constriction of central and peripheral visual field due to isopter contraction comes under generalized depression. If all the isopters show similar depression to the same point, it is then called a contraction of visual field. Relative paracentral scotomas are the areas where smaller and dimmer targets are not visualized by the patient. Larger and brighter targets can be seen. Small paracentral depressions, mainly superonasal are seen in normal tension glaucoma (NTG). The generalized depression of the entire field may be seen in cataract also. Baring of blind spot: "Baring of blind spot" means exclusion of blind spot from the central field due to inward curve of the outer boundary of 30° central field. It is only an early non-specific visual field change, without much diagnostic value in glaucoma. Small wing-shaped Paracentral scotoma: Small wing-shaped Paracentral scotoma within Bjerrums area is the earliest clinically significant field defect seen in glaucoma. It may also be associated with nasal steps. Scotoma may be seen above or below the blind spot. Siedels sickle-shaped scotoma: Paracentral scotoma joins with the blind spot to form the Seidel sign. Arcuate or Bjerrums scotoma: It is formed at later stages of glaucoma by extension of Seidels scotoma in an area either above or below the fixation point to reach the horizontal line. Peripheral breakthrough may occur due to damage of nerve fibers. Ring or Double arcuate scotoma: Two arcuate scotomas join to form a Ring or Double arcuate scotoma. This defect is seen in advanced stages of glaucoma. Roennes central nasal step: It is created when two arcuate scotomas run in different arcs to form a right angled defect. This is also seen in advanced stages of glaucoma. Peripheral field defects: Peripheral field defects may occur in early or late stages of glaucoma. Roennes peripheral nasal steps occur due to contraction of peripheral isopter. Tubular vision: Since macular fibers are the most resistant to glaucomatous damage, the central vision remains unaffected until end stages of glaucoma. Tubular vision or Tunnel vision is the loss of peripheral vision with retention of central vision, resulting in a constricted circular tunnel-like field of vision. It is seen in the end stages of glaucoma. Retinitis pigmentosa is another disease that causes tubular vision. Temporal island of vision: It is also seen in end stages of glaucoma. The temporal islands lie outside of the central 24 to 30° visual field, so it may not be visible with standard central field measurements done in glaucoma. Screening The United States Preventive Services Task Force stated, as of 2013, that there was insufficient evidence to recommend for or against screening for glaucoma. Therefore, there is no national screening program in the US. Screening, however, is recommended starting at age 40 by the American Academy of Ophthalmology.There is a glaucoma screening program in the UK. Those at risk are advised to have a dilated eye examination at least once a year. Treatment The modern goals of glaucoma management are to avoid glaucomatous damage and nerve damage, and preserve visual field and total quality of life for patients, with minimal side-effects. This requires appropriate diagnostic techniques and follow-up examinations, and judicious selection of treatments for the individual patient. Although intraocular pressure (IOP) is only one of the major risk factors for glaucoma, lowering it via various pharmaceuticals and/or surgical techniques is currently the mainstay of glaucoma treatment. A review of people with primary open-angle glaucoma and ocular hypertension concluded that medical IOP-lowering treatment slowed down the progression of visual field loss.Vascular flow and neurodegenerative theories of glaucomatous optic neuropathy have prompted studies on various neuroprotective therapeutic strategies, including nutritional compounds, some of which may be regarded by clinicians as safe for use now, while others are on trial. Mental stress is also considered as consequence and cause of vision loss which means that stress management training, autogenic training and other techniques to cope with stress can be helpful. Medication Intraocular pressure can be lowered with medication, usually eye drops. Several classes of medications are used to treat glaucoma, with several medications in each class. By reducing pressure, eye drops also help to lower the risk of sight loss. Latanoprost, for example, seems to halve this risk.Each of these medicines may have local and systemic side effects. Wiping the eye with an absorbent pad after the administration of eye drops may result in fewer adverse effects, like the growth of eyelashes and hyperpigmentation in the eyelid. Initially, glaucoma drops may reasonably be started in either one or in both eyes.The possible neuroprotective effects of various topical and systemic medications are also being investigated. Prostaglandin analogs, such as latanoprost, bimatoprost and travoprost, increase uveoscleral outflow of aqueous humor. Bimatoprost also increases trabecular outflow. Topical beta-adrenergic receptor antagonists, such as timolol, levobunolol, and betaxolol, decrease aqueous humor production by the epithelium of the ciliary body. Alpha2-adrenergic agonists, such as brimonidine and apraclonidine, work by a dual mechanism, decreasing aqueous humor production and increasing uveoscleral outflow. Less-selective alpha agonists, such as epinephrine, decrease aqueous humor production through vasoconstriction of ciliary body blood vessels, useful only in open-angle glaucoma. Epinephrines mydriatic effect, however, renders it unsuitable for closed-angle glaucoma due to further narrowing of the uveoscleral outflow (i.e. further closure of trabecular meshwork, which is responsible for absorption of aqueous humor). Miotic agents (parasympathomimetics), such as pilocarpine, work by contraction of the ciliary muscle, opening the trabecular meshwork and allowing increased outflow of the aqueous humour. Echothiophate, an acetylcholinesterase inhibitor, is used in chronic glaucoma. Carbonic anhydrase inhibitors, such as dorzolamide, brinzolamide, and acetazolamide, lower secretion of aqueous humor by inhibiting carbonic anhydrase in the ciliary body. Adherence Poor compliance with medications and follow-up visits is a major reason for vision loss in glaucoma patients. A 2003 study of patients in an HMO found half failed to fill their prescriptions the first time, and one-quarter failed to refill their prescriptions a second time. Patient education and communication must be ongoing to sustain successful treatment plans for this lifelong disease with no early symptoms. Adherence to medication protocol can be confusing and expensive; if side effects occur, the patient must be willing either to tolerate them or to communicate with the treating physician to improve the drug regimen. Initially, glaucoma drops may reasonably be started in either one or in both eyes. Laser Argon laser trabeculoplasty (ALT) may be used to treat open-angle glaucoma, but this is a temporary solution, not a cure. A 50-μm argon laser spot is aimed at the trabecular meshwork to stimulate the opening of the mesh to allow more outflow of aqueous fluid. Usually, half of the angle is treated at a time. Traditional laser trabeculoplasty uses a thermal argon laser in an argon laser trabeculoplasty procedure. Nd:YAG laser peripheral iridotomy (LPI) may be used in patients susceptible to or affected by angle closure glaucoma or pigment dispersion syndrome. During laser iridotomy, laser energy is used to make a small, full-thickness opening in the iris to equalize the pressure between the front and back of the iris, thus correcting any abnormal bulging of the iris. In people with narrow angles, this can uncover the trabecular meshwork. In some cases of intermittent or short-term angle closure, this may lower the eye pressure. Laser iridotomy reduces the risk of developing an attack of acute angle closure. In most cases, it also reduces the risk of developing chronic angle closure or of adhesions of the iris to the trabecular meshwork. Diode laser cycloablation lowers IOP by reducing aqueous secretion by destroying secretory ciliary epithelium. Surgery Both laser and conventional surgeries are performed to treat glaucoma. Surgery is the primary therapy for those with congenital glaucoma. Generally, these operations are a temporary solution, as there is not yet a cure for glaucoma. Canaloplasty Canaloplasty is a nonpenetrating procedure using microcatheter technology. To perform a canaloplasty, an incision is made into the eye to gain access to the Schlemms canal in a similar fashion to a viscocanalostomy. A microcatheter will circumnavigate the canal around the iris, enlarging the main drainage channel and its smaller collector channels through the injection of a sterile, gel-like material called viscoelastic. The catheter is then removed and a suture is placed within the canal and tightened. By opening the canal, the pressure inside the eye may be relieved, although the reason is unclear, since the canal (of Schlemm) does not have any significant fluid resistance in glaucoma or healthy eyes. Long-term results are not available. Trabeculectomy The most common conventional surgery performed for glaucoma is the trabeculectomy. Here, a partial thickness flap is made in the scleral wall of the eye, and a window opening is made under the flap to remove a portion of the trabecular meshwork. The scleral flap is then sutured loosely back in place to allow fluid to flow out of the eye through this opening, resulting in lowered intraocular pressure and the formation of a bleb or fluid bubble on the surface of the eye. Scarring can occur around or over the flap opening, causing it to become less effective or lose effectiveness altogether. Traditionally, chemotherapeutic adjuvants, such as mitomycin C (MMC) or 5-fluorouracil (5-FU), are applied with soaked sponges on the wound bed to prevent filtering blebs from scarring by inhibiting fibroblast proliferation. Contemporary alternatives to prevent the scarring of the meshwork opening include the sole or combinative implementation of nonchemotherapeutic adjuvants such as the Ologen collagen matrix, which has been clinically shown to increase the success rates of surgical treatment.Collagen matrix prevents scarring by randomizing and modulating fibroblast proliferation in addition to mechanically preventing wound contraction and adhesion. Glaucoma drainage implants The first glaucoma drainage implant was developed in 1966. Since then, several types of implants have followed on from the original: the Baerveldt tube shunt, or the valved implants, such as the Ahmed glaucoma valve implant or the ExPress Mini Shunt and the later generation pressure ridge Molteno implants. These are indicated for glaucoma patients not responding to maximal medical therapy, with previous failed guarded filtering surgery (trabeculectomy). The flow tube is inserted into the anterior chamber of the eye, and the plate is implanted underneath the conjunctiva to allow a flow of aqueous fluid out of the eye into a chamber called a bleb. The first-generation Molteno and other nonvalved implants sometimes require the ligation of the tube until the bleb formed is mildly fibrosed and water-tight. This is done to reduce postoperative hypotony—sudden drops in postoperative intraocular pressure. Valved implants, such as the Ahmed glaucoma valve, attempt to control postoperative hypotony by using a mechanical valve. Ab interno implants, such as the Xen Gel Stent, are transscleral implants by an ab interno procedure to channel aqueous humor into the non-dissected Tenons space, creating a subconjunctival drainage area similar to a bleb. The implants are transscleral and different from other ab interno implants that do not create a transscleral drainage, such as iStent, CyPass, or Hydrus.The ongoing scarring over the conjunctival dissipation segment of the shunt may become too thick for the aqueous humor to filter through. This may require preventive measures using antifibrotic medications, such as 5-fluorouracil or mitomycin-C (during the procedure), or other nonantifibrotic medication methods, such as collagen matrix implant, or biodegradable spacer, or later on create a necessity for revision surgery with the sole or combinative use of donor patch grafts or collagen matrix implant. And for glaucomatous painful blind eye and some cases of glaucoma, cyclocryotherapy for ciliary body ablation could be considered to be performed. Laser-assisted nonpenetrating deep sclerectomy The most common surgical approach currently used for the treatment of glaucoma is trabeculectomy, in which the sclera is punctured to alleviate intraocular pressure. Nonpenetrating deep sclerectomy (NPDS) surgery is a similar, but modified, procedure, in which instead of puncturing the scleral bed and trabecular meshwork under a scleral flap, a second deep scleral flap is created, excised, with further procedures of deroofing the Schlemms canal, upon which, percolation of liquid from the inner eye is achieved and thus alleviating intraocular pressure, without penetrating the eye. NPDS is demonstrated to have significantly fewer side effects than trabeculectomy. However, NPDS is performed manually and requires higher level of skills that may be assisted with instruments. In order to prevent wound adhesion after deep scleral excision and to maintain good filtering results, NPDS as with other non-penetrating procedures is sometimes performed with a variety of biocompatible spacers or devices, such as the Aquaflow collagen wick, ologen Collagen Matrix, or Xenoplast glaucoma implant.Laser-assisted NPDS is performed with the use of a CO2 laser system. The laser-based system is self-terminating once the required scleral thickness and adequate drainage of the intraocular fluid have been achieved. This self-regulation effect is achieved as the CO2 laser essentially stops ablating as soon as it comes in contact with the intraocular percolated liquid, which occurs as soon as the laser reaches the optimal residual intact layer thickness. Lens extraction For people with chronic closed-angle glaucoma, lens extraction can relieve the block created by the pupil and help regulate the intraocular pressure. Prognosis In open-angle glaucoma, the typical progression from normal vision to complete blindness takes about 25 years to 70 years without treatment, depending on the method of estimation used. The intraocular pressure can also have an effect, with higher pressures reducing the time until blindness. Epidemiology As of 2010, there were 44.7 million people in the world with open angle glaucoma. The same year, there were 2.8 million people in the United States with open angle glaucoma. By 2020, the prevalence is projected to increase to 58.6 million worldwide and 3.4 million in the United States.Both internationally and in the United States, glaucoma is the second-leading cause of blindness. Globally, cataracts are a more common cause. Glaucoma is also the leading cause of blindness in African Americans, who have higher rates of primary open-angle glaucoma. Bilateral vision loss can negatively affect mobility and interfere with driving.A meta-analysis published in 2009 found that people with primary open angle glaucoma do not have increased mortality rates, or increased risk of cardiovascular death. History The association of elevated intraocular pressure (IOP) and glaucoma was first described by Englishman Richard Banister in 1622: "...that the Eye be grown more solid and hard, then naturally it should be...". Angle-closure glaucoma was treated with cataract extraction by John Collins Warren in Boston as early as 1806. The invention of the ophthalmoscope by Hermann Helmholtz in 1851 enabled ophthalmologists for the first time to identify the pathological hallmark of glaucoma, the excavation of the optic nerve head due to retinal ganglion cell loss. The first reliable instrument to measure intraocular pressure was invented by Norwegian ophthalmologist Hjalmar August Schiøtz in 1905. About half a century later, Hans Goldmann in Berne, Switzerland, developed his applanation tonometer which still today - despite numerous new innovations in diagnostics - is considered the gold standard of determining this crucial pathogenic factor. In the late 20th century, further pathomechanisms beyond elevated IOP were discovered and became the subject of research like insufficient blood supply – often associated with low or irregular blood pressure – to the retina and optic nerve head. The first drug to reduce IOP, pilocarpine, was introduced in the 1870s; other major innovations in pharmacological glaucoma therapy were the introduction of beta blocker eye drops in the 1970s and of prostaglandin analogues and topical (locally administered) carbonic anhydrase inhibitors in the mid-1990s.. Early surgical techniques like iridectomy and fistulating methods have recently been supplemented by less invasive procedures like small implants, a range of options now widely called MIGS (micro-invasive glaucoma surgery). Etymology The word "glaucoma" comes from the Ancient Greek γλαύκωμα, a derivative of γλαυκóς, which commonly described the color of eyes which were not dark (i.e. blue, green, light gray). Eyes described as γλαυκóς due to disease might have had a gray cataract in the Hippocratic era, or, in the early Common Era, the greenish pupillary hue sometimes seen in angle-closure glaucoma. Research Eye drops vs. other treatments The TAGS randomised controlled trial investigated if eye drops or trabeculectomy is more effective in treating advanced primary open-angle glaucoma. After two years researchers found that vision and quality of life are similar in both treatments. At the same time eye pressure was lower in people who underwent surgery and in the long-run surgery is more cost-effective.The LiGHT trial compared the effectiveness of eye drops and selective laser trabeculoplasty for open angle glaucoma. Both contributed to a similar quality of life but most people undergoing laser treatment were able to stop using eye drops. Laser trabeculoplasty was also shown to be more cost-effective. Rho kinase inhibitors Rho kinase inhibitors, such as ripasudil, work by inhibition of the actin cytoskeleton, resulting in the morphological changes in the trabecular meshwork and increased aqueous outflow. More compounds in this class are being investigated in phase 2 and phase 3 trials. Neuroprotective agents A 2013 Cochrane Systematic Review compared the effect of brimonidine and timolol in slowing the progression of open angle glaucoma in adult participants. The results showed that participants assigned to brimonidine showed less visual field progression than those assigned to timolol, though the results were not significant, given the heavy loss-to-followup and limited evidence. The mean intraocular pressures for both groups were similar. Participants in the brimonidine group had a higher occurrence of side effects caused by medication than participants in the timolol group. Cannabis Studies in the 1970s reported that the use of cannabis may lower intraocular pressure. In an effort to determine whether marijuana, or drugs derived from it, might be effective as a glaucoma treatment, the US National Eye Institute supported research studies from 1978 to 1984. These studies demonstrated some derivatives of marijuana lowered intraocular pressure when administered orally, intravenously, or by smoking, but not when topically applied to the eye. In 2003, the American Academy of Ophthalmology released a position statement stating that cannabis was not more effective than prescription medications. Furthermore, no scientific evidence has been found that demonstrates increased benefits and/or diminished risks of cannabis use to treat glaucoma compared with the wide variety of pharmaceutical agents now available.In 2010 the American Glaucoma Society published a position paper discrediting the use of cannabis as a legitimate treatment for elevated intraocular pressure, for reasons including short duration of action and side effects that limit many activities of daily living. Health disparities in glaucoma In diagnosis A study conducted in UK showed that people living in an area of high deprivation were likely to be diagnosed in the later stage of the disease. It also showed that there were lack of professional ophthalmic services in the area of high deprivation. In treatment A study in 2017 shows that there is a huge difference in the volume of glaucoma testing depending on the type of insurance in the US. Researchers reviewed 21,766 persons age ≥ 40 years old with newly diagnosed open-angle glaucoma (OAG) and found that Medicaid recipients had substantially lower volume of glaucoma testing performed compared to patients with commercial health insurance. In research and clinical trials Results from a meta-analysis of 33,428 primary open-angle glaucoma (POAG) participants published in 2021 suggest that there are substantial ethnic and racial disparities in clinical trials in the US. Although ethnic and racial minorities have a higher disease burden, the 70.7% of the study participants was White as opposed to 16.8% Black and 3.4% Hispanic/Latino. References External links Glaucoma at Curlie GeneReview/NCBI/NIH/UW entry on Primary Congenital Glaucoma

Adolescent idiopathic scoliosis

Adolescent idiopathic scoliosis is a rather common disorder in which the spine starts abnormally curving (scoliosis) at the age of 10–18 years old. This disorder generally occurs during the growth spurt that occurs right before and during adolescence. In some teens, the curvature is progressive, meaning that it generally gets worse over time, however this is rare, since it is more common for this variant of scoliosis to show itself as a mild curvature. Causes The cause of this disorder in most teens is generally unknown. Although it is thought to be caused by both genetic and environmental factors.For example, 30% (3 in 10) of teens with the disorder have a family history of AIS, but even then, a common genetic cause for this condition has not been found. Epidemiology This condition affects between 1-4% of teens (1 in 100–1 in 25). But only 0.25% (1 in 400) of them need treatment for it. And an even smaller portion of them die prematurely due to a severe curvature. and the symptoms it causes.Although mild curvatures affect females and males equally (incidence-wise), severe curvatures tend to affect female teens more than male teens (also incidence-wise). == References ==

Medulloblastoma

Medulloblastoma is a common type of primary brain cancer in children. It originates in the part of the brain that is towards the back and the bottom, on the floor of the skull, in the cerebellum, or posterior fossa.The brain is divided into two main parts, the larger cerebrum on top and the smaller cerebellum below towards the back. They are separated by a membrane called the tentorium. Tumors that originate in the cerebellum or the surrounding region below the tentorium are, therefore, called infratentorial. Historically medulloblastomas have been classified as a primitive neuroectodermal tumor (PNET), but it is now known that medulloblastoma is distinct from supratentorial PNETs and they are no longer considered similar entities.Medulloblastomas are invasive, rapidly growing tumors that, unlike most brain tumors, spread through the cerebrospinal fluid and frequently metastasize to different locations along the surface of the brain and spinal cord. Metastasis all the way down to the cauda equina at the base of the spinal cord is termed "drop metastasis". The cumulative relative survival rate for all age groups and histology follow-up was 60%, 52%, and 47% at 5 years, 10 years, and 20 years, respectively, with children doing better than adults. Signs and symptoms Signs and symptoms are mainly due to secondary increased intracranial pressure due to blockage of the fourth ventricle and tumors are usually present for 1 to 5 months before diagnosis is made. The child typically becomes listless, with repeated episodes of vomiting, and a morning headache, which may lead to a misdiagnosis of gastrointestinal disease or migraine. Soon after, the child will develop a stumbling gait, truncal ataxia, frequent falls, diplopia, papilledema, and sixth cranial nerve palsy. Positional vertigo and nystagmus are also frequent, and facial sensory loss or motor weakness may be present. Decerebrate attacks appear late in the disease. Extraneural metastasis to the rest of the body is rare, and when it occurs, it is in the setting of relapse, more commonly in the era prior to routine chemotherapy. Pathogenesis Medulloblastomas are usually found in the vicinity of the fourth ventricle, between the brainstem and the cerebellum. Tumors with similar appearance and characteristics originate in other parts of the brain, but they are not identical to medulloblastoma.Although medulloblastomas are thought to originate from immature or embryonal cells at their earliest stage of development, the cell of origin depends on the subgroup of medulloblastoma. WNT tumors originate from the lower rhombic lip of the brainstem, while SHH tumors originate from the external granular layer.Currently, medulloblastomas are thought to arise from cerebellar stem cells that have been prevented from dividing and differentiating into their normal cell types. This accounts for the histologic variants seen on biopsy. Both perivascular pseudorosette and Homer Wright pseudorosette formations are highly characteristic of medulloblastomas and are seen in up to half of cases. The classic rosette with tumor cells around a central lumen can be seen.In the past, medulloblastoma was classified using histology, but recent integrated genomic studies have revealed that medulloblastoma is composed of four distinct molecular and clinical variants termed WNT/β-catenin, Sonic Hedgehog, Group 3, and Group 4. Of these subgroups, WNT patients have an excellent prognosis and group 3 patients have a poor prognosis. Also, a subgroup-specific alternative splicing further confirms the existence of distinct subgroups and highlights the transcriptional heterogeneity between subgroups. Amplification of the Sonic Hedgehog pathway is the best characterized subgroup, with 25% of human tumors having mutations in Patched, Sufu (Suppressor of Fused Homolog), Smoothened, or other genes in this pathway. Medulloblastomas are also seen in Gorlin syndrome as well as Turcot syndrome. Recurrent mutations in the genes CTNNB1, PTCH1, MLL2, SMARCA4, DDX3X, CTDNEP1, KDM6A, and TBR1 were identified in individuals with medulloblastoma. Additional pathways disrupted in some medulloblastomas include MYC, Notch, BMP, and TGF-β signaling pathways. Diagnosis The tumor is distinctive on T1- and T2-weighted MRI with heterogeneous enhancement and a typical location adjacent to and extension into the fourth ventricle. Histologically, the tumor is solid, pink-gray in color, and is well circumscribed. The tumor is very cellular, with high mitotic activity, little cytoplasm, and a tendency to form clusters and rosettes. The Chang staging system can be used in making the diagnosis [1]. Correct diagnosis of medulloblastoma may require ruling out atypical teratoid rhabdoid tumor. Treatment Treatment begins with maximal surgical removal of the tumor. The addition of radiation to the entire neuraxis and chemotherapy may increase the disease-free survival. Some evidence indicates that proton beam irradiation reduces the impact of radiation on the cochlear and cardiovascular areas and reduces the cognitive late effects of cranial irradiation. This combination may permit a 5-year survival in more than 80% of cases. The presence of desmoplastic features such as connective tissue formation offers a better prognosis. Prognosis is worse if the child is less than 3 years old, degree of resection is inadequate, or if any CSF, spinal, supratentorial, or systemic spread occurs. Dementia after radiotherapy and chemotherapy is a common outcome appearing two to four years following treatment. Side effects from radiation treatment can include cognitive impairment, psychiatric illness, bone growth retardation, hearing loss, and endocrine disruption. Increased intracranial pressure may be controlled with corticosteroids or a ventriculoperitoneal shunt. A new approach to monitor tumor development and treatment response by liquid biopsy is promising, but remains challenging. Chemotherapy Chemotherapy is often used as part of treatment. Evidence of benefit, however, is not clear as of 2013. A few different chemotherapeutic regimens for medulloblastoma are used; most involve a combination of lomustine, cisplatin, carboplatin, vincristine, or cyclophosphamide. In younger patients (less than 3–4 years of age), chemotherapy can delay, or in some cases possibly even eliminate, the need for radiotherapy. However, both chemotherapy and radiotherapy often have long-term toxicity effects, including delays in physical and cognitive development, higher risk of second cancers, and increased cardiac disease risks. Outcomes Array-based karyotyping of 260 medulloblastomas resulted in the following clinical subgroups based on cytogenetic profiles: Poor prognosis: gain of 6q or amplification of MYC or MYCN Intermediate: gain of 17q or an i(17q) without gain of 6q or amplification of MYC or MYCN Excellent prognosis: 6q and 17q balanced or 6q deletionTranscriptional profiling shows the existence of four main subgroups (Wnt, Shh, Group 3, and Group 4). Very good prognosis: WNT group, CTNNB1 mutation Infants good prognosis, others intermediate: SHH group, PTCH1/SMO/SUFU mutation, GLI2 amplification, or MYCN amplification Poor prognosis: Group 3, MYC amplification, photoreceptor/GABAergic gene expression Intermediate prognosis: Group 4, gene expression of neuronal/glutamatergic, CDK6 amplification, MYCN amplification Survival The historical cumulative relative survival rate for all age groups and histology follow-up was 60%, 52%, and 47% at 5 years, 10 years, and 20 years, respectively. Patients diagnosed with a medulloblastoma or PNET are 50 times more likely to die than a matched member of the general population. The most recent population-based (SEER) 5-year relative survival rates are 69% overall: 72% in children (1–9 years) and 67% in adults (20+ years). The 20-year survival rate is 51% in children. Children and adults have different survival profiles, with adults faring worse than children only after the fourth year after diagnosis (after controlling for increased background mortality). Before the fourth year, survival probabilities are nearly identical. Long-term sequelae of standard treatment include hypothalamic-pituitary and thyroid dysfunction and intellectual impairment. The hormonal and intellectual deficits created by these therapies causes significant impairment of the survivors.In current clinical studies, the patients are divided into low-, standard- and high-risk groups: Depending on the study, healing rates of up to 100% are achieved in the low-risk group (usually WNT-activated). The current efforts are therefore moving in the direction of reducing the intensity of the therapy and thus the negative long-term consequences while confirming the high healing rates. In the HIT-SIOP PNET 4 study, in which 340 children and adolescents of the standard-risk group between the ages of four and 21 from several European countries participated, the 5-year survival rate was between 85% and 87% depending on the randomization. Around 78% of the patients remained without relapse for 5 years and are therefore considered to be cured. After a relapse, the prognosis was very poor. Despite intensive treatment, only four of 66 patients were still alive 5 years after a relapse. A US study involved 161 patients between the ages of three and 21 with a high-risk profile. Depending on the randomization, half of the patients additionally received carboplatin daily during the radiation. The 5-year survival rate of patients with carboplatin was 82%, those without 68%. The European SIOP PNET 5 study is currently taking place and will run until April 2024, in which an attempt is made to confirm the promising results with carboplatin during irradiation in the standard risk group. Epidemiology Medulloblastomas affect just under two people per million per year, and affect children 10 times more than adults. Medulloblastoma is the second-most frequent brain tumor in children after pilocytic astrocytoma and the most common malignant brain tumor in children, comprising 14.5% of newly diagnosed brain tumors. In adults, medulloblastoma is rare, comprising fewer than 2% of CNS malignancies.The rate of new cases of childhood medulloblastoma is higher in males (62%) than females (38%), a feature that is not seen in adults. Medulloblastoma and other PNET`s are more prevalent in younger children than older children. About 40% of medulloblastoma patients are diagnosed before the age of five, 31% are between the ages of 5 and 9, 18.3% are between the ages of 10 and 14, and 12.7% are between the ages of 15 and 19. Research models Using gene transfer of SV40 large T-antigen in neuronal precursor cells of rats, a brain tumor model was established. The PNETs were histologically indistinguishable from the human counterparts and have been used to identify new genes involved in human brain tumor carcinogenesis. The model was used to confirm p53 as one of the genes involved in human medulloblastomas, but since only about 10% of the human tumors showed mutations in that gene, the model can be used to identify the other binding partners of SV40 Large T- antigen, other than p53. Recently a SHH-type mouse model with high incidence of medulloblastoma, a Patched 1 heterozygous mice knockout for the medulloblastoma suppressor Tis21 (Patched1+-/Tis21 KO). The high medulloblastoma frequency appears to be caused by the down regulation of Cxcl3, being Cxcl3 induced by Tis21. Consistently, the treatment with Cxcl3 completely prevents the growth of medulloblastoma lesions in a Shh-type mouse model of medulloblastoma. Thus, CXCL3 is a target for medulloblastoma therapy. References External links Brain and Spinal Tumors: Hope Through Research (National Institute of Neurological Disorders and Stroke) Medulloblastoma Images MedPix Medical Image Database

Normal pressure hydrocephalus

Normal-pressure hydrocephalus (NPH), also called malresorptive hydrocephalus, is a form of communicating hydrocephalus in which excess cerebrospinal fluid (CSF) occurs in the ventricles, and with normal or slightly elevated cerebrospinal fluid pressure. As the fluid builds up, it causes the ventricles to enlarge and the pressure inside the head to increase, compressing surrounding brain tissue and leading to neurological complications. The disease presents in a classic triad of symptoms, which are memory impairment, urinary frequency, and balance problens/gait deviations (note: this diagnosis method is obsolete). The disease was first described by Salomón Hakim and Adams in 1965.The treatment is surgical placement of a ventriculoperitoneal shunt to drain excess CSF into the lining of the abdomen where the CSF will eventually be absorbed. NPH is often misdiagnosed as other conditions including Parkinsons disease (due to gait) or Alzheimers disease (due to cognitive dysfunction). Signs and symptoms NPH exhibits a classic triad of clinical findings (known as the Adams triad or Hakims triad). The triad consists of walking difficulty, reduced attention span, and urinary frequency or incontinence. The triad is considered obsolete for diagnosis purposes and newer guidelines are available.Gait deviations are present in nearly all patients and usually the first symptom. This is caused by expansion of the lateral ventricles to impinge on the corticospinal tract motor fibers. The typical gait abnormality in NPH is a broad-based, slow, short-stepped, "stuck to the floor", or "magnetic" movement. The gait abnormalities in NPH may bear resemblance to a gait associated with Parkinsons disease. The gait deviation can be classified as mild, marked, or severe: "marked" is when the patient has difficulty walking because of considerable instability; "severe" is when it is not possible for the patient to walk without aids (such as a cane or a wheeled walker).Dementia presents as progressive cognitive impairment which is present in 60% of patients at time of treatment. This is caused by distortions predominantly at the frontal lobe and the subcortex. Initial deficits involve planning, organization, attention, and concentration. Further deficits include difficulty managing finances, taking medications, driving, keeping track of appointments, daytime sleeping, short-term memory impairments, and psychomotor slowing. Late stage features include apathy, reduced drive, slowed thinking, and reduced speech. Urinary incontinence appears late in the illness, and is present in 50% of patients at time of treatment. Urinary dysfunction begins as increased frequency often at night, and progresses to urge incontinence and permanent incontinence. Pathogenesis Every day, the body makes roughly 600–700 ml of CSF, and about the same amount is reabsorbed into the bloodstream. Hydrocephalus is due to an imbalance between the amount of fluid produced and its absorption rate. Enlarged ventricles put increased pressure on the adjacent cortical tissue and cause myriad effects in the patient, including distortion of the fibers in the corona radiata. This leads to an increase in intracranial pressure (ICP). The ICP gradually falls, but still remains slightly elevated, and the CSF pressure reaches a high normal level of 150 to 200 mm H2O. Measurements of ICP, therefore, are not usually elevated. Because of this, patients do not exhibit the classic signs that accompany increased intracranial pressure such as headache, nausea, vomiting, or altered consciousness, although some studies have shown pressure elevations to occur intermittently.The exact pathogenesis is unknown, but consensus on some mechanisms include: An imbalance exists between production and resorption of CSF. The resistance to CSF outflow is often elevated. The disease is not caused by overproduction of CSF or obstruction of CSF flow at the ventricles.The syndrome is often divided into two groups, primary (also called idiopathic) and secondary, based on cause. The underlying etiology of primary NPH has not yet been identified. Primary NPH affects adults age 40 years or older, most commonly affecting the elderly. Secondary NPH can affect persons of any age and occurs due to conditions such as subarachnoid hemorrhage, meningitis, brain surgery, brain radiation, or traumatic brain injury. Diagnosis Patients with suspected NPH should have typical symptoms in addition to ventricular enlargement on neuroimaging. The international evidenced-based diagnostic criteria for primary NPH are: Gradual onset after age 40 years, symptoms duration of ≥ 3–6 months, clinical evidence of gait or balance impairment, and impairment of cognition or urinary incontinence Imaging from magnetic resonance imaging (MRI) or computed tomography (CT) is needed to demonstrate enlarged ventricles and no macroscopic obstruction to cerebrospinal fluid flow. Imaging should show an enlargement to at least one of the temporal horns of lateral ventricles, and impingement against the falx cerebri resulting in a callosal angle ≤ 90° on the coronal view, showing evidence of altered brain water content, or normal active flow (which is referred to as "flow void") at the cerebral aqueduct and fourth ventricle.MRI scans are the preferred imaging. The distinction between normal and enlarged ventricular size by cerebral atrophy is difficult to ascertain. Up to 80% of cases are unrecognized and untreated due to difficulty of diagnosis. Imaging should also reveal the absence of any cerebral mass lesions or any signs of obstructions. Although all patients with NPH have enlarged ventricles, not all elderly patients with enlarged ventricles have primary NPH. Cerebral atrophy can cause enlarged ventricles, as well, and is referred to as hydrocephalus ex vacuo. The Miller Fisher test involves a high-volume lumbar puncture (LP) with removal of 30–50 ml of CSF. Gait and cognitive function are typically tested just before and within 2–3 hours after the LP to assess for signs of symptomatic improvement. The CSF infusion test and the lumbar test are similar tests to Miller Fisher test. The tests have a positive predictive value over 90%, but a negative predictive value less than 50%. The LP should show normal or mildly elevated CSF pressure. CSF should have normal cell contents, glucose levels, and protein levels. Treatment Ventriculoperitoneal shunts For suspected cases of NPH, CSF shunting is the first-line treatment. The most common type used to treat NPH is ventriculoperitoneal (VP) shunts, which drain CSF fluid to the peritoneal cavity. Adjustable valves allow fine-tuning of CSF drainage. NPH symptoms reportedly improve in 70–90% of patients with CSF shunt. Risk-benefit analyses have shown beyond any doubt that surgery for NPH is far better than conservative treatment or the natural course.Gait symptoms improve in ≥ 85% patients. Cognitive symptoms improve in up to 80% of patients when surgery is performed early in the disease course. Urgency and incontinence improves in up to 80% of patients, but only in ≤ 50–60% of patients with shunt implanted late in disease course. The most likely patients to show improvement are those who show only gait deviation, mild or no incontinence, and mild dementia. The risk of adverse events related to shunt placement is 11%, including shunt failure, infections such as ventriculitis, shunt obstruction, over- or under-drainage, and development of a subdural hematoma. Medications No medications are effective for primary NPH. Acetazolamide and other diuretics are not recommended except for limited use in patients who are not candidates for placement of a shunt. Epidemiology The majority of cases are primary NPH. Incidence is estimated to 0.3–3% in patients older than 60 years and raising with older age Its prevalence is reported to be less than 1% in persons under the age of 65, and up to 3% for persons aged 65 or older. No difference in incidence is seen between men and women. Among individuals with dementia, the incidence of NPH is thought to be between 2 and 6%. See also Low pressure hydrocephalus References External links The Normal Pressure Hydrocephalus Center at Johns Hopkins Bayview Medical Center Normal Pressure Hydrocephalus at Cleveland Clinic normal_pressure_hydrocephalus at NINDS When it really is NPH at Likvor Hydrocephalus in Adults at Spina Bifida Resource Center

Abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a localized enlargement of the abdominal aorta such that the diameter is greater than 3 cm or more than 50% larger than normal. They usually cause no symptoms, except during rupture. Occasionally, abdominal, back, or leg pain may occur. Large aneurysms can sometimes be felt by pushing on the abdomen. Rupture may result in pain in the abdomen or back, low blood pressure, or loss of consciousness, and often results in death.AAAs occur most commonly in those over 50 years old, in men, and among those with a family history. Additional risk factors include smoking, high blood pressure, and other heart or blood vessel diseases. Genetic conditions with an increased risk include Marfan syndrome and Ehlers–Danlos syndrome. AAAs are the most common form of aortic aneurysm. About 85% occur below the kidneys with the rest either at the level of or above the kidneys. In the United States, screening with abdominal ultrasound is recommended for males between 65 and 75 years of age with a history of smoking. In the United Kingdom and Sweden, screening all men over 65 is recommended. Once an aneurysm is found, further ultrasounds are typically done on a regular basis.Abstinence from cigarette smoking is the single best way to prevent the disease. Other methods of prevention include treating high blood pressure, treating high blood cholesterol, and avoiding being overweight. Surgery is usually recommended when the diameter of an AAA grows to >5.5 cm in males and >5.0 cm in females. Other reasons for repair include the presence of symptoms and a rapid increase in size, defined as more than one centimeter per year. Repair may be either by open surgery or endovascular aneurysm repair (EVAR). As compared to open surgery, EVAR has a lower risk of death in the short term and a shorter hospital stay, but may not always be an option. There does not appear to be a difference in longer-term outcomes between the two. Repeat procedures are more common with EVAR.AAAs affect 2-8% of males over the age of 65. They are five times more common in men. In those with an aneurysm less than 5.5 cm, the risk of rupture in the next year is below 1%. Among those with an aneurysm between 5.5 and 7 cm, the risk is about 10%, while for those with an aneurysm greater than 7 cm the risk is about 33%. Mortality if ruptured is 85% to 90%. During 2013, aortic aneurysms resulted in 168,200 deaths, up from 100,000 in 1990. In the United States AAAs resulted in between 10,000 and 18,000 deaths in 2009. Signs and symptoms The vast majority of aneurysms are asymptomatic. However, as the abdominal aorta expands and/or ruptures, the aneurysm may become painful and lead to pulsating sensations in the abdomen or pain in the chest, lower back, legs, or scrotum. Complications The complications include rupture, peripheral embolization, acute aortic occlusion, and aortocaval (between the aorta and inferior vena cava) or aortoduodenal (between the aorta and the duodenum) fistulae. On physical examination, a palpable and pulsatile abdominal mass can be noted. Bruits can be present in case of renal or visceral arterial stenosis.The signs and symptoms of a ruptured AAA may include severe pain in the lower back, flank, abdomen or groin. A mass that pulses with the heart beat may also be felt. The bleeding can lead to a hypovolemic shock with low blood pressure and a fast heart rate, which may cause fainting. The mortality of AAA rupture is as high as 90 percent. 65 to 75 percent of patients die before they arrive at the hospital and up to 90 percent die before they reach the operating room. The bleeding can be retroperitoneal or into the abdominal cavity. Rupture can also create a connection between the aorta and intestine or inferior vena cava. Flank ecchymosis (appearance of a bruise) is a sign of retroperitoneal bleeding and is also called Grey Turners sign. Causes The exact causes of the degenerative process remain unclear. There are, however, some hypotheses and well-defined risk factors. Tobacco smoking: More than 90% of people who develop an AAA have smoked at some point in their lives. Alcohol and hypertension: The inflammation caused by prolonged use of alcohol and hypertensive effects from abdominal edema which leads to hemorrhoids, esophageal varices, and other conditions, is also considered a long-term cause of AAA. Genetic influences: The influence of genetic factors is high. AAA is four to six times more common in male siblings of known patients, with a risk of 20–30%. The high familial prevalence rate is most notable in male individuals. There are many hypotheses about the exact genetic disorder that could cause higher incidence of AAA among male members of the affected families. Some presumed that the influence of alpha 1-antitrypsin deficiency could be crucial, while other experimental works favored the hypothesis of X-linked mutation, which would explain the lower incidence in heterozygous females. Other hypotheses of genetic causes have also been formulated. Connective tissue disorders, such as Marfan syndrome and Ehlers-Danlos syndrome, have also been strongly associated with AAA. Both relapsing polychondritis and pseudoxanthoma elasticum may cause abdominal aortic aneurysm. Atherosclerosis: The AAA was long considered to be caused by atherosclerosis, because the walls of the AAA frequently carry an atherosclerotic burden. However, this hypothesis cannot be used to explain the initial defect and the development of occlusion, which is observed in the process. Other causes of the development of AAA include: infection, trauma, arteritis, and cystic medial necrosis. Pathophysiology The most striking histopathological changes of the aneurysmatic aorta are seen in the tunica media and intima layers. These changes include the accumulation of lipids in foam cells, extracellular free cholesterol crystals, calcifications, thrombosis, and ulcerations and ruptures of the layers. Adventitial inflammatory infiltrate is present. However, the degradation of the tunica media by means of a proteolytic process seems to be the basic pathophysiologic mechanism of AAA development. Some researchers report increased expression and activity of matrix metalloproteinases in individuals with AAA. This leads to elimination of elastin from the media, rendering the aortic wall more susceptible to the influence of blood pressure. Other reports have suggested the serine protease granzyme B may contribute to aortic aneurysm rupture through the cleavage of decorin, leading to disrupted collagen organization and reduced tensile strength of the adventitia. There is also a reduced amount of vasa vasorum in the abdominal aorta (compared to the thoracic aorta); consequently, the tunica media must rely mostly on diffusion for nutrition, which makes it more susceptible to damage.Hemodynamics affect the development of AAA, which has a predilection for the infrarenal aorta. The histological structure and mechanical characteristics of the infrarenal aorta differ from those of the thoracic aorta. The diameter decreases from the root to the aortic bifurcation, and the wall of the infrarenal aorta also contains a lesser proportion of elastin. The mechanical tension in the abdominal aortic wall is therefore higher than in the thoracic aortic wall. The elasticity and distensibility also decline with age, which can result in gradual dilatation of the segment. Higher intraluminal pressure in patients with arterial hypertension markedly contributes to the progression of the pathological process. Suitable hemodynamic conditions may be linked to specific intraluminal thrombus (ILT) patterns along the aortic lumen, which in turn may affect AAAs development. Diagnosis An abdominal aortic aneurysm is usually diagnosed by physical exam, abdominal ultrasound, or CT scan. Plain abdominal radiographs may show the outline of an aneurysm when its walls are calcified. However, the outline will be visible by X-ray in less than half of all aneurysms. Ultrasonography is used to screen for aneurysms and to determine their size if present. Additionally, free peritoneal fluid can be detected. It is noninvasive and sensitive, but the presence of bowel gas or obesity may limit its usefulness. CT scan has nearly 100% sensitivity for an aneurysm and is also useful in preoperative planning, detailing the anatomy and possibility for endovascular repair. In the case of suspected rupture, it can also reliably detect retroperitoneal fluid. Alternative less often used methods for visualization of an aneurysm include MRI and angiography.An aneurysm ruptures if the mechanical stress (tension per area) exceeds the local wall strength; consequently, peak wall stress (PWS) and peak wall rupture risk (PWRR) have been found to be more reliable parameters than diameter to assess AAA rupture risk. Medical software allows computing these rupture risk indices from standard clinical CT data and provides a patient-specific AAA rupture risk diagnosis. This type of biomechanical approach has been shown to accurately predict the location of AAA rupture. Classification Abdominal aortic aneurysms are commonly divided according to their size and symptomatology. An aneurysm is usually defined as an outer aortic diameter over 3 cm (normal diameter of the aorta is around 2 cm), or more than 50% of normal diameter. If the outer diameter exceeds 5.5 cm, the aneurysm is considered to be large. Ruptured AAA should be suspected in any person older than 60 who experiences collapse, unexplained low blood pressure, or sudden-onset back or abdominal pain. Abdominal pain, shock, and a pulsatile mass is only present in a minority of cases. Although an unstable person with a known aneurysm may undergo surgery without further imaging, the diagnosis will usually be confirmed using CT or ultrasound scanning.The suprarenal aorta normally measures about 0.5 cm larger than the infrarenal aorta. Differential diagnosis Aortic aneurysm rupture may be mistaken for the pain of kidney stones, or muscle related back pain. Prevention Smoking cessation Treatment of hypertension Screening The U.S. Preventive Services Task Force (USPSTF) recommends a single screening abdominal ultrasound for abdominal aortic aneurysm in males age 65 to 75 years who have a history of smoking. Among this group who does not smoke, screening may be selective. It is unclear if screening is useful in women who have smoked and the USPSTF recommend against screening in women who have never smoked.In the United Kingdom the NHS AAA Screening Programme invites men in England for screening during the year they turn 65. Men over 65 can contact the programme to arrange to be screened.In Sweden one time screening is recommended in all males over 65 years of age. This has been found to decrease the risk of death from AAA by 42% with a number needed to screen of just over 200. In those with a close relative diagnosed with an aortic aneurysm, Swedish guidelines recommend an ultrasound at around 60 years of age.Australia has no guideline on screening.Repeat ultrasounds should be carried out in those who have an aortic size greater than 3.0 cm. In those whose aorta is between 3.0 and 3.9 cm this should be every three years, if between 4.0 and 4.4 cm every two years, and if between 4.5 and 5.4 cm every year. Management The treatment options for asymptomatic AAA are conservative management, surveillance with a view to eventual repair, and immediate repair. Two modes of repair are available for an AAA: open aneurysm repair, and endovascular aneurysm repair (EVAR). An intervention is often recommended if the aneurysm grows more than 1 cm per year or it is bigger than 5.5 cm. Repair is also indicated for symptomatic aneurysms. Ten years after open AAA repair, the overall survival rate was 59%. Mycotic abdominal aorta aneurysm (MAAA) is a rare and life-threatening condition. Because of its rarity, there is a lack of adequately powered studies and consensus on its treatment and follow up. A management protocol on the management of mycotic abdominal aortic aneurysm was recently published in the Annals of Vascular Surgery by Premnath et al. Conservative Conservative management is indicated in people where repair carries a high risk of mortality and in patients where repair is unlikely to improve life expectancy. The mainstay of the conservative treatment is smoking cessation.Surveillance is indicated in small asymptomatic aneurysms (less than 5.5 cm) where the risk of repair exceeds the risk of rupture. As an AAA grows in diameter, the risk of rupture increases. Surveillance until an aneurysm has reached a diameter of 5.5 cm has not been shown to have a higher risk as compared to early intervention. Medication No medical therapy has been found to be effective at decreasing the growth rate or rupture rate of asymptomatic AAAs. Blood pressure and lipids should, however, be treated per usual. Surgery The threshold for repair varies slightly from individual to individual, depending on the balance of risks and benefits when considering repair versus ongoing surveillance. The size of an individuals native aorta may influence this, along with the presence of comorbidities that increase operative risk or decrease life expectancy. Evidence, however, does not usually support repair if the size is less than 5.5 cm. Open repair Open repair is indicated in young patients as an elective procedure, or in growing or large, symptomatic or ruptured aneurysms. The aorta must be clamped during the repair, denying blood to the abdominal organs and sections of the spinal cord; this can cause a range of complications. As it is essential to perform the critical part of the operation quickly, the incision is typically made large enough to facilitate the fastest repair. Recovery after open AAA surgery takes significant time. The minimums are a few days in intensive care, a week total in the hospital and a few months before full recovery. Endovascular repair Endovascular repair first became practical in the 1990s and although it is now an established alternative to open repair, its role is yet to be clearly defined. It is generally indicated in older, high-risk patients or patients unfit for open repair. However, endovascular repair is feasible for only a portion of AAAs, depending on the morphology of the aneurysm. The main advantages over open repair are that there is less peri-operative mortality, less time in intensive care, less time in hospital overall and earlier return to normal activity. Disadvantages of endovascular repair include a requirement for more frequent ongoing hospital reviews and a higher chance of further required procedures. According to the latest studies, the EVAR procedure does not offer any benefit for overall survival or health-related quality of life compared to open surgery, although aneurysm-related mortality is lower. In patients unfit for open repair, EVAR plus conservative management was associated with no benefit, more complications, subsequent procedures and higher costs compared to conservative management alone. Endovascular treatment for paraanastomotic aneurysms after aortobiiliac reconstruction is also a possibility. A 2017 Cochrane review found tentative evidence of no difference in outcomes between endovascular and open repair of ruptured AAA in the first month. Rupture In those with aortic rupture of the AAA, treatment is immediate surgical repair. There appear to be benefits to allowing permissive hypotension and limiting the use of intravenous fluids during transport to the operating room. Prognosis Although the current standard of determining rupture risk is based on maximum diameter, it is known that smaller AAAs that fall below this threshold (diameter<5.5 cm) may also rupture, and larger AAAs (diameter>5.5 cm) may remain stable. In one report, it was shown that 10–24% of ruptured AAAs were less than 5 cm in diameter. It has also been reported that of 473 non-repaired AAAs examined from autopsy reports, there were 118 cases of rupture, 13% of which were less than 5 cm in diameter. This study also showed that 60% of the AAAs greater than 5 cm (including 54% of those AAAs between 7.1 and 10 cm) never experienced rupture. Vorp et al. later deduced from the findings of Darling et al. that if the maximum diameter criterion were followed for the 473 subjects, only 7% (34/473) of cases would have died from rupture prior to surgical intervention as the diameter was less than 5 cm, with 25% (116/473) of cases possibly undergoing unnecessary surgery since these AAAs may never have ruptured.Alternative methods of rupture assessment have been recently reported. The majority of these approaches involve the numerical analysis of AAAs using the common engineering technique of the finite element method (FEM) to determine the wall stress distributions. Recent reports have shown that these stress distributions have been shown to correlate to the overall geometry of the AAA rather than solely to the maximum diameter. It is also known that wall stress alone does not completely govern failure as an AAA will usually rupture when the wall stress exceeds the wall strength. In light of this, rupture assessment may be more accurate if both the patient-specific wall stress is coupled together with patient-specific wall strength. A noninvasive method of determining patient-dependent wall strength was recently reported, with more traditional approaches to strength determination via tensile testing performed by other researchers in the field. Some of the more recently proposed AAA rupture-risk assessment methods include: AAA wall stress; AAA expansion rate; degree of asymmetry; presence of intraluminal thrombus (ILT); a rupture potential index (RPI); a finite element analysis rupture index (FEARI); biomechanical factors coupled with computer analysis; growth of ILT; geometrical parameters of the AAA; and also a method of determining AAA growth and rupture based on mathematical models.The postoperative mortality for an already ruptured AAA has slowly decreased over several decades but remains higher than 40%. However, if the AAA is surgically repaired before rupture, the postoperative mortality rate is substantially lower, approximately 1-6%. Epidemiology The occurrence of AAA varies by ethnicity. In the United Kingdom, the rate of AAA in Caucasian men older than 65 years is about 4.7%, while in Asian men it is 0.45%. It is also less common in individuals of African, and Hispanic heritage. They occur four times more often in men than in women.There are at least 13,000 deaths yearly in the U.S. secondary to AAA rupture. The peak number of new cases per year among males is around 70 years of age, and the percentage of males affected over 60 years is 2–6%. The frequency is much higher in smokers than in non-smokers (8:1), and the risk decreases slowly after smoking cessation. In the U.S., the incidence of AAA is 2–4% in the adult population.Rupture of the AAA occurs in 1–3% of men aged 65 or more, for whom the mortality rate is 70–95%. History The first historical records about AAA are from Ancient Rome in the 2nd century AD, when Greek surgeon Antyllus tried to treat the AAA with proximal and distal ligature, central incision and removal of thrombotic material from the aneurysm. However, attempts to treat the AAA surgically were unsuccessful until 1923. In that year, Rudolph Matas (who also proposed the concept of endoaneurysmorrhaphy), performed the first successful aortic ligation on a human. Other methods that were successful in treating the AAA included wrapping the aorta with polyethene cellophane, which induced fibrosis and restricted the growth of the aneurysm. Endovascular aneurysm repair was first performed in the late 1980s and has been widely adopted in the subsequent decades. Endovascular repair was first used for treating a ruptured aneurysm in Nottingham in 1994. Society and culture Theoretical physicist Albert Einstein underwent an operation for an abdominal aortic aneurysm in 1949 that was performed by Rudolph Nissen, who wrapped the aorta with polyethene cellophane. Einsteins aneurysm ruptured on April 13, 1955. He declined surgery, saying, "I want to go when I want. It is tasteless to prolong life artificially. I have done my share, it is time to go. I will do it elegantly." He died five days later at age 76.Actress Lucille Ball died April 26, 1989, from an abdominal aortic aneurysm. At the time of her death, she was in Cedars-Sinai Medical Center recovering from emergency surgery performed just six days earlier because of a dissecting aortic aneurysm near her heart. Ball was at increased risk as she had been a heavy smoker for decades.Musician Conway Twitty died in June 1993 from an abdominal aortic aneurysm at the age of 59, two months before the release of what would be his final studio album, Final Touches.Actor George C. Scott died in 1999 from a ruptured abdominal aortic aneurysm at age 71.In 2001, former presidential candidate Bob Dole underwent surgery for an abdominal aortic aneurysm in which a team led by vascular surgeon Kenneth Ouriel inserted a stent graft: Ouriel said that the team inserted a Y-shaped tube through an incision in Doles leg and placed it inside the weakened portion of the aorta. The aneurysm will eventually contract around the stent, which will remain in place for the rest of Doles life. — Associated Press Actor Robert Jacks, who played Leatherface in Texas Chainsaw Massacre: The Next Generation, died from an abdominal aneurysm on August 8, 2001, one day shy of his 42nd birthday. His father also died from the same cause when Jacks was a child. Actor Tommy Ford died of abdominal aneurysm in October 2016 at 52 years old.Gary Gygax, co-creator of Dungeons and Dragons, died in 2008 from an abdominal aortic aneurysm at the age of 69. Research Risk assessment There have been many calls for alternative approaches to rupture risk assessment over the past number of years, with many believing that a biomechanics-based approach may be more suitable than the current diameter approach. Numerical modeling is a valuable tool to researchers allowing approximate wall stresses to be calculated, thus revealing the rupture potential of a particular aneurysm. Experimental models are required to validate these numerical results and provide a further insight into the biomechanical behavior of the AAA. In vivo, AAAs exhibit a varying range of material strengths from localised weak hypoxic regions to much stronger regions and areas of calcifications.Finding ways to predict future AAA growth is seen as a research priority. Experimental models Experimental models can now be manufactured using a novel technique involving the injection-moulding lost-wax manufacturing process to create patient-specific anatomically correct AAA replicas. Work has also focused on developing more realistic material analogues to those in vivo, and recently a novel range of silicone-rubbers was created allowing the varying material properties of the AAA to be more accurately represented. These rubber models can also be used in a variety of experimental situations, from stress analysis using the photoelastic method New endovascular devices are being developed that are able to treat more complex and tortuous anatomies. Prevention and treatment An animal study showed that removing a single protein prevents early damage in blood vessels from triggering a later-stage, complications. By eliminating the gene for a signaling protein called cyclophilin A (CypA) from a strain of mice, researchers were able to provide complete protection against abdominal aortic aneurysm.Other recent research identified Granzyme B (GZMB) (a protein-degrading enzyme) to be a potential target in the treatment of abdominal aortic aneurysms. Elimination of this enzyme in mice models both slowed the progression of aneurysms and improved survival. Preclinical Research The mechanisms that lead to AAA development are still not completely understood at a cellular and molecular level. In order to better understand the pathophysiology of AAA, it is often necessary to use experimental animal models. It is often questioned how well do these models translate to human disease. Even though there is no animal model that exactly represents the human condition, all the existing ones focus on one different pathophysiological aspect of the disease. Combining the results from different animal models with clinical research can provide a better overview of the AAA pathophysiology. The most common animal models are rodents (mice and rats), although for certain studies, such as testing preclinical devices or surgical procedures, large animal models (pig, sheep) are more frequently used. The rodent models of AAA can be classified according to different aspects. There are dissecting models vs non-dissecting models and genetically determined models vs chemically induced models. The most commonly used models are the angiotensin-II infusion into ApoE knockout mice (dissecting model, chemically induced), the calcium chloride model (non-dissecting, chemically induced) and the elastase model (non-dissecting, chemically induced model). A recent study has shown that β-Aminopropionitrile plus elastase application to abdominal aorta causes more severe aneurysm in mice as compared to elastase alone. References External links Cochrane Peripheral Vascular Diseases Review Group

Prolactinoma

A prolactinoma is a benign tumor (adenoma) of the pituitary gland that produces the hormone prolactin. It is the most common type of functioning pituitary tumor. Symptoms of prolactinoma are due to abnormally high levels of prolactin in the blood (hyperprolactinemia), or due to pressure of the tumor on surrounding tissues. Based on size, a prolactinoma can be classified as a microprolactinoma (<10 mm diameter) or a macroprolactinoma (>10 mm diameter). Signs and symptoms The symptoms due to a prolactinoma are broadly divided into those that are caused by increased prolactin levels or mass effect. Those that are caused by increased prolactin levels are: Amenorrhea (disappearance of ovulation periods) Galactorrhea (Milk production; infrequent in men) Loss of axillary and pubic hair Hypogonadism (Reduced function of the gonads.) Gynecomastia (an increase in male breast size) Erectile dysfunction (in males)Those that are caused by mass effect are: Headaches Vision Changes-visual field deficits, blurred vision, decreased visual acuity Cranial nerve palsies-especially with invasive tumors or with pituitary apoplexy Seizures, Hydrocephalus, Unilateral exophthalmos are rare presentations Hypopituitarism Pituitary apoplexy is a medical emergency because of spontaneous hemorrhage into the pituitary tumor and presents with severe headaches, vision changes, and acute panhypopituitarism. Causes The cause of pituitary tumors remains unknown. Though most pituitary tumors are sporadic, some genetic syndromes include increased risk for pituitary adenomas including Multiple endocrine neoplasia type 1 (caused by a mutation in the MEN1 gene) and Familial isolated pituitary adenoma (FIPA). The majority of moderately raised prolactin levels (up to 5000 mIU/L) are not due to microprolactinomas but other causes. The effects of some prescription drugs are the most common. Other causes are other pituitary tumours and normal pregnancy and breastfeeding. This is discussed more under hyperprolactinaemia.The xenoestrogenic chemical Bisphenol-A has been shown to lead to hyperprolactinaemia and growth of prolactin-producing pituitary cells. The increasing and prolonged exposure of Bisphenol-A from childhood on, may contribute to the growth of a Prolactinoma. Diagnosis A doctor will test for prolactin blood levels in women with unexplained milk secretion (galactorrhea) or irregular menses or infertility, and in men with impaired sexual function and, in rare cases, milk secretion. If prolactin is high, a doctor will test thyroid function and ask first about other conditions and medications known to raise prolactin secretion. The doctor will also request a magnetic resonance imaging (MRI), which is the most sensitive test for detecting pituitary tumors and determining their size. MRI scans may be repeated periodically to assess tumor progression and the effects of therapy. Computed Tomography (CT scan) also gives an image of the pituitary, but it is less sensitive than the MRI.In addition to assessing the size of the pituitary tumor, doctors also look for damage to surrounding tissues and perform tests to assess whether production of other pituitary hormones is normal. Depending on the size of the tumor, the doctor may request an eye exam with measurement of visual fields. Treatments The goal of treatment is to return prolactin secretion to normal, reduce tumor size, correct any visual abnormalities, and restore normal pituitary function. As mentioned above, the impact of stress should be ruled out before the diagnosis of prolactinoma is given. Exercise can significantly reduce stress and, thereby, prolactin levels. In the case of very large tumors, only partial reduction of the prolactin levels may be possible. Medications Dopamine is the chemical that normally inhibits prolactin secretion, so clinicians may treat prolactinoma with drugs that act like dopamine such as bromocriptine and cabergoline. This type of drug is called a dopamine agonist. These drugs shrink the tumor and return prolactin levels to normal in approximately 80% of patients. Both bromocriptine and cabergoline have been approved by the Food and Drug Administration for the treatment of hyperprolactinemia. Bromocriptine is associated with side-effects such as nausea and dizziness and hypotension in patients with already low blood pressure readings. To avoid these side-effects, it is important for bromocriptine treatment to start slowly.Bromocriptine treatment should not be interrupted without consulting a qualified endocrinologist. Prolactin levels often rise again in most people when the drug is discontinued. In some, however, prolactin levels remain normal, so the doctor may suggest reducing or discontinuing treatment every two years on a trial basis. Recent studies have shown increased success in remission of prolactin levels after discontinuation, in patients having been treated for at least 2 years prior to cessation of bromocriptine treatment.Cabergoline is also associated with side effects such as nausea and dizziness, but these may be less common and less severe than with bromocriptine. However, people with low blood pressure should use caution when starting cabergoline treatment, as the long half-life of the drug (4–7 days) may inadvertently affect their ability to keep their blood pressure within normal limits, creating intense discomfort, dizziness, and even fainting upon standing and walking until the single first dose clears from their system. As with bromocriptine therapy, side effects may be avoided or minimized if treatment is started slowly. If a patients prolactin level remains normal for 6 months, a doctor may consider stopping treatment. Cabergoline should not be interrupted without consulting a qualified endocrinologist.Other dopamine agonists that have been used less commonly to suppress prolactin include dihydroergocryptine, ergoloid, lisuride, metergoline, pergolide, quinagolide, and terguride. Surgery Surgery should be considered if medical therapy cannot be tolerated or if it fails to reduce prolactin levels, restore normal reproduction and pituitary function, and reduce tumor size. If medical therapy is only partially successful, this therapy should continue, possibly combined with surgery or radiation treatment.The results of surgery depend a great deal on tumor size and prolactin level. The higher the prolactin level the lower the chance of normalizing serum prolactin. In the best medical centers, surgery corrects prolactin levels in 80% of patients with a serum prolactin less than 250 ng/ml. Even in patients with large tumors that cannot be completely removed, drug therapy may be able to return serum prolactin to the normal range after surgery. Depending on the size of the tumor and how much of it is removed, studies show that 20 to 50% will recur, usually within five years. Prognosis People with microprolactinoma generally have an excellent prognosis. In 95% of cases, the tumor will not show any signs of growth after a 4 to 6-year period.Macroprolactinomas often require more aggressive treatment otherwise they may continue to grow. There is no way to reliably predict the rate of growth, as it is different for every individual. Regular monitoring by a specialist to detect any major changes in the tumor is recommended. Osteoporosis risk Hyperprolactinemia can cause reduced estrogen production in women and reduced testosterone production in men. Although estrogen/testosterone production may be restored after treatment for hyperprolactinemia, even a year or two without estrogen/testosterone can compromise bone strength, and patients should protect themselves from osteoporosis by increasing exercise and calcium intake through diet or supplementation, and by avoiding smoking. Patients may want to have bone density measurements to assess the effect of estrogen/testosterone deficiency on bone density. They may also want to discuss testosterone/estrogen replacement therapy with their physician. Pregnancy and oral birth control If a woman has one or more small prolactinoma, there is no reason that she cannot conceive and have a normal pregnancy after successful medical therapy. The pituitary enlarges and prolactin production increases during normal pregnancy in women without pituitary disorders. Women with prolactin-secreting tumors may experience further pituitary enlargement and must be closely monitored during pregnancy. However, damage to the pituitary or eye nerves occurs in less than one percent of pregnant women with prolactinoma. In women with large tumors, the risk of damage to the pituitary or eye nerves is greater, and some doctors consider it as high as 25%. If a woman has completed a successful pregnancy, the chances of her completing further successful pregnancies are extremely high.A woman with a prolactinoma should discuss her plans to conceive with her physician, so she can be carefully evaluated prior to becoming pregnant. This evaluation will include a magnetic resonance imaging (MRI) scan to assess the size of the tumor and an eye examination with measurement of visual fields. As soon as a patient is pregnant, her doctor will usually advise that she stop taking bromocriptine or cabergoline, the common treatments for prolactinoma. Most endocrinologists see patients every two months throughout the pregnancy. The patient should consult her endocrinologist promptly if she develops symptoms — in particular, headaches, visual changes, nausea, vomiting, excessive thirst or urination, or extreme lethargy. Bromocriptine or cabergoline treatment may be renewed and additional treatment may be required if the patient develops symptoms from growth of the tumor during pregnancy.At one time, oral contraceptives were thought to contribute to the development of prolactinomas. However, this is no longer thought to be true. Patients with prolactinoma treated with bromocriptine or cabergoline may also take oral contraceptives. Likewise, post-menopausal estrogen replacement is safe in patients with prolactinoma treated with medical therapy or surgery. Epidemiology Autopsy studies indicate that 6-25% of the U. S. population have small pituitary tumors. Forty percent of these pituitary tumors produce prolactin, but most are not considered clinically significant. Clinically significant pituitary tumors affect the health of approximately 14 out of 100,000 people. In non-selective surgical series, this tumor accounts for approximately 25-30% of all pituitary adenomas. Some growth hormone (GH)–producing tumors also co-secrete prolactin. Microprolactinomas are much more common than macroprolactinomas. See also Hypothalamic–pituitary–prolactin axis Hyperprolactinaemia References Adapted from Prolactinoma. U. S. National Institutes of Health Publication No. 02-3924 June 2002. Public Domain Source External links Prolactinoma at Curlie

Benign paroxysmal positional vertigo

Benign paroxysmal positional vertigo (BPPV) is a disorder arising from a problem in the inner ear. Symptoms are repeated, brief periods of vertigo with movement, characterized by a spinning sensation upon changes in the position of the head. This can occur with turning in bed or changing position. Each episode of vertigo typically lasts less than one minute. Nausea is commonly associated. BPPV is one of the most common causes of vertigo.BPPV is a type of balance disorder along with labyrinthitis and Ménières disease. It can result from a head injury or simply occur among those who are older. Often, a specific cause is not identified. When found, the underlying mechanism typically involves a small calcified otolith moving around loose in the inner ear. Diagnosis is typically made when the Dix–Hallpike test results in nystagmus (a specific movement pattern of the eyes) and other possible causes have been ruled out. In typical cases, medical imaging is not needed.BPPV is easily treated with a number of simple movements such as the Epley maneuver ( in case of diagonal/rotational nystagmus ), the Lempert maneuver ( in case of horizontal nystagmus ), the deep head hanging maneuver ( in case of vertical nystagmus ) or sometimes the less effective Brandt–Daroff exercises. Medications, including antihistamines such as meclizine, may be used to help with nausea. There is tentative evidence that betahistine may help with vertigo, but its use is not generally needed. BPPV is not a serious medical condition, but may present serious risks of injury through falling or other spatial disorientation-induced accidents. When untreated, it might resolve in days to months; however, it may recur in some people. One can needlessly suffer from BPPV for years despite there being a simple an very effective cure. Short-term self-resolution of BPPV is unlikely because the effective cure maneuvers induce strong vertigo which the patient will naturally resist and not accidentally perform. The first medical description of the condition occurred in 1921 by Róbert Bárány. Approximately 2.4% of people are affected at some point in time. Among those who live until their 80s, 10% have been affected. BPPV affects females twice as often as males. Onset is typically in people between the ages of 50 and 70. Signs and symptoms Symptoms: Paroxysmal—appears suddenly, and in episodes of short duration: lasts only seconds to minutes Positional—is induced by a change in position, even slight Vertigo—a spinning dizziness, which must have a rotational component Torsional nystagmus—a diagnostic symptom where the top of the eye rotates toward the affected ear in a beating or twitching fashion, which has a latency and can be fatigued (vertigo should lessen with deliberate repetition of the provoking maneuver): nystagmus should only last for 30 seconds to one minute Pre-syncope—(feeling faint) or syncope (fainting) is unusual, but possible Visual disturbance—due to associated nystagmus, making it difficult to read or see during an attack Nausea—is often associated Vomiting—is common, depending on the strength of vertigo itself and the causes for this illnessMany people will report a history of vertigo as a result of fast head movements. Many are also capable of describing the exact head movements that provoke their vertigo. Purely horizontal nystagmus and symptoms of vertigo lasting more than one minute can also indicate BPPV occurring in the horizontal semicircular canal. The spinning sensation experienced from BPPV is usually triggered by movement of the head, will have a sudden onset, and can last anywhere from a few seconds to several minutes. The most common movements people report triggering a spinning sensation are tilting their heads upward in order to look at something and when rolling over in bed.People with BPPV do not experience other neurological deficits such as numbness or weakness. If those symptoms are present, a more serious etiology, such as posterior circulation stroke or ischemia, must be considered. The most significant symptom is nystagmus as it is essential to determine the kind of nystagmus ( horizontal, vertical, or diagonal ) to select the correct cure maneuver. Cause Within the labyrinth of the inner ear lie collections of calcium crystals known as otoconia or otoliths. In people with BPPV, the otoconia are dislodged from their usual position within the utricle, and over time, migrate into one of the three semicircular canals (the posterior canal is most commonly affected due to its anatomical position). When the head is reoriented relative to gravity, the gravity-dependent movement of the heavier otoconial debris (colloquially "ear rocks") within the affected semicircular canal causes abnormal (pathological) endolymph fluid displacement and a resultant sensation of vertigo. This more common condition is known as canalithiasis. There is a direct link between the kind of nystagmus and which of the three semicircular canals is affected. With horizontal nystagmus ( left-right eye movement ) the horizontal ( also called lateral ) canal is affected, with vertical nystagmus ( up-down eye movement ) the superior ( also called anterior ) canal is affected, and with diagonal nystagmus ( diagonal or rotational eye movement ) the posterior canal is affected. Diagonal eye movement is easily confused with horizontal movement. This is important since it might result in selecting a wrong and thus ineffective cure maneuver. In rare cases, the crystals themselves can adhere to a semicircular canal cupula, rendering it heavier than the surrounding endolymph. Upon reorientation of the head relative to gravity, the cupula is weighted down by the dense particles, thereby inducing an immediate and sustained excitation of semicircular canal afferent nerves. This condition is termed cupulolithiasis.There is evidence in the dental literature that malleting of an osteotome during closed sinus floor elevation, otherwise known as osteotome sinus elevation or lift, transmits percussive and vibratory forces capable of detaching otoliths from their normal location and thereby leading to the symptoms of BPPV.BPPV can be triggered by any action that stimulates the posterior semi-circular canal including: Looking up or down Following head injury Sudden head movement Rolling over in bed Tilting the headBPPV may be made worse by any number of modifiers which may vary among individuals: Changes in barometric pressure – people may feel increased symptoms up to two days before rain or snow Lack of sleep (required amounts of sleep may vary widely) StressAn episode of BPPV may be triggered by dehydration, such as that caused by diarrhea. For this reason, it commonly occurs in people with post-operative diarrhea induced by post-operative antibiotics.BPPV is one of the most common vestibular disorders in people presenting with dizziness; a migraine is implicated in idiopathic cases. Proposed mechanisms linking the two are genetic factors and vascular damage to the labyrinth.Although BPPV can occur at any age, it is most often seen in people older than the age of 60. Besides aging, there are no major risk factors known for BPPV, although previous episodes of head trauma, or the inner ear infection labyrinthitis, may predispose to the future development of BPPV. Mechanism The inside of the ear is composed of an organ called the vestibular labyrinth. The vestibular labyrinth includes three semicircular canals, which contain fluids and fine hairlike sensors that act as a monitor to the rotations of the head. An important structure in the inner ear includes the otolith organs that contain crystals that are sensitive to gravity. These crystals are responsible for sensitivity to head positions, and can also be dislocated, causing them to lodge inside one of the semicircular canals, which causes dizziness. Diagnosis The condition is diagnosed by the persons history, and by performing the Dix–Hallpike test or the roll test, or both. The patient can also be asked to induce vertigo by performing a movement that the patient knows to induce vertigo. The eyes of the patient can then easily be observed for which kind ( horizontal, vertical, or diagonal ) of nystagmus is present, to determine which semicircular canal ( horizontal, superior, or posterior ) is affected. The Dix–Hallpike test is a common test performed by examiners to determine whether the posterior semicircular canal is involved. It involves a reorientation of the head to align the posterior semicircular canal (at its entrance to the ampulla) with the direction of gravity. This test will reproduce vertigo and nystagmus characteristic of posterior canal BPPV.When performing the Dix–Hallpike test, people are lowered quickly to a supine position, with the neck extended by the person performing the maneuver. For some people, this maneuver may not be indicated, and a modification may be needed that also targets the posterior semicircular canal. Such people include those who are too anxious about eliciting the uncomfortable symptoms of vertigo, and those who may not have the range of motion necessary to comfortably be in a supine position. The modification involves the person moving from a seated position to side-lying without their head extending off the examination table, such as with Dix–Hallpike. The head is rotated 45 degrees away from the side being tested, and the eyes are examined for nystagmus. A positive test is indicated by the patient report of a reproduction of vertigo and clinician observation of nystagmus. Both the Dix–Hallpike and the side-lying testing position have yielded similar results, and as such the side-lying position can be used if the Dix–Hallpike cannot be performed easily.The roll test can determine whether the horizontal semicircular canal is involved. The roll test requires the person to be in a supine position with their head in 30° of cervical flexion. Then the examiner quickly rotates the head 90° to the left side, and checks for vertigo and nystagmus. This is followed by gently bringing the head back to the starting position. The examiner then quickly rotates the head 90° to the right side and checks again for vertigo and nystagmus. In this roll test, the person may experience vertigo and nystagmus on both sides, but rotating toward the affected side will trigger a more intense vertigo. Similarly, when the head is rotated toward the affected side, the nystagmus will beat toward the ground and be more intense.As mentioned above, both the Dix–Hallpike and roll test provoke the signs and symptoms in subjects with archetypal BPPV. The signs and symptoms people with BPPV experience are typically a short-lived vertigo and observed nystagmus. In some people, although rarely, vertigo can persist for years. Assessment of BPPV is best done by a medical health professional skilled in the management of dizziness disorders, commonly a physiotherapist, audiologist, or other physician.The nystagmus associated with BPPV has several important characteristics that differentiate it from other types of nystagmus. Latency of onset: there is a 5–10 second delay prior to onset of nystagmus Nystagmus lasts for 5–60 seconds Positional: the nystagmus occurs only in certain positions Repeated stimulation, including via Dix–Hallpike maneuvers, cause the nystagmus to fatigue or disappear temporarily Rotatory/torsional component is present, or (in the case of lateral canal involvement) the nystagmus beats in either a geotropic (toward the ground) or ageotropic (away from the ground) fashion Visual fixation suppresses nystagmus due to BPPVAlthough rare, CNS disorders can sometimes present as BPPV. A practitioner should be aware that if a person whose symptoms are consistent with BPPV, but does not show improvement or resolution after undergoing different particle repositioning maneuvers — detailed in the Treatment section below — need to have a detailed neurological assessment and imaging performed to help identify the pathological condition. Differential diagnosis Vertigo, a distinct process sometimes confused with the broader term, dizziness, accounts for about six million clinic visits in the United States every year; between 17 and 42% of these people are eventually diagnosed with BPPV. Other causes of vertigo include: Motion sickness/motion intolerance: a disjunction between visual stimulation, vestibular stimulation, and/or proprioception Visual exposure to nearby moving objects (examples of optokinetic stimuli include passing cars and falling snow) Other diseases: (labyrinthitis, Ménières disease, and migraine, etc.) Treatment Repositioning maneuvers A number of maneuvers have been found to be effective including the Epley maneuver, the Semont maneuver, and to a lesser degree Brandt–Daroff exercises. Both the Epley and the Semont maneuvers are equally effective. None of these maneuvers addresses the presence of the particles (otoconia); rather it changes their location. The maneuvers aim to move these particles from some locations in the inner ear that cause symptoms such as vertigo and reposition them to where they do not cause these problems. These maneuvers are easily performed at home and online resources are available to patients. The Epley maneuver is the most popular of the maneuvers because it is designed to address particles in the posterior semicircular canal, the most common cause of BPPV. This might give the wrong impression that the Epley maneuver is the cure for all BPPV. Misdiagnosing which semicircular canal is affected, typically by confusing horizontal and diagonal nystagmus, or simply ignoring the identification of the affected canal, results regularly in no cure. Using the appropriate maneuver for the affected canal is essential. The maneuvers are uncomfortable for the patient as they induce strong vertigo and the patient might resist performing them. If the maneuver is not uncomfortable then most likely the wrong maneuver has been selected by a misdiagnosis of the affected semicircular canal. All the maneuvers consist of a series of steps in which the head is held in a specific position, typically for 30 to 60 seconds until nystagmus stops. Movement from one position to the position of the next step has to be done fluently to give the particles enough momentum to move. A position has to be held until nystagmus has completely resided, which indicates that the particles have stopped moving, before one proceeds to the next step. Epley maneuver The Epley maneuver employs gravity to move the calcium crystal build-up from the posterior semicercular canal ( resulting in diagonal nystagmus ) that causes the condition. This maneuver can be performed during a clinic visit by health professionals, or taught to people to perform at home, or both. Postural restriction after the Epley maneuver increases its effect somewhat.When practiced at home, the Epley maneuver is more effective than the Semont maneuver. The most effective repositioning treatment for posterior canal BPPV is the therapist-performed Epley combined with home-practiced Epley maneuvers. Devices such as the DizzyFIX can help users conduct the Epley maneuver at home, and are available for the treatment of BPPV. Lempert maneuver or Roll maneuver For the lateral (horizontal) canal, resulting in horizontal nystagmus, the Lempert maneuver has been used for productive results. It is unusual for the lateral canal to respond to the canalith repositioning procedure used for the posterior canal BPPV. Treatment is therefore geared toward moving the canalith from the lateral canal into the vestibule.The roll maneuver or its variations are used, and involve rolling the person 360 degrees in a series of steps to reposition the particles. This maneuver is generally performed by a trained clinician who begins seated at the head of the examination table with the person supine There are four stages, each a minute apart, and at the third position the horizontal canal is oriented in a vertical position with the persons neck flexed and on forearm and elbows. When all four stages are completed, the head roll test is repeated, and if negative, treatment ceases. Deep head hanging maneuver For the superior ( also called anterior ) semicircular canal, resulting in vertical nystagmus, the Deep head hanging maneuver is used. The patient lays down on their back on a bed with their head overhanging the bed. In the first step the head is turned as backward (hanging) as possible. In the following step, the patient remains lying but lifts their head with the chin close to the chest. In the last step, the patient sits upright with the head in the normal position. Before going to the next step, one has to wait until the nystagmus fully resides ( typical 30 to 60 seconds ) and progression from one step to the next has to happen in a fluid movement. Semont maneuver The Semont maneuver has a cure rate of 90.3%. It is performed as follows: The person is seated on a treatment table with their legs hanging off the side of the table. The therapist then turns the persons head 45 degrees toward the unaffected side. The therapist then quickly tilts the person so they are lying on the affected side. The head position is maintained, so their head is turned up 45 degrees. This position is maintained for 3 minutes. The purpose is to allow the debris to move to the apex of the semicircular duct. The person is then quickly moved so they are lying on the unaffected side with their head in the same position (now facing downward 45 degrees). This position is also held for 3 minutes. The purpose of this position is to allow the debris to move toward the exit of the semicircular duct. Finally, the person is slowly brought back to an upright seated position. The debris should then fall into the utricle of the canal and the symptoms of vertigo should decrease or end completely.Some people will only need one treatment, but others may need multiple treatments, depending on the severity of their BPPV. In the Semont maneuver, as with the Epley maneuver, people are able to achieve canalith repositioning by themselves. Brandt–Daroff exercises The Brandt–Daroff exercises may be prescribed by the clinician as a home treatment method, usually in conjunction with particle-repositioning maneuvers or in lieu of the particle-repositioning maneuver. The exercise is a form of habituation exercise, designed to allow the person to become accustomed to the position that causes the vertigo symptoms. The Brandt–Daroff exercises are performed in a similar fashion to the Semont maneuver; however, as the person rolls onto the unaffected side, the head is rotated toward the affected side. The exercise is typically performed 3 times a day with 5–10 repetitions each time, until symptoms of vertigo have resolved for at least 2 days. Medications Medical treatment with anti-vertigo medications may be considered in acute, severe exacerbation of BPPV, but in most cases are not indicated. These primarily include drugs of the antihistamine and anticholinergic class, such as meclizine and hyoscine butylbromide (scopolamine), respectively. The medical management of vestibular syndromes has become increasingly popular over the last decade, and numerous novel drug therapies (including existing drugs with new indications) have emerged for the treatment of vertigo/dizziness syndromes. These drugs vary considerably in their mechanisms of action, with many of them being receptor- or ion channel-specific. Among them are betahistine or dexamethasone/gentamicin for the treatment of Ménières disease, carbamazepine/oxcarbazepine for the treatment of paroxysmal dysarthria and ataxia in multiple sclerosis, metoprolol/topiramate or valproic acid/tricyclic antidepressant for the treatment of vestibular migraine, and 4-aminopyridine for the treatment of episodic ataxia type 2 and both downbeat and upbeat nystagmus. These drug therapies offer symptomatic treatment, and do not affect the disease process or resolution rate. Medications may be used to suppress symptoms during the positioning maneuvers if the persons symptoms are severe and intolerable. More dose-specific studies are required, however, in order to determine the most effective drug(s) for both acute symptom relief and long-term remission of the condition. Surgery Surgical treatments, such as a semi-circular canal occlusion, exist for severe and persistent cases that fail vestibular rehabilitation (including particle repositioning and habituation therapy). As they carry the same risks as any neurosurgical procedure, they are reserved as last resorts. References Further reading == External links ==

Hiatal hernia

A hiatal hernia or hiatus hernia is a type of hernia in which abdominal organs (typically the stomach) slip through the diaphragm into the middle compartment of the chest. This may result in gastroesophageal reflux disease (GERD) or laryngopharyngeal reflux (LPR) with symptoms such as a taste of acid in the back of the mouth or heartburn. Other symptoms may include trouble swallowing and chest pains. Complications may include iron deficiency anemia, volvulus, or bowel obstruction.The most common risk factors are obesity and older age. Other risk factors include major trauma, scoliosis, and certain types of surgery. There are two main types: sliding hernia, in which the body of the stomach moves up; and paraesophageal hernia, in which an abdominal organ moves beside the esophagus. The diagnosis may be confirmed with endoscopy or medical imaging. Endoscopy is typically only required when concerning symptoms are present, symptoms are resistant to treatment, or the person is over 50 years of age.Symptoms from a hiatal hernia may be improved by changes such as raising the head of the bed, weight loss, and adjusting eating habits. Medications that reduce gastric acid such as H2 blockers or proton pump inhibitors may also help with the symptoms. If the condition does not improve with medications, a surgery to carry out a laparoscopic fundoplication may be an option. Between 10% and 80% of people in the United States are affected. Signs and symptoms Hiatal hernia has often been called the "great mimic" because its symptoms can resemble many disorders. Among them, a person with a hiatal hernia can experience dull pains in the chest, shortness of breath (caused by the hernias effect on the diaphragm), heart palpitations (due to irritation of the vagus nerve), and swallowed food "balling up" and causing discomfort in the lower esophagus until it passes on to the stomach. In addition, hiatal hernias often result in heartburn but may also cause chest pain or pain with eating.In most cases however, a hiatal hernia does not cause any symptoms. The pain and discomfort that a patient experiences is due to the reflux of gastric acid, air, or bile. While there are several causes of acid reflux, it occurs more frequently in the presence of hiatal hernia. In newborns, the presence of Bochdalek hernia can be recognised from symptoms such as difficulty breathing fast respiration, increased heart rate. Causes The following are potential causes of a hiatal hernia. Increased pressure within the abdomen caused by: Heavy lifting or bending over Frequent or hard coughing Hard sneezing Violent vomiting Straining during defecation (i.e., the Valsalva maneuver)Obesity and age-related changes to the diaphragm are also general risk factors. Diagnosis The diagnosis of a hiatal hernia is typically made through an upper GI series, endoscopy, high resolution manometry, esophageal pH monitoring, and computed tomography (CT). Barium swallow as in upper GI series allows the size, location, stricture, stenosis of oesophagus to be seen. Besides, it can also evaluate the oesophageal movements. Endoscopy can analyse the eosophageal internal surface for erosions, ulcers, and tumours. Meanwhile, manometry can determine the integrity of esophageal movements, and the presence of esophageal achalasia. pH testings allows the quantitative analysis of acid reflux episodes. CT scan is useful in diagnosing complications of hiatal hernia such as gastric volvulus, perforation, pneumoperitoneum, and pneumomediastinum. Classification Four types of esophageal hiatal hernia are identified:Type I: A type I hernia, also known as a sliding hiatal hernia, occurs when part of the stomach slides up through the hiatal opening in the diaphragm. There is a widening of the muscular hiatal tunnel and circumferential laxity of the phrenoesophageal ligament, allowing a portion of the gastric cardia to herniate upward into the posterior mediastinum. The clinical significance of type I hernias is in their association with reflux disease. Sliding hernias are the most common type and account for 95% of all hiatal hernias. (C) Type II: A type II hernia, also known as a paraesophageal or rolling hernia, occurs when the fundus and greater curvature of the stomach roll up through the diaphragm, forming a pocket alongside the esophagus. It results from a localized defect in the phrenoesophageal ligament while the gastroesophageal junction remains fixed to the pre aortic fascia and the median arcuate ligament. The gastric fundus then serves as the leading point of herniation. Although type II hernias are associated with reflux disease, their primary clinical significance lies in the potential for mechanical complications. (D) Type III: Type III hernias have elements of both types I and II hernias. With progressive enlargement of the hernia through the hiatus, the phrenoesophageal ligament stretches, displacing the gastroesophageal junction above the diaphragm, thereby adding a sliding element to the type II hernia. Type IV: Type IV hiatus hernia is associated with a large defect in the phrenoesophageal ligament, allowing other organs, such as colon, spleen, pancreas and small intestine to enter the hernia sac. The end stage of type I and type II hernias occurs when the whole stomach migrates up into the chest by rotating 180° around its longitudinal axis, with the cardia and pylorus as fixed points. In this situation the abnormality is usually referred to as an intrathoracic stomach. Treatment In the great majority of cases, people experience no significant discomfort, and no treatment is required. People with symptoms should elevate the head of their beds and avoid lying down directly after meals. If the condition has been brought on by stress, stress reduction techniques may be prescribed, or if overweight, weight loss may be indicated. Medications Antisecretory drugs such as proton pump inhibitors and H2 receptor blockers can be used to reduce acid secretion. Medications that reduce the lower esophageal sphincter (LES) pressure should be avoided. Procedures There is tentative evidence from non-controlled trials that oral neuromuscular training may improve symptoms. This has been approved by the UK National Health Service (NHS) for supply on prescription from 1 May 2022. Surgery In some unusual instances, as when the hiatal hernia is unusually large, or is of the paraesophageal type, it may cause esophageal stricture or severe discomfort. About 5% of hiatal hernias are paraesophageal. If symptoms from such a hernia are severe for example if chronic acid reflux threatens to severely injure the esophagus or is causing Barretts esophagus, surgery is sometimes recommended. However surgery has its own risks including death and disability, so that even for large or paraesophageal hernias, watchful waiting may on balance be safer and cause fewer problems than surgery. Complications from surgical procedures to correct a hiatal hernia may include gas bloat syndrome, dysphagia (trouble swallowing), dumping syndrome, excessive scarring, and rarely, achalasia. Surgical procedures sometimes fail over time, requiring a second surgery to make repairs. One surgical procedure used is called Nissen fundoplication. In fundoplication, the gastric fundus (upper part) of the stomach is wrapped, or plicated, around the inferior part of the esophagus, preventing herniation of the stomach through the hiatus in the diaphragm and the reflux of gastric acid. The procedure is now commonly performed laparoscopically. With proper patient selection, laparoscopic fundoplication studies in the 21st century have indicated relatively low complication rates, quick recovery, and relatively good long term results. Regarding the discussion of partial versus complete fundoplication procedures, significant variations in the postoperative outcome emphasize the increased prevalence of dysphagia after Nissen. The statistics given support the superiority of laparoscopic over traditional surgery, owing to the greater aesthetic result, shorter admission time – with lower costs – and faster social reintegration. Epidemiology Incidence of hiatal hernias increases with age; approximately 60% of individuals aged 50 or older have a hiatal hernia. Of these, 9% are symptomatic, depending on the competence of the lower esophageal sphincter (LES). 95% of these are "sliding" hiatal hernias, in which the LES protrudes above the diaphragm along with the stomach, and only 5% are the "rolling" type (paraesophageal), in which the LES remains stationary, but the stomach protrudes above the diaphragm.Hiatal hernias are most common in North America and Western Europe and rare in rural African communities. Some have proposed that insufficient dietary fiber and the use of a high sitting position for defecation may increase the risk. References == External links ==

Medullary sponge kidney

Medullary sponge kidney is a congenital disorder of the kidneys characterized by cystic dilatation of the collecting tubules in one or both kidneys. Individuals with medullary sponge kidney are at increased risk for kidney stones and urinary tract infection (UTI). Patients with MSK typically pass twice as many stones per year as do other stone formers without MSK. While having a low morbidity rate, as many as 10% of patients with MSK have an increased risk of morbidity associated with frequent stones and UTIs. While many patients report increased chronic kidney pain, the source of the pain, when a UTI or blockage is not present, is unclear at this time. Renal colic (flank and back pain) is present in 55% of patients. Women with MSK experience more stones, UTIs, and complications than men. MSK was previously believed not to be hereditary but there is more evidence coming forth that may indicate otherwise. Signs and symptoms Most cases are asymptomatic or are discovered during an investigation of blood in the urine. Symptomatic patients typically present as middle-aged adults with renal colic, kidney stones, nephrocalcinosis and/or recurrent urinary tract infections; however, MSK also may affect children very rarely. In addition to the typical clinical phenotype of recurrent stone disease, other clinical profiles have now been recognized, that is, an indolent, almost asymptomatic MSK, and a rare form characterized by intractable pain. Complications Complications associated with medullary sponge kidney include the following: Kidney stones Urinary tract infection (UTI) Blood in the urine Distal renal tubular acidosis (Type 1 RTA) Chronic kidney disease (rarely) Marked chronic pain Cause In recent studies, insight has been obtained on the genetic basis of this disease, supporting the hypothesis that MSK is due to a disruption at the ureteric bud-metanephric mesenchyme interface. This explains why so many tubular defects coexist in this disease, and particularly a distal tubular acidification defect of which the highly prevalent metabolic bone disease is one very important consequence. In addition to the typical clinical phenotype of recurrent stone disease, other clinical profiles have now been recognized, that is, an indolent, almost asymptomatic MSK, and a rare form characterized by intractable, excruciating pain. It was previously believed that most cases of medullary sponge kidney were sporadic; however, recent studies show familial clustering of MSK is common and has an autosomal dominant inheritance, a reduced penetrance, and variable expressivity. Other theories suggest that dilatation of a collecting duct may occur, caused by occlusion by uric acid during fetal life or resulting from tubular obstruction due to calcium oxalate calculi secondary to infantile hypercalciuria.A rare, autosomal recessive form is associated with Caroli disease. Diagnosis Classically, MSK is seen as hyperechoic papillae with clusters of small stones on ultrasound examination of the kidney or with an abdominal x-ray. The irregular (ectatic) collecting ducts are often seen in MSK, which are sometimes described as having a "paintbrush-like" appearance, are best seen on intravenous urography. However, IV urography has been largely replaced by contrast-enhanced, high-resolution helical CT with digital reconstruction. Treatment Often, aggressive treatment is unnecessary for people with MSK disease that does not cause any symptoms (asymptomatic). In such cases, treatment may consist of maintaining adequate fluid intake, with the goal of decreasing the risk of developing kidney stones (nephrolithiasis). Cases of recurrent kidney stone formation may warrant evaluation for possible underlying metabolic abnormalities.In patients with low levels of citrate in the urine (hypocitraturia) and incomplete distal renal tubular acidosis, treatment with potassium citrate helps prevent the formation of new kidney stones. Urinary tract infections, when they occur, should also be treated.Patients with the more rare form of MSK marked by chronic pain typically require pain management. Non-obstructing stones in MSK can be associated with significant and chronic pain even if theyre not passing. It is not certain what causes this pain, but researchers have proposed that the small numerous stones seen in MSK may cause obstruction of the small tubules and collecting ducts in the kidney. This pain can be constant, can often be debilitating and treatment is challenging. Narcotic medication, even in large quantities, is sometimes not adequate. Some success with pain control has been reported using laser lithotripsy (called "ureteroscopic laser papillotomy"). Epidemiology In the general population, the frequency of medullary sponge kidney disease is reported to be 0.02–0.005%; that is, 1 in 5000 to 1 in 20,000. The frequency of medullary sponge kidney has been reported by various authors to be 12 – 21% in patients with kidney stones. The disease is bilateral in 70% of cases. References == External links ==

HELLP syndrome

HELLP syndrome is a complication of pregnancy; the acronym stands for hemolysis, elevated liver enzymes, and low platelet count. It usually begins during the last three months of pregnancy or shortly after childbirth. Symptoms may include feeling tired, retaining fluid, headache, nausea, upper right abdominal pain, blurry vision, nosebleeds, and seizures. Complications may include disseminated intravascular coagulation, placental abruption, and kidney failure.The cause is unknown. The condition occurs in association with pre-eclampsia or eclampsia. Other risk factors include previously having the syndrome and a mother older than 25 years. The underlying mechanism may involve abnormal placental development. Diagnosis is generally based on blood tests finding signs of red blood cell breakdown (lactate dehydrogenase greater than 600 U/L), an aspartate transaminase greater than 70 U/L, and platelets less than 100×109/l. If not all the criteria are present, the condition is incomplete.Treatment generally involves delivery of the baby as soon as possible. This is particularly true if the pregnancy is beyond 34 weeks of gestation. Medications may be used to decrease blood pressure and blood transfusions may be required.HELLP syndrome occurs in about 0.7% of pregnancies and affects about 15% of women with eclampsia or severe pre-eclampsia. Death of the mother is uncommon (< 1%). Outcomes in the babies are generally related to how premature they are at birth. The syndrome was first named in 1982 by American gynaecologist Louis Weinstein. Signs and symptoms The first signs of HELLP usually start appearing midway through the third trimester, though the signs can appear in earlier and later stages. Symptoms vary in severity and between individuals and are commonly mistaken with normal pregnancy symptoms, especially if they are not severe.HELLP syndrome patients experience general discomfort followed by severe epigastric pain or right upper abdominal quadrant pain, accompanied by nausea, vomiting, backache, anaemia, and hypertension. Some patients may also have a headache and visual issues. These symptoms may also become more severe at night. As the condition progresses and worsens, a spontaneous hematoma occurs following the rupture of the liver capsule, which occurs more frequently in the right lobe. The presence of any combinations of these symptoms, subcapsular liver hematoma in particular, warrants an immediate check-up due to the high morbidity and mortality rates of this condition. Risk factors Elevated body mass index and metabolic disorders, as well as antiphospholipid syndrome, significantly increase the risk of HELLP syndrome in all female patients. Females who have had or are related to a female with previous HELLP syndrome complications tend to be at a higher risk in all their subsequent pregnancies.The risk of HELLP syndrome is not conclusively associated with a specific genetic variation, but likely a combination of genetic variations, such as FAS gene, VEGF gene, glucocorticoid receptor gene and the tol-like receptor gene, increase the risk. Pathophysiology The pathophysiology is still unclear and an exact cause is yet to be found. However, it shares a common mechanism, which is endothelial cell injury, with other conditions, such as acute kidney injury and thrombotic thrombocytopenic purpura. Increasing the understanding of HELLP syndromes pathophysiology will enhance diagnostic accuracy, especially in the early stages. This will lead to advancements in the prevention, management, and treatment of the condition, which will increase the likelihood of both maternal and fetal survival and recovery. Inflammation and coagulation As a result of endothelial cell injury, a cascade of pathological reactions manifests and become increasingly severe and even fatal as signs and symptoms progress. Following endothelial injury, vasospasms and platelet activation occur alongside the decreased release of the endothelium-derived relaxing factor and increased the release of von Willebrand factor (vWF), leading to general activation of the coagulation cascade and inflammation. Placental components, such as inflammatory cytokines and syncytiotrophoblast particles interact with the maternal immune system and endothelial cells, further promoting coagulation and inflammation. These interactions also elevate leukocyte numbers and interleukin concentrations, as well as increase complement activity. Low platelet count vWF degradation in HELLP syndrome is inhibited due to decreased levels of degrading proteins, leading to an increased exposure of platelets to vWF. As a result, thrombotic microangiopathies develop and lead to thrombocytopenia. Blood breakdown As a result of the high number of angiopathies, the erythrocytes fragment as they pass through the blood vessels with damaged endothelium and large fibrin networks, leading to macroangiopathic haemolytic anaemia. As a consequence of hemolysis, lactic acid dehydrogenase (LDH) and hemoglobin are released, with the latter binding to serum bilirubin or haptoglobin. Liver During the coagulation cascade, fibrin is deposited in the liver and leads to hepatic sinusoidal obstruction and vascular congestion, which increase intrahepatic pressure. Placenta-derived FasL (CD95L), which is toxic to human hepatocytes, leads to hepatocyte apoptosis and necrosis by inducing the expression of TNFα and results in the release of liver enzymes. Hepatic damages are worsened by the disrupted portal and total hepatic blood flow that result as a consequence of the microangiopathies. Collectively, widespread endothelial dysfunction and hepatocellular damage result in global hepatic dysfunction often leading to liver necrosis, haemorrhages, and capsular rupture. Diagnosis Early and accurate diagnosis, which relies on laboratory tests and imaging exams, is essential for treatment and management and significantly reduces the morbidity rate. However, diagnosis of the syndrome is challenging, especially due to the variability in the signs and symptoms and the lack of consensus amongst healthcare professionals. Similarities to other conditions, as well as normal pregnancy features, commonly lead to misdiagnosed cases or more often, delayed diagnosis.There is a general consensus regarding the main three diagnostic criteria of HELLP syndrome, which include hepatic dysfunction, thrombocytopenia and microangiopathic haemolytic anaemia in patients suspected to have preeclampsia. A blood smear will often exhibit abnormalities, such as schistocytes, bur cells, and helmet cells, which indicate erythrocyte damage. Thrombocytopenia, which is the earliest coagulopathy present in all HELLP syndrome patients, is indicated by low platelet count (below 100 x 109 L-1) or by testing the levels of fibrin metabolites and antithrombin III. Elevated serum levels of certain proteins, in particular, LDH, alanine transaminase (ALT) and aspartate transaminase (AST), are indicative of hepatic dysfunction. Extremely high serum levels of these proteins, specifically LDH levels > 1,400 IU/L, AST levels > 150 IU/L and ALT levels > 100 IU/L, significantly elevate the risk of maternal mortality.A number of other, but less conclusive, clinical diagnostic criteria are also used in diagnosis alongside the main clinical diagnostic criteria for HELLP syndrome. De novo manifestation of hypertension with systolic pressure and diastolic pressure above 160mmHg and 110 mmHg, respectively. Proteinuria, leucocytosis and elevated uric acid concentrations > 7.8 mg. Decreased serum haptoglobin and haemoglobin levels. Increased serum bilirubin levels and visual disturbances.Imaging tests, such as ultrasound, tomography or magnetic resonance imaging (MRI), are instrumental in the correct diagnosis of HELLP syndrome in patients with suspected liver dysfunction. Unurgent cases must undergo MRI, but laboratory tests, such as glucose determination, are more encouraged in mild cases of HELLP syndrome. Classification A classification system, which was developed in Mississippi, measures the severity of the syndrome using the lowest observed platelet count in the patients alongside the appearance of the other two main clinical criteria. Class I is the most severe, with a relatively high risk of morbidity and mortality, compared to the other two classes. Class I HELLP syndrome is characterised by a platelet count below 50,000/µL. Class II HELLP syndrome is characterised by a platelet count of 50,000-100,000/µL. Class III HELLP syndrome is characterised by a platelet count of 100,000-150,000/µL.Another classification system, introduced in Memphis, categorises HELLP syndrome based on its expression. Partial expression of the condition is characterised by the manifestation of one or two of the main diagnostic criteria. The complete expression of the condition is characterised by the manifestation of all three main diagnostic criteria. Treatment The only current recommended and most effective treatment is delivery of the baby, as the signs and symptoms diminish and gradually disappear following the delivery of the placenta. Prompt delivery is the only viable option in cases with multiorgan dysfunction or multiorgan failure, haemorrhage and considerable danger to the fetus. Certain medications are also used to target and alleviate specific symptoms.Corticosteroids are of unclear benefit, though there is tentative evidence that they can increase the mothers platelet count. Prognosis With treatment, maternal mortality is about 1 percent, although complications such as placental abruption, acute kidney injury, subcapsular liver hematoma, permanent liver damage, and retinal detachment occur in about 25% of women. Perinatal mortality (stillbirths plus death in infancy) is between 73 and 119 per 1000 babies of woman with HELLP, while up to 40% are small for gestational age. In general, however, factors such as gestational age are more important than the severity of HELLP in determining the outcome in the baby. Epidemiology HELLP syndrome affects 10-20% of pre-eclampsia patients and is a complication in 0.5-0.9% of all pregnancies. Caucasian women over 25 years of age comprise most of the diagnosed HELLP syndrome cases. In 70% of cases before childbirth, the condition manifests in the third trimester, but 10% and 20% of the cases exhibit symptoms before and after the third trimester, respectively. Postpartum occurrences are also observed in 30% of all HELLP syndrome cases. History HELLP syndrome was identified as a distinct clinical entity (as opposed to severe pre-eclampsia) by Dr. Louis Weinstein in 1982. In a 2005 article, Weinstein wrote that the unexplained postpartum death of a woman who had haemolysis, abnormal liver function, thrombocytopenia, and hypoglycemia motivated him to review the medical literature and to compile information on similar women. He noted that cases with features of HELLP had been reported as early as 1954. See also Acute fatty liver of pregnancy Hypertrophic decidual vasculopathy References == External links ==

Tension headache

Tension headache, also known as stress headache, or tension-type headache (TTH), is the most common type of primary headache. The pain can radiate from the lower back of the head, the neck, eyes or other muscle groups in the body typically affecting both sides of the head. Tension-type headaches account for nearly 90% of all headaches. Pain medications, such as paracetamol and ibuprofen, are effective for the treatment of tension headache. Tricyclic antidepressants appear to be useful for prevention. Evidence is poor for SSRIs, propranolol and muscle relaxants.As of 2016, tension headaches affect about 1.89 billion people and are more common in women than men (23% to 18% respectively). Signs and symptoms According to the third edition of the International Classification of Headache Disorders, the attacks must meet the following criteria: A duration of between 30 minutes and 7 days. At least two of the following four characteristics: bilateral location pressing or tightening (non-pulsating) quality mild or moderate intensity not aggravated by routine physical activity such as walking or climbing stairs Both of the following: no nausea or vomiting no more than one of photophobia (sensitivity to bright light) or phonophobia (sensitivity to loud sounds)Tension-type headaches may be accompanied by tenderness of the scalp on manual pressure during an attack. Risk factors Various precipitating factors may cause tension-type headaches in susceptible individuals: Anxiety Stress Sleep problems Young age Poor health Mechanism Although the musculature of the head and neck and psychological factors such as stress may play a role in the overall pathophysiology of TTH, neither is currently believed to be the sole cause of the development of TTH. The pathologic basis of TTH is most likely derived from a combination of personal factors, environmental factors, and alteration of both peripheral and central pain pathways. Peripheral pain pathways receive pain signals from pericranial (around the head) myofascial tissue (protective tissue of muscles) and alteration of this pathway likely underlies episodic tension-type headache (ETTH). In addition to these myofascial tissue pain signals, pericranial muscle tenderness, inflammation, and muscle ischemia have been postulated in headache literature to be causal factors in the peripheral pathophysiology of TTH. However, multiple studies have failed to illustrate evidence for a pathologic role of either ischemia or inflammation within the muscles. Pericranial tenderness is also not likely a peripheral causal factor for TTH, but may instead act to trigger a chronic pain cycle in which the peripheral pain response is transformed over time into a centralized pain response. It is then these prolonged alterations in the peripheral pain pathways that lead to increased excitability of the central nervous system pain pathways, resulting in the transition of episodic tension-type headache into chronic tension type headache (CTTH). Specifically, the hyperexcitability occurs in central nociceptive neurons (the trigeminal spinal nucleus, thalamus, and cerebral cortex) resulting in central sensitization, which manifests clinically as allodynia and hyperalgesia of CTTH. Additionally, CTTH patients exhibit decreased thermal and pain thresholds which further bolsters support for central sensitization occurring in CTTH.The alterations in physiology that lead to overall process of central sensitization involve changes at the level of neural tracts, neurotransmitters and their receptors, the neural synapse, and the post-synaptic membrane. Evidence suggests dysfunction in supraspinal descending inhibitory pain pathways may contribute to the pathogenesis of central sensitization in CTTH. Neurotransmitters Specific neuronal receptors and neurotransmitters thought to be most involved include NMDA and AMPA receptors, glutamate, serotonin (5-HT), β-endorphin, and nitric oxide (NO). Of the neurotransmitters, NO plays a major role in central pain pathways and likely contributes to the process of central sensitization. Briefly, the enzyme nitric oxide synthase (NOS) forms NO which ultimately results in vasodilatation and activation of central nervous system pain pathways. Serotonin may also be of significant importance and involved in malfunctioning pain filter located in the brain stem. The view is that the brain misinterprets information—for example from the temporal muscle or other muscles—and interprets this signal as pain. Evidence for this theory comes from the fact that chronic tension-type headaches may be successfully treated with certain antidepressants such as nortriptyline. However, the analgesic effect of nortriptyline, as well as amitriptyline in chronic tension-type headache, is not solely due to serotonin reuptake inhibition, and likely other mechanisms are involved. Synapses Regarding synaptic level changes, homosynaptic facilitation and heterosynaptic facilitation are both likely to be involved in central sensitization. Homosynaptic facilitation occurs when synapses normally involved in pain pathways undergo changes involving receptors on the post-synaptic membrane as well as the molecular pathways activated upon synaptic transmission. Lower pain thresholds of CTTH result from this homosynaptic facilitation. In contrast, heterosynaptic facilitation occurs when synapses not normally involved in pain pathways become involved. Once this occurs innocuous signals are interpreted as painful signals. Allodynia and hyperalgesia of CTTH represent this heterosynaptic facilitation clinically. Stress In the literature, stress is mentioned as a factor and may be implicated via the adrenal axis. This ultimately results in downstream activation of NMDA receptor activation, NFκB activation, and upregulation of iNOS with subsequent production of NO leading to pain as described above. Diagnosis With TTH, the physical exam is expected to be normal with perhaps the exception of either pericranial tenderness upon palpation of the cranial muscles, or presence of either photophobia or phonophobia. Classification The International Headache Societys most current classification system for headache disorders is the International Classification of Headache Disorders 3rd edition (ICHD-3) as of 2018. This classification system separates tension-type headache (TTH) into two main groups: episodic (ETTH) and chronic (CTTH). CTTH is defined as fifteen days or more per month with headache for greater than three months, or one-hundred eighty days or more, with headache per year. ETTH is less than fifteen days per month with headache or less than one-hundred eighty days with headache per year. However, ETTH is further sub-divided into frequent and infrequent TTH. Frequent TTH is defined as ten or more episodes of headache over the course of one to fourteen days per month for greater than three months, or at least twelve days per year, but less than one-hundred eighty days per year. Infrequent TTH is defined as ten or more episodes of headache for less than one day per month or less than twelve days per year. Furthermore, all sub-classes of TTH can be classified as having presence or absence of pericranial tenderness, which is tenderness of the muscles of the head. Probable TTH is utilized for patients with some characteristics, but not all characteristics of a given sub-type of TTH. Differential diagnosis Extensive testing is not needed as TTH is diagnosed by history and physical. However, if symptoms indicative of a more serious diagnosis are present, a contrast enhanced MRI may be utilized. Furthermore, giant cell arteritis should be considered in those 50 years of age and beyond. Screening for giant cell arteritis involves the blood tests of erythrocyte sedimentation rate (ESR) and c-reactive protein. Migraine Oromandibular dysfunction Sinus disease Eye disease Cervical spine disease Infection in immunocompromised Intracranial mass Idiopathic intracranial hypertension Medication overuse headache Secondary headache (headache due to other disorder) Giant cell arteritis ( ≥50 years of age) Dermatochalasis Prevention Lifestyle Good posture might prevent headaches if there is neck pain.Drinking alcohol can make headaches more likely or severe.Drinking water and avoiding dehydration helps in preventing tension headache.People who have jaw clenching might develop headaches, and getting treatment from a dentist might prevent those headaches.Using stress management and relaxing often makes headaches less likely.Biofeedback techniques may also help. Medications People who have 15 or more headaches in a month may be treated with certain types of daily antidepressants which act to prevent continued tension headaches from occurring. In those who are predisposed to tension type headaches the first-line preventative treatment is amitriptyline, whereas mirtazapine and venlafaxine are second-line treatment options. Tricyclic antidepressants appear to be useful for prevention. Tricyclic antidepressants have been found to be more effective than SSRIs but have greater side effects. Evidence is poor for the use of SSRIs, propranolol, and muscle relaxants for prevention of tension headaches. Treatment Treatment for a current tension headache is to drink water and confirm that there is no dehydration. If symptoms do not resolve within an hour for a person who has had water, then stress reduction might resolve the issue. Exercise Evidence supports simple neck and shoulder exercises in managing ETTH and CTTH for headaches associated with neck pain. Exercises include stretching, strengthening and range of motion exercises. CTTH can also benefit from combined therapy from stress therapy, exercises and postural correction. Medications Episodic Over-the-counter drugs, like paracetamol, or NSAIDs (ibuprofen, aspirin, naproxen, ketoprofen), can be effective but tend to only be helpful as a treatment for a few times in a week at most. For those with gastrointestinal problems (ulcers and bleeding), acetaminophen is the better choice over aspirin, though both provide roughly equivalent pain relief. It is important to note that large daily doses of paracetamol should be avoided as it may cause liver damage especially in those that consume 3 or more drinks/day and those with pre-existing liver disease. Ibuprofen, one of the NSAIDs listed above, is a common choice for pain relief but may also lead to gastrointestinal discomfort.Analgesic/caffeine combinations are popular such as the aspirin-caffeine combination or the aspirin, paracetamol and caffeine combinations. Frequent use (daily or skipping just one day in between use for 7–10 days) of any of the above analgesics may, however, lead to medication overuse headache.Analgesic/sedative combinations are widely used (e.g., analgesic/antihistamine combinations, analgesic/barbiturate combinations such as Fiorinal).Muscle relaxants are typically used for and are helpful with acute post-traumatic TTH rather than ETTH. Opioid medications are not utilized to treat ETTH. Botulinum toxin does not appear to be helpful. Chronic Classes of medications involved in treatment of CTTH include tricyclic antidepressants (TCAs), SSRIs, benzodiazepine (Clonazepam in small evening dose), and muscle relaxants. The most commonly utilized TCA is amitriptyline due to the postulated role in decreasing central sensitization and analgesic relief. Another popular TCA used is Doxepine. SSRIs may also be utilized for management of CTTH. For patients with concurrent muscle spasm and CTTH, the muscle relaxant Tizanidine can be a helpful option.These medications however, are not effective if concurrent overuse of over the counter medications or other analgesics is occurring. Stopping overuse must occur prior to proceeding with other forms of treatment. Manual therapy Current evidence for acupuncture is slight. A 2016 systematic review suggests better evidence among those with frequent tension headaches, but concludes that further trials comparing acupuncture with other treatment options are needed.People with tension-type headache often use spinal manipulation, soft tissue therapy, and myofascial trigger point treatment. Studies of effectiveness are mixed. A 2006 systematic review found no rigorous evidence supporting manual therapies for tension headache. A 2005 structured review found only weak evidence for the effectiveness of chiropractic manipulation for tension headache, and that it was probably more effective for tension headache than for migraine. A 2004 Cochrane review found that spinal manipulation may be effective for migraine and tension headache, and that spinal manipulation and neck exercises may be effective for cervicogenic headache. Two other systematic reviews published between 2000 and May 2005 did not find conclusive evidence in favor of spinal manipulation. A 2012 systematic review of manual therapy found that hands-on work may reduce both the frequency and the intensity of chronic tension-type headaches. More current literature also appears to be mixed however, CTTH patients may benefit from massage and physiotherapy as suggested by a systemic review examining these modalities via RCTs specifically for this patient population Despite being helpful, the review also makes a point to note that there is no difference in effectiveness long term (6 months) between those CTTH patients utilizing TCAs and physiotherapy. Another systemic review comparing manual therapy to pharmacologic therapy also supports little long term difference in outcome regarding TTH frequency, duration, and intensity. Epidemiology As of 2016 tension headaches affect about 1.89 billion people and are more common in women than men (23% to 18% respectively). Despite its benign character, tension-type headache, especially in its chronic form, can impart significant disability on patients as well as burden on society at large. References External links American Council for Headache Education National Headache Foundation World Headache Alliance

Ehlers–Danlos syndromes

Ehlers–Danlos syndromes (EDS) are a group of 13 genetic connective-tissue disorders in the current classification, with a 14th type discovered in 2018. Symptoms include loose joints, joint pain, stretchy velvety skin, and abnormal scar formation. These may be noticed at birth or in early childhood. Complications may include aortic dissection, joint dislocations, scoliosis, chronic pain, or early osteoarthritis.EDS occurs due to variations of more than 19 genes that are present at birth. The specific gene affected determines the type of EDS. Some cases result from a new variation occurring during early development, while others are inherited in an autosomal dominant or recessive manner. Typically, these variations result in defects in the structure or processing of the protein collagen.Diagnosis is often based on symptoms and confirmed by genetic testing or skin biopsy, but people may initially be misdiagnosed with hypochondriasis, depression, or chronic fatigue syndrome.No cure is known and treatment is supportive in nature. Physical therapy and bracing may help strengthen muscles and support joints. Some forms of EDS result in a normal life expectancy, but those that affect blood vessels generally decrease it.The hypermobile type of EDS (hEDS) affects at least one in 5,000 people globally; other types occur at lower frequencies. The prognosis depends on the specific disorder. Excess mobility was first described by Hippocrates in 400 BC. The syndromes are named after two physicians, Edvard Ehlers and Henri-Alexandre Danlos, who described them at the turn of the 20th century. Types In 2017, 13 subtypes of EDS were classified using specific diagnostic criteria. According to the Ehlers–Danlos Society, the syndromes can also be grouped by the symptoms determined by specific gene mutations. Group A disorders are those that affect primary collagen structure and processing. Group B disorders affect collagen folding and crosslinking. Group C are disorders of structure and function of myomatrix. Group D disorders are those that affect glycosaminoglycan biosynthesis. Group E disorders are characterized by defects in the complement pathway. Group F are disorders of intracellular processes, and Group G is considered to be unresolved forms of EDS. Hypermobile EDS Hypermobile EDS (hEDS, formerly categorized as type 3) is mainly characterized by hypermobility that affects both large and small joints. It may lead to frequent joint subluxations (partial dislocations) and dislocations. In general, people with this variant have skin that is soft, smooth, and velvety and bruises easily, and may have chronic muscle and/or bone pain. It affects the skin less than other forms. It has no available genetic test. hEDS is the most common of the 19 types of connective tissue disorders. Since no genetic test exists, providers have to diagnose hEDS based on what they know about the condition and the patients physical attributes. Other than the general signs, attributes can include faulty connective tissues throughout the body, musculoskeletal issues, and family history. Along with these general signs and side effects, patients can have trouble healing.Women who are pregnant should be warned about things such as pre-labor rupture of membranes, drop in blood pressure with anesthesia, precipitate birth (very fast, active labor), malposition of bleeding, and more. New mothers with hEDS should pay extra attention to taking care of their babies. Mothers may have trouble taking care of babies because of the risk of dropping a baby due to weak connective tissue in arms and legs, falling, postpartum depression (more than the general population), and healing from the birthing process. Genetics of Hypermobile EDS While 12 of the 13 subtypes of EDS have genetic variations that can be tested for by genetic testing, there is no known genetic cause of hEDS. Despite the unknown gene, hEDS appears to follow an autosomal dominant pattern of inheritance. This means that in order to be affected, a person needs a mutation in only one copy of the responsible gene in each cell. This mutation can be inherited from a parent or a de novo (new) mutation. A person with hEDS has a 50% chance of passing their mutated gene on to their children.Recently, several labs and research initiatives have been attempting to uncover a potential hEDS gene. In 2018, the Ehlers–Danlos Society began the Hypermobile Ehlers–Danlos Genetic Evaluation (HEDGE) study. The ongoing study has screened over 1,000 people who have been diagnosed with hEDS by the 2017 criteria to evaluate their genome for a common mutation. To date, 200 people with hEDS have had whole genome sequencing, and 500 have had whole exome sequencing; this study aims to increase those numbers significantly.Promising outcomes of this increased screening have been reported by the Norris Lab, led by Russell Norris, in the Department of Regenerative Medicine and Cell Biology at Medical University of South Carolina. Using CRISPR Cas-9 mediated genome editing on mouse models of the disease, the lab has recently identified a "very strong candidate gene" for hEDS. This finding, and a greater understanding of cardiac complications associated with the majority of EDS subtypes, has led to the development of multiple druggable pathways involved in aortic and mitral valve diseases. While this candidate gene has not been publicly identified, the Norris lab has conducted several studies involving small population genome sequencing and come up with a working list of possible hEDS genes. A mutation in COL3A1 in a single family with autosomal dominant hEDS phenotype was found to cause reduced collagen secretion and an over-modification of collagen. In 35 families, copy number alterations in TPSAB1, encoding alpha-tryptase, were associated with increased basal serum tryptase levels, associated with autonomic dysfunction, gastrointestinal disorders, allergic and cutaneous symptoms, and connective tissue abnormalities, all concurrent with hEDS phenotype. Lastly, Tenascin X, an extracellular matrix protein important for collagen mutation encoded by the TNXB gene, has been associated with hEDS in patients with Tenascin X deficiency. Another way the Norris lab is attempting to find this gene is by looking at genes involved in the formation of the aorta and mitral valves, as these valves are often prolapsed or malformed as a symptom of EDS. Because hEDS is such a complex, multi-organ disease, focusing on one hallmark trait has proven successful. One gene found this way is DZIP1, which regulates cardiac valve development in mammals through a Cby1-beta-catenin mechanism. Mutations at this gene affect the beta-catenin cascade involved in development, causing malformation of the extra-cellular matrix, resulting in loss of collagen. A lack of collagen here is both consistent with hEDS and explains the "floppy" mitral and aortic valve heart defects. A second genetic study specific to mitral valve prolapse focused on the PDGF signaling pathway, which is involved in growth factor ligands and receptor isoforms. Mutations in this pathway affect the ability to localize cilia in various cell types, including cardiac cells. With the resulting ciliopathies, structures such as the cardiac outflow tract, heart tube assembly, and cardiac fusion are limited and/or damaged. Classical EDS Classical EDS (formerly categorized as type 1) is characterized by extremely elastic skin that is fragile and bruises easily and hypermobility of the joints. Molluscoid pseudotumors (calcified hematomas that occur over pressure points) and spheroids (cysts that contain fat occurring over forearms and shins) are also often seen. A side complication of the hyperelasticity presented in many EDS cases makes wounds closing on their own more difficult. Sometimes, motor development is delayed and hypotonia occurs. The variation causing this type of EDS is in the genes COL5A2, COL5A1, and less frequently COL1A1. It involves the skin more than hEDS. In classical EDS, large variation in symptom presentation is seen. Because of this variance, EDS has often been underdiagnosed. Without genetic testing, healthcare professionals may be able to provide a provisional diagnosis based on careful examination of the mouth, skin, and bones, as well as by neurological assessment. The hyperelasticity of EDS patients skin can be difficult to use in diagnosis because there is no good standardized way to measure and assess the elasticity, but hyperelasticity is still a good indicator of EDS, along with other symptoms.A good way to begin the diagnosis process is looking at family history. EDS is an autosomal dominant condition, so is often inherited from parents. Genetic testing remains the most reliable way to diagnose EDS. No cure for type 1 EDS has been found, but a course of non-weight-bearing exercise can help with muscular tension, which can help correct some EDS symptoms. Anti-inflammatory drugs and lifestyle changes can help with joint pain. Lifestyle choices should also be made with children who have EDS to try to prevent wounds to the skin. Protective garments can help with this. In a wound, deep stitches are often used and left in place for longer than normal. Vascular EDS Vascular EDS (formerly categorized as type 4) is identified by skin that is thin, translucent, extremely fragile, and bruises easily. It is also characterized by fragile blood vessels and organs that can easily rupture. Affected people are frequently short, and have thin scalp hair. It also has characteristic facial features, including large eyes, an undersized chin, sunken cheeks, a thin nose and lips, and ears without lobes. Joint hypermobility is present, but generally confined to the small joints (fingers, toes). Other common features include club foot, tendon and/or muscle rupture, acrogeria (premature aging of the skin of the hands and feet), early-onset varicose veins, pneumothorax (collapse of a lung), the recession of the gums, and a decreased amount of fat under the skin. It can be caused by the variations in the COL3A1 gene. Rarely, COL1A1 variations can also cause it. Kyphoscoliosis EDS Kyphoscoliosis EDS (formerly categorized as type 6) is associated with severe hypotonia at birth, delayed motor development, progressive scoliosis (present from birth), and scleral fragility. People may also have easy bruising, fragile arteries that are prone to rupture, unusually small corneas, and osteopenia (low bone density). Other common features include a "marfanoid habitus" characterized by long, slender fingers (arachnodactyly), unusually long limbs, and a sunken chest (pectus excavatum) or protruding chest (pectus carinatum). It can be caused by variations in the gene PLOD1, or rarely, in the FKBP14 gene. Arthrochalasia EDS Arthrochalasia EDS (formerly categorized as types 7A and B) is characterized by severe joint hypermobility and congenital hip dislocation. Other common features include fragile, elastic skin with easy bruising, hypotonia, kyphoscoliosis (kyphosis and scoliosis), and mild osteopenia. Type-I collagen is usually affected. It is very rare, with about 30 cases reported. It is more severe than the hypermobility type. Variations in the genes COL1A1 and COL1A2 cause it. Dermatosparaxis EDS Dermatosparaxis EDS (formerly categorized as type 7C) is associated with extremely fragile skin leading to severe bruising and scarring; saggy, redundant skin, especially on the face; hypermobility ranging from mild to serious; and hernias. Variations in the ADAMTS2 gene cause it. It is extremely rare, with around 11 cases reported. Brittle-cornea syndrome Brittle-cornea syndrome is characterized by the progressive thinning of the cornea, early-onset progressive keratoglobus or keratoconus, nearsightedness, hearing loss, and blue sclerae. Classic symptoms, such as hypermobile joints and hyperelastic skin, are also seen often. It has two types. Type 1 occurs due to variations in the ZNF469 gene. Type 2 is due to variations in the PRDM5 gene. Classical-like EDS Classical-like EDS is characterized by skin hyperextensibility with velvety skin texture and absence of atrophic scarring, generalized joint hypermobility with or without recurrent dislocations (most often shoulder and ankle), and easily bruised skin or spontaneous ecchymoses (discolorations of the skin resulting from bleeding underneath). It can be caused by variations in the TNXB gene. Spondylodysplastic EDS Spondylodysplastic EDS is characterized by short stature (progressive in childhood), muscle hypotonia (ranging from severe congenital to mild later-onset), and bowing of limbs. It can be caused by variations in both copies of the B4GALT7 gene. Other cases can be caused by variations in the B3GALT6 gene. People with variations in this gene can have kyphoscoliosis, tapered fingers, osteoporosis, aortic aneurysms, and problems with the lungs. Other cases can be caused by the SLC39A13 gene. Those with variations in this gene have protuberant eyes, wrinkled palms of the hands, tapering fingers, and distal joint hypermobility. Musculocontractural EDS Musculocontractural EDS is characterized by congenital multiple contractures, characteristically adduction-flexion contractures and/or talipes equinovarus (clubfoot), characteristic craniofacial features, which are evident at birth or in early infancy, and skin features such as skin hyperextensibility, bruising, skin fragility with atrophic scars, and increased palmar wrinkling. It can be caused by variations in the CHST14 gene. Some other cases can be caused by variations in the DSE gene. Myopathic EDS Myopathic EDS (mEDS) is characterized by three major criteria: congenital muscle hypotonia and/or muscle atrophy that improves with age, proximal joint contractures of the knee, hip, and elbow, and hypermobility of distal joints (ankles, wrists, feet, and hands). Four minor criteria may also contribute to a diagnosis of mEDS. This disorder can be inherited through either an autosomal dominant or an autosomal recessive pattern. Molecular testing must be completed to verify that mutations in the COL12A1 gene are present; if not, other collagen-type myopathies should be considered. Periodontal EDS Periodontal EDS (pEDS) is an autosomal-dominant disorder characterized by four major criteria of severe and intractable periodontitis of early-onset (childhood or adolescence), lack of attached gingiva, pretibial plaques, and family history of a first-degree relative who meets clinical criteria. Eight minor criteria may also contribute to the diagnosis of pEDS. Molecular testing may reveal mutations in C1R or C1S genes affecting the C1r protein. Cardiac-valvular EDS Cardiac-valvular EDS (cvEDS) is characterized by three major criteria: severe progressive cardiac-valvular problems (affecting aortic and mitral valves), skin problems such as hyperextensibility, atrophic scarring, thin skin, and easy bruising, and joint hypermobility (generalized or restricted to small joints). Four minor criteria may aid in diagnosis of cvEDS. cvEDS is an autosomal recessive disorder, inherited through variation in both alleles of the gene COL1A2. Signs and symptoms This group of disorders affects connective tissues across the body, with symptoms most typically present in the joints, skin, and blood vessels. However, as connective tissue is found throughout the body, EDS may result in an array of unexpected impacts with any degree of severity, and the condition is not limited to joints, skin, and blood vessels. Effects may range from mildly loose joints to life-threatening cardiovascular complications. Due to the diversity of subtypes within the EDS family, symptoms may vary widely between individuals diagnosed with EDS. Musculoskeletal Musculoskeletal symptoms include hyperflexible joints that are unstable and prone to sprain, dislocation, subluxation, and hyperextension. There can be an early onset of advanced osteoarthritis, chronic degenerative joint disease, swan-neck deformity of the fingers, and Boutonniere deformity of the fingers. Tearing of tendons or muscles may occur. Deformities of the spine, such as scoliosis (curvature of the spine), kyphosis (a thoracic hump), tethered spinal cord syndrome, craniocervical instability, and occipitoatlantoaxial hypermobility may also be present. There can also be myalgia (muscle pain) and arthralgia (joint pain), which may be severe and disabling. Trendelenburgs sign is often seen, which means that when standing on one leg, the pelvis drops on the other side. Osgood–Schlatter disease, a painful lump on the knee, is common as well. In infants, walking can be delayed (beyond 18 months of age), and bottom-shuffling instead of crawling occurs. Skin The weak connective tissue causes abnormal skin. This may present as stretchy or in other types simply be velvet soft. In all types, some increased fragility occurs, but the degree varies depending on the underlying subtype. The skin may tear and bruise easily, and may heal with abnormal atrophic scars; atrophic scars that look like cigarette paper are a sign seen including in those whose skin might appear otherwise normal. In some subtypes, though not the hypermobile subtype, redundant skin folds occur, especially on the eyelids. Redundant skin folds are areas of excess skin lying in folds.Other skin symptoms include molluscoid pseudotumors, especially on pressure points, petechiae, subcutaneous spheroids, livedo reticularis, and piezogenic papules are less common. In vascular EDS, skin can also be thin and translucent. In dermatosparaxis EDS, the skin is extremely fragile and saggy. Cardiovascular Thoracic outlet syndrome Arterial rupture Valvular heart disease, such as mitral valve prolapse, creates an increased risk for infective endocarditis during surgery. This may progress to a life-threatening degree. Heart conduction abnormalities have been found in those with hypermobility form of EDS. Dilation and/or rupture (aneurysm) of ascending aorta Cardiovascular autonomic dysfunction such as postural orthostatic tachycardia syndrome Raynauds phenomenon Varicose veins Heart murmur Heart conduction abnormalities Other manifestations Hiatal hernia Gastroesophageal reflux Poor gastrointestinal motility Dysautonomia Gorlins sign (touch tongue to nose) Anal prolapse Flat feet Tracheobronchomalacia / tracheal collapse Collapsed lung (spontaneous pneumothorax) Nerve disorders (carpal tunnel syndrome, acroparesthesia, neuropathy, including small fiber neuropathy) Insensitivity to local anesthetics Arnold–Chiari malformation Platelet aggregation failure (platelets do not clump together properly) Mast cell disorders (including mast cell activation syndrome and mastocytosis) Pregnancy complications: increased pain, mild to moderate peripartum bleeding, cervical insufficiency, uterine tearing, or premature rupture of membranes Hearing loss may occur in some types Eye: Nearsightedness, retinal tearing and retinal detachment, keratoconus, blue sclera, dry eye, Sjogrens syndrome, lens subluxation, angioid streaks, epicanthal folds, strabismus, corneal scarring, brittle cornea syndrome, cataracts, carotid-cavernous sinus fistulas, macular degeneration Craniocervical instability: caused by trauma(s) to the head and neck areas such as concussion and whiplash. Ligaments in neck are unable to heal properly, so the neck structure does not have the ability to support the skull, which can then sink into the brain stem, blocking the flow of cerebrospinal fluid, leading to issues related to the autonomic nervous system failing to work properly. Osteoporosis and osteopenia are associated with EDS and symptomatic joint hypermobility There is some evidence that EDS may be associated with greater than expected frequencies of neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) and other learning, communication and motor issues, including autism spectrum conditions and Tourette syndrome. Because it is often undiagnosed or misdiagnosed in childhood, some instances of EDS have been mischaracterized as child abuse. The pain may also be misdiagnosed as a behavior disorder or Munchausen by proxy.The pain associated with EDS ranges from mild to debilitating. Causes Every type of EDS except the hypermobile type (which affects the vast majority of people with EDS) can be positively tied to specific genetic variation. Variations in these genes can cause EDS: Collagen primary structure and collagen processing: ADAMTS2, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2 Collagen folding and collagen cross-linking: PLOD1, FKBP14 Structure and function of myomatrix: TNXB, COL12A1 Glycosaminoglycan biosynthesis: B4GALT7, B3GALT6, CHST14, DSE Complement pathway: C1R, C1S Intracellular processes: SLC39A13, ZNF469, PRDM5Variations in these genes usually alter the structure, production, or processing of collagen or proteins that interact with collagen. Collagen provides structure and strength to connective tissue. A defect in collagen can weaken connective tissue in the skin, bones, blood vessels, and organs, resulting in the features of the disorder. Inheritance patterns depend on the specific syndrome. Most forms of EDS are inherited in an autosomal dominant pattern, which means only one of the two copies of the gene in question must be altered to cause a disorder. A few are inherited in an autosomal recessive pattern, which means both copies of the gene must be altered for a person to be affected. It can also be an individual (de novo or "sporadic") variation. Sporadic variations occur without any inheritance. Diagnosis A diagnosis can be made by an evaluation of medical history and clinical observation. The Beighton criteria are widely used to assess the degree of joint hypermobility. DNA and biochemical studies can help identify affected people. Diagnostic tests include collagen gene-variant testing, collagen typing via skin biopsy, echocardiogram, and lysyl hydroxylase or oxidase activity, but these tests are not able to confirm all cases, especially in instances of an unmapped variation, so clinical evaluation remains important. If multiple members of a family are affected, prenatal diagnosis may be possible using a DNA information technique known as a linkage study. Knowledge about EDS among all kinds of practitioners is poor. Research is ongoing to identify genetic markers for all types. Differential diagnosis Several disorders share some characteristics with EDS. For example, in cutis laxa, the skin is loose, hanging, and wrinkled. In EDS, the skin can be pulled away from the body, but is elastic and returns to normal when let go. In Marfan syndrome, the joints are very mobile and similar cardiovascular complications occur. People with EDS tend to have a "marfanoid" appearance (e.g., tall, skinny, long arms and legs, "spidery" fingers), but physical appearance and features in several types of EDS also have characteristics including short stature, large eyes, and the appearance of a small mouth and chin, due to a small palate. The palate can have a high arch, causing dental crowding. Blood vessels can sometimes be easily seen through translucent skin, especially on the chest. The genetic connective tissue disorder Loeys–Dietz syndrome also has symptoms that overlap with EDS.In the past, Menkes disease, a copper metabolism disorder, was thought to be a form of EDS. People are commonly misdiagnosed with fibromyalgia, bleeding disorders, or other disorders that can mimic EDS symptoms. Because of these similar disorders and complications that can arise from an unmonitored case of EDS, a correct diagnosis is important. Pseudoxanthoma elasticum is worth consideration in diagnosis. Management No cure for Ehlers–Danlos syndromes is known, and treatment is supportive. Close monitoring of the cardiovascular system, physiotherapy, occupational therapy, and orthopedic instruments (e.g., wheelchairs, bracing, casting) may be helpful. This can help stabilize the joints and prevent injury. Orthopedic instruments are helpful for the prevention of further joint damage, especially for long distances. People should avoid activities that cause the joint to lock or overextend.A physician may prescribe casting to stabilize joints. Physicians may refer a person to an orthotist for orthotic treatment (bracing). Physicians may also consult a physical and/or occupational therapist to help strengthen muscles and to teach people how to properly use and preserve their joints.Aquatic therapy promotes muscular development and coordination. With manual therapy, the joint is gently mobilized within the range of motion and/or manipulations. If conservative therapy is not helpful, surgical joint repair may be necessary. Medication to decrease pain or manage cardiac, digestive, or other related conditions may be prescribed. To decrease bruising and improve wound healing, some people have responded to vitamin C. Medical care workers often take special precautions because of the sheer number of complications that tend to arise in people with EDS. In vascular EDS, signs of chest or abdominal pain are considered trauma situations.Cannabinoids and medical marijuana have shown some efficacy in reducing pain levels.In general, medical intervention is limited to symptomatic therapy. Before pregnancy, people with EDS should have genetic counseling and familiarize themselves with the risks pregnancy poses. Children with EDS should be given information about the disorder so they can understand why they should avoid contact sports and other physically stressful activities. Children should be taught that they should not demonstrate the unusual positions they can maintain due to loose joints, as this may cause early degeneration of the joints. Emotional support along with behavioral and psychological therapy can be useful. Support groups can be immensely helpful for people dealing with major lifestyle changes and poor health. Family members, teachers, and friends should be informed about EDS so they can accept and assist the child. Pain management Successful treatment of chronic pain in EDS requires a multidisciplinary team. The ways to manage pain can be to modify pain management techniques used in the normal population. Chronic pain has two types. The first type is nociceptive, which is caused by an injury sustained to tissues. The second type is neuropathic pain, caused by abnormal signals by the nervous system. In most cases, the pain is an unequal mix of the two. Physiotherapy (exercise rehabilitation) can be helpful, especially stabilizing the core and the joints. Stretching exercises must be reduced to slow and gentle stretching to reduce the risks of dislocations or subluxations. Usable methods may include posture reeducation, muscle release, joint mobilization, trunk stabilization, and manual therapy for overworked muscles. Cognitive behavioural therapy is used in all chronic pain patients, especially those who have severe, chronic, life-controlling pain that is unresponsive to treatment. It had not been checked for efficiency in clinical trials. The state of pain management with EDS is considered insufficient. Medications Nonsteroidal anti-inflammatory drugs (NSAIDs) may help if the pain is caused by inflammation. But long-term use of NSAIDs is often a risk factor for gastrointestinal, renal, and blood-related side effects. It can worsen symptoms of mast cell activation syndrome, a disease that may be associated with EDS. Acetaminophen can be used to avoid the bleeding-related side effects of NSAIDs.Opioids have shown efficiency in some EDS cases for the management of both acute and chronic pain.112 Lidocaine can be applied topically after subluxations and painful gums. It can also be injected into painful areas in the case of musculoskeletal pain.If the pain is neuropathic in origin, tricyclic antidepressants in low doses, anticonvulsants, and selective norepinephrine reuptake inhibitors can be used. Dislocation and subluxation management When a dislocation or subluxation does occur, muscle spasms and stress tend to occur, increasing pain and reducing the chances of the dislocation/subluxation naturally relieving. Methods to support a joint after such an incident include usage of a sling to hold the joint in place and allow it to relax. Orthopedic casts are not advised as there could be pain if unrelaxed muscles are still trying to spasm out against the cast. Other solutions to promote relaxation are heat, gentle massaging, and mental distractions. Surgery The instability of joints, leading to subluxations and joint pain, often requires surgical intervention in people with EDS. Instability of almost all joints can happen, but appears most often in the lower and upper extremities, with the wrist, fingers, shoulder, knee, hip, and ankle being most common.Common surgical procedures are joint debridement, tendon replacements, capsulorrhaphy, and arthroplasty. After surgery, the degree of stabilization, pain reduction, and peoples satisfaction can improve, but surgery does not guarantee an optimal result; affected peoples and surgeons report being dissatisfied with the results. The consensus is that conservative treatment is more effective than surgery, particularly since people have extra risks of surgical complications due to the disease. Three basic surgical problems arise due to EDS – the strength of the tissues is decreased, which makes the tissue less suitable for surgery; the fragility of the blood vessels can cause problems during surgery; and wound healing is often delayed or incomplete. If considering surgical intervention, seeking care from a surgeon with extensive knowledge and experience in treating people with EDS and joint hypermobility issues would be prudent.Local anesthetics, arterial catheters, and central venous catheters cause a higher risk of bruise formation in people with EDS. Some people with EDS also show a resistance to local anaesthetics. Resistance to lidocaine and bupivacaine is not uncommon, and mepivacaine tends to work better in people with EDS. Special recommendations for anesthesia are given for people with EDS. Detailed recommendations for anesthesia and perioperative care of people with EDS should be used to improve safety.Surgery in people with EDS requires careful tissue handling and a longer immobilization afterward. Prognosis The outcome for individuals with EDS depends on the specific type of EDS they have. Symptoms vary in severity, even in the same disorder, and the frequency of complications varies. Some people have negligible symptoms, while others are severely restricted in daily life. Extreme joint instability, chronic musculoskeletal pain, degenerative joint disease, frequent injuries, and spinal deformities may limit mobility. Severe spinal deformities may affect breathing. In the case of extreme joint instability, dislocations may result from simple tasks such as rolling over in bed or turning a doorknob. Secondary conditions such as autonomic dysfunction or cardiovascular problems, occurring in any type, can affect prognosis and quality of life. Severe mobility-related disability is seen more often in hEDS than in classical EDS or vascular EDS.Although all types of EDS are potentially life-threatening, most people have a normal lifespan. Those with blood vessel fragility, though, have a high risk of fatal complications, including spontaneous arterial rupture, which is the most common cause of sudden death. The median life expectancy in the population with vascular EDS is 48 years. Complications Vascular Pseudoaneurysm Vascular lesions (nature is disputed) due to tears in the lining of the arteries or deterioration of congenitally thin and fragile tissue Enlarged arteries Gastrointestinal A 50% risk of colonic perforation exists. Obstetric Pregnancy increases the likelihood of uterine rupture. Maternal mortality is around 12%. Uterine hemorrhage can occur during the postpartum recovery. Epidemiology Ehlers–Danlos syndromes are estimated to occur in about one in 5,000 births worldwide. Initially, prevalence estimates ranged from one in 250,000 to 500,000 people, but these were soon found to be low, as medical professionals became more adept at diagnosis. EDS may be far more common than the currently accepted estimate due to the wide range of severities with which the disorder presents.The prevalence of the disorders differs dramatically. The most common is hypermobile EDS, followed by classical EDS. The others are very rare. For example, fewer than 10 infants and children with dermatosparaxis EDS have been described worldwide. Some types of EDS are more common in Ashkenazi Jews. For example, the chance of being a carrier for dermatosparaxis EDS is one in 2,000 in the general population but one in 248 among Ashkenazi Jews. History Until 1997, the classification system for EDS included 10 specific types and acknowledged that other extremely rare types existed. At this time, the classification system underwent an overhaul and was reduced to six major types using descriptive titles. Genetic specialists recognize that other types of this condition exist, but have only been documented in single families. Except for hypermobility (type 3), the most common type of all 10 types, some of the specific variations involved have been identified, and they can be precisely identified by genetic testing; this is valuable due to a great deal of variation in individual cases. Negative genetic test results, though, do not rule out the diagnosis, since not all of the variations have been discovered; therefore, the clinical presentation is very important.Forms of EDS in this category may present with soft, mildly stretchable skin, shortened bones, chronic diarrhea, joint hypermobility and dislocation, bladder rupture, or poor wound healing. Inheritance patterns in this group include X-linked recessive, autosomal dominant, and autosomal recessive. Examples of types of related syndromes other than those above reported in the medical literature include: 305200: type 5 130080: type 8 – unspecified gene, locus 12p13 225310: type 10 – unspecified gene, locus 2q34 608763: Beasley–Cohen type 130070: progeroid form – B4GALT7 130090: type unspecified 601776: D4ST1-deficient Ehlers–Danlos syndrome (adducted thumb-clubfoot syndrome) CHST14 Society and culture EDS may have contributed to the virtuoso violinist Niccolò Paganinis skill, as he was able to play wider fingerings than a typical violinist.Many sideshow performers have EDS. Several of them were billed as the Elastic Skin Man, the India Rubber Man, and Frog Boy. They included such well-known individuals (in their time) as Felix Wehrle, James Morris, and Avery Childs. Two performers with EDS currently hold world records. Contortionist Daniel Browning Smith has hypermobile EDS and holds the current Guinness World Record for the most flexible man as of 2018, while Gary "Stretch" Turner, sideshow performer in the Circus Of Horrors, has held the current Guinness World Record for the most elastic skin since 1999, for his ability to stretch the skin on his stomach 6.25 inches. Notable cases Actress Cherylee Houston has hypermobile EDS. She uses a wheelchair and was the first full-time disabled actress on Coronation Street Drag queen and winner of the 11th season of RuPauls Drag Race Yvie Oddly Eric the Actor, a regular caller to The Howard Stern Show Actress and activist Jameela Jamil Writer and actress Lena Dunham Australian singer Sia Singer Halsey YouTuber and disability rights activist Annie Elainey Miss America 2020 Camille Schrier Deaf singer/songwriter Mandy Harvey Pornographic actress and writer Lorelei Lee Reality show contestant Trevor Jones, dead from the vascular form of the disorder Scrunchie creator Rommy Hunt Revson, dead from a ruptured aorta Other species Ehlers–Danlos-like syndromes have been shown to be hereditary in Himalayan cats, some domestic shorthair cats, and certain breeds of cattle. It is seen as a sporadic condition in domestic dogs. It has a similar treatment and prognosis. Animals with the condition should not be bred, as the condition can be inherited. Animal EDS Degenerative suspensory ligament desmitis is a similar condition seen in many breeds of horses. It was originally notated in the Peruvian Paso and thought to be a condition of overwork and older age, but it is being recognized in all age groups and all activity levels. It has been noted in newborn foals. See also Hypermobility spectrum disorder References External links Ehlers–Danlos syndromes at Curlie

Viral meningitis

Viral meningitis, also known as aseptic meningitis, is a type of meningitis due to a viral infection. It results in inflammation of the meninges (the membranes covering the brain and spinal cord). Symptoms commonly include headache, fever, sensitivity to light and neck stiffness.Viruses are the most common cause of aseptic meningitis. Most cases of viral meningitis are caused by enteroviruses (common stomach viruses). However, other viruses can also cause viral meningitis, such as West Nile virus, mumps, measles, herpes simplex types I and II, varicella and lymphocytic choriomeningitis (LCM) virus. Based on clinical symptoms, viral meningitis cannot be reliably differentiated from bacterial meningitis, although viral meningitis typically follows a more benign clinical course. Viral meningitis has no evidence of bacteria present in cerebral spinal fluid (CSF). Therefore, lumbar puncture with CSF analysis is often needed to identify the disease.In most cases, there is no specific treatment, with efforts generally aimed at relieving symptoms (headache, fever or nausea). A few viral causes, such as HSV, have specific treatments. In the United States, viral meningitis is the cause of more than half of all cases of meningitis. With the prevalence of bacterial meningitis in decline, the viral disease is garnering more and more attention. The estimated incidence has a considerable range, from 0.26 to 17 cases per 100,000 people. For enteroviral meningitis, the most common cause of viral meningitis, there are up to 75,000 cases annually in the United States alone. While the disease can occur in both children and adults, it is more common in children. Signs and symptoms Viral meningitis characteristically presents with fever, headache and neck stiffness. Fever is the result of cytokines released that affect the thermoregulatory (temperature control) neurons of the hypothalamus. Cytokines and increased intracranial pressure stimulate nociceptors in the brain that lead to headaches. Neck stiffness is the result of inflamed meninges stretching due to flexion of the spine. The various layers of meninges act form a separation between the brain and the skull. In contrast to bacterial meningitis, symptoms associated with viral meningitis are often less severe and do not progress as quickly. Nausea, vomiting and photophobia (light sensitivity) also commonly occur, as do general signs of a viral infection, such as muscle aches and malaise. Increased cranial pressure from viral meningitis stimulates the area postrema, which causes nausea and vomiting. Widened pulse pressure (systolic - diastolic blood pressure), bradycardia, and irregular respiration would be alarming for Cushings reflex, a sign of acutely elevated intracranial pressure. Photophobia is due to meningeal irritation. In severe cases, people may experience concomitant encephalitis (meningoencephalitis), which is suggested by symptoms such as altered mental status, seizures or focal neurologic deficits.Babies with viral meningitis may only appear irritable, sleepy or have trouble eating. Infection in the neonatal period may be the result of infection during pregnancy. In severe cases, people may experience concomitant encephalitis (meningoencephalitis), which is suggested by symptoms such as altered mental status, seizures or focal neurologic deficits. The pediatric population may show some additional signs and symptoms that include jaundice and bulging fontanelles. A biphasic fever is more often seen in children compared to adults. The first fever arrives with the onset of general constitutional symptoms, and the second accompanying the onset of the neurological symptoms.Symptoms can vary depending on the virus responsible for infection. Enteroviral meningitis (the most common cause) typically presents with the classic headache, photophobia, fever, nausea, vomiting, and nuchal rigidity. With coxsackie and echo virus specifically, a maculopapular rash may be present, or even the typical vesicles seen with Herpangina. Lymphocytic choriomeningitis virus (LCMV) can be differentiated from the common presenting meningeal symptoms by the appearance of a prodromal influenza-like sickness about 10 days before other symptoms begin. Mumps meningitis can present similarly to isolated mumps, with possible parotid and testicular swelling. Interestingly, research has shown that HSV-2 meningitis most often occurs in people with no history of genital herpes, and that a severe frontal headache is among the most common presenting symptoms. Patients with varicella zoster meningitis may present with herpes zoster (Shingles) in conjunction with classic meningeal signs. Meningitis can be an indication that an individual with HIV is undergoing seroconversion, the time when the human body is forming antibodies in response to the virus. Causes The most common causes of viral meningitis in the United States are non-polio enteroviruses. The viruses that cause meningitis are typically acquired from sick contacts. However, in most cases, people infected with viruses that may cause meningitis do not actually develop meningitis.Viruses that can cause meningitis include: Mechanism Viral Meningitis is mostly caused by an infectious agent that has colonized somewhere in its host. People who are already in an immunocompromised state are at the highest risk of pathogen entry. Some of the most common examples of immunocompromised individuals include those with HIV, cancer, diabetes, malnutrition, certain genetic disorders, and patients on chemotherapy. Potential sites for this include the skin, respiratory tract, gastrointestinal tract, nasopharynx, and genitourinary tract. The organism invades the submucosa at these sites by invading host defenses, such as local immunity, physical barriers, and phagocytes or macrophages. After pathogen invasion, the immune system is activated. An infectious agent can enter the central nervous system and cause meningeal disease via invading the bloodstream, a retrograde neuronal pathway, or by direct contiguous spread. Immune cells and damaged endothelial cells release matrix metalloproteinases (MMPs), cytokines, and nitric oxide. MMPs and NO induce vasodilation in the cerebral vasculature. Cytokines induce capillary wall changes in the blood brain barrier, which leads to expression of more leukocyte receptors, thus increasing white blood cell binding and extravasation.The barrier that the meninges create between the brain and the bloodstream are what normally protect the brain from the bodys immune system. Damage to the meninges and endothelial cells increases cytotoxic reactive oxygen species production, which damages pathogens as well as nearby cells. In meningitis, the barrier is disrupted, so once viruses have entered the brain, they are isolated from the immune system and can spread. This leads to elevated intracranial pressure, cerebral edema, meningeal irritation, and neuronal death. Diagnosis The diagnosis of viral meningitis is made by clinical history, physical exam, and several diagnostic tests. Kernig and Brudzinski signs may be elucidated with specific physical exam maneuvers, and can help diagnose meningitis at the bedside. Most importantly however, cerebrospinal fluid (CSF) is collected via lumbar puncture (also known as spinal tap). This fluid, which normally surrounds the brain and spinal cord, is then analyzed for signs of infection. CSF findings that suggest a viral cause of meningitis include an elevated white blood cell count (usually 10-100 cells/µL) with a lymphocytic predominance in combination with a normal glucose level. Increasingly, cerebrospinal fluid PCR tests have become especially useful for diagnosing viral meningitis, with an estimated sensitivity of 95-100%. Additionally, samples from the stool, urine, blood and throat can also help to identify viral meningitis. CSF vs serum c-reactive protein and procalcitonin have not been shown to elucidate whether meningitis is bacterial or viral.In certain cases, a CT scan of the head should be done before a lumbar puncture such as in those with poor immune function or those with increased intracranial pressure. If the patient has focal neurological deficits, papilledema, a Glasgow Coma Score less than 12, or a recent history of seizures, lumbar puncture should be reconsidered.Differential diagnosis for viral meningitis includes meningitis caused by bacteria, mycoplasma, fungus, and drugs such as NSAIDS, TMP-SMX, IVIG. Further considerations include brain tumors, lupus, vasculitis, and Kawasaki disease in the pediatric population. Treatment Because there is no clinical differentiation between bacterial and viral meningitis, people with suspected disease should be sent to the hospital for further evaluation. Treatment for viral meningitis is generally supportive. Rest, hydration, antipyretics, and pain or anti-inflammatory medications may be given as needed. However, if there is initial uncertainty as to whether the meningitis is bacterial or viral in origin, empiric antibiotics are often given until bacterial infection is ruled out.Herpes simplex virus, varicella zoster virus and cytomegalovirus have a specific antiviral therapy. For herpes the treatment of choice is aciclovir. If encephalitis is suspected, empiric treatment with IV aciclovir is often warranted.Surgical management is indicated where there is extremely increased intracranial pressure, infection of an adjacent bony structure (e.g. mastoiditis), skull fracture, or abscess formation.The majority of people that have viral meningitis get better within 7–10 days. Epidemiology From 1988 to 1999, about 36,000 cases occurred each year. As recently as 2017, the incidence in the U.S. alone increased to 75,000 cases per year for enteroviral meningitis. With the advent and implementation of vaccinations for organisms such as Streptococcus pneumoniae, Haemophilus influenza type B, and Neisseria meningitis, rates of bacterial meningitis have been in decline, making viral meningitis more common. Countries without high rates of immunization still carry higher rates of bacterial disease. While the disease can occur in both children and adults, it is more common in children. Rates of infection tend to reach a peak in the summer and fall. During an outbreak in Romania and in Spain viral meningitis was more common among adults. While, people aged younger than 15 made up 33.8% of cases. In contrast in Finland in 1966 and in Cyprus in 1996, Gaza 1997, China 1998 and Taiwan 1998, the incidence of viral meningitis was higher among children. Recent research It has been proposed that viral meningitis might lead to inflammatory injury of the vertebral artery wall.The Meningitis Research Foundation is conducting a study to see if new genomic techniques can improve the speed, accuracy and cost of diagnosing meningitis in children in the UK. The research team will develop a new method to be used for the diagnosis of meningitis, analysing the genetic material of microorganisms found in CSF (cerebrospinal fluid). The new method will first be developed using CSF samples where the microorganism is known, but then will be applied to CSF samples where the microorganism is unknown (estimated at around 40%) to try and identify a cause. There is also research investigating whether high-throughput sequencing, wherein the investigator does not need to compare DNA results with known genomic sequences, could be used in specifically diagnosing unknown causes of viral meningitis.While there is some emerging evidence that bacterial meningitis may have a negative impact on cognitive function, there is no such evidence for viral meningitis. References == External links ==

Craniopharyngioma

A craniopharyngioma is a rare type of brain tumor derived from pituitary gland embryonic tissue that occurs most commonly in children, but also affects adults. It may present at any age, even in the prenatal and neonatal periods, but peak incidence rates are childhood-onset at 5–14 years and adult-onset at 50–74 years. People may present with bitemporal inferior quadrantanopia leading to bitemporal hemianopsia, as the tumor may compress the optic chiasm. It has a point prevalence around two per 1,000,000. Craniopharyngiomas are distinct from Rathkes cleft tumours and intrasellar arachnoid cysts. Symptoms and signs Craniopharyngiomas are almost always benign. However, as with many brain tumors, their treatment can be difficult, and significant morbidities are associated with both the tumor and treatment. Headache (obstructive hydrocephalus) Hypersomnia Myxedema Postsurgical weight gain Polydipsia Polyuria (diabetes insipidus) Vision loss (bitemporal hemianopia) VomitingOften occurs after treatment Growth hormone (GH) insufficiency, caused by the reduction in GH production - symptoms include: Stunted growth and delayed puberty (in children) General fatigue, loss of muscle mass and tone (in adults) Pituitary insufficiency Often occurs to some degree because craniopharyngiomas develop in the area of the pituitary stalk, which can affect the function of the pituitary gland and many other hormones Reduction in prolactin production is very uncommon and occurs with severe pituitary insufficiency. Large pituitary tumors can paradoxically elevate blood prolactin levels due to the "stalk effect". This elevation occurs as a result of the compression of the pituitary stalk, which interferes with the brains control of prolactin production. In premenopausal women, elevated prolactin can lead to reduction or loss of menstrual periods and/or breast milk production (galactorrhea). With stalk effect, prolactin levels are usually only slightly elevated, as opposed to prolactinomas in which the prolactin level is usually very high. Diabetes insipidus occurs due to the absence of a posterior pituitary hormone called antidiuretic hormone. Symptoms include: Excessive thirst Excessive urination Adrenal insufficiency occurs because of a reduction in ACTH production, a reduction in cortisol. In severe cases, it can be fatal. Symptoms include: Fatigue Low blood pressure Electrolyte abnormalities Mechanisms Craniopharyngioma is a rare, usually suprasellar neoplasm, which may be cystic, that develops from nests of epithelium derived from Rathkes pouch. Rathkes pouch is an embryonic precursor of the anterior pituitary.Craniopharyngiomas are typically very slow-growing tumors. They arise from the cells along the pituitary stalk, specifically from nests of odontogenic (tooth-forming) epithelium within the suprasellar/diencephalic region, so contain deposits of calcium that are evident on an X-ray. Diagnosis Imaging scans for craniopharyngioma A physician can conduct a few scans and tests to diagnose a person with craniopharyngioma. High-resolution magnetic resonance imaging (MRI) is valuable because it allows the neuroradiologist to view the tumor from different angles.In some cases, a powerful 3T (Tesla) MRI scanner can help define the location of critical brain structures affected by the tumor. The histologic pattern consists of nesting of squamous epithelium bordered by radially arranged cells. It is frequently accompanied by calcium deposition and may have a microscopic papillary architecture. A computed tomography (CT) scan is also a good diagnostic tool, as it detects calcification in the tumor.Two distinct types are recognized: Adamantinomatous craniopharyngiomas, which resemble ameloblastomas (the most common type of odontogenic tumor), are characterized by activating CTNNB1 mutations. Papillary craniopharyngiomas are characterized by BRAFv600E mutations.In the adamantinomatous type, calcifications are visible on neuroimaging and are helpful in diagnosis. The papillary type rarely calcifies. A vast majority of craniopharyngiomas in children are adamantiomatous, whereas both subtypes are common in adults. Mixed-type tumors also occur.On macroscopic examination, craniopharyngiomas are cystic or partially cystic with solid areas. On light microscopy, the cysts are seen to be lined by stratified squamous epithelium. Keratin pearls may also be seen. The cysts are usually filled with a yellow, viscous fluid rich in cholesterol crystals. Of a long list of possible symptoms, the most common presentations include headaches, growth failure, and bitemporal hemianopsia. Malignant craniopharyngioma Craniopharyngiomas are usually successfully managed with a combination of adjuvant chemotherapy and neurosurgery. Recent research describes the rare occurrence of malignant transformations of these normally benign tumors. Malignant craniopharyngiomas can occur at any age, are slightly more common in females, and are usually of the adamantinomatous type.The malignant transformations can take years to occur (although one in five of the diagnosed cases were de novo transformations), hence the need for lengthier follow-up in patients diagnosed with the more common benign forms.No link has been found between malignancy and initial chemoradiotherapy treatment, and the overall survival rate was very poor with median survival being 6 months after diagnosis of malignancy. Prevention Although the causes of craniopharyngioma are unknown, it can occur in both children and adults, with a peak in incidence at 9 to 14 years of age. About 120 cases are diagnosed each year in the United States in patients under the age of 19. More than 50% of all patients with craniopharyngioma are under the age of 18 years. No clear association of the tumor exists with a particular gender or race. Craniopharyngiomas do not appear to "run in families" or to be directly inherited from the parents. Treatment Treatment generally consists of subfrontal or transsphenoidal excision. Endoscopic surgery through the nose often performed by a joint team of neurosurgeons and ENT, is increasingly being considered as an alternative to transcranial surgery done by making an opening in the skull. Because of the location of the craniopharyngioma near the brain and skullbase, a surgical navigation system might be used to verify the position of surgical tools during the operation.Additional radiotherapy is also used if total removal is not possible. Due to the poor outcomes associated with damage to the pituitary and hypothalamus from surgical removal and radiation, experimental therapies using intracavitary phosphorus-32, yttrium, or bleomycin delivered via an external reservoir are sometimes employed, especially in young patients. The tumor, being in the pituitary gland, can cause secondary health problems. The immune system, thyroid levels, growth hormone levels, and testosterone levels can be compromised from craniopharygioma. All of these health problems can be treated with modern medicine. No high quality evidence has evaluated the use of bleomycin in this condition.Proton therapy affords a reduction in dose to critical structures compared to conventional photon radiation, including IMRT, for patients with craniopharyngioma.The most effective treatment package for the malignant craniopharyngiomas described in literature is a combination gross total resective surgery with adjuvant chemoradiotherapy. The chemotherapy drugs paclitaxel and carboplatin have shown a clinical (but not statistical) significance in increasing the survival rate in patients who have had gross total resections of their malignant tumours. Prognosis Craniopharyngiomas are generally benign but are known to recur after resection. Recent research has demonstrated a malignant (but rare) tendency of craniopharyngiomas. These malignant craniopharyngiomas are very rare but are associated with poor prognosis. Recent research Current research has shown ways of treating the tumors in a less invasive way while others have shown how the hypothalamus can be stimulated along with the tumor to prevent the child and adult with the tumor to become obese. Craniopharyngioma of childhood are commonly cystic in nature. Limited surgery minimizing hypothalamic damage may decrease the severe obesity rate at the expense of the need for radiotherapy to complete the treatment.Role of radiotherapy: Aggressive attempts at total removal do result in prolonged progression-free survival in most patients, but for tumors that clearly involve the hypothalamus, complications associated with radical surgery have prompted to adopt a combined strategy of conservative surgery and radiation therapy to residual tumor with as high a rate of cure. This strategy seems to offer the best long-term control rates with acceptable morbidity. But optimal management of craniopharyngiomas remains controversial. Although it is generally recommended that radiotherapy is given following subtotal excision of a craniopharyngioma, it remains unclear as to whether all patients with residual tumour should receive immediate or differed at relapse radiotherapy. Surgery and radiotherapy are the cornerstones in therapeutic management of craniopharyngioma. Radical excision is associated with a risk of mortality or morbidity particularly as hypothalamic damage, visual deterioration, and endocrine complication between 45 and 90% of cases. The close proximity to neighboring eloquent structures poses a particular challenge to radiation therapy. Modern treatment technologies including fractionated 3-D conformal radiotherapy, intensity modulated radiation therapy, and recently proton therapy are able to precisely cover the target while preserving surrounding tissue, Tumor controls in excess of 90% can be achieved. Alternative treatments consisting of radiosurgery, intracavitary application of isotopes, and brachytherapy also offer an acceptable tumor control and might be given in selected cases. More research is needed to establish the role of each treatment modality. References External links Cancer.Net: Craniopharyngioma - Childhood Malignant transformation in craniopharyngiomas

Cerebral arteriovenous malformation

A cerebral arteriovenous malformation (cerebral AVM, CAVM, cAVM) is an abnormal connection between the arteries and veins in the brain—specifically, an arteriovenous malformation in the cerebrum. Signs and symptoms The most frequently observed problems, related to an AVM, are headaches and seizures, cranial nerve deficits, backaches, neckaches and eventual nausea, as the coagulated blood makes its way down to be dissolved in the individuals spinal fluid. It is supposed that 15% of the population, at detection, have no symptoms at all. Other common symptoms are a pulsing noise in the head, progressive weakness and numbness and vision changes as well as debilitating, excruciating pain.In serious cases, the blood vessels rupture and there is bleeding within the brain (intracranial hemorrhage). Nevertheless, in more than half of patients with AVM, hemorrhage is the first symptom. Symptoms due to bleeding include loss of consciousness, sudden and severe headache, nausea, vomiting, incontinence, and blurred vision, amongst others. Impairments caused by local brain tissue damage on the bleed site are also possible, including seizure, one-sided weakness (hemiparesis), a loss of touch sensation on one side of the body and deficits in language processing (aphasia). Ruptured AVMs are responsible for considerable mortality and morbidity.AVMs in certain critical locations may stop the circulation of the cerebrospinal fluid, causing accumulation of the fluid within the skull and giving rise to a clinical condition called hydrocephalus. A stiff neck can occur as the result of increased pressure within the skull and irritation of the meninges. Pathophysiology AVMs are an abnormal connection between the arteries and veins in the human brain. Arteriovenous malformations are most commonly of prenatal origin. In a normal brain oxygen enriched blood from the heart travels in sequence through smaller blood vessels going from arteries, to arterioles and then capillaries. Oxygen is removed in the latter vessel to be used by the brain. After the oxygen is removed blood reaches venules and later veins which will take it back to the heart and lungs. On the other hand, when there is an AVM blood goes directly from arteries to veins through the abnormal vessels disrupting the normal circulation of blood. Diagnosis An AVM diagnosis is established by neuroimaging studies after a complete neurological and physical examination. Three main techniques are used to visualize the brain and search for AVM: computed tomography (CT), magnetic resonance imaging (MRI), and cerebral angiography. A CT scan of the head is usually performed first when the subject is symptomatic. It can suggest the approximate site of the bleed. MRI is more sensitive than CT in the diagnosis of AVMs and provides better information about the exact location of the malformation. More detailed pictures of the tangle of blood vessels that compose an AVM can be obtained by using radioactive agents injected into the blood stream. If a CT is used in conjunctiangiogram, this is called a computerized tomography angiogram; while, if MRI is used it is called magnetic resonance angiogram. The best images of an AVM are obtained through cerebral angiography. This procedure involves using a catheter, threaded through an artery up to the head, to deliver a contrast agent into the AVM. As the contrast agent flows through the AVM structure, a sequence of X-ray images are obtained. Grading Spetzler-Martin (SM) Grade A common method of grading cerebral AVMs is the Spetzler-Martin (SM) grade. This system was designed to assess the patients risk of neurological deficit after open surgical resection (surgical morbidity), based on characteristics of the AVM itself. Based on this system, AVMs may be classified as grades 1 - 5. This system was not intended to characterize risk of hemorrhage. "Eloquent" is defined as areas within the brain that, if removed will result in loss of sensory processing or linguistic ability, minor paralysis, or paralysis. These include the basal ganglia, language cortices, sensorimotor regions, and white matter tracts. Importantly, eloquent areas are often defined differently across studies where deep cerebellar nuclei, cerebral peduncles, thalamus, hypothalamus, internal capsule, brainstem, and the visual cortex could be included. The risk of post-surgical neurological deficit (difficulty with language, motor weakness, vision loss) increases with increasing Spetzler-Martin grade. Supplemented Spetzler-Martin (SM-supp, Lawton-Young) Grade A limitation of the Spetzler-Martin Grading system is that it does not include the following factors: Patient age, hemorrhage, diffuseness of nidus, and arterial supply. In 2010 a new supplemented Spetzler-Martin system (SM-supp, Lawton-Young) was devised adding these variables to the SM system. Under this new system AVMs are classified from grades 1 - 10. It has since been determined to have greater predictive accuracy that Spetzler-Martin grades alone. Treatment Treatment depends on the location and size of the AVM and whether there is bleeding or not.The treatment in the case of sudden bleeding is focused on restoration of vital function.Medical management Anticonvulsant medications such as phenytoin are often used to control seizure; medications or procedures may be employed to relieve intracranial pressure. Eventually, curative treatment may be required to prevent recurrent hemorrhage. However, any type of intervention may also carry a risk of creating a neurological deficit.Preventive treatment of as yet unruptured brain AVMs has been controversial, as several studies suggested favorable long-term outcome for unruptured AVM patients not undergoing intervention. The NIH-funded longitudinal ARUBA study ("A Randomized trial of Unruptured Brain AVMs) compares the risk of stroke and death in patients with preventive AVM eradication versus those followed without intervention. Interim results suggest that fewer strokes occur as long as patients with unruptured AVM do not undergo intervention. Because of the higher than expected event rate in the interventional arm of the ARUBA study, NIH/NINDS stopped patient enrollment in April 2013, while continuing to follow all participants to determine whether the difference in stroke and death in the two arms changes over time.Surgical management Surgical elimination of the blood vessels involved is the preferred curative treatment for many types of AVM. Surgery is performed by a neurosurgeon who temporarily removes part of the skull (craniotomy), separates the AVM from surrounding brain tissue, and resects the abnormal vessels. While surgery can result in an immediate, complete removal of the AVM, risks exist depending on the size and the location of the malformation. The AVM must be resected en bloc, for partial resection will likely cause severe hemorrhage. The preferred treatment of Spetzler-Martin grade 1 and 2 AVMs in young, healthy patients is surgical resection due to the relatively small risk of neurological damage compared to the high lifetime risk of hemorrhage. Grade 3 AVMs may or may not be amenable to surgery. Grade 4 and 5 AVMs are not usually surgically treated.Radiosurgical management Radiosurgery has been widely used on small AVMs with considerable success. The Gamma Knife is an apparatus used to precisely apply a controlled radiation dosage to the volume of the brain occupied by the AVM. While this treatment does not require an incision and craniotomy (with their own inherent risks), three or more years may pass before the complete effects are known, during which time patients are at risk of bleeding. Complete obliteration of the AVM may or may not occur after several years, and repeat treatment may be needed. Radiosurgery is itself not without risk. In one large study, nine percent of patients had transient neurological symptoms, including headache, after radiosurgery for AVM. However, most symptoms resolved, and the long-term rate of neurological symptoms was 3.8%.Neuroendovascular therapy Embolization is performed by interventional neuroradiologists and the occlusion of blood vessels most commonly is obtained with Ethylene-vinyl alcohol copolymer (Onyx) or N-butyl cyanoacrylate (NBCA). These substances are introduced by a radiographically guided catheter, and block vessels responsible for blood flow into the AVM. Embolization is frequently used as an adjunct to either surgery or radiation treatment. Embolization reduces the size of the AVM and during surgery it reduces the risk of bleeding. However, embolization alone may completely obliterate some AVMs. In high flow intranidal fistulas balloons can also be used to reduce the flow so that embolization can be done safely. Prognosis The main risk is intracranial hemorrhage. This risk is difficult to quantify since many patients with asymptomatic AVMs will never come to medical attention. Small AVMs tend to bleed more often than do larger ones, the opposite of cerebral aneurysms. If a rupture or bleeding incident occurs, the blood may penetrate either into the brain tissue (cerebral hemorrhage) or into the subarachnoid space, which is located between the sheaths (meninges) surrounding the brain (subarachnoid hemorrhage). Bleeding may also extend into the ventricular system (intraventricular hemorrhage). Cerebral hemorrhage appears to be most common. One long-term study (mean follow up greater than 20 years) of over 150 symptomatic AVMs (either presenting with bleeding or seizures) found the risk of cerebral hemorrhage to be approximately 4% per year, slightly higher than the 2-3% seen in other studies. A simple, rough approximation of a patients lifetime bleeding risk is 105 - (patient age in years), assuming a 3% bleed risk annually. For example, a healthy 30-year-old patient would have approximately a 75% lifetime risk of at least one bleeding event. Ruptured AVMs are a significant source of morbidity and mortality; post rupture, as many as 29% of patients will die, and only 55% will be able to live independently. Epidemiology The annual new detection rate incidence of AVMs is approximately 1 per 100,000 a year. The point prevalence in adults is approximately 18 per 100,000. AVMs are more common in males than females, although in females pregnancy may start or worsen symptoms due to the increase in blood flow and volume it usually brings. There is a significant preponderance (15-20%) of AVM in patients with hereditary hemorrhagic telangiectasia (Osler–Weber–Rendu syndrome). Research directions No randomized, controlled clinical trial has established a survival benefit for treating patients (either with open surgery or radiosurgery) with AVMs that have not yet bled. References == External links ==

Varicocele

A varicocele is an abnormal enlargement of the pampiniform venous plexus in the scrotum. This plexus of veins drains blood from the testicles back to the heart. The vessels originate in the abdomen and course down through the inguinal canal as part of the spermatic cord on their way to the testis. Varicoceles occur in around 15% to 20% of all men. The incidence of varicocele increase with age. Signs and symptoms Varicocele might be noticed as soft lumps, usually above the testicle and mostly on the left side of the scrotum. Right-sided and bilateral varicocele does also occur. Men with varicocele can feel symptoms of pain or heaviness in their scrotum. Large varicoceles present as plexus of veins and may be described as "bag of worms". Varicocele is sometimes discovered when investigating the cause of male infertility. Cause There are three main theories as to the anatomical cause; the first has to do with the geometry of the veins, wherein the vein on the left side connects to the larger outflowing vein at a right angle, which tends to fail; the second is that valves that are supposed to prevent backflow fail (venous insufficiency); the third is due to excessive pressure in upstream arteries, created by nutcracker syndrome. Pathophysiology Often the greatest concern with respect to varicocele is its effect on male fertility. The relationship between varicocele and infertility is unclear. Some men with the condition are fertile, some have sperm that are normal in shape and move normally but are compromised in function, and some have sperm with abnormal shapes or that do not move well. Theories as to how varicocele affects sperm function include damage via excess heat caused by the blood pooling and oxidative stress on sperm.Tobacco smoking and mutations in the gene expressing glutathione S-transferase Mu 1 both put men at risk for infertility; these factors may also exacerbate the risk that varicocele will affect fertility. Diagnosis Following discovery of the sign of swelling comprising a mass, varicocele can be confirmed with scrotal ultrasound, which will show dilation of the vessels of the pampiniform plexus to be greater than 2 mm. Imaging Manual examination of scrotum is required for proper interpretation of ultrasound images. During ultrasound examination, diameters of veins in pampiniform plexus are measured and regurgitation is measured. The subject is then instructed to stand up and Valsalva maneuver is performed. The diameter is then measured and changes in blood flow direction is recorded to assess any regurgitation. Treatment The two most common surgical approaches are retroperitoneal (abdominal using laparoscopic surgery), infrainguinal/subinguinal (below the groin) and inguinal (groin using percutaneous embolization). Possible complications of this procedure include hematoma (bleeding into tissues), hydrocele (accumulation of fluid around the affected testicle), infection, or injury to the scrotal tissue or structures. In addition, injury to the artery that supplies the testicle may occur, resulting in a loss of a testicle. Prognosis Whether having varicocele surgery or embolization improves male fertility is controversial, as good clinical data is lacking. There is tentative evidence that varicocelectomy may improve fertility in those with obvious findings and abnormal sperm; however, this has a number needed to treat of 7 for varicocelectomy and 17 for embolization. There are also studies showing that the regular surgery has no significant effect on infertility. A 2012 Cochrane review (updated in 2021) found tentative but unclear evidence of improved fertility among males treated for varicocele. Evidence for sclerotherapy is unclear as of 2015. Epidemiology Around 15% to 20% of all adult males, up to 35% to 40% of men who are evaluated for male infertility, and around 80% of men who are infertile due to some other cause, have varicocele. == References ==

Astigmatism

Astigmatism is a type of refractive error due to rotational asymmetry in the eyes refractive power. This results in distorted or blurred vision at any distance. Other symptoms can include eyestrain, headaches, and trouble driving at night. Astigmatism often occurs at birth and can change or develop later in life. If it occurs in early life and is left untreated, it may result in amblyopia.The cause of astigmatism is unclear; however, it is believed to be partly related to genetic factors. The underlying mechanism involves an irregular curvature of the cornea or abnormalities in the lens of the eye. Diagnosis is by an eye examination, through objective and subjective refraction.Three treatment options are available: glasses, contact lenses, and surgery. Glasses are the simplest. Contact lenses can provide a wider field of vision. Refractive surgery permanently changes the shape of the eye.In Europe and Asia, astigmatism affects between 30 and 60% of adults. People of all ages can be affected by astigmatism. Astigmatism was first reported by Thomas Young in 1801. Signs and symptoms Although astigmatism may be asymptomatic, higher degrees of astigmatism may cause symptoms such as blurred vision, double vision, squinting, eye strain, fatigue, or headaches. Some research has pointed to the link between astigmatism and higher prevalence of migraine headaches. Causes Congenital The cause of congenital astigmatism is unclear, however it is believed to be partly related to genetic factors. Genetics, based on twin studies, appear to play only a small role in astigmatism as of 2007.Genome-wide association studies (GWAS) have been used to investigate the genetic foundation of astigmatism. Although no conclusive result has been shown, various candidates have been identified. In a study conducted in 2011 on various Asian populations, variants in the PDGFRA gene on chromosome 4q12 were identified to be associated with corneal astigmatism. A follow-up study in 2013 on the European population, however, found no variant significantly associated with corneal astigmatism at the genome-wide level (single-nucleotide polymorphism rs7677751 at PDGFRA). Facing the inconsistency, a study by Shah and colleagues in 2018 included both populations with Asian and Northern European ancestry. They successfully replicated the previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, with a further success of identifying three novel candidate genes: CLDN7, ACP2, and TNFAIP8L3. Other GWAS studies also provided inconclusive results: Lopes and colleagues identified a susceptibility locus with lead single nucleotide polymorphism rs3771395 on chromosome 2p13.3 in the VAX2 gene (VAX2 plays an important role in the development of the dorsoventral axis of the eye); Li and associates, however, found no consistent or strong genetic signals for refractive astigmatism while suggesting a possibility of widespread genetic co-susceptibility for spherical and astigmatic refractive errors. They also found that the TOX gene region previously identified for spherical equivalent refractive error was the second most strongly associated region. Another recent follow-up study again had identified four novel loci for corneal astigmatism, with two also being novel loci for astigmatism: ZC3H11B (associated with axial length), NPLOC4 (associated with myopia), LINC00340 (associated with spherical equivalent refractive error) and HERC2 (associated with eye color). Acquired Astigmatism may also occur following a cataract surgery or a corneal injury. Contraction of the scar due to wound or cataract extraction causes astigmatism due to flattening of the cornea in one direction. In keratoconus, progressive thinning and steepening of the cornea cause irregular astigmatism. Pathophysiology Axis of the principal meridian Regular astigmatism – principal meridians are perpendicular. (The steepest and flattest meridians of the eye are called principal meridians.) With-the-rule astigmatism – the vertical meridian is steepest (a rugby ball or American football lying on its side). Against-the-rule astigmatism – the horizontal meridian is steepest (a rugby ball or American football standing on its end). Oblique astigmatism – the steepest curve lies in between 120 and 150 degrees and 30 and 60 degrees. Irregular astigmatism – principal meridians are not perpendicular.In with-the-rule astigmatism, the eye has too much "plus" cylinder in the horizontal axis relative to the vertical axis (i.e., the eye is too "steep" along the vertical meridian relative to the horizontal meridian). Vertical beams of light focus in front (anterior) to horizontal beams of light, in the eye. This problem may be corrected using spectacles which have a "minus" cylinder placed on this horizontal axis. The effect of this will be that when a vertical beam of light in the distance travels towards the eye, the "minus" cylinder (which is placed with its axis lying horizontally – meaning in line with the patients horizontal meridian relative to the excessively steep vertical meridian) will cause this vertical beam of light to slightly "diverge", or "spread out vertically", before it reaches the eye. This compensates for the fact that the patients eye converges light more powerfully in the vertical meridian than the horizontal meridian. Hopefully, after this, the eye will focus all light on the same location at the retina, and the patients vision will be less blurred.In against-the-rule astigmatism, a plus cylinder is added in the horizontal axis (or a minus cylinder in the vertical axis).Axis is always recorded as an angle in degrees, between 0 and 180 degrees in a counter-clockwise direction. Both 0 and 180 degrees lie on a horizontal line at the level of the center of the pupil, and as seen by an observer, 0 lies on the right of both the eyes.Irregular astigmatism, which is often associated with prior ocular surgery or trauma, is also a common naturally occurring condition. The two steep hemimeridians of the cornea, 180° apart in regular astigmatism, may be separated by less than 180° in irregular astigmatism (called nonorthogonal irregular astigmatism); and/or the two steep hemimeridians may be asymmetrically steep—that is, one may be significantly steeper than the other (called asymmetric irregular astigmatism). Irregular astigmatism is quantified by a vector calculation called topographic disparity. Focus of the principal meridian With accommodation relaxed: Simple astigmatism Simple hyperopic astigmatism – first focal line is on the retina, while the second is located behind the retina. Simple myopic astigmatism – first focal line is in front of the retina, while the second is on the retina. Compound astigmatism Compound hyperopic astigmatism – both focal lines are located behind the retina. Compound myopic astigmatism – both focal lines are located in front of the retina. Mixed astigmatism – focal lines are on both sides of the retina (straddling the retina). Throughout the eye Astigmatism, whether it is regular or irregular, is caused by some combination of external (corneal surface) and internal (posterior corneal surface, human lens, fluids, retina, and eye-brain interface) optical properties. In some people, the external optics may have the greater influence, and in other people, the internal optics may predominate. Importantly, the axes and magnitudes of external and internal astigmatism do not necessarily coincide, but it is the combination of the two that by definition determines the overall optics of the eye. The overall optics of the eye are typically expressed by a persons refraction; the contribution of the external (anterior corneal) astigmatism is measured through the use of techniques such as keratometry and corneal topography. One method analyzes vectors for planning refractive surgery such that the surgery is apportioned optimally between both the refractive and topographic components. Diagnosis A number of tests are used during eye examinations to determine the presence of astigmatism and to quantify its amount and axis. A Snellen chart or other eye charts may initially reveal reduced visual acuity. A keratometer may be used to measure the curvature of the steepest and flattest meridians in the corneas front surface. Corneal topography may also be used to obtain a more accurate representation of the corneas shape. An autorefractor or retinoscopy may provide an objective estimate of the eyes refractive error and the use of Jackson cross cylinders in a phoropter or trial frame may be used to subjectively refine those measurements. An alternative technique with the phoropter requires the use of a "clock dial" or "sunburst" chart to determine the astigmatic axis and power. A keratometer may also be used to estimate astigmatism by finding the difference in power between the two primary meridians of the cornea. Javals rule can then be used to compute the estimate of astigmatism. A method of astigmatism analysis by Alpins may be used to determine both how much surgical change of the cornea is needed and after surgery to determine how close treatment was to the goal.Another rarely used refraction technique involves the use of a stenopaeic slit (a thin slit aperture) where the refraction is determined in specific meridians – this technique is particularly useful in cases where the patient has a high degree of astigmatism or in refracting patients with irregular astigmatism. Classification There are three primary types of astigmatism: myopic astigmatism, hyperopic astigmatism, and mixed astigmatism. Cases can be classified further, such as regular or irregular and lenticular or corneal. Treatment Astigmatism may be corrected with eyeglasses, contact lenses, or refractive surgery. Glasses are the simplest and safest, although contact lenses can provide a wider field of vision. Refractive surgery can eliminate the need to wear corrective lenses altogether by permanently changing the shape of the eye but, like all elective surgery, comes with both greater risk and expense than the non-invasive options. Various considerations involving eye health, refractive status, and lifestyle determine whether one option may be better than another. In those with keratoconus, certain contact lenses often enable patients to achieve better visual acuity than eyeglasses. Once only available in a rigid, gas-permeable form, toric lenses are now also available as soft lenses. In older people, astigmatism can also be corrected during cataract surgery. This can either be done by inserting a toric intraocular lens or by performing special incisions (limbal relaxing incisions). Toric intraocular lenses probably provide a better outcome with respect to astigmatism in these cases than limbal relaxing incisions.Toric intraocular lenses can additionally be used in patients with complex ophthalmic history, such as previous ophthalmic surgery. In such complex cases, toric intraocular lenses seems to be as effective as in non-complex cases for correction of concurrent corneal astigmatism. Epidemiology According to an American study, nearly three in ten children (28.4%) between the ages of five and seventeen have astigmatism. A Brazilian study published in 2005 found that 34% of the students in one city were astigmatic. Regarding the prevalence in adults, a recent study in Bangladesh found that nearly 1 in 3 (32.4%) of those over the age of 30 had astigmatism.A Polish study published in 2005 revealed "with-the-rule astigmatism" may lead to the onset of myopia.A number of studies have found the prevalence of astigmatism increases with age. History As a student, Thomas Young discovered that he had problems with one eye in 1793. In the following years he did research on his vision problems. He presented his findings in a Bakerian Lecture in 1801.Independent from Young, George Biddell Airy discovered the phenomenon of astigmatism on his own eye. Airy presented his observations on his own eye in February 1825 at the Cambridge Philosophical Society. Airy produced lenses to correct his vision problems by 1825, while other sources put this into 1827 when Airy obtained cylindrical lenses from an optician from Ipswich. The name for the condition was given by William Whewell.By the 1860s astigmatism was a well established concept in ophthalmology, and chapters in books described the discovery of astigmatism.In 1849, Irish English physicist and mathematician George Stokes invented Stokes lens to detect astigmatism. In 1887 American ophthalmologist Edward Jackson revised the Stokes lens concept and made a cross cylinder lens to refine power and axis of astigmatism. In 1907 Jackson described determination of the axis of a correcting cylinder in astigmatism using a cross cylinder. See also Near-sightedness Far-sightedness References External links The dictionary definition of astigmatism at Wiktionary Media related to Astigmatism (eye) at Wikimedia Commons Astigmatism at Curlie

Phytophotodermatitis

Phytophotodermatitis, also known as berloque dermatitis or margarita photodermatitis, is a cutaneous phototoxic inflammatory reaction resulting from contact with a light-sensitizing botanical agent followed by exposure to ultraviolet light (from the sun, for instance). Symptoms include erythema, edema, blisters (vesicles and/or bullae), and delayed hyperpigmentation. Heat and moisture tend to exacerbate the reaction. A reaction may be elicited in any person who has been exposed to adequate amounts of both a photosensitizer and ultraviolet light. Phytophotodermatitis is not an immunologic response; no prior exposure to the photosensitizing agent is required. The photosensitizing substances found in phototoxic plants belong to a class of chemical compounds called the furanocoumarins, which are activated by long-wavelength ultraviolet (UVA) light. The most toxic of these organic compounds are the linear furanocoumarins, so called since they exhibit a linear chemical structure. Bergapten and xanthotoxin (also known as methoxsalen), two linear furanocoumarins derived from psoralen, are invariably found in plants associated with phytophotodermatitis. Symptoms and signs A reaction typically begins within 24 hours of exposure and peaks at 48–72 hours after exposure. Initially, the skin turns red and starts to itch and burn. Large blisters (or bullae) form within 48 hours. The blisters may leave black, brown, or purplish scars that can last for several years. This hyperpigmentation of the skin is caused by the production of melanin triggered by the furanocoumarins. Although media reports have suggested that eye exposure to the agent can lead to temporary or permanent blindness, the risk of permanent blindness is not supported by existing research.Phytophotodermatitis can affect people of any age. In children, it has sometimes been mistaken for child abuse. Phototoxic species Plants associated with phytophotodermatitis mainly come from four plant families: the carrot family (Apiaceae), the citrus family (Rutaceae), the mulberry family (Moraceae), and the legume family (Fabaceae). Apiaceae The carrot family Apiaceae (or Umbelliferae) is the main family of plants associated with phytophotodermatitis. Of all the plant species that have been reported to induce phytophotodermatitis, approximately half belong to the family Apiaceae.False bishops weed (Ammi majus), the worlds major source of the linear furanocoumarin xanthotoxin, has been used since antiquity to treat vitiligo but accidental or inappropriate use of this plant can lead to phytophotodermatitis. Despite this danger, A. majus continues to be cultivated for its furanocoumarins, which are still used for the treatment of skin disease. Numerous species in the family Apiaceae are cultivated as food products, some of which exhibit phototoxic effects. In particular, celery, parsnip, and parsley have been reported to cause phytophotodermatitis among agricultural workers, grocery workers, and other occupational food handlers.A number of phototoxic plant species in the carrot family have become invasive species, including wild parsnip (Pastinaca sativa) and the tall hogweeds of the genus Heracleum, namely, Persian hogweed (Heracleum persicum), Sosnowskys hogweed (Heracleum sosnowskyi), and giant hogweed (Heracleum mantegazzianum). In particular, the public health risks of giant hogweed are well known.Other plant species in the family Apiaceae that are associated with phytophotodermatitis include blister bush (Notobubon galbanum), cow parsley (Anthriscus sylvestris), wild carrot (Daucus carota), various species of the genus Angelica (e.g., Korean angelica Angelica gigas), and most (if not all) species of the genus Heracleum (esp. the tall invasive hogweeds and the cow parsnips, Heracleum sphondylium and Heracleum maximum). Rutaceae The citrus family Rutaceae is the second most widely distributed family of plants associated with phytophotodermatitis. Numerous citrus fruits in the family Rutaceae exhibit phototoxic effects. Of these, perhaps the best known is lime. Phytophotodermatitis associated with limes is sometimes colloquially referred to as "lime disease," not to be confused with Lyme disease. In the family Rutaceae, the most severe reactions are caused by the essential oil of the bergamot orange (Citrus bergamia). Bergamot essential oil has a higher concentration of bergapten (3000–3600 mg/kg) than any other citrus-based essential oil, even lime oil, which contains 1700–3300 mg/kg of bergapten.Other plant species in the family Rutaceae that are associated with phytophotodermatitis include burning bush (Dictamnus albus), common rue (Ruta graveolens), and other plants in the genus Ruta. Moraceae The mulberry family Moraceae is often associated with phytophotodermatitis. Multiple species in the genus Ficus are known to exhibit phototoxic effects. Of these, the common fig (Ficus carica) is well known and thoroughly documented. Like Ammi majus in the family Apiaceae, the common fig has been used since antiquity to treat vitiligo but the milky sap of fig leaves can cause phytophotodermatitis if used accidentally or inappropriately. A literature search revealed 19 cases of fig leaf-induced phytophotodermatitis reported between 1984 and 2012. In Brazil, several hospitals reported more than 50 cases of fig leaf-induced burn in one summer. In most cases, patients reportedly used the leaves of the fig plant for folk remedies, tanning, or gardening. Other plant species in the family Moraceae that are associated with phytophotodermatitis include Ficus pumila and Brosimum gaudichaudii. Like Ficus carica, the South American species Brosimum gaudichaudii has been shown to contain both psoralen and bergapten. Prevention The first and best line of defense against phytophotodermatitis is to avoid contact with phototoxic substances in the first place: Avoid contact with the plant family Apiaceae, citrus fruits, and other biological agents known to have phototoxic effects. Do not incinerate phototoxic plants and agents since this will serve to disperse the phototoxic substances more widely. In outdoor situations where contact with phototoxic plants is likely, wear long pants and a long-sleeve shirt. Wear gloves and protective eyewear before handling such plants. If protective clothing is not available, apply sunscreen to exposed areas. This will provide some measure of protection if contact is made. After an outdoor activity, take a shower or a bath as soon as possible. Wash your clothing and then wash your hands after handling the dirty clothes.A second line of defense is to avoid sunlight, so as not to activate a phototoxic substance: If you come in contact with a phototoxic substance, immediately wash the affected area with soap and cold water, and avoid any further exposure to sunlight for at least 48 hours. Heat and moisture can worsen the skin reaction, which is why it’s important to wash the affected area with soap and cold water. Stay indoors, if possible. Be sure to avoid light shining through windows. If staying indoors is not an option, cover the affected area with sun protective clothing. In lieu of sun-protective clothing, apply sunscreen to the affected areas after washing.Phytophotodermatitis is triggered by long wavelength ultraviolet light (called UVA) in the range of 320–380 nanometers, so the best sun-protective clothing and sunscreen products will block these wavelengths of UVA radiation. In 2011, the U.S. Food and Drug Administration (FDA) established a "broad spectrum" test for determining a sunscreen products UVA protection. Sunscreen products that pass the test are allowed to be labeled as "Broad Spectrum" sunscreens, which protect against both UVA and UVB rays. There is no equivalent test or FDA-approved labeling for sun-protective clothing. Some clothing is labeled with an Ultraviolet Protection Factor (UPF) but test results from Consumer Reports suggest that UPF is an unreliable indicator of UV protection. Treatment Many different topical and oral medications may be used to treat the inflammatory reaction of phytophotodermatitis. A dermatologist may also prescribe a whitening cream to help treat the hyperpigmentation and return the skin pigmentation back to normal. If the patient does not receive treatment, the affected sites may develop permanent hyperpigmentation or hypopigmentation. History The photosensitizing effects of plants have been known since antiquity. In Egypt around 2000 B.C., the juice of Ammi majus "was rubbed on patches of vitiligo after which patients were encouraged to lie in the sun." In A.D. 50, the Greek physician Dioscorides observed that pigment would return to patches of vitiligo if "cataplasmed with ye leaves or ye boughes of ye Black Figge," an apparent reference to Ficus carica, the common fig. These ancient practices acknowledged the hyperpigmentation effects now known to accompany phytophotodermatitis. One of the earliest reports of plant-based dermatitis was given by Chaumton in 1815, who noted that the outer rind and root of cow parsnip (a common name for any Heracleum species of plant) contained an acrid sap sufficiently strong to inflame and ulcerate the skin. Similarly in 1887 Sornevin reported that Heracleum sphondylium caused dermatitis. However, neither of these early reports recognized the crucial role of ultraviolet radiation. "Berloque dermatitis" (from the French word "berloque" meaning trinket or charm) is a term coined by Rosenthal in 1925 to describe the pendant-like streaks of pigmentation observed on the neck, face, and arms of patients. He was unaware that, in 1916, Freund had correctly observed that these pigmentation effects were due to sun exposure after the use of Eau de Cologne, a perfume infused with bergamot oil. It is now known that bergamot oil contains a significant amount of bergapten, a linear furanocoumarin that gets its name from the bergamot orange. In 1937, dermatitis from Heracleum mantegazzianum was reported by Miescher and Burckhardt who suspected the possibility of light sensitization. A few years later, Kuske confirmed this hypothesis. In 1942, Klaber introduced the term "phytophotodermatitis" to emphasize that both plants and light were required to affect a reaction.Darrell Wilkinson, a British dermatologist, gave an accurate description of the disease in the 1950s. In 1961, Efremov reported 357 cases of phytophotodermatitis from Heracleum dulce (sweet cow parsnip). He "noted the requirement for sunlight in evoking the dermatitis since inunction of the juice of the plant without exposure to sunlight was harmless." Between 1962 and 1976, numerous reports of phytophotodermatitis from giant hogweed (Heracleum mantegazzianum) were reported. By 1980, the photosensitizing effects of various plant species had become well known (as evidenced by the comprehensive work of Mitchell and Rook). See also List of cutaneous conditions Photodermatitis Psoralen Photosensitivity in humans Stinging plant, plants with fragile silica hairs that inject venoms References External links Media related to Phytophotodermatitis at Wikimedia Commons

Trigonocephaly

Trigonocephaly is a congenital condition of premature fusion of the metopic suture (from the Greek metopon, "forehead"), leading to a triangular forehead. The merging of the two frontal bones leads to transverse growth restriction and parallel growth expansion. It may occur syndromic, involving other abnormalities, or isolated. The term is from the Greek trigonon, "triangle", and kephale, "head". Cause Trigonocephaly can either occur syndromatic or isolated. Trigonocephaly is associated with the following syndromes: Opitz syndrome, Muenke syndrome, Jacobsen syndrome, Baller–Gerold syndrome and Say–Meyer syndrome. The etiology of trigonocephaly is mostly unknown although there are three main theories. Trigonocephaly is probably a multifactorial congenital condition, but due to limited proof of these theories this cannot safely be concluded. Intrinsic bone malformation The first theory assumes that the origin of pathological synostosis lies within disturbed bone formation early on in the pregnancy. Causes can either be genetic (9p22–24, 11q23, 22q11, FGFR1 mutation), metabolic (TSH suppletion in hypothyroidism) or pharmaceutical (valproate in epilepsy). Fetal-head constraint The second theory says that synostosis begins when the fetal head gets hindered in the pelvic outlet during birth. Intrinsic brain malformation The third theory predominates disturbed brain formation of the two frontal lobes as the main issue behind synostosis. Limited growth of the frontal lobes leads to an absence of stimuli for cranial growth, therefore causing premature fusion of the metopic suture. Diagnosis Diagnosis can be characterized by typical facial and cranial deformities.Observatory signs of trigonocephaly are: a triangular forehead seen from top view leading to a smaller anterior cranial fossa a visible and palpable midline ridge hypotelorism inducing ethmoidal hypoplasiaImaging techniques (3D-CT, Röntgenography, MRI) show: epicanthal folds in limited cases teardrop-shaped orbits angulated towards the midline of the forehead (surprised coon sign) in severe cases a contrast difference between a röntgenograph of a normal and a trigonocephalic skull anterior curving of the metopic suture seen from lateral view of the cranium on a röntgenograph a normal cephalic index (maximum cranium width / maximum cranium length) however, there is bitemporal shortening and biparietal broadeningThe neuropsychological development is not always affected. These effects are only visible in a small percentage of children with trigonocephaly or other suture synostoses. Neuropsychological signs are: problems in behaviour, speech and language mental retardation neurodevelopmental delays such as attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), autism spectrum disorder (ASD), and conduct disorder (CD). Many of these delays become evident at school age. Treatment Treatment is surgical with attention to form and volume. Surgery usually takes place before the age of one since it has been reported that the intellectual outcome is better. Fronto-supraorbital advancement and remodelling A form of surgery is the so-called fronto-supraorbital advancement and remodelling. Firstly, the supraorbital bar is remodelled by a wired greenstick fracture to straighten it. Secondly, the supraorbital bar is moved 2 cm. forward and fixed only to the frontal process of the zygoma without fixation to the cranium. Lastly, the frontal bone is divided into two, rotated and attached to the supraorbital bar causing a nude area (craniectomy) between the parietal bone and frontal bone. Bone will eventually regenerate since the dura mater lies underneath (the dura mater has osteogenic capabilities). This results in an advancement and straightening of the forehead. Floating forehead technique The so-called floating forehead technique combined with the remodelling of the supraorbital bar is derived from the fronto-supraorbital advancement and remodelling. The supraorbital bar is remodelled as described above. The frontal bone is split in two pieces. Instead of using both pieces as in fronto-supraorbital advancement and remodelling, only one piece is rotated and attached to the supraorbital bar. This technique also leaves a craniectomy behind. Other SuturectomyThe simplest form of surgery for trigonocephaly was suturectomy. However, as this technique was insufficient to correct the deformities, it is not used anymore. Distraction osteogenesisDistraction osteogenesis is based on creating more cranial space for the brain by gradually moving the bones apart. This can be achieved by using springs. Minimal invasive endoscopic surgeryThese approaches are 2D solutions for a 3D problem, therefore the results are not optimal. Distraction osteogenesis and minimal invasive endoscopic surgery are yet in experimental phase. Outcomes Surgical Trigonocephaly seems to be the most compliant form of craniosynostosis for surgery. Because of standardization of current surgical approaches there is no surgical mortality and complications are few to none. The simple suturectomy is presently insufficient to adjust the complicated growth restrictions caused by metopic synostosis. On the other hand, the fronto-supraorbital advancement and remodelling and the floating forehead technique create sufficient space for brain growth and result in a normal horizontal axis of the orbits and supraorbital bar. The fronto-supraorbital advancement and remodelling is the most used method nowadays. Over the past few years distraction osteogenesis has been gradually acknowledged since it has a positive effect on hypotelorism. Expanding the distance between the orbits using springs seems to be successful. However, there are discussions whether hypotelorism really needs to be corrected. The minimal invasive endoscopic surgery has been gaining attention since the early 90s, however, it has technical limitations (only strip craniectomy is possible). Attempts have been made to reach beyond these limits. Aesthetic Aesthetic outcome of metopic synostosis surgery is persistently good with reoperation hazards below 20%. In 1981 Anderson advised that craniofacial operations for synostosis should be as extensive as necessary after a study of 107 cases of metopic and coronal synostosis. Surgery does not provide a 100% natural outcome, mostly there will be minor irregularities. Reoperations are usually performed on more severe cases (including syndromic metopic synostosis). The hypotelorism and temporal hollowing are the most difficult to correct: the hypotelorism usually remains under corrected and a second operation is often needed for correction of temporal hollowing. Neurological The highest rate of neurological problems of single suture synostosis are seen in patients with trigonocephaly. Surgery is performed generally before the age of one because of claims of better intellectual outcome. Seemingly surgery does not influence the high incidence of neurodevelopment problems in patients with metopic synostosis. Neurological disorders such as ADHD, ASD, ODD and CD are seen in patients with trigonocephaly. These disorders are usually also associated with decreased IQ. The presence of ADHD, ASD and ODD is higher in cases with an IQ below 85. This is not the case with CD which showed an insignificant increase at an IQ below 85. Epidemiology The incidence of metopic synostosis is roughly between 1:700 and 1:15,000 newborns globally (differs per country). Trigonocephaly is seen more in males than females ranging from 2:1 to 6.5:1. Hereditary relations in metopic synostosis have been found of which 5.5% were well defined syndromic. Maternal age and a birth weight of less than 2500g may also play a role in trigonocephaly. These data are based on estimations and do not give factual information. Only one article gives valuable and reliable information regarding the incidence of metopic synostosis in the Netherlands. The incidence in the Netherlands showed an increase from 0.6 (1997) to 1.9 (2007) for every 10,000 live births. History In former times people born with malformed skulls were rejected based upon their appearance. This still persists today in various parts of the world even though the intellectual development is often normal. The Austrian physician Franz Joseph Gall presented the science of phrenology in the early 19th century through his work The Anatomy and Physiology of the Nervous System in General, and of the Brain in Particular.Hippocrates described trigonocephaly as follows: Mens heads are by no means all like to one another, nor are the sutures of the head of all men constructed in the same form. Thus, whoever has a prominence in the anterior part of the head (by prominence is meant the round protuberant part of the bone which projects beyond the rest of it), in him the sutures of the head take the form of the Greek letter tau, τ.Hermann Welcker coined the term trigonocephaly in 1862. He described a child with a V-shaped skull and a cleft lip. Popular culture Via a photo shown on a Facebook page, the mother of a child previously diagnosed with this condition recognised the symptoms and reported them to the family involved, resulting in an immediate diagnosis that medical professionals had overlooked in all earlier consultations. References == External links ==

Urogenital fistula

A urogenital fistula is an abnormal tract that exists between the urinary tract and bladder, ureters, or urethra. A urogenital fistula can occur between any of the organs and structures of the pelvic region. A fistula allows urine to continually exit through and out the urogenital tract. This can result in significant disability, interference with sexual activity, and other physical health issues, the effects of which may in turn have a negative impact on mental or emotional state, including an increase in social isolation. Urogenital fistulas vary in etiology (medical cause). Fistulas are usually caused by injury or surgery, but they can also result from malignancy, infection, prolonged and obstructed labor and deliver in childbirth, hysterectomy, radiation therapy or inflammation. Of the fistulas that develop from difficult childbirth, 97 percent occur in developing countries. Congenital urogenital fistulas are rare; only ten cases have been documented. Abnormal passageways can also exist between the vagina and the organs of the gastrointestinal system, and these may also be termed fistulas.: 673 Classification Abnormal passageways or fistulas can exist between the vagina and bladder, ureters, uterus, and rectum with the resulting passage of urine from the vagina, or intestinal gas and feces into the vagina, in the case of a vaginal–rectal fistula. These vaginal fistulas are named according to the origin of the defect: vesicovaginal urethrovaginal ureterovaginal vesicocervical vesicouterine vesicouretovaginal uterocervical vesicocervical uretercervical ureteruterineThe vagina is susceptible to fistula formation because the gastrointestinal tract and urinary system are relatively close to the vagina. A small number of vaginal fistulas are congenital. The presence of a vaginal fistula has a profound effect on the quality of life since there is little control over the passage of urine and feces through the vagina.Urogenital fistulas are often classified according to their cause: obstetric fistula, congenital fistula and iatrogenic fistula. Urogenital fistulas can be classified by size and more specific anatomical location such as upper vagina or posterior vaginal wall. Causes In developed countries, the causes of fistulas are iatrogenic (caused by surgical accidents). Physician error and lack of training contribute to the unsuccessful treatment of obstetric fistulas in developing countries. Injuries to pelvic organs are a cause of fistulas. Most of those not caused by obstructed labor develop from injuries. An example of this would be the improper placement of an instrument during a hysterectomy. Fistulas can form after long-term pessary use, hysterectomies, malignant disease and pelvic irradiation, pelvic surgery, cancer or a pelvic fracture. Fistulas are sometimes found after a cesarean section. Providers can also inadvertently cause a fistula when performing obstetric or gynecological surgery. The more training the physician has had, the less likely a uro-vaginal fistula will occur. Some women develop more than one fistula. Treatment Surgery is often needed to correct a fistula leading to the vagina. Conservative treatment with an in-dwelling catheter can be effective for small and recently formed urinary fistulas. It has a success rate of 93%. Collagen plugs are used but have been found not to be successful. The surgical treatment to correct can be approached in different ways. Surgery through the vagina is successful 90% of the time. Surgical correction can be accomplished by abdominal surgery, by laparoscopic and robot-assisted laparoscopic surgery. The various treatments vary in frequency. The transvaginal approach is used 39% of the time, transabdominal/transvesical approach is used 36% of the time, the laparoscopic/robotic approach is used to treat 15% of urogenital fistulas and a combination of transabdominal-transvaginal approach is used 3% of the time. Epidemiology Globally, 75 percent of urogenital fistulas are obstructive labor fistulas. The average age of a woman who develops a fistula due to prolonged labor is 28 years old. The average age of a woman who develops a fistula from other causes is 42 years old. Women with a small pelvis are more likely to develop a fistula. Though rare, a fistula can form after the minimally invasive oocyte retrieval part of infertility treatment. Urogenital fistulas (vesicovaginal) caused by surgical complications occur at a frequency of 0.8 per 1000. Rectovaginal fistulas Abnormal passage of stool through the vagina is caused by a rectovaginal fistula. Treatment is often surgical with the use of tissue grafts. The presence of bowel disease increases the risk of a rectovaginal fistula. An entero-vaginal fistula can form between the bowel and the vagina. Rectovaginal fistulae result from inflammatory bowel disease, Chrohns disease trauma, or iatrogenic injury and diversions to other organs. Episiotomies can cause the formation of a rectovaginal fistula. See also Reproductive organs Urinary system Urogenital triangle Vaginal cysts == References ==

Senter syndrome

Senter syndrome is a cutaneous condition characterized by similar skin changes and congenital hearing impairment to keratitis–ichthyosis–deafness syndrome, but is associated with glycogen storage leading to hepatomegaly, hepatic cirrhosis, growth failure and intellectual disability. See also HID syndrome List of cutaneous conditions References == External links ==

Stye

A stye, also known as a hordeolum, is a bacterial infection of an oil gland in the eyelid. This results in a red tender bump at the edge of the eyelid. The outside or the inside of the eyelid can be affected.The cause of a stye is usually a bacterial infection by Staphylococcus aureus. The internal ones are due to infection of the meibomian gland while the external ones are due to an infection of the gland of Zeis. A chalazion on the other hand is a blocked oil gland without infection. A chalazion is typically in the middle of the eyelid and not painful.Often a stye will go away without any specific treatment in a few days or weeks. Recommendations to speed improvement include warm compresses. Occasionally antibiotic eye ointment may be recommended. While these measures are often recommended, there is little evidence for use in internal styes. The frequency at which styes occur is unclear, though they may occur at any age. Signs and symptoms The first sign of a stye is a small, yellowish spot at the center of the bump that develops as pus and expands in the area.Other stye symptoms may include: A lump on the top or bottom eyelid Localized swelling of the eyelid Localized pain Redness Tenderness Crusting of the eyelid margins Burning in the eye Droopiness of the eyelid Scratchy sensation on the eyeball (itching) Blurred vision Mucous discharge in the eye Irritation of the eye Light sensitivity Tearing Discomfort during blinking Sensation of a foreign body in the eye Complications Stye complications occur in very rare cases. However, the most frequent complication of styes is progression to a chalazion that causes cosmetic deformity, corneal irritation, and often requires surgical removal. Complications may also arise from the improper surgical lancing, and mainly consist of disruption of lash growth, lid deformity or lid fistula. Large styes may interfere with ones vision. Eyelid cellulitis is another potential complication of eye styes, which is a generalized infection of the eyelid. Progression of a stye to a systemic infection (spreading throughout the body) is extremely rare, and only a few instances of such spread have been recorded. Cause A stye is caused by a bacterial infection. The bacteria are Staphylococcus aureus in about 95% of cases. The infection leads to the blocking of an oil gland at the base of the eyelash. Styes are experienced by people of all ages. Styes can be triggered by poor nutrition, sleep deprivation, lack of hygiene, lack of water, and rubbing of the eyes. Styes can be secondary to blepharitis or a deficiency in immunoglobulin. Prevention Stye prevention is closely related to proper hygiene. Proper hand washing can reduce the risks of developing not only styes, but also many other types of infections. Upon awakening, application of a warm washcloth to the eyelids for one to two minutes may be beneficial in decreasing the occurrence of styes by liquefying the contents of the oil glands of the eyelid and thereby preventing blockage.To prevent styes, cosmetics and cosmetic eye tools should not be shared among people. Like with all infections, regular hand washing is essential, and the eyes should not be rubbed or touched with unclean hands. Contaminated eye makeup should be discarded and sharing of washcloths or face towels should be curtailed, to avoid spreading the infection between individuals. Breaking the stye may spread bacteria contained in the pus and should be avoided. Treatment Most cases of styes resolve on their own within one to two weeks, without professional care. The primary treatment is application of warm compresses. As a part of self-care at home, people may cleanse the affected eyelid with tap water or with a mild, nonirritating soap or shampoo (such as baby shampoo) to help clean crusted discharge. Cleansing must be done gently and while the eyes are closed to prevent eye injuries.People with styes should avoid eye makeup (e.g., eyeliner), lotions, and wearing contact lenses, since these can aggravate and spread the infection (sometimes to the cornea). People are advised not to lance the stye themselves, as serious infection can occur. Pain relievers such as acetaminophen may be used. Antibiotics Evidence to support the use of antibiotic eye ointment is poor. Occasionally erythromycin ophthalmic ointment is recommended. Other antibiotics, such as chloramphenicol or amoxicillin may also be used. Chloramphenicol is used successfully in many parts of the world, but contains a black box warning in the United States due to concerns about aplastic anemia, which on rare occasions can be fatal. Antibiotics are normally given to people with multiple styes or with styes that do not seem to heal, and to people who have blepharitis or rosacea. Procedures Incision and drainage is performed if resolution does not begin in the next 48 hours after warm compresses are started. Medical professionals will sometimes lance a particularly persistent or irritating stye with a needle to accelerate its draining.Surgery is the last resort in stye treatment. Styes that do not respond to any type of therapies are usually surgically removed. Stye surgery is performed by an ophthalmologist, and generally under local anesthesia. The procedure consists of making a small incision on the inner or outer surface of the eyelid, depending if the stye is pointing externally or not. After the incision is made, the pus is drained out of the gland, and very small sutures are used to close the lesion. Sometimes the removed stye is sent for a histopathological examination to investigate possibility of skin cancer. Alternative medicine A 2017 Cochrane review found low-certainty evidence that acupuncture helps in hordeolum compared with antibiotics or warm compresses. There was also low-certainty evidence that acupuncture plus usual treatment may increase the chance of hordeolum getting better, though they could not rule out placebo or observer effect, since the studies reviewed either had no positive control, were not blinded, or both. Prognosis Although styes are harmless in most cases and complications are very rare, styes often recur. They do not cause intraocular damage, meaning they do not affect the eye. Styes normally heal on their own by rupturing within a few days to a week causing the relief of symptoms, but if it does not improve or it worsens within two weeks, a doctors opinion should be sought. Few people require surgery as part of stye treatment. With adequate treatment, styes tend to heal quickly and without complications. The prognosis is better if one does not attempt to squeeze or puncture the stye, as infection may spread to adjacent tissues. Also, patients are recommended to call a doctor if they encounter problems with vision, the eyelid bump becomes very painful, the stye bleeds or reoccurs, or the eyelid or eyes becomes red. Etymology The word stye (first recorded in the 17th century) is probably a back-formation from styany (first recorded in the 15th century), which in turn comes from styan plus eye, the former of which in turn comes from the old English stīġend, meaning "riser", from the verb stīgan, "to rise". The older form styan is still used in Ulster Scots today. The homonym sty found in the combination pigsty has a slightly different origin, namely it comes from the Old English stiġ-fearh—fearh (farrow) is the Old English word for "piglet"—where stiġ meant "hall" (cf. steward), possibly an early Old Norse loanword, which could be cognate with the word stīgan above.The synonymous late Latin expression is hordeolum a modulation of the word hordeolus simply related to hordeum ("barley"), after its resemblance to a barleycorn. In Czech, a sty is called ječné zrno (from ječmen "barley" and zrno "seed or grain"); in German, it is called Gerstenkorn (barleycorn). In Hebrew it is called "שעורה" Seh-oh-Ráh (Barley) See also Boil References External links Merck Manual Willmann, D.; Guier, C. P.; Patel, B. C.; Melanson, S. W. (2021). "Stye". NIH - StatPearls - Stye. StatPearls. PMID 29083787.

Vitamin deficiency

Vitamin deficiency is the condition of a long-term lack of a vitamin. When caused by not enough vitamin intake it is classified as a primary deficiency, whereas when due to an underlying disorder such as malabsorption it is called a secondary deficiency. An underlying disorder may be metabolic – as in a genetic defect for converting tryptophan to niacin – or from lifestyle choices that increase vitamin needs, such as smoking or drinking alcohol. Government guidelines on vitamin deficiencies advise certain intakes for healthy people, with specific values for women, men, babies, the elderly, and during pregnancy or breastfeeding. Many countries have mandated vitamin food fortification programs to prevent commonly occurring vitamin deficiencies.Conversely, hypervitaminosis refers to symptoms caused by vitamin intakes in excess of needs, especially for fat-soluble vitamins that can accumulate in body tissues.The history of the discovery of vitamin deficiencies progressed over centuries from observations that certain conditions – for example, scurvy – could be prevented or treated with certain foods having high content of a necessary vitamin, to the identification and description of specific molecules essential for life and health. During the 20th century, several scientists were awarded the Nobel Prize in Physiology or Medicine or the Nobel Prize in Chemistry for their roles in the discovery of vitamins. Defining deficiency A number of regions have published guidelines defining vitamin deficiencies and advising specific intakes for healthy people, with different recommendations for women, men, infants, the elderly, and during pregnancy and breast feeding including Japan, the European Union, the United States, and Canada. These documents have been updated as research is published. In the US, Recommended Dietary Allowances (RDAs) were first set in 1941 by the Food and Nutrition Board of the National Academy of Sciences. There were periodic updates, culminating in the Dietary Reference Intakes. Updated in 2016, the US Food and Drug Administration published a set of tables that define Estimated Average Requirements (EARs) and (RDAs). RDAs are higher to cover people with higher than average needs. Together, these are part of Dietary Reference Intakes. For a few vitamins, there is not sufficient information to set EARs and RDAs. For these, an Adequate Intake is shown, based on an assumption that what healthy people consume is sufficient. Countries do not always agree on the amounts of vitamins needed to safeguard against deficiency. For example, for vitamin C, the RDAs for women for Japan, the European Union (called Population Reference Intakes) and the US are 100, 95 and 75 mg/day, respectively. India sets its recommendation at 40 mg/day. Individual vitamin deficiencies Water-soluble vitamins |-abc 0.54jdb Fat-soluble vitamins Prevention Food fortification Food fortification is the process of adding micronutrients (essential trace elements and vitamins) to food as a public health policy which aims to reduce the number of people with dietary deficiencies within a population. Staple foods of a region can lack particular nutrients due to the soil of the region or from inherent inadequacy of a normal diet. Addition of micronutrients to staples and condiments can prevent large-scale deficiency diseases in these cases.As defined by the World Health Organization (WHO) and the Food and Agriculture Organization of the United Nations (FAO), fortification refers to "the practice of deliberately increasing the content of an essential micronutrient, i.e., vitamins and minerals in a food irrespective of whether the nutrients were originally in the food before processing or not, so as to improve the nutritional quality of the food supply and to provide a public health benefit with minimal risk to health", whereas enrichment is defined as "synonymous with fortification and refers to the addition of micronutrients to a food which are lost during processing". The Food Fortification Initiative lists all countries in the world that conduct fortification programs, and within each country, what nutrients are added to which foods. Vitamin fortification programs exist in one or more countries for folate, niacin, riboflavin, thiamin, vitamin A, vitamin B6, vitamin B12, vitamin D and vitamin E. As of 21 December 2018, 81 countries required food fortification with one or more vitamins. The most commonly fortified vitamin – as used in 62 countries – is folate; the most commonly fortified food is wheat flour. Genetic engineering Starting in 2000, rice was experimentally genetically engineered to produce higher than normal beta-carotene content, giving it a yellow/orange color. The product is referred to as golden rice (Oryza sativa). Biofortified sweet potato, maize, and cassava were other crops introduced to enhance the content of beta-carotene and certain minerals.When eaten, beta-carotene is a provitamin, converted to retinol (vitamin A). The concept is that in areas of the world where vitamin A deficiency is common, growing and eating this rice would reduce the rates of vitamin A deficiency, particularly its effect on childhood vision problems. As of 2018, fortified golden crops were still in the process of government approvals, and were being assessed for taste and education about their health benefits to improve acceptance and adoption by consumers in impoverished countries. Hypervitaminosis Some vitamins cause acute or chronic toxicity, a condition called hypervitaminosis, which occurs mainly for fat-soluble vitamins if over-consumed by excessive supplementation. Hypervitaminosis A and hypervitaminosis D are the most common examples. Vitamin D toxicity does not result from sun exposure or consuming foods rich in vitamin D, but rather from excessive intake of vitamin D supplements, possibly leading to hypercalcemia, nausea, weakness, and kidney stones.The United States, European Union and Japan, among other countries, have established "tolerable upper intake levels" for those vitamins which have documented toxicity. History In 1747, the Scottish surgeon James Lind discovered that citrus foods helped prevent scurvy, a particularly deadly disease in which collagen is not properly formed, causing poor wound healing, bleeding of the gums, severe pain, and death. In 1753, Lind published his Treatise on the Scurvy, which recommended using lemons and limes to avoid scurvy, which was adopted by the British Royal Navy. This led to the nickname limey for British sailors. Linds discovery, however, was not widely accepted by individuals in the Royal Navys Arctic expeditions in the 19th century, where it was widely believed that scurvy could be prevented by practicing good hygiene, regular exercise, and maintaining the morale of the crew while on board, rather than by a diet of fresh food.During the late 18th and early 19th centuries, the use of deprivation studies allowed scientists to isolate and identify a number of vitamins. Lipid from fish oil was used to cure rickets in rats, and the fat-soluble nutrient was called "antirachitic A". Thus, the first "vitamin" bioactivity ever isolated, which cured rickets, was initially called "vitamin A"; however, the bioactivity of this compound is now called vitamin D. In 1881, Russian medical doctor Nikolai I. Lunin studied the effects of scurvy at the University of Tartu. He fed mice an artificial mixture of all the separate constituents of milk known at that time, namely the proteins, fats, carbohydrates, and salts. The mice that received only the individual constituents died, while the mice fed by milk itself developed normally. He made a conclusion that substances essential for life must be present in milk other than the known principal ingredients. However, his conclusions were rejected by his advisor, Gustav von Bunge.In East Asia, where polished white rice was the common staple food of the middle class, beriberi resulting from lack of vitamin B1 was endemic. In 1884, Takaki Kanehiro, a British-trained medical doctor of the Imperial Japanese Navy, observed that beriberi was endemic among low-ranking crew who often ate nothing but rice, but not among officers who consumed a Western-style diet. With the support of the Japanese Navy, he experimented using crews of two battleships; one crew was fed only white rice, while the other was fed a diet of meat, fish, barley, rice, and beans. The group that ate only white rice documented 161 crew members with beriberi and 25 deaths, while the latter group had only 14 cases of beriberi and no deaths. This convinced Takaki and the Japanese Navy that diet was the cause of beriberi, but they mistakenly believed that sufficient amounts of protein prevented it. That diseases could result from some dietary deficiencies was further investigated by Christiaan Eijkman, who in 1897 discovered that feeding unpolished rice instead of the polished variety to chickens helped to prevent beriberi. The following year, Frederick Hopkins postulated that some foods contained "accessory factors" — in addition to proteins, carbohydrates, fats etc. — that are necessary for the functions of the human body. Hopkins and Eijkman were awarded the Nobel Prize for Physiology or Medicine in 1929 for their discoveries. In 1910, the first vitamin complex was isolated by Japanese scientist Umetaro Suzuki, who succeeded in extracting a water-soluble complex of micronutrients from rice bran and named it aberic acid (later Orizanin). He published this discovery in a Japanese scientific journal. When the article was translated into German, the translation failed to state that it was a newly discovered nutrient, a claim made in the original Japanese article, and hence his discovery failed to gain publicity. In 1912 Polish-born biochemist Casimir Funk, working in London, isolated the same complex of micronutrients and proposed the complex be named "vitamine". It was later to be known as vitamin B3 (niacin), though he described it as "anti-beri-beri-factor" (which would today be called thiamine or vitamin B1). Funk proposed the hypothesis that other diseases, such as rickets, pellagra, coeliac disease, and scurvy could also be cured by vitamins. Max Nierenstein, a friend and reader of Biochemistry at Bristol University, reportedly suggested the "vitamine" name (from "vital amine"). The name soon became synonymous with Hopkins "accessory factors", and by the time it was shown that not all vitamins are amines the word was already ubiquitous. In 1920, Jack Cecil Drummond proposed that the final "e" be dropped to deemphasize the "amine" reference, after researchers began to suspect that not all "vitamines" (in particular, vitamin A) have an amine component.In 1930, Paul Karrer elucidated the correct structure for beta-carotene, the main precursor of vitamin A, and identified other carotenoids. Karrer and Norman Haworth confirmed Albert Szent-Györgyis discovery of ascorbic acid and made significant contributions to the chemistry of flavins, which led to the identification of lactoflavin. For their investigations on carotenoids, flavins and vitamins A and B2, Karrer and Haworth jointly received the Nobel Prize in Chemistry in 1937. In 1931, Albert Szent-Györgyi and a fellow researcher Joseph Svirbely suspected that "hexuronic acid" was actually vitamin C, and gave a sample to Charles Glen King, who proved its anti-scorbutic activity in his long-established guinea pig scorbutic assay. In 1937, Szent-Györgyi was awarded the Nobel Prize in Physiology or Medicine for this discovery. In 1938, Richard Kuhn was awarded the Nobel Prize in Chemistry for his work on carotenoids and vitamins, specifically B2 and B6. In 1943, Edward Adelbert Doisy and Henrik Dam were awarded the Nobel Prize in Physiology or Medicine for their discovery of vitamin K and its chemical structure. In 1967, George Wald was awarded the Nobel Prize in Physiology or Medicine (jointly with Ragnar Granit and Haldan Keffer Hartline) for the discovery that vitamin A could participate directly in a physiological process. See also Mineral deficiency Essential nutrient Malnutrition Vitamin Hypervitaminosis References == External links ==

Euthyroid sick syndrome

Euthyroid sick syndrome (ESS) is a state of adaptation or dysregulation of thyrotropic feedback control wherein the levels of T3 and/or T4 are abnormal, but the thyroid gland does not appear to be dysfunctional. This condition may result from allostatic responses of hypothalamus-pituitary-thyroid feedback control, dyshomeostatic disorders, drug interferences, and impaired assay characteristics in critical illness. The classical phenotype of this condition is often seen in starvation, critical illness, or patients in the intensive care unit. Similar endocrine phenotypes are observed in fetal life and in hibernating mammals. The most common hormone pattern in nonthyroidal illness syndrome is low total and free T3, elevated rT3, and normal T4 and TSH levels, although T4 and TSH suppression may occur in more severe or chronic illness. This classical pattern results from type 1 allostatic load, i.e. a stress response resulting from lacking energy, oxygen, and glutathione.An alternative phenotype with a largely inverse hormonal pattern is seen in several physiological and pathological conditions, including pregnancy, obesity, endurance training, and psychiatric diseases. It is typically associated with high-T3 syndrome, increased plasma protein binding of thyroid hormones, and an elevated set point of the homeostatic system. It represents a response to type-2 allostatic load. Classical phenotype (type 1 thyroid allostasis) Causes Causes of classical euthyroid sick syndrome include a number of acute and chronic conditions, including pneumonia, fasting, starvation, anorexia nervosa, sepsis, trauma, cardiopulmonary bypass, malignancy, stress, heart failure, hypothermia, myocardial infarction, kidney failure, cirrhosis, diabetic ketoacidosis, surgery, infection, brain injury, shock, cancer, and HIV.Outside the hospital setting, euthyroid sick syndrome (nonthyroidal illness syndrome - NTIS) has been assumed closely related with a series of chronic diseases, such as inflammatory bowel disease, chronic fatigue syndrome, and autoimmune diseases.Additionally, an NTIS-like phenotype can be present in major depressive disorder, as well as overexercise. Pathophysiology In critical illness, the activity of different deiodinases is altered. Humoral and neuronal inputs at the level of the hypothalamus may adjust the set point of thyroid homeostasis. This may play an important role in the pathogenesis of the central component of thyroid allostasis in critical illness, tumors, uremia and starvation (TACITUS). In addition, both illness and medication (e.g. salicylates and heparin) may impair plasma protein binding of thyroid hormones, resulting in reduced levels of total hormones, while free hormone concentrations may be temporarily elevated.Euthyroid sick syndrome probably represents an overlap of an allostatic response with pathologic reactions and drug interferences. Allostatic overload may result in wasting syndrome and myxedema coma. Thyroid storm, though, represents allostatic failure, where the organism is unable to develop NTIS in the situation of thyrotoxicosis. Deiodinases Three primary deiodinases are responsible for thyroid hormone conversion and breakdown. Type 1 (D1) deiodinates T4 to the biologically active T3, as well as the hormonally inactive and possibly inhibitory rT3. Type 2 (D2) converts T4 into T3, and breaks down rT3. D3 produces rT3 from T4, and breaks down T3. The balance of D2 and D3 is important for overall T3/rT3 balance.In NTIS, the concentrations of these deiodinases are altered, although whether NTIS is the cause or effect of this in peripheral tissues is unclear; in some studies, the alterations in thyroid hormone concentrations occurred before the changes in deiodinase activity. Typically, peripheral D1 and D2 are downregulated, while peripheral D3 is upregulated; this is associated with lower T4 and increased rT3. Hypothalamic-pituitary-thyroid axis downregulation Thyrotropin releasing hormone (TRH) neurons in the hypothalamus integrate global signals about the bodys energy state. They may be stimulated by signals such as leptin, alpha-MSH, and catecholamines; and inhibited by glucocorticoids, neuropeptide Y, and agouti-related peptide. In critical illness, inflammation increases tanycyte D2 in the paraventricular nucleus (PVN) of the hypothalamus, leading to local tissue hyperthyroidism. There may also be decreased central D3. This causes negative feedback on the HPT axis, and therefore reduced TRH gene expression in the PVN. This is exemplified by the common NTIS phenotype of low TSH even in the face of peripheral hypothyroidism. Cytokines Illness can cause inflammation, which often involves an increase in cytokines such as TNFa, IL-1, and IL-6. Cytokines are implicated in NTIS. IL-1β has been shown to decrease liver D1, as well as thyroid hormone receptor (THR) levels. IL-6 and TNFa downregulate D1 and suppress TSH, are negatively correlated with fT3, and are positively correlated with rT3. NF-κB also inhibits D1, and decreases the expression of Thyroid receptors α and β. IFNy inhibits thyroid and Tg release, and also inhibits the upregulation of TSH receptors. Thyroid hormone receptors In chronic liver and renal (kidney) failure, increased THR expression occurs. In contrast, in acute illness such as sepsis and trauma, decreased THR expression occurs. Thyroid hormone transporters During NTIS, alterations arise in the concentrations of thyroid hormone transporters such as MCT8 and MCT10, although whether the levels are increased or decreased depends on the study. The altered concentrations are thought to be a result of NTIS, rather than a cause; a study in rabbits showed that administering thyroid hormones normalized transporter expression. Binding proteins Decreased thyroxine-binding globulin (TBG) occurs following bypass surgery, and in chronic illness, a less effective form of TBG with lower affinity for thyroxine is synthesized. Reduced quantities of bound thyroid result, leading to decreased total thyroid measurements. Decreases in total thyroid may be more severe than alternations in free hormone levels. Drugs Dopamine and corticosteroids, commonly given in the hospital setting, can suppress TSH and suppress conversion of T4 to T3. Other drugs such as estrogen, contraceptives, salicylates, and phenytoin can alter the binding of TBG to TH, resulting in different TH concentrations. Additionally, lithium disrupts thyroid function, and thyromimetic endocrine disrupters may downregulate the HPT axis. Fasting Fasting is a common response in inflammation and critical illness. Originally, selenium deficiency as a result of malnutrition was thought to reduce D1 catalytic activity, but this theory has not been supported as a cause of NTIS. NTIS as a result of fasting may be regarded as a healthy and adaptive mechanism that reduces energy expenditure. Fasting in healthy, euthyroid people causes reduced T3 and elevated rT3, although TSH is usually unchanged. Even moderate weight loss can lower T3.This may be primarily via reduced levels of leptin (the satisfaction hormone). Low leptin levels can downregulate hypothalamic TRH neurons and cause a reduction in TSH. Ιn fasting animals, administering leptin reverses NTIS symptoms and restores thyroid hormone concentrations. In obesity, increased leptin increases TSH and T3, and lowers rT3, possibly as an attempt to increase energy expenditure and return to weight set point.Other signals associated with hunger also affect the HPT axis. Insulin and bile acids, which are elevated after a meal, lead to increased D2 activity, therefore increasing T3 and reducing rT3. Low leptin increases NPY and AGRP (associated with appetite), which inhibit TRH gene expression; this effect is enhanced by ghrelin (the hunger hormone). a-MSH stimulates TRH gene expression in the PVN. This is enhanced by leptin, and inhibited by low leptin. a-MSH is also antagonized by AGRP. Alternative phenotype (type 2 thyroid allostasis) An anti-NTIS phenotype is observed in some circumstances, wherein TSH, T3, and T4 are generally elevated rather than suppressed. This can occur during pregnancy, obesity, cold adaptation, stay in high altitudes, endurance exercise, acute psychosis, and post-traumatic stress disorder.According to newer theories, elevated concentrations of TSH and thyroid hormones in type 2 allostasis result from an up-regulated set point of the feedback loop, which ensues from increased TRH expression in the basolateral amygdala and the paraventricular nucleus of the hypothalamus in response to stress.High-T3 syndrome in thyroid carcinoma may result from autonomous thyroid hormone secretion or overexpression of type 2 deiodinase in cancer cells rather than from type 2 allostasis. Conditions with mixed phenotypes Psychiatry Stress suppresses TSH, and alterations in thyroid hormone levels may arise in psychiatric illness. In major depressive disorder, an NTIS-like phenotype may be observed, with reduced T3 and increased rT3. T4 may be elevated, and TSH is usually normal, although TSHs normal circadian rhythm may be disrupted. Bipolar 1 and PTSD can exemplify an anti-NTIS phenotype, with upregulation of the HPT axis and increased T3. This may also occur during acute schizophrenic episodes. Exercise After exercise, a transient increase occurs in TSH, T4, and T3, but this is thought to be due to increased blood concentration as a result of dehydration. The effects normalize after rest. After long-term heavy strain, levels of thyroid hormones decrease. This is exacerbated by other stressors such as undernutrition and lack of sleep, such as in a military training setting. During endurance exercise, before exhaustion, elevated thyroid hormone levels may happen due to increased expected energy demand (type 2 allostatic load). Environmental conditions Cold exposure and stay at high altitude may lead to type 1 or type 2 phenotype, depending on duration and other boundary conditions (which determine whether or not stress is associated with energy deprivation). Diagnosis Affected patients may have normal, low, or slightly elevated TSH depending on the spectrum and phase of illness. Total T4 and T3 levels may be altered by binding protein abnormalities, and medications. Reverse T3 levels are generally increased, while FT3 is decreased. FT4 levels may have a transient increase, before becoming subnormal during severe illness. Correspondingly, in the majority of cases calculated sum activity of peripheral deiodinases (SPINA-GD) is reduced. Generally the levels of free T3 will be lowered, followed by the lowering of free T4 in more severe disease. Several studies described elevated concentrations of 3,5-T2, an active thyroid hormone, in NTIS. 3,5-T2 levels were also observed to correlate with concentrations of rT3 (reverse T3) in patients with euthyroid sick syndrome. NTIS is a component of a complex endocrine adaptation process, so affected patients might also have hyperprolactinemia and elevated levels of corticosteroids (especially cortisol) and growth hormone. NTIS can be difficult to distinguish from other forms of thyroid dysfunction in the hospital setting. Both NTIS and primary hypothyroidism may have reduced fT3 and fT4, and elevated TSH (which is common in the hospital, during the recovery phase of NTIS). Prescribing thyroxine to treat this may lead to lifelong thyroid overtreatment.Hyperthyroidism may be assumed due to decreased TSH and a transient fT4 increase. In some cases, this can be distinguished from NTIS by a thyroid ultrasound, which is commonly available in the hospital intensive care unit.NTIS looks similar to central hypopituitarism; both frequently have reduced TSH and thyroid hormone levels. Treatment Debate is ongoing as to whether NTIS is an adaptive or maladaptive mechanism in response to physiological stress. Some sources indicate that NTIS is beneficial as an acute-phase response, but detrimental during the chronic phase of illness. Several trials have investigated a possible therapy for NTIS, but they yielded inconsistent and partly contradictory results. This may be due to the heterogeneity of investigated populations, and to the lack of a consistent definition of NTIS.Administering exogenous T3 and T4 has variable results, but overall seems to confer no improvements to health outcome. Administering TRH to patients with chronic illness, however, seems to normalize thyroid levels and improve catabolic function.When NTIS is caused by the normal fasting response to illness, early parenteral nutrition has been shown to attenuate alterations in thyroid hormone (TSH, T3, T4, rT3) levels, whereas late parenteral nutrition exacerbates it. Late parenteral nutrition, though, also reduced complications and accelerated recovery in one study. History In 1968, a reduced T4 half-life in athletes was discovered. This was the first awareness of thyroid hormone concentration alterations that were not a result of thyroid gland or pituitary dysfunction. In 1971, they also found a transient increase in T4 during bicycle training.In 1973, Rothenbuchner et al. discovered that starvation is correlated with reduced T3 concentration. Following this, a similar phenotype was noted in patients with critical illness, tumors, and uremia.The alternative phenotype of type-2 thyroid allostasis was first predicted in 1968, when John W. Mason expected the concentrations of thyroid hormones to rise in situations of psychosocial stress. Masons postulate was later confirmed by numerous studies. See also Thyroid storm References Further reading McIver B, Gorman CA (February 1997). "Euthyroid sick syndrome: an overview". Thyroid. 7 (1): 125–32. doi:10.1089/thy.1997.7.125. PMID 9086580. == External links ==

Intertrigo

Intertrigo refers to a type of inflammatory rash (dermatitis) of the superficial skin that occurs within a persons body folds. These areas are more susceptible to irritation and subsequent infection due to factors that promote skin breakdown such as moisture, friction, and exposure to bodily secretions such as sweat, urine, or feces. Areas of the body which are more likely to be affected by intertrigo include the inframammary fold, intergluteal cleft, armpits, and spaces between the fingers or toes. Skin affected by intertrigo is more prone to infection than intact skin.The term "intertrigo" commonly refers to a secondary infection with bacteria (such as Corynebacterium minutissimum), fungi (such as Candida albicans), or viruses. A frequent manifestation is candidal intertrigo. Intertrigo occurs more often in warm and humid conditions. Generally, intertrigo is more common in people with a weakened immune system including children, the elderly, and immunocompromised people. The condition is also more common in people who experience urinary incontinence and decreased ability to move. Cause An intertrigo usually develops from the chafing of warm, moist skin in the areas of the inner thighs and genitalia, the armpits, under the breasts, the underside of the belly, behind the ears, and the web spaces between the toes and fingers. An intertrigo usually appears red and raw-looking, and may also itch, ooze, and be sore. Intertrigos occur more often among overweight individuals, those with diabetes, those restricted to bed rest or diaper use, and those who use medical devices, like artificial limbs, that trap moisture against the skin. Also, there are several skin diseases that can cause an intertrigo to develop, such as dermatitis or inverse psoriasis. Bacterial Bacterial intertrigo can be caused by Streptococci and Corynebacterium minutissimum. Diagnosis Intertrigo can be diagnosed clinically by a medical professional after taking a thorough history and performing a detailed physical examination. Many other skin conditions can mimic intertrigos appearance including erythrasma, inverse psoriasis, scabies, pyoderma, atopic dermatitis, candidiasis, seborrheic dermatitis, and fungal infections of the superficial skin caused by Tinea versicolor or Tinea corporis. Treatment Intertrigo is treated by addressing associated infections, by removing moisture from the site, and by using substances at the site to help maintain skin integrity. If the individual is overweight, losing weight may also help. Relapses of intertrigo are common.Keeping the area of the intertrigo dry and exposed to the air can help prevent recurrences, as can removing moisture from the area using absorbent fabrics or body powders, including plain cornstarch and judiciously used antiperspirants.Greases, oils, and barrier ointments may help by protecting skin from moisture and from friction. Antifungal powders, most commonly clotrimazole 1%, may also be used in conjunction with a barrier ointment. Diaper rash ointment can also help.Fungal infections associated with intertrigo may be treated with prescription antifungals applied directly to the skin (in most cases) or systemic antifungals, including fluconazole, nystatin, and griseofulvin.Intertrigo is also a known symptom of vitamin B6 deficiency. See also Diaper rash List of skin diseases References External links A.O.C.D.: Intertrigo eMedicine: Intertrigo (by Samuel Selden, M.D.) DERMAdoctor: Intertrigo (by Audrey Kunin, M.D.)

Palmoplantar keratoderma

Palmoplantar keratodermas are a heterogeneous group of disorders characterized by abnormal thickening of the stratum corneum of the palms and soles. Autosomal recessive, dominant, X-linked, and acquired forms have all been described.: 505 : 211 Types Clinically, three distinct patterns of palmoplantar keratoderma may be identified: diffuse, focal, and punctate.: 505 Diffuse Diffuse palmoplantar keratoderma is a type of palmoplantar keratoderma that is characterized by an even, thick, symmetric hyperkeratosis over the whole of the palm and sole, usually evident at birth or in the first few months of life.: 505  Restated, diffuse palmoplantar keratoderma is an autosomal dominant disorder in which hyperkeratosis is confined to the palms and soles. The two major types can have a similar clinical appearance: Diffuse epidermolytic palmoplantar keratoderma (also known as "Palmoplantar keratoderma cum degeneratione granulosa Vörner," "Vörners epidermolytic palmoplantar keratoderma", and "Vörner keratoderma") is one of the most common patterns of palmoplantar keratoderma, an autosomal dominant condition that presents within the first few months of life, characterized by a well-demarcated, symmetric thickening of palms and soles, often with a "dirty" snakeskin appearance due to underlying epidermolysis.: 506  Diffuse nonepidermolytic palmoplantar keratoderma (also known as "Diffuse orthohyperkeratotic keratoderma," "Hereditary palmoplantar keratoderma," "Keratosis extremitatum progrediens," "Keratosis palmoplantaris diffusa circumscripta," "Tylosis," "Unna–Thost disease", and "Unna–Thost keratoderma") is inherited as an autosomal dominant condition and is present from infancy, characterized by a well-demarcated, symmetric, often "waxy" keratoderma involving the whole of the palms and soles.: 506–8 : 213 Focal Focal palmoplantar keratoderma, a type of palmoplantar keratoderma in which large, compact masses of keratin develop at sites of recurrent friction, principally on the feet, although also on the palms and other sites, a pattern of calluses that may be discoid (nummular) or linear. Focal palmoplantar keratoderma with oral mucosal hyperkeratosis (also known as "Focal epidermolytic palmoplantar keratoderma," "Hereditary painful callosities," "Hereditary painful callosity syndrome," "Keratosis follicularis," "Keratosis palmoplantaris nummularis", and "Nummular epidermolytic palmoplantar keratoderma") is an autosomal dominant keratoderma that represents a clinical overlap syndrome with pachyonychia congenita type I but without the classic nail involvement.: 510 Punctate Punctate palmoplantar keratoderma is a form of palmoplantar keratoderma in which many tiny "raindrop" keratoses involve the palmoplantar surface, skin lesions which may involve the whole of the palmoplantar surface, or may be more restricted in their distribution.: 505  Type 1: Keratosis punctata palmaris et plantaris (also known as "Autosomal-dominant hereditary punctate keratoderma associated with malignancy," "Buschke–Fischer–Brauer disease," "Davis Colley disease," "Keratoderma disseminatum palmaris et plantaris," "Keratosis papulosa," "Keratoderma punctatum," "Keratodermia punctata," "Keratoma hereditarium dissipatum palmare et plantare," "Palmar and plantar seed dermatoses," "Palmar keratoses," "Papulotranslucent acrokeratoderma," "Punctate keratoderma," "Punctate keratoses of the palms and soles," and "Maculosa disseminata") is a skin condition, an autosomal dominant palmoplantar keratoderma with variable penetrance, characterized clinically by multiple, tiny, punctate keratoses over the entire palmoplantar surfaces, beginning over the lateral edge of the digits.: 509 : 212–213  It has been linked to 15q22-q24. Type 2: Spiny keratoderma (also known as "Porokeratosis punctata palmaris et plantaris," "Punctate keratoderma," and "Punctate porokeratosis of the palms and soles") is an autosomal dominant keratoderma of late onset that develops in patients aged 12 to 50, characterized by multiple tiny keratotic plugs, resembling the spines on a music box, involving the entire palmoplantar surfaces.: 509  Type 3: Focal acral hyperkeratosis (also known as "Acrokeratoelastoidosis lichenoides," and "Degenerative collagenous plaques of the hand") is a late-onset keratoderma, inherited as an autosomal dominant condition, characterized by oval or polygonal crateriform papules developing along the border of the hands, feet, and wrists.: 509  It is considered similar to Costa acrokeratoelastoidosis. Ungrouped Palmoplantar keratoderma and spastic paraplegia (also known as "Charcot–Marie–Tooth disease with palmoplantar keratoderma and nail dystrophy") is an autosomal dominant or x-linked dominant condition that begins in early childhood with thick focal keratoderma over the soles and, to a lesser extent, the palms.: 513  Palmoplantar keratoderma of Sybert (also known as "Greither palmoplantar keratoderma," "Greither syndrome," "Keratosis extremitatum hereditaria progrediens," "Keratosis palmoplantaris transgrediens et progrediens" "Sybert keratoderma," and "Transgrediens and progrediens palmoplantar keratoderma") is an extremely rare autosomal dominant keratoderma (a skin condition involving horn-like growths) with symmetric severe involvement of the whole palmoplantar surface in a glove-and-stocking distribution.: 509  It was characterized by Aloys Greither in 1952. It was characterized by Virginia Sybert in 1988. An autosomal recessive form which is known as Mal de Meleda has been described. This is associated with mutations in the Secreted Ly-6/uPAR-related protein 1 (SLURP1) gene. Striate palmoplantar keratoderma (also known as "Acral keratoderma," "Brünauer-Fuhs-Siemens type of palmoplantar keratoderma," "Focal non-epidermolytic palmoplantar keratoderma," "Keratosis palmoplantaris varians," "Palmoplantar keratoderma areata," "Palmoplantar keratoderma striata," "Wachter keratoderma,": 778, 785  and "Wachters palmoplantar keratoderma") is a cutaneous condition, an autosomal dominant keratoderma principally involving the soles with onset in infancy or the first few years of life.: 509 Type 1: 148700: DSG1 Type 2: 612908: DSP Type 3: 607654: KRT1 Carvajal syndrome (also known as "Striate palmoplantar keratoderma with woolly hair and cardiomyopathy" and "Striate palmoplantar keratoderma with woolly hair and left ventricular dilated cardiomyopathy,") is a cutaneous condition inherited in an autosomal recessive fashion, and due to a defect in desmoplakin.: 811  Striate palmoplantar keratoderma, woolly hair, and left ventricular dilated cardiomyopathy has been described in both autosomal dominant and autosomal recessive forms, but only the recessive forms have a clear association with dilated cardiomyopathy.: 513  The skin disease presents as a striate palmoplantar keratoderma with some nonvolar involvement, particularly at sites of pressure or abrasion.: 513  Scleroatrophic syndrome of Huriez (also known as "Huriez syndrome," "Palmoplantar keratoderma with scleroatrophy," "Palmoplantar keratoderma with sclerodactyly," "Scleroatrophic and keratotic dermatosis of the limbs," and "Sclerotylosis") is an autosomal dominant keratoderma with sclerodactyly present at birth with a diffuse symmetric keratoderma of the palms and soles.: 513 : 576  An association with 4q23 has been described. It was characterized in 1968. Vohwinkel syndrome (also known as "Keratoderma hereditaria mutilans," "Keratoma hereditaria mutilans," "Mutilating keratoderma of Vohwinkel",: 213  "Mutilating palmoplantar keratoderma") is a diffuse autosomal dominant keratoderma with onset in early infancy characterized by a honeycombed keratoderma involving the palmoplantar surfaces.: 512  Mild to moderate sensorineural hearing loss is often associated. It has been associated with GJB2. It was characterized in 1929. Olmsted syndrome (also known as "Mutilating palmoplantar keratoderma with periorificial keratotic plaques," "Mutilating palmoplantar keratoderma with periorificial plaques" and "Polykeratosis of Touraine") is a keratoderma of the palms and soles, with flexion deformity of the digits, that begins in infancy.: 510 : 214  Treatment with retinoids has been described. It has been associated with mutations in TRPV3. Aquagenic keratoderma, also known as acquired aquagenic palmoplantar keratoderma,: 788  transient reactive papulotranslucent acrokeratoderma, aquagenic syringeal acrokeratoderma, and aquagenic wrinkling of the palms, is a skin condition characterized by the development of white papules on the palms after water exposure.: 215  The condition causes irritation of the palms when touching certain materials after being wet, e.g., paper, cloth. An association with cystic fibrosis has been suggested. The association with cystic fibrosis suggests an increased salt content in the skin. Genetics Epidermolytic palmoplantar keratoderma has been associated with keratin 9 and keratin 16.Nonepidermolytic palmoplantar keratoderma has been associated with keratin 1 and keratin 16. Treatment Usually, a common form of treatment for the condition is a type of hand cream which moisturises the hard skin. Currently, the condition is incurable. See also Keratoderma List of cutaneous conditions References == External links ==

Tuberculosis cutis orificialis

Tuberculosis cutis orificialis (also known as "acute tuberculous ulcer") is a form of cutaneous tuberculosis that occurs at the mucocutaneous borders of the nose, mouth, anus, urinary meatus, and vagina, and on the mucous membrane of the mouth or tongue.: 335 See also Scrofuloderma Skin lesion List of cutaneous conditions == References ==

Lentiginosis

Lentiginosis refers to the presence of lentigines in large numbers or in a distinctive configuration. These are spotted areas created by accumulation in the skin due to sun exposure. Due to a high irregularity any distinction from randomness defines lentiginosis. Although lentigines are benign, they be the signal of an underlying problem such as progressive cardiomyopathic lentiginosis, which can cause retardation in children. See also Lentigines Skin cancer List of cutaneous conditions References == External links ==

Congenital ichthyosiform erythroderma

Congenital ichthyosiform erythroderma (CIE), also known as nonbullous congenital ichthyosiform erythroderma,: 484  is a rare type of the ichthyosis family of skin diseases which occurs in 1 in 200,000 to 300,000 births. CIE comes under the umbrella term autosomal recessive congenital ichthyosis (ARCI), which include non-syndromic congenital ichthyoses such as harlequin ichthyosis and lamellar ichthyosis. Symptoms and signs Infants are often born in a collodion membrane, a shiny, wax outer layer on the skin and usually with ectropion, a condition in which the eyelids turn outwards. When the membrane is shed, the skin is red with a generalized white scale. Palms, soles and areas on the joints are often affected with hyperkeratosis, a thickening of the layer of dead skin cells on the surface of the skin forming scales. Eclabium (eversion of the lips), ectropion and alopecia (hair loss) are more common in CIE than in lamellar ichthyosis (LI).CIE can present very similarly to LI and they often share characteristics, though the two conditions can often be differentiated by the appearance of the scales. Scales on patients with CIE are fine and white on skin with erythema while appear larger and greyer on the limbs, compared to LI where scales appear large and dark. Genetics CIE is an autosomal recessive genetic disorder. This means a child must inherit a defective pair of genes (one from each parent) to show the symptoms. Parents who are carriers of the defective genes show no symptoms but their children have a 25% chance of having CIE.There are several genetic faults which can produce CIE. Known genes involved include TGM1, ALOX12B, ALOXE3, NIPAL4, ABCA12, CYP4F22, LIPN, CERS3, PNPLA1, ST14, and CASP14. Diagnosis Diagnosis of this condition is done via: Sequencing of genes- TG1,ALOXE3, ALOX12B, NIPAL4,CYP4F2, CERS3, LIPN etc..Measuring insitu TG1 activity in cryostat sectionelectron microscopy- cholesterol clefts in stratum corneum Treatment See also Ichthyosis Lamellar ichthyosis Collodion baby List of cutaneous conditions References External links GeneReviews/NCBI/NIH/UW entry on Autosomal Recessive Congenital Ichthyosis

Focal and diffuse brain injury

Focal and diffuse brain injury are ways to classify brain injury: focal injury occurs in a specific location, while diffuse injury occurs over a more widespread area. It is common for both focal and diffuse damage to occur as a result of the same event; many traumatic brain injuries have aspects of both focal and diffuse injury. Focal injuries are commonly associated with an injury in which the head strikes or is struck by an object; diffuse injuries are more often found in acceleration/deceleration injuries, in which the head does not necessarily contact anything, but brain tissue is damaged because tissue types with varying densities accelerate at different rates. In addition to physical trauma, other types of brain injury, such as stroke, can also produce focal and diffuse injuries. There may be primary and secondary brain injury processes. Focal A focal traumatic injury results from direct mechanical forces (such as occur when the head strikes a windshield in a vehicle accident) and is usually associated with brain tissue damage visible to the naked eye. A common cause of focal injury is penetrating head injury, in which the skull is perforated, as frequently occurs in auto accidents, blows, and gunshot wounds. Focal injuries typically have symptoms that are related to the damaged area of the brain. Stroke can produce focal damage that is associated with signs and symptoms that correspond to the part of the brain that was damaged. For example, if a speech center of the brain such as Brocas area is damaged, problems with speech are common.Focal injuries include the following: Cerebral contusion is a bruise of brain tissue that commonly results from contact of the brain with the inside of the skull. Cerebral laceration is a brain injury in which the pia-arachnoid is torn. Epidural hemorrhage is bleeding between the dura mater and the skull. It is commonly associated with damage to the middle meningeal artery, often resulting from a skull fracture. Subdural hemorrhage is bleeding between the dura mater and the arachnoid. Intracerebral hemorrhage is bleeding within the brain tissue itself. Intraventricular hemorrhage is bleeding within the ventricles of the brain. Diffuse Diffuse injuries, also called multifocal injuries, include brain injury due to hypoxia, meningitis, and damage to blood vessels. Unlike focal injuries, which are usually easy to detect using imaging, diffuse injuries may be difficult to detect and define; often, much of the damage is microscopic. Diffuse injuries can result from acceleration/deceleration injuries. Rotational forces are a common cause of diffuse injuries; these forces are common in diffuse injuries such as concussion and diffuse axonal injury. The term "diffuse" has been called a misnomer, since injury is often actually multifocal, with multiple locations of injury.Diffuse injuries include the following: Diffuse axonal injury is widespread damage to the white matter of the brain that usually results from acceleration/deceleration types of injury. Ischemic brain injury resulting from an insufficient blood supply to the brain, is one of the leading causes of secondary brain damage after head trauma. Vascular injury usually causes death shortly after an injury. Although it is a diffuse type of brain injury itself, diffuse vascular injury is generally more likely to be caused by focal than diffuse injury. Swelling, commonly seen after TBI, can lead to dangerous increases in intracranial pressure. Though swelling itself is a diffuse type of injury, it can result from either focal or diffuse injury. See also Focal neurologic deficit References == External links ==

Gleichs syndrome

Gleichs syndrome is a rare disease in which the body swells up episodically (angioedema), associated with raised antibodies of the IgM type and increased numbers of eosinophil granulocytes, a type of white blood cells, in the blood (eosinophilia). It was first described in 1984.Its cause is unknown, but it is unrelated to capillary leak syndrome (which may cause similar swelling episodes) and eosinophilia-myalgia syndrome (which features eosinophilia but alternative symptoms). Some studies have shown that edema attacks are associated with degranulation (release of enzymes and mediators from eosinophils), and others have demonstrated antibodies against endothelium (cells lining blood vessels) in the condition.Gleichs syndrome is not a form of the idiopathic hypereosinophilic syndrome in that there is little or no evidence that it leads to organ damage. Rather, recent studies report that a subset of T cells (a special form of lymphocyte blood cell) found in several Gleich syndrome patients have an abnormal immunophenotype, i.e. they express CD3-, CD4+ cluster of differentiation cell surface antigens. These same aberrant T cell immunophenotypes are found in lymphocyte-variant eosinophilia, a disease in which the aberrant T cells overproduce cytokines such as interleukin 5 which simulate the proliferation of eosinophil precursor cells and are thereby responsible for the eosinophilia. It is suggested that most forms of Gleichs syndrome are due to a similar aberrant T cell mechanism and are a subtype of lymphocyte-variant eosinophilia.Gleich syndrome has a good prognosis. Attack severity may improve with steroid treatment. == References ==

Non scarring hair loss

Non scarring hair loss, also known as noncicatricial alopecia is the loss of hair without any scarring being present. There is typically little inflammation and irritation, but hair loss is significant. This is in contrast to scarring hair loss during which hair follicles are replaced with scar tissue as a result of inflammation. Hair loss may be spread throughout the scalp (diffuse) or at certain spots (focal). The loss may be sudden or gradual with accompanying stress. The most common cause is androgenetic alopecia, also known as male pattern or female pattern hair loss due to the effects of dihydrotestosterone (DHT) on the hair follicles. A variety of factors may lead to this condition such as hormonal effects, age, diet, autoimmunity, emotional stress, physical stress, drug effects, genetics, or infections. Depending on the cause, treatment options include: topical minoxidil, oral finasteride, anti-fungal medications, steroids, hair transplantation, or platelet rich plasma (PRP) therapy. Alternatives for total hair loss include the use of hairpieces or hair fibers. Signs and Symptoms Patients will notice either focal or diffuse loss of hair. This may occur due to thinning or shedding of the hair over a sudden or gradual period of time. Stress may be present, and the emotional impact of hair loss is important as it may cause significant distress. Other signs may point to specific causes of the condition. Poor diet may lead to tiredness, other side effects of chemotherapy drugs may be seen, infection can cause itching, stress may lead to pulling of hair or falling of hair. Hair loss may be present in the family, highlighting genetic causes. Causes Causes of noncicatricial alopecia can be separated based on focal or diffuse hair loss:Diffuse: Androgenetic alopecia: androgenic DHT leads to catagenic miniaturization of hair follicles. Diffuse alopecia areata: diffuse autoimmune destruction of hair follicles Alopecia totalis: unknown but thought to be autoimmune Telogen effluvium: emotional or physiologic stress Anagen effluvium: cancer treatments such as radiation and alkylating agents Dermatopathia pigmentosa reticularis: genetic autosomal dominant conditionFocal: Alopecia areata: autoimmune destruction of hair follicles Tinea capitis: fungal infection Traction alopecia: pulling force applied to hair Trichotillomania (Trichotillosis) Diagnosis There are a number of conditions that may cause non scarring hair loss and the first step is to determine the pattern: focal or diffuse. The next step is to identify if the hair loss is scarring or non scarring. A history and physical examination is necessary as this will provide clues to the ultimate diagnosis. It is essential to ask about the onset, observed pattern, hairstyles, family history, diet, and social history.Diffuse: Androgenetic alopecia: history of gradual thinning of hair and characteristic pattern. Males start to lose hair in the front and temples while females lose hair at the top of the head Diffuse alopecia areata: exclamation point hairs Alopecia totalis: concomitant loss of facial and skull hair Telogen effluvium: history of emotional or physiologic stress Anagen effluvium: history cancer treatments such as radiation and alkylating agents Dermatopathia pigmentosa reticularis: genetic autosomal dominant conditionFocal: Alopecia areata: smooth and round lesions Tinea capitis: black dots with broken hair strands, may see red, scaly lesions and swollen lymph nodes on the back of head. Traction alopecia: history of tight hairstyles and marginal hairline Trichotillomania: history of pulling hair or evidence of traumatic folliclesPull Test This test is performed to estimate the severity of hair loss and refine the differential diagnosis. A clinician grabs sections of hair and observes for active hair loss. A positive pull test is usually caused by telogen effluvium, androgenetic alopecia, and alopecia areata.Tug Test A doctor holds the top and bottom of a strand of hair and observes for a break in the middle which may be caused by a hair shaft abnormality.Card Test A part in the hair is created and a small card is placed to contrast the color of the hair and visualize thin strands of hair (seen in telogen effluvium) vs short broken strands (seen in hair shaft abnormalities).Fungal Culture Scalp is scraped and the specimen is incubated for fungal growth commonly seen in tinea capitis.Scalp biopsy If the diagnosis of hair loss is unclear or not responsive to the treatment, a scalp biopsy may be required. Scalp biopsy will show evidence of inflammation, location, and change in the follicles. This will frequently refine the diagnosis.Blood Tests In the case of suspected iron deficiency, thyroid disease, or androgen excess a blood test may be necessary to rule in these causes.Trichoscopy A new technique which allows for magnified visualization of the hair and scalp, providing a high definition, detailed look at follicles. Treatment Steroids Steroids may be used for the short-term treatment of autoimmune causes of hair loss such as alopecia areata. Topical or oral preparations may be used for a few weeks to reduce inflammation. Long term use of topical steroids has not shown benefits for growth and the use of long term oral steroids has many risks that typically outweigh the benefits.Immunotherapy Diphenylcyclopropenone or squaric acid may be used topically for the treatment of alopecia areata as an alternative to steroids. This treatment may cause a local skin reaction.Minoxidil Minoxidil is a topical treatment that comes in a solution or foam. The foam provides increased delivery of the drug and less irritation. This drug has been shown to decrease telogen and increase anagen phase of hair follicles, increase VEGF expression, and have indirect vasodilation effects. FDA has approved this drug for use in androgenetic alopecia, but frequent offlabel uses include alopecia areata, chemotherapy induced alopecia, telogen effluvium, and traction alopecia.Redensyl Redensyl is emerging as an alternative hair loss treatment containing a newly discovered molecule called dihydroquercetin-glucoside (DHQG), a compound derived from plant extracts known to target the stem cells in hair follicles and encourages the division of the cells. Still in development stage it has been approved by FDA as many of its medication are available widelyHormone modulating Androgenetic alopecia is routinely treated with drugs that alter hormonal function, in particular DHTs effects. Male pattern hair loss is treated with oral finasteride which is a 5-alpha reductase inhibitor that blocks the formation of DHT from testosterone. Finasteride may cause sexual dysfunction, but it is typically reversed upon discontinuation of the treatment. Female pattern hair loss is treated with spironolactone or flutamide that block the effects of DHT receptors.Anti-fungal Topical anti-fungal treatments such as ketoconazole and pyrithione zinc shampoo are sometimes effective for male pattern hair loss. Topical therapy is not usually effective for tinea capitis for which oral therapy with terbinafine, fluconazole, or griseofulvin is superior.PRP Patients may benefit from injections of plasma into the scalp to promote the delivery of nutrients in the plasma to the hair follicles. This has been shown to promote growth, blood supply, and collagen production.Surgical The two common surgical methods to treat hair loss are hair transplantation and scalp reduction. Hair transplantation involves the transfer of intact growing hair follicles from areas such as the back of the head to balding spots. This occurs in multiple visits as the number of transplanted follicles increased to restore a natural look. Scalp reduction is a technique that removes balding spots of skin and stretches the remaining skin that has normal hair growth. This is typically only possible in the back and top of the head and may cover up to half of the balding area. Prognosis It is important to note that treatment response to hair loss may be unpredictable and variable depending on the cause. 8.5% of patients with alopecia totalis may achieve complete recovery. Certain conditions such as tinea capitis and trichotillomania usually respond once the infection or hair pulling behaviors are stopped. Despite this many patients will achieve at least a temporary or partial recovery of hair loss. Complications Patients with hair loss are at risk for psychological conditions such as increased anxiety and depression. Autoimmune causes of hair loss may put patients at risk for other autoimmune conditions such as hypothyroidism, hyperthyroidism, and vitiligo. Alopecia areata patients may develop insulin resistance putting them at a risk for type 2 diabetes. == References ==

Chylothorax

A chylothorax is an abnormal accumulation of chyle, a type of lipid-rich lymph, in the space surrounding the lung. The lymphatics of the digestive system normally returns lipids absorbed from the small bowel via the thoracic duct, which ascends behind the esophagus to drain into the left brachiocephalic vein. If normal thoracic duct drainage is disrupted, either due to obstruction or rupture, chyle can leak and accumulate within the negative-pressured pleural space. In people on a normal diet, this fluid collection can sometimes be identified by its turbid, milky white appearance, since chyle contains emulsified triglycerides. Chylothorax is a rare but serious condition, as it signals leakage of the thoracic duct or one of its tributaries. There are many treatments, both surgical and conservative. About 2–3% of all fluid collections surrounding the lungs (pleural effusions) are chylothoraces. It is important to distinguish a chylothorax from a pseudochylothorax (a pleural effusion that happens to be high in cholesterol), which has a similar appearance visually but is caused by more chronic inflammatory processes and requires a different treatment. Signs and symptoms The symptoms of a chylothorax depend its size and the underlying cause. A small chylothorax may not cause any symptoms and only be detected on a chest X-ray performed for another reason. A large chylothorax may lead to breathlessness or a feeling of pressure in the chest, caused by fluid restricting the expansion of the lungs, although large chylothoraces may remain asymptomatic if the chylothorax has accumulated slowly, as the lungs may have had time to become used to the pressure. Fever or chest pain are not usually associated with chylothorax, as chyle does not generate inflammation by itself.On examination, chylothorax may lead to reduced breath sounds on the affected side, associated with a dull sound when the chest is tapped or percussed. In cases of postoperative chylothorax, the first sign may be persistent drainage from intercostal drains. Large chylothoraces may cause signs related to the loss of nutrients, including features of malnutrition or decreased ability to fight infections. Rapidly accumulating chylothoraces can cause a sudden drop in blood volume, leading to low blood pressure. Causes There are three main types of chylothorax: traumatic, non-traumatic, and idiopathic. Historically the most common form of chylothorax was non-traumatic, but traumatic chylothoraces now represent the majority of cases, with most arising as postoperative complications of surgery. The most common cause of non-traumatic chylothoraces is cancer. Chylothoraces can also be classified as low- or high-output based on the rate of chyle accumulation: low-output chylothoraces accumulate <500 mL of chyle per 24 hours, while high-output chylothoraces accumulate >1000 mL per 24 hours. Non-traumatic Malignancies are the most frequent cause of non-traumatic chylothorax. Cancers like chronic lymphocytic leukemia, lung cancer, lymphoma, Kaposi sarcoma, metastatic carcinoma or esophageal cancer are potential causes of chylothorax. Infectious causes are also observed, most often in developing countries. The most common cause of an infectious chylothorax is a complication of tuberculous lymphadenitis. Other possible causative infections include aortitis, histoplasmosis, and filariasis. Chylothorax can also be congenital, and may co-occur with other lymphatic malformations like lymphangiectasis and lymphangiomatosis. Other conditions like tuberous sclerosis, congenital heart disease, trisomy 21 (Down syndrome), Noonan syndrome, or Turner syndrome (missing X chromosome) are also possible causes of congenital chylothorax. Other, more rare causes of congenital chylothorax include Castlemans disease, yellow nail syndrome, Waldenströms macroglobulinemia, sarcoidosis, venous thrombosis, thoracic radiation, macroglobulinemia, amyloidosis, and a goiter. These diseases cause chylothorax by obstructing or destroying the thoracic duct. Also, parenteral nutrition has been a possible cause; a quick dose of total parenteral nutrition can overwhelm the thoracic duct, causing the chyle to leak into the surrounding pleural space. Traumatic Iatrogenic chylothorax after surgery is the most common variety of chylothorax. It is a common and serious complication of a pneumonectomy. It is especially common in surgeries requiring mediastinal dissection. The probability of chylothorax depends on the type of surgery. The surgery with the highest risk of chylothorax is an esophagostomy, with a 5-10% risk of chylothorax. Lung resection and mediastinal node dissection have the second highest risk, with 3-7% risk. Other operations like mediastinal tumor resection, thoracic aneurysm repair, sympathectomy, and any other surgeries that take place in the lower neck or the mediastinum can lead to chylothorax. Chylotharax after trauma but not after surgery has also been described after central line placement, pacemaker implantation, and embolization of a pulmonary arteriovenous malformation. Blunt trauma to the chest region is another cause of chylothorax, which has occurred after blast injuries and even simple injuries from coughing or sneezing. Mechanism The main mechanism of chylothorax is the leaking of chyle from the thoracic duct, usually caused by a disturbance affecting the structural integrity of the thoracic duct. For example, placement of a central venous catheter can potentially disrupt drainage of lymph into the subclavian veins, followed by the thoracic duct, resulting in chylothorax. The disturbances cause the pressure in the thoracic duct to increase. Soon, collateral channels form, which eventually drain into the thorax. Trauma affecting the thoracic duct is the most common disturbing mechanism. Whether a chylothorax occurs in the left or right pleural space is a consequence of the thoracic ducts anatomic location in the body and depends on the level where the duct was injured. If the thoracic duct is injured above the fifth thoracic vertebra, then a left-sided chylothorax results. Conversely, a thoracic duct injury below that level will lead to the formation of a right-sided chylothorax. Chylothoraces most commonly occur in the right pleural space (50% of cases). Left-sided and bilateral chylothoraces are less common and occur in 33% and 17% of cases, respectively.In the case of cancer, invasion into the thoracic duct or collateral lymph channels can obstruct lymph. In the case of mediastinal lymphadenopathy, the enlarged lymph node causes compression of the lymphatic channels and thoracic duct. This impedes the centripetal drainage of the flow of lymph from the edges of the lung parenchyma and pleural surfaces. This causes the chyle to ooze extensively into the pleural cavity, leading to a chylothorax. In the case of yellow nail syndrome, or lymphedema, chylothorax is caused by hypoplasia or dilation of the lymph vessels. In rare cases, like in hepatic chylothorax, chylous ascites crosses the diaphragm into the pleural cavity. In idiopathic cases like genetic disorders, the mechanism is not known. Up to three liters of chyle can easily drain into the pleural space daily. Diagnosis Chest X-rays can detect a chylothorax. It appears as a dense, homogeneous area that obscures the costophrenic and cardiophrenic angles. Ultrasounds can also detect a chylothorax, which appears as an echoic region that is isodense with no septation or loculation. However, neither a normal chest x-ray nor an ultrasound can differentiate a chylothorax from any other type of pleural effusion. The cisterna chyli can be found in a thoracic MRI, making it possible to confirm chylothorax. However, MRI is not the ideal method to scan the thorax, and so it is rarely used. Another diagnostic technique is conventional lymphangiography. It is rarely used since there are equally sensitive yet less invasive techniques available to identify a chylothorax. Lymphangiography procedures use the contrast dye agent lipiodol, which is injected into the lymphatic vessels. The chylothorax shows up on the images and identifies the source any leak in the thoracic duct.Another, more commonly used type of lymphogram is nuclear lymphoscintigraphy; this procedure requires human pentetic acid labeled Tc99m to be injected into the subcutaneous lesions of both sides of the dorsum of the foot. Then two images, anterior and posterior, are obtained using gamma-ray cameras. This test can be used with an integrated low-dose CT-scan with photon emission to get images that are more precise. Once pleural effusion is detected, a thoracentesis is recommended.The fluid of a chylothorax may appear milky, serous or serosanguineous. If the appearance of the fluid is not milky, that does not exclude a chylothorax from consideration. Since chyle is rich in triglycerides, a pleural effusion that is rich in triglycerides (>110 mg/dL) confirms the presence of a chylothorax; a pleural effusion that is low in triglyceride content (<50 mg/dL) virtually excludes the diagnosis. If a pleural effusion contains triglycerides between 50 and 110 mg/dL, analysis of the lipoprotein content of the pleural effusion to evaluate for chylomicrons is recommended. If that procedure detects chylomicrons in the fluid, that confirms a chylothorax. Chylothoraces are typically exudative and often contain a high number of lymphocytes and have low levels of the enzyme lactate dehydrogenase (LDH). However, atypical chylothoraces can occur and are transudative in 14% of cases. A milky appearance of pleural fluid is insufficient to confirm the diagnosis of chylothorax as pseudochylothoraces and empyemas can mimic this appearance. Conversely, the absence of a milky appearance does not mean a chylothorax is not present as they may instead appear serous or bloody. Treatment The treatment for chylothorax depends on the underlying cause but may include dietary modification, medication to prevent chyle formation including somatostatin/octreotide, midodrine and sirolimus, pleurodesis, and surgical treatment including ligation of the thoracic duct, pleurovenous or pleuroperitoneal shunting or thoracic duct embolization. Initial The initial treatment of a chylothorax is usually drainage of the fluid from the pleural space. This may be necessary to restore lung function compromised by the pressure exerted by the chyle on the lungs. Those with large chylothoraces may need nutritional support due to the nutrients lost, primarily to correct protein and electrolyte losses. Once the affected person is hemodynamically and nutritionally stable, then specific treatment can begin. Conservative A conservative treatment is changing diet to include fewer long-chain fatty acids, in particular free fatty acids. Since chyle is formed from these acids, chyle formation will reduce, allowing the defects to heal spontaneously. However, this can lead to fat deficiency and malnutrition over time. A possible response to this drawback is a venous fat hemorrhage, in which small and medium-chain fatty acids are given by diet, and long-chain fatty acids are given intravenously. Thoracentesis and an indwelling catheter for use at home is generally used to drain the chylothorax. If a malignant neoplastic chylothorax is present, then treatment with radiotherapy and/or chemotherapy is warranted. Surgical Surgery is indicated if the case is post-traumatic, iatrogenic, or refractory to other treatments, in which cases surgery reduces mortality by 40%. One invasive surgical intervention called a thoracic duct ligation involves closing off the thoracic ducts. Surgical pleurodesis is another option and can be undertaken if the affected person fails to respond to conservative treatment and is not a candidate for surgical intervention.Another treatment option is pleuroperitoneal shunting (creating a communication channel between the pleural space and peritoneal cavity). Since surgery to close the leak is not reliable, talc pleurodesis is recommended; in a case study of 19 people with refractory malignant chylothorax due to lymphoma, it resulted in success for all affected individuals. Chemical pleurodesis is an option, since the leaking of lymphatic fluids is stopped by irritating the lungs and chest wall, resulting in a sterile inflammation. This causes the lung and the chest wall to fuse together, thus preventing lymphatic fluids from leaking into the pleural space. Prognosis The morbidity and mortality rates associated with chylothorax have declined as treatments have improved. Malignant, bilateral, and chronic chylothoraces have an inferior prognosis to other types. Currently, the mortality and morbidity rates are about 10% if treated surgically. If cases are post-operative and treated conservatively, mortality rates approach 50%. Complications Complications of chylothorax include malnutrition, immunosuppression, dehydration, and respiratory distress. The severity of the complications depends on how quickly the chylothorax accumulated, its size, and its chronicity. Epidemiology Chylothoraces are rare and usually occur as a complication of surgeries in the neck and mediastinum. It has no gender or age predisposition. A chylothorax occurs in 0.2-1% of cardiothoracic surgeries, 5-10% of esophagostomies, and 3-7% of lung resections. Other animals Horses Chylothorax is uncommon in horses. Clinical signs and symptoms in foals include difficulty breathing, fast breathing, cough, fever, and lethargy. The fluid generally appears opalescent and milky without any odor. A line of fluid is observed on percussion and there are reduced lung sounds. To differentiate between chyle is pseudochyle, which does not clear after centrifugation. There is not much information on the treatment of chylothorax in horses. Supportive care, antimicrobials, drainage of the thorax, and dietary management have been used with success. Surgery has been done in other animals with limited success, but has not yet been reported in horses. Although success has been reported, the prognosis is relatively unknown due to the lack of data. References == External links ==

Hydroa vacciniforme

Hydroa vacciniforme (HV) is a very rare, chronic photodermatitis-type skin condition with usual onset in childhood. It was first described in 1862 by Bazin. It is sometimes called "Bazins hydroa vacciniforme". A study published in Scotland in 2000 reviewed the cases of 17 patients and estimated a prevalence of 0.34 cases per 100,000 population. In this study they reported an average age of onset of 7.9 years. Frequently the rash first appeared in the spring or summer months and involved sun-exposed skin. The rash starts as a vesicular eruption, later becoming umbilicated, and resulted in vacciniform scarring. It is most frequently found on the nose, cheeks, ears, dorsum of the hand, and arms (places that are most exposed to light). Causes Hydroa vacciniforme is commonly associated with reactivation of a latent Epstein-Barr virus (EBV) formerly acquired by an asymptomatic or infectious mononucleosis-causing infection. It is therefore classified as one of the Epstein-Barr virus-associated lymphoproliferative diseases and termed EBV+ HV. These cases of EBV+ HV may progress to another EBV+ lymphoproliferative disease such as T cell lymphoma, T cell leukemia, B cell lymphoma, and B cell leukemia. Natural History In many children hydroa vacciniforme (HV) regresses spontaneously by early adulthood. In the 29 patients followed by Iwatuski et al., 11 of the 18 with definite or probable HV were available for follow-up and all were alive without progression of their symptoms. Some had recurrent eruptions of HV. In contrast out of 11 severe patients in this study, 6 had evidence of chronic EBV infection, 5 had hypersensitivity to mosquito bites, 4 had virus-associated hemophagocytic syndrome. 6 of the severe group had natural killer cell lymphocytosis in the peripheral blood. Diagnosis Histology of the affected area commonly shows dense perivascular lymphocytic infiltration with reticulated degeneration of the epidermis. A study by Iwatsuki et al. detected Epstein-Barr virus (EBV) positive T-cells in the perivascular infiltration on biopsy in 28/29 patients tested. Antibody titers to EBV were measured in 14 of these patients and only five had abnormal antibody patterns consistent with chronic active EBV infection. Treatment Antiviral treatment has been tried with some success in a small number of patients. See also List of cutaneous conditions Epstein-Barr virus References == External links ==

Afterimage

An afterimage is an image that continues to appear in the eyes after a period of exposure to the original image. An afterimage may be a normal phenomenon (physiological afterimage) or may be pathological (palinopsia). Illusory palinopsia may be a pathological exaggeration of physiological afterimages. Afterimages occur because photochemical activity in the retina continues even when the eyes are no longer experiencing the original stimulus.The remainder of this article refers to physiological afterimages. A common physiological afterimage is the dim area that seems to float before ones eyes after briefly looking into a light source, such as a camera flash. Palinopsia is a common symptom of visual snow. Negative afterimages Negative afterimages are caused when the eyes photoreceptors, primarily known as rods and cones, adapt to overstimulation and lose sensitivity. Newer evidence suggests there is cortical contribution as well. Normally, the overstimulating image is moved to a fresh area of the retina with small eye movements known as microsaccades. However, if the image is large or the eye remains too steady, these small movements are not enough to keep the image constantly moving to fresh parts of the retina. The photoreceptors that are constantly exposed to the same stimulus will eventually exhaust their supply of photopigment, resulting in a decrease in signal to the brain. This phenomenon can be seen when moving from a bright environment to a dim one, like walking indoors on a bright snowy day. These effects are accompanied by neural adaptations in the occipital lobe of the brain that function similar to color balance adjustments in photography. These adaptations attempt to keep vision consistent in dynamic lighting. Viewing a uniform background while these adaptations are still occurring will allow an individual to see the afterimage because localized areas of vision are still being processed by the brain using adaptations that are no longer needed. The Young-Helmholtz trichromatic theory of color vision postulated that there were three types of photoreceptors in the eye, each sensitive to a particular range of visible light: short-wavelength cones, medium-wavelength cones, and long-wavelength cones. Trichromatic theory, however, can not explain all afterimage phenomena. Specifically, afterimages are the complementary hue of the adapting stimulus, and trichromatic theory fails to account for this fact.The failure of trichromatic theory to account for afterimages indicates the need for an opponent-process theory such as that articulated by Ewald Hering (1878) and further developed by Hurvich and Jameson (1957). The opponent process theory states that the human visual system interprets color information by processing signals from cones and rods in an antagonistic manner. The opponent color theory suggests that there are three opponent channels: red versus green, blue versus yellow, and black versus white. Responses to one color of an opponent channel are antagonistic to those of the other color. Therefore, a green image will produce a magenta afterimage. The green color fatigues the green photoreceptors, so they produce a weaker signal. Anything resulting in less green, is interpreted as its paired primary color, which is magenta, i.e. an equal mixture of red and blue.Example video which produces a distorted illusion after one watches it and looks away. See motion aftereffect. Positive afterimages Positive afterimages, by contrast, appear the same color as the original image. They are often very brief, lasting less than half a second. The cause of positive afterimages is not well known, but possibly reflects persisting activity in the brain when the retinal photoreceptor cells continue to send neural impulses to the occipital lobe.A stimulus which elicits a positive image will usually trigger a negative afterimage quickly via the adaptation process. To experience this phenomenon, one can look at a bright source of light and then look away to a dark area, such as by closing the eyes. At first one should see a fading positive afterimage, likely followed by a negative afterimage that may last for much longer. It is also possible to see afterimages of random objects that are not bright, only these last for a split second and go unnoticed by most people. On empty shape An afterimage in general is an optical illusion that refers to an image continuing to appear after exposure to the original image has ceased. Prolonged viewing of the colored patch induces an afterimage of the complementary color (for example, yellow color induces a bluish afterimage). The "afterimage on empty shape" effect is related to a class of effects referred to as contrast effects.In this effect, an empty (white) shape is presented on a colored background for several seconds. When the background color disappears (becomes white), an illusionary color similar to the original background is perceived within the shape. The mechanism of the effect is still unclear, and may be produced by one or two of the following mechanisms: During the presentation of the empty shape on a colored background, the colored background induces an illusory complementary color ("induced color") inside the empty shape. After the disappearance of the colored background an afterimage of the "induced color" might appear inside the "empty shape". Thus, the expected color of the shape will be complementary to the "induced color", and therefore similar to the color of the original background. After the disappearance of the colored background, an afterimage of the background is induced. This induced color has a complementary color to that of the original background. It is possible that this background afterimage induces simultaneous contrast on the "empty shape". Simultaneous contrast is a psychophysical phenomenon of the change in the appearance of a color (or an achromatic stimulus) caused by the presence of a surrounding average color (or luminance). Gallery See also Book of Optics Emmerts law Lilac chaser McCollough effect Motion aftereffect Neural adaptation Palinopsia Persistence of vision Screen burn-in Spectropia Visual perception Notes External links The Palinopsia Foundation is dedicated to increasing awareness of palinopsia, to funding research into the causes, prevention and treatments for palinopsia, and to advocating for the needs of individuals with palinopsia and their families. Eye On Vision Foundation raises money and awareness for persistent visual conditions Afterimages, a small demonstration. afterimage examples The Color Dove Illusion

Granulomatous mastitis

Granulomatous mastitis can be divided into idiopathic granulomatous mastitis (also known as granular lobular mastitis) and granulomatous mastitis occurring as a rare secondary complication of a great variety of other conditions such as tuberculosis and other infections, sarcoidosis and granulomatosis with polyangiitis. Special forms of granulomatous mastitis occur as complication of diabetes. Some cases are due to silicone injection (Silicone-induced granulomatous inflammation) or other foreign body reactions.Idiopathic granulomatous mastitis (IGM) is defined as granulomatous mastitis without any other attributable cause such as those above mentioned. It occurs on average two years and almost exclusively up to six years after pregnancy, usual age range is 17 to 42 years. Some cases have been reported that were related to drug induced hyperprolactinemia. Exceptionally rarely it has been diagnosed during pregnancy and in men.Primary presentation of any of these conditions as mastitis is very rare and in many cases probably predisposed by other breast or systemic conditions. Although granulomatous mastitis is easily confused with cancer it is a completely benign (non-cancerous) condition. Treatment is radically different for idiopathic granulomatous mastitis and other granulomatous lesions of the breast, so the precise diagnosis is therefore very important. Symptoms Patients mostly present with a hard lump in one breast without any sign of a systemic disease. Other possible symptoms include nipple retraction, pain, inflammation of the overlying skin, nipple discharge, fistula, enlarged lymph nodes, in rare case peau dorange-like changes. Presentation is mostly unilateral although a significant share of cases is bilateral, also in many cases contralateral or bilateral recurrences were documented. Several cases occurring together with fever, polyarthralgia and erythema nodosum were documented. Diagnosis Characteristic for idiopathic granulomatous mastitis are multinucleated giant cells and epithelioid histiocytes forming non-caseating granulomas around lobules. Often minor ductal and periductal inflammation is present. The lesion is in some cases very difficult to distinguish from breast cancer and other causes such as infections (tuberculosis, syphilis, corynebacterial infection, mycotic infection), autoimmune diseases (sarcoidosis, granulomatosis with polyangiitis), foreign body reaction and granulomatous reaction in a carcinoma must be excluded.The condition is diagnosed very rarely. As the diagnosis is a lengthy differential diagnosis of exclusion there is considerable uncertainty about incidence. It has been suspected that some cases diagnosed as IGM in developing countries may have other explanations. On the other hand, IGM is usually diagnosed only after complications and referral to a secondary breast care center so light cases may resolve spontaneously or after symptomatic treatment and thus never be diagnosed as IGM. As a completely pathogen free breast will be exceedingly rare even in completely healthy population there is also uncertainty when to consider pathogens as causative or as mere coincidental finding. Causes of idiopathic granulomatous mastitis Causes are not known. The histology is suggestive of an autoimmune reaction. The high rate of relapses as well as relatively high proportion of bilateral cases is highly suggestive of a systemic predisposition. Presently most evidence points towards an important role of elevated prolactin levels or overt hyperprolactinemia with additional triggers such as local trauma or irritation. Alpha 1-antitrypsin deficiency was documented in one case, interferon-alpha therapy in another case. Similar cases of granulomatous mastitis were reported in IgG4-related disease though the exact relationship to IGM remains to be elucidated. Other contributing factors of IGM were investigated such as oral contraceptives usage. Many cases were reported after use of prolactin elevating medications such as antipsychotics.Elevated prolactin levels have the direct effects of increasing secretory activity of breast lobules, maintaining tight junctions of the ductal epithelium, preventing involution of the breast gland after weaning and are known to stimulate the immune system, contributing to both physiological and pathological granulomatous lesions and non-caseating granulomas. PRL is also secreted locally in the breast and local secretion by lymphocytes may be enhanced during inflammatory reactions. Autoimmune reaction to extravasated fat and protein rich luminal fluid (denaturized milk) resulting from the secretory activity is assumed to be one of the triggers of IGM. Several other hormones can contribute to PRL signaling in the breast gland, high levels of insulin caused for example by peripheral insulin resistance (resulting from pregnancy, gestational diabetes or developing diabetes mellitus type 2) will enhance the galactogenic and antiapoptotic effects of PRL and growth hormone by acting synergistically with IGF-1. Microbiology The presence of Corynebacterium in granulomatous mastitis was first reported in 1996. Since then multiple reports have confirmed the presence of this genus in granulomatous mastitis. The most commonly isolated species is Corynebacterium kroppenstedtii. A selective medium for the isolation of this species has been described. This organism, first isolated from human sputum in 1998, requires lipids for its growth which may help to explain its association with this condition. Treatment Treatment protocols are not well established. Some sources report that approximately half of the patients will fully recover after 2–24 months management.One review recommended complete resection or corticosteroid therapy, stating also that long-term follow-up was indicated due to a high rate of recurrence. Treatment with steroids usually requires about 6 months. While some source report very good success with steroids, most report a considerable risk of recurrence after a treatment with steroids alone. Steroids are known to cause elevation of prolactin levels and increase risk of several conditions such as diabetes, and other endocrinopathies which in turn increase the risk of IGM. For surgical treatment, recurrence rates of 5-50% have been reported.Treatment with a combination of glucocorticoids and prolactin lowering medications such as bromocriptine or cabergoline was used with good success in Germany. Prolactin-lowering medication has also been reported to reduce the risk of recurrence. In cases of drug-induced hyperprolactinemia (such as antipsychotics) prolactin-sparing medication can be tried.Methotrexate alone or in combination with steroids has been used with good success. Its principal mechanism of action is immunomodulating activity, with a side effect profile that is more favorable for treating IGM.Colchicine, azathioprine, and NSAIDs have also been used. References == External links ==

Acantholytic dyskeratotic epidermal nevus

Acantholytic dyskeratotic epidermal nevus is a cutaneous condition identical to the generalized form of Dariers disease.: 849  "Acantholytic dyskeratotic epidermal nevus" is probably the same disorder.: 849 See also Acrokeratosis verruciformis List of cutaneous conditions == References ==

Acne miliaris necrotica

Acne miliaris necrotica is a rare condition consisting of follicular vesicopustules, sometimes occurring as solitary lesions that are usually very itchy. The condition affects middle aged and elderly individuals. Affected areas can include the scalp, frontal hairline, face, and chest. Causes It has been hypothesized that the body overreacts to an organism such as the S. aureus bacterium. Diagnosis Treatment There are multiple medications that are able to treat acne varioliformis. Topical Clindamycin 1% lotion or Benzoyl peroxide/clindamycin gel Erythromycin 2% gel 1% hydrocortisone cream Systemic Doxycycline 50 mg twice daily Isotretinoin 0.5 mg/kg daily See also List of cutaneous conditions References == External links ==

Heart valve dysplasia

Heart valve dysplasia is a congenital heart defect which affects the aortic, pulmonary, mitral, and tricuspid heart valves. Dysplasia of the mitral and tricuspid valves can cause leakage of blood or stenosis.Dysplasia of the mitral and tricuspid valves - also known as the atrioventricular (AV) valves - can appear as thickened, shortened, or notched valves. The chordae tendinae can be fused or thickened. The papillary muscles can be enlarged or atrophied. The cause is unknown, but genetics play a large role. Dogs and cats with tricuspid valve dysplasia often also have an open foramen ovale, an atrial septal defect, or inflammation of the right atrial epicardium. In dogs, tricuspid valve dysplasia can be similar to Ebsteins anomaly in humans.Mitral valve stenosis is one of the most common congenital heart defects in cats. In dogs, it is most commonly found in Great Danes, German Shepherd Dogs, Bull Terriers, Golden Retrievers, Newfoundlands, and Mastiffs. Tricuspid valve dysplasia is most common in the Old English Sheepdog, German Shepherd Dog, Weimaraner, Labrador Retriever, Great Pyrenees, and sometimes the Papillon. It is inherited in the Labrador Retriever.The disease and symptoms are similar to progression of acquired valve disease in older dogs. Valve leakage leads to heart enlargement, arrhythmias, and congestive heart failure. Heart valve dysplasia can be tolerated for years or progress to heart failure in the first year of life. Diagnosis is with an echocardiogram. The prognosis is poor with significant heart enlargement. == References ==

Uveitis

Uveitis () is the inflammation of the uvea, the pigmented layer that lies between the inner retina and the outer fibrous layer composed of the sclera and cornea. The uvea consists of the middle layer of pigmented vascular structures of the eye and includes the iris, ciliary body, and choroid. Uveitis is described anatomically, by the part of the eye affected, as anterior, intermediate or posterior, from front to back. In the panuveitic form, all parts are involved. The most common form is the anterior one. Symptoms include pain, floaters and blurred vision, and clinical examination may show redness and an irregular pupil, while ophthalmic examination shows dilated ciliary blood vessels and the presence of cells in the anterior chamber. Uveitis may arise spontaneously and associated with some genetic factors, or be associated with a wide range of conditions including autoimmune disease and infections. While the eye is a relatively protected environment, its immune mechanisms may be overcome resulting in inflammation and tissue destruction associated with T-cell activation. The incidence is approximately 1:4500, most commonly between the ages of 20–60. Uveitis is an ophthalmic emergency and requires a thorough examination by an ophthalmologist or optometrist, including dilation of the pupil to allow better visualisation. Urgent treatment is required to control the inflammation. Further procedures may be required to identify any underlying disease. Treatment usually involves the use of steroids, most commonly as eye drops. Any underlying disease, for instance herpes zoster (shingles) will also require treatment. While initial treatment is usually successful, complications include other ocular disorders, such as uveitic glaucoma, retinal detachment, optic nerve damage, cataracts, and in some cases, a permanent loss of vision. In the United States uveitis accounts for about 10%-20% of cases of blindness. Signs and symptoms The signs and symptoms of uveitis include the following; Anterior uveitis (Iritis) Pain in the eye(s) Redness of the eye(s) Blurred vision Photophobia Irregular pupil Signs of anterior uveitis include dilated ciliary vessels, presence of cells and flare in the anterior chamber, and keratic precipitates ("KP") on the posterior surface of the cornea. In severe inflammation there may be evidence of a hypopyon. Old episodes of uveitis are identified by pigment deposits on lens, KPs, and festooned pupil on dilation of pupil. Busacca nodules, inflammatory nodules located on the surface of the iris in granulomatous forms of anterior uveitis such as Fuchs heterochromic iridocyclitis (FHI). Synechia Intermediate uveitis Most common: Floaters, which are dark spots that float in the visual field Blurred visionIntermediate uveitis usually affects one eye. Less common is the presence of pain and photophobia. Posterior uveitis Inflammation in the back of the eye is commonly characterized by: Floaters Blurred vision Causes Uveitis is usually an isolated illness, but can be associated with many other medical conditions. In anterior uveitis, no associated condition or syndrome is found in approximately one-half of cases. However, anterior uveitis is often one of the syndromes associated with HLA-B27. Presence of this type of HLA allele has a relative risk of evolving this disease by approximately 15%.The most common form of uveitis is acute anterior uveitis (AAU). It is most commonly associated with HLA-B27, which has important features: HLA-B27 AAU can be associated with ocular inflammation alone or in association with systemic disease. HLA-B27 AAU has characteristic clinical features including male preponderance, unilateral alternating acute onset, a non-granulomatous appearance, and frequent recurrences, whereas HLA-B27 negative AAU has an equivalent male to female onset, bilateral chronic course, and more frequent granulomatous appearance. Rheumatoid arthritis is not uncommon in Asian countries as a significant association of uveitis. Noninfectious or autoimmune causes Sympathetic ophthalmia Behçet disease Crohns disease Fuchs heterochromic iridocyclitis Granulomatosis with polyangiitis HLA-B27 related uveitis Spondyloarthritis (especially seen in ankylosing spondylitis) Juvenile idiopathic arthritis Sarcoidosis Tubulointerstitial nephritis and uveitis syndrome Infectious causes Uveitis may be an immune response to fight an infection inside the eye. While representing the minority of patients with uveitis, such possible infections include: brucellosis herpesviruses (herpes zoster ophthalmicus - shingles of the eye) leptospirosis Lyme disease presumed ocular histoplasmosis syndrome syphilis toxocariasis toxoplasmic chorioretinitis tuberculosis Zika fever Associated with systemic diseases Systemic disorders that can be associated with uveitis include: Enthesitis Ankylosing spondylitis Juvenile rheumatoid arthritis psoriatic arthritis reactive arthritis Behçets disease inflammatory bowel disease Whipples disease systemic lupus erythematosus polyarteritis nodosa Kawasakis disease chronic granulomatous disease sarcoidosis multiple sclerosis Vogt–Koyanagi–Harada disease Drug related side effects Rifabutin, a derivative of Rifampin, has been shown to cause uveitis. Several reports suggest the use of quinolones, especially Moxifloxacin, may lead to uveitis. White Dot syndromes Occasionally, uveitis is not associated with a systemic condition: the inflammation is confined to the eye and has unknown cause. In some of these cases, the presentation in the eye is characteristic of a described syndrome, which are called white dot syndromes, and include the following diagnoses: acute posterior multifocal placoid pigment epitheliopathy birdshot chorioretinopathy multifocal choroiditis and panuveitis multiple evanescent white dot syndrome punctate inner choroiditis serpiginous choroiditis acute zonal occult outer retinopathy Masquerade syndromes Masquerade syndromes are those conditions that include the presence of intraocular cells but are not due to immune-mediated uveitis entities. These may be divided into neoplastic and non-neoplastic conditions. Non-neoplastic:retinitis pigmentosa intraocular foreign body juvenile xanthogranuloma retinal detachmentNeoplastic:retinoblastoma lymphoma malignant melanoma leukemia reticulum cell sarcoma Pathophysiology Immunologic factors Onset of uveitis can broadly be described as a failure of the ocular immune system and the disease results from inflammation and tissue destruction. Uveitis is driven by the Th17 T cell sub-population that bear T-cell receptors specific for proteins found in the eye. These are often not deleted centrally whether due to ocular antigen not being presented in the thymus (therefore not negatively selected) or a state of anergy is induced to prevent self targeting.Autoreactive T cells must normally be held in check by the suppressive environment produced by microglia and dendritic cells in the eye. These cells produce large amounts of TGF beta and other suppressive cytokines, including IL-10, to prevent damage to the eye by reducing inflammation and causing T cells to differentiate to inducible T reg cells. Innate immune stimulation by bacteria and cellular stress is normally suppressed by myeloid suppression while inducible Treg cells prevent activation and clonal expansion of the autoreactive Th1 and Th17 cells that possess potential to cause damage to the eye. Whether through infection or other causes, this balance can be upset and autoreactive T cells allowed to proliferate and migrate to the eye. Upon entry to the eye, these cells may be returned to an inducible Treg state by the presence of IL-10 and TGF-beta from microglia. Failure of this mechanism leads to neutrophil and other leukocyte recruitment from the peripheral blood through IL-17 secretion. Tissue destruction is mediated by non-specific macrophage activation and the resulting cytokine cascades. Serum TNF-α is significantly elevated in cases while IL-6 and IL-8 are present in significantly higher quantities in the aqueous humour in patients with both quiescent and active uveitis. These are inflammatory markers that non-specifically activate local macrophages causing tissue damage. Genetic factors The cause of non-infectious uveitis is unknown but there are some strong genetic factors that predispose disease onset including HLA-B27 and the PTPN22 genotype. Infectious agents Recent evidence has pointed to reactivation of herpes simplex, varicella zoster and other viruses as important causes of developing what was previously described as idiopathic anterior uveitis. Bacterial infection is another significant contributing factor in developing uveitis. Diagnosis Diagnosis includes dilated fundus examination to rule out posterior uveitis, which presents with white spots across the retina along with retinitis and vasculitis. Laboratory testing is usually used to diagnose specific underlying diseases, including rheumatologic tests (e.g. antinuclear antibody, rheumatoid factor) and serology for infectious diseases (Syphilis, Toxoplasmosis, Tuberculosis). Major histocompatibility antigen testing may be performed to investigate genetic susceptibility to uveitis. The most common antigens include HLA-B27, HLA-A29 (in birdshot chorioretinopathy) and HLA-B51 (in Behçet disease).Radiology X-ray may be used to show coexisting arthritis and chest X-ray may be helpful in sarcoidosis. Classification Uveitis is classified anatomically into anterior, intermediate, posterior, and panuveitic forms—based on the part of the eye primarily affected. Prior to the twentieth century, uveitis was typically referred to in English as "ophthalmia." Anterior uveitis includes iridocyclitis and iritis. Iritis is the inflammation of the anterior chamber and iris. Iridocyclitis is inflammation of the iris and ciliary body with inflammation predominantly confined to ciliary body. Anywhere from two-thirds to 90% of uveitis cases are anterior in location (iritis). This condition can occur as a single episode and subside with proper treatment or may take on a recurrent or chronic nature. Intermediate uveitis, also known as pars planitis, consists of vitritis—which is inflammation of cells in the vitreous cavity, sometimes with snowbanking, or deposition of inflammatory material on the pars plana. There are also "snowballs," which are inflammatory cells in the vitreous. Posterior uveitis or chorioretinitis is the inflammation of the retina and choroid. Pan-uveitis is the inflammation of all layers of the uvea(Iris, ciliary body and choroid). Treatment Uveitis is typically treated with glucocorticoid steroids, either as topical eye drops (prednisolone acetate) or as oral therapy. Prior to the administration of corticosteroids, corneal ulcers must be ruled out. This is typically done using a fluorescence dye test. In addition to corticosteroids, topical cycloplegics, such as atropine or homatropine, may be used. Successful treatment of active uveitis increases T-regulatory cells in the eye, which likely contributes to disease regression. In severe cases an injection of posterior subtenon triamcinolone acetate may also be given to reduce the swelling of the eye. Antimetabolite medications, such as methotrexate are often used for recalcitrant or more aggressive cases of uveitis. Experimental treatments with Infliximab or other anti-TNF infusions may prove helpful. The anti-diabetic drug metformin is reported to inhibit the process that causes the inflammation in uveitis.In the case of herpetic uveitis, anti-viral medications, such as valaciclovir or aciclovir, may be administered to treat the causative viral infection. Prognosis The prognosis is generally good for those who receive prompt diagnosis and treatment, but serious complication including cataracts, uveitic glaucoma, band keratopathy, macular edema and permanent vision loss may result if left untreated. The type of uveitis, as well as its severity, duration, and responsiveness to treatment or any associated illnesses, all factor into the outlook. Epidemiology Uveitis affects approximately 1 in 4500 people and is most common between the ages 20 to 60 with men and women affected equally. In western countries, anterior uveitis accounts for between 50% and 90% of uveitis cases. In Asian countries the proportion is between 28% and 50%. Uveitis is estimated to be responsible for approximately 10%-20% of the blindness in the United States. See also List of systemic diseases with ocular manifestations Intermediate uveitis Uveitis–Glaucoma–Hyphema syndrome References == Bibliography ==

Secondary hypertension

Secondary hypertension (or, less commonly, inessential hypertension) is a type of hypertension which by definition is caused by an identifiable underlying primary cause. It is much less common than the other type, called essential hypertension, affecting only 5-10% of hypertensive patients. It has many different causes including endocrine diseases, kidney diseases, and tumors. It also can be a side effect of many medications. Types Kidney Renovascular hypertension It has two main causes: fibromuscular dysplasia and atherosclerosis of the renal artery resulting in stenosis. See main article at Renovascular hypertension. Kidney Other well known causes include diseases of the kidney. This includes diseases such as polycystic kidney disease which is a cystic genetic disorder of the kidneys, PKD, which is characterized by the presence of multiple cysts (hence, "polycystic") in both kidneys, can also damage the liver, pancreas, and rarely, the heart and brain. It can be autosomal dominant or autosomal recessive, with the autosomal dominant form being more common and characterized by progressive cyst development and bilaterally enlarged kidneys with multiple cysts, with concurrent development of hypertension, chronic kidney disease and kidney pain. Or chronic glomerulonephritis which is a disease characterized by inflammation of the glomeruli, or small blood vessels in the kidneys.Hypertension can also be produced by diseases of the renal arteries supplying the kidney. This is known as renovascular hypertension; it is thought that decreased perfusion of renal tissue due to stenosis of a main or branch renal artery activates the renin–angiotensin system.Also, some renal tumors can cause hypertension. The differential diagnosis of a renal tumor in a young patient with hypertension includes Juxtaglomerular cell tumor, Wilms tumor, and renal cell carcinoma, all of which may produce renin. Hypertension secondary to other renal disorders Chronic kidney disease Kidney disease / renal artery stenosis – the normal physiological response to low blood pressure in the renal arteries is to increase cardiac output (CO) to maintain the pressure needed for glomerular filtration.Here, however, increased CO cannot solve the structural problems causing renal artery hypotension, with the result that CO remains chronically elevated. Renal segmental hypoplasia (Ask-Upmark kidney) Hypertension secondary to endocrine disorders Neurogenic hypertension – excessive secretion of norepinephrine and epinephrine which promotes vasoconstriction resulting from chronic high activity of the sympathoadrenal system, the sympathetic nervous system and the adrenal gland. The specific mechanism involved is increased release of the "stress hormones", epinephrine (adrenaline) and norepinephrine which increase blood output from the heart and constrict arteries. People with neurogenic hypertension respond poorly to treatment with diuretics as the underlying cause of their hypertension is not addressed.Pheochromocytoma – a tumor which results in an excessive secretion of norepinephrine and epinephrine which promotes vasoconstriction Hyperaldosteronism (Conns syndrome) – idiopathic hyperaldosteronism, liddles syndrome (also called pseudoaldosteronism), glucocorticoid remediable aldosteronism Cushings syndrome – an excessive secretion of glucocorticoids causes the hypertension Hyperparathyroidism Acromegaly Hyperthyroidism Hypothyroidism Adrenal A variety of adrenal cortical abnormalities can cause hypertension, In primary aldosteronism there is a clear relationship between the aldosterone-induced sodium retention and the hypertension.Congenital adrenal hyperplasia, a group of autosomal recessive disorders of the enzymes responsible for steroid hormone production, can lead to secondary hypertension by creating atypically high levels of mineralocorticoid steroid hormones. These mineralocorticoids cross-react with the aldosterone receptor, activating it and raising blood pressure. 17 alpha-hydroxylase deficiency causes an inability to produce cortisol. Instead, extremely high levels of the precursor hormone corticosterone are produced, some of which is converted to 11-Deoxycorticosterone (DOC), a potent mineralocorticoid not normally clinically important in humans. DOC has blood-pressure raising effects similar to aldosterone, and abnormally high levels result in hypokalemic hypertension. 11β-hydroxylase deficiency, aka apparent mineralocorticoid excess syndrome, involves a defect in the gene for 11β-hydroxysteroid dehydrogenase, an enzyme that normally inactivates circulating cortisol to the less-active metabolite cortisone. At high concentrations cortisol can cross-react and activate the mineralocorticoid receptor, leading to aldosterone-like effects in the kidney, causing hypertension. This effect can also be produced by prolonged ingestion of liquorice (which can be of potent strength in liquorice candy), by causing inhibition of the 11β-hydroxysteroid dehydrogenase enzyme and likewise leading to secondary apparent mineralocorticoid excess syndrome. Frequently, if liquorice is the cause of the high blood pressure, a low blood level of potassium will also be present. Cortisol induced hypertension cannot be completely explained by the activity of Cortisol on Aldosterone receptors. Experiments show that treatment with Spironolactone (an inhibitor of the aldosterone receptor), does not prevent hypertension with excess cortisol. It seems that inhibition of nitric oxide synthesis may also play a role in cortisol induced hypertension.Yet another related disorder causing hypertension is glucocorticoid remediable aldosteronism, which is an autosomal dominant disorder in which the increase in aldosterone secretion produced by ACTH is no longer transient, causing of primary hyperaldosteronism, the Gene mutated will result in an aldosterone synthase that is ACTH-sensitive, which is normally not. GRA appears to be the most common monogenic form of human hypertension.Compare these effects to those seen in Conns disease, an adrenocortical tumor which causes excess release of aldosterone, that leads to hypertension.Another adrenal related cause is Cushings syndrome which is a disorder caused by high levels of cortisol. Cortisol is a hormone secreted by the cortex of the adrenal glands. Cushings syndrome can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone (ACTH). More than 80% of patients with Cushings syndrome develop hypertension., which is accompanied by distinct symptoms of the syndrome, such as central obesity, lipodystrophy, moon face, sweating, hirsutism and anxiety.Neuroendocrine tumors are also a well known cause of secondary hypertension. Pheochromocytoma (most often located in the adrenal medulla) increases secretion of catecholamines such as epinephrine and norepinephrine, causing excessive stimulation of adrenergic receptors, which results in peripheral vasoconstriction and cardiac stimulation. This diagnosis is confirmed by demonstrating increased urinary excretion of epinephrine and norepinephrine and/or their metabolites (vanillylmandelic acid). Other secondary hypertension Hormonal contraceptives Neurologic disorders Obstructive sleep apnea Liquorice (when consumed in excessive amounts) Scleroderma Neurofibromatosis Pregnancy: unclear cause. Cancers: tumours in the kidney can operate in the same way as kidney disease. More commonly, however, tumors cause inessential hypertension by ectopic secretion of hormones involved in normal physiological control of blood pressure. Drugs: In particular, alcohol, nasal decongestants with adrenergic effects, NSAIDs, MAOIs, adrenoceptor stimulants, and combined methods of hormonal contraception (those containing ethinylestradiol) can cause hypertension while in use. Heavy alcohol use Steroid use Nicotine use. Malformed aorta, slow pulse, ischemia: these cause reduced blood flow to the renal arteries, with physiological responses as already outlined. Coarctation of the aorta Atherosclerosis Anemia: unclear cause. Fever: unclear cause. White coat hypertension, that is, elevated blood pressure in a clinical setting but not in other settings, probably due to the anxiety some people experience during a clinic visit. Perioperative hypertension is development of hypertension just before, during or after surgery. It may occur before surgery during the induction of anesthesia; intraoperatively e.g. by pain-induced sympathetic nervous system stimulation; in the early postanesthesia period, e.g. by pain-induced sympathetic stimulation, hypothermia, hypoxia, or hypervolemia from excessive intraoperative fluid therapy; and in the 24 to 48 hours after the postoperative period as fluid is mobilized from the extravascular space. In addition, hypertension may develop perioperatively because of discontinuation of long-term antihypertensive medication. Medication side effects Certain medications, including NSAIDs (Motrin/Ibuprofen) and steroids can cause hypertension. Other medications include estrogens (such as those found in oral contraceptives with high estrogenic activity), certain antidepressants (such as venlafaxine), buspirone, carbamazepine, bromocriptine, clozapine, and cyclosporine. High blood pressure that is associated with the sudden withdrawal of various antihypertensive medications is called rebound hypertension. The increases in blood pressure may result in blood pressures greater than when the medication was initiated. Depending on the severity of the increase in blood pressure, rebound hypertension may result in a hypertensive emergency. Rebound hypertension is avoided by gradually reducing the dose (also known as "dose tapering"), thereby giving the body enough time to adjust to reduction in dose. Medications commonly associated with rebound hypertension include centrally-acting antihypertensive agents, such as clonidine and methyl-dopa.Other herbal or "natural products" which have been associated with hypertension include Ephedra, St Johns wort, and licorice. Pregnancy Few women of childbearing age have high blood pressure, up to 11% develop hypertension of pregnancy. While generally benign, it may herald three complications of pregnancy: pre-eclampsia, HELLP syndrome and eclampsia. Follow-up and control with medication is therefore often necessary. Sleep disturbances Another common and under-recognized cause of hypertension is sleep apnea, which is often best treated with nocturnal nasal continuous positive airway pressure (CPAP), but other approaches include the Mandibular advancement splint (MAS), UPPP, tonsillectomy, adenoidectomy, septoplasty, or weight loss. Another cause is an exceptionally rare neurological disease called Binswangers disease, causing dementia; it is a rare form of multi-infarct dementia, and is one of the neurological syndromes associated with hypertension. Arsenic exposure Because of the ubiquity of arsenic in ground water supplies and its effect on cardiovascular health, low dose arsenic poisoning should be inferred as a part of the pathogenesis of idiopathic hypertension. Idiopathic and essential are both somewhat synonymous with primary hypertension. Arsenic exposure has also many of the same signs of primary hypertension such as headache, somnolence, confusion, proteinuria visual disturbances, and nausea and vomiting Potassium deficiency Due to the role of intracellular potassium in regulation of cellular pressures related to sodium, establishing potassium balance has been shown to reverse hypertension. Diagnosis The ABCDE mnemonic can be used to help determine a secondary cause of hypertension A: Accuracy, Apnea, Aldosteronism B: Bruits, Bad Kidney C: Catecholamines, Coarctation of the Aorta, Cushings Syndrome D: Drugs, Diet E: Erythropoietin, Endocrine Disorders References == External links ==

Vibration white finger

Vibration white finger (VWF), also known as hand-arm vibration syndrome (HAVS) or dead finger, is a secondary form of Raynauds syndrome, an industrial injury triggered by continuous use of vibrating hand-held machinery. Use of the term vibration white finger has generally been superseded in professional usage by broader concept of HAVS, although it is still used by the general public. The symptoms of vibration white finger are the vascular component of HAVS. HAVS is a widespread recognized industrial disease affecting tens of thousands of workers. It is a disorder that affects the blood vessels, nerves, muscles, and joints of the hand, wrist, and arm. Its best known effect is vibration-induced white finger (VWF), a term introduced by the Industrial Injury Advisory Council in 1970. Injury can occur at frequencies between 5 and 2000 Hz but the greatest risk for fingers is between 50 and 300 Hz. The total risk exposure for hand and arm is calculated by the use of ISO 5349-1, which stipulates maximum damage between 8 and 16 Hz and a rapidly declining risk at higher frequencies. The ISO 5349-1 frequency risk assessment has been criticized as corresponding poorly to observational data; more recent research suggests that medium and high frequency vibrations also increase HAVS risk. Effects Excessive exposure to hand arm vibrations can result in various patterns of diseases casually known as HAVS or VWF. This can affect nerves, joints, muscles, blood vessels or connective tissues of the hand and forearm: Tingling whiteness or numbness in the fingers (blood vessels and nerves affected): This may not be noticeable at the end of a working day, and in mild cases may affect only the tips of the fingers. As the condition becomes more severe, the whole finger down to the knuckles may become white. Feeling may also be lost. Fingers change colour (blood vessels affected): With continued exposure the person may experience periodic attacks in which the fingers change colour when exposed to the cold. Initially the fingers rapidly become pale and feeling is lost. This phase is followed by an intense red flush (sometimes preceded by a dusky bluish phase) signalling the return of blood circulation to the fingers and is usually accompanied by uncomfortable throbbing. Loss of manual dexterity (nerves and muscles affected): In more severe forms, attacks may occur frequently in cold weather, not only at work, but during leisure activities, such as gardening, car washing or even watching outdoor sports and may last up to an hour causing considerable pain and loss of manual dexterity and reduced grip strength.In extreme cases, the affected person may lose fingers. The effects are cumulative. When symptoms first appear, they may disappear after a short time. If exposure to vibration continues over months or years, the symptoms can worsen and become permanent. Prevention The Control of Vibration at Work Regulations 2005, created under the Health and Safety at Work etc. Act 1974. is the legislation in the UK that governs exposure to vibration and assists with preventing HAVS occurring. Good practice in industrial health and safety management requires that worker vibration exposure is assessed in terms of acceleration, amplitude, and duration. Using a tool that vibrates slightly for a long time can be as damaging as using a heavily vibrating tool for a short time. The duration of use of the tool is measured as trigger time, the period when the worker actually has their finger on the trigger to make the tool run, and is typically quoted in hours per day. Vibration amplitude is quoted in metres per second squared, and is measured by an accelerometer on the tool or given by the manufacturer. Amplitudes can vary significantly with tool design, condition and style of use, even for the same type of tool.In the UK, Health and Safety Executive gives the example of a hammer drill which can vary from 6 m/s² to 25 m/s². HSE publishes a list of typically observed vibration levels for various tools, and graphs of how long each day a worker can be exposed to particular vibration levels. This makes managing the risk relatively straightforward. Tools are given an Exposure Action Value (EAV, the time which a tool can be used before action needs to be taken to reduce vibration exposure) and an Exposure Limit Value (ELV, the time after which a tool may not be used).In the United States, the National Institute for Occupational Safety and Health published a similar database where values for sound power and vibrations for commonly found tools from large commercial vendors in the United States were surveyed. Further testing is underway for more and newer tools.The effect of legislation in various countries on worker vibration limits has been to oblige equipment providers to develop better-designed, better-maintained tools, and for employers to train workers appropriately. It also drives tool designers to innovate to reduce vibration. Some examples are the easily manipulated mechanical arm (EMMA) and the suspension mechanism designed into chainsaws. Anti-vibration gloves Anti vibration gloves are traditionally made with a thick and soft palm material to insulate from the vibrations. The protection is highly dependent on frequency range; most gloves provide no protection in palm and wrist below ~50 Hz and in fingers below ~400 Hz. Factors such as high grip force, cold hands or vibration forces in shear direction can have a reducing effect and or increase damage to the hands and arms. Gloves do help to keep hands warm but to get the desired effect, the frequency output from the tool must match the properties of the vibration glove that is selected. Anti-vibration gloves in many cases amplify the vibrations at frequencies lower than those mentioned in the text above. Reactive monitoring A simpler system, known as re-active monitoring, may be used by, for example, monitoring rates of usage of consumable items. Such a system was introduced by Carl West at a fabrication workshop in Rotherham, England. In this system, the vibration levels of the angle grinding tools in use was measured, as was the average life of a grinding disk. Thus by recording numbers of grinding disks used, vibration exposure may be calculated. History The symptoms were first described by Professor Giovanni Loriga in Italy in 1911, although the link was not made between the symptoms and vibrating hand tools until a study undertaken by Alice Hamilton MD in 1918. She formed her theory through following the symptoms reported by quarry cutters and carvers in Bedford, Indiana. She also discovered the link between an increase in HAV symptoms and cold weather as 1918 was a particularly harsh winter.The first scale for assessing the condition, the Taylor-Pelmear scale, was published in 1975, but it was not listed as a prescribed disease in the United Kingdom until 1985, and the Stockholm scale was introduced in 1987. In 1997, the UK High Court awarded £127,000 in compensation to seven coal miners for vibration white finger. A UK government fund set up to cover subsequent claims by ex-coalminers had exceeded £100 million in payments by 2004. See also List of cutaneous conditions Hypothenar hammer syndrome References External links BBC News article on coal miners claims "Noise and vibration". Trades Union Congress. Archived from the original on 2013-05-25. – basic facts UK Health and Safety Executive NIOSH Power Tools Sound Power and Vibrations Database HSE webpage HAV case studies

Cerebellar stroke syndrome

Cerebellar stroke syndrome is a condition in which the circulation to the cerebellum is impaired due to a lesion of the superior cerebellar artery, anterior inferior cerebellar artery or the posterior inferior cerebellar artery.Cardinal signs include vertigo, headache, vomiting, and ataxia. Cerebellar strokes account for only 2-3% of the 600,000 strokes that occur each year in the United States. They are far less common than strokes which occur in the cerebral hemispheres. In recent years mortality rates have decreased due to advancements in health care which include earlier diagnosis through MRI and CT scanning. Advancements have also been made which allow earlier management for common complications of cerebellar stroke such as brainstem compression and hydrocephalus.Research is still needed in the area of cerebellar stroke management; however, several factors may lead to poor outcomes in individuals who have a cerebellar stroke. These factors include: Declining levels of consciousness New signs of brainstem involvement Progressing Hydrocephalus Stroke to the midline of the cerebellum (a.k.a. the vermis) References Further reading Macdonell, R.A.; Kalnins, R.M.; Donnan, G.A. (1987). "Cerebellar infarction: Natural history, prognosis, and pathology". Stroke. 18 (5): 849–55. doi:10.1161/01.STR.18.5.849. PMID 3629642. Edlow, J.A.; Newman-Toker, D.E.; Savitz, S.I. (2008). "Diagnosis and initial management of cerebellar infarction". The Lancet Neurology. 7 (10): 951–64. doi:10.1016/S1474-4422(08)70216-3. PMID 18848314. S2CID 25118582. Norrving, Bo (2014). Oxford Textbook of Stroke and Cerebrovascular Disease. Oxford University Press. pp. 90–1. ISBN 9780199641208. Nowe, Tim; Jütter, Eric (2014). "Ch. 17: Critical Care of Cerebellar Stroke". In Schwab, Stefan; Hanley, Daniel; Mendelow, A. David (eds.). Critical Care of the Stroke Patient. Cambridge University Press. pp. 206–25. ISBN 9780521762564. Manto, Mario Ubaldo (2010). "Ch. 8: Cerebellar Stroke". Cerebellar Disorders: A Practical Approach to Diagnosis and Management. Cambridge University Press. pp. 88–101. ISBN 9780521878135. External links Image of cerebellar stroke Images of cerebellar stroke at MedPix

Electrical burn

An electrical burn is a burn that results from electricity passing through the body causing rapid injury. Approximately 1000 deaths per year due to electrical injuries are reported in the United States, with a mortality rate of 3-5%. Electrical burns differ from thermal or chemical burns in that they cause much more subdermal damage. They can exclusively cause surface damage, but more often tissues deeper underneath the skin have been severely damaged. As a result, electrical burns are difficult to accurately diagnose, and many people underestimate the severity of their burn. In extreme cases, electricity can cause shock to the brain, strain to the heart, and injury to other organs.For a burn to be classified as electrical, electricity must be the direct cause. For example, burning a finger on a hot electric steam iron would be thermal, not electrical. According to Joules first law: electricity passing through resistance creates heat, so there is no current entering the body in this type of burn. Likewise, a fire that is ruled to be "electrical" in origin, does not necessarily mean that any injuries or deaths are due to electrical burns. Unless someone was injured at the exact moment that the fire began, it is unlikely that any electrical burns would occur. Causes Electrical burns can be caused by a variety of ways such as touching or grasping electrically live objects, short-circuiting, inserting fingers into electrical sockets, and falling into electrified water. Lightning strikes are also a cause of electrical burns, but this is a less common event. With the advances in technology, electrical injuries are becoming more common and are the fourth leading cause of work-related traumatic death. One third of all electrical traumas and most high-voltage injuries are job related, and more than 50% of these injuries result from power line contact.Electrical burns can be classified into six categories, and any combination of these categories may be present on an electrical burn victim: Low-voltage burn. A burn produced by contact with a power source of 500 volts or less is classified as a low-voltage burn. The current at this voltage is not enough to cause tissue damage along its path except at the contact site. This type of burn may be mild, superficial, or severe depending on the contact time. High voltage burn. This burn is very severe as the victim makes direct contact with the high voltage supply and the damage runs its course throughout the body. Exterior injuries are misleading as most of the damage occurs underneath the skin. In this case, subdermal tissues are severely damaged. Arc burn. This type of burn occurs when electrical energy passes from a high-resistance area to a low-resistance area. No contact is required with an arc burn as the electricity ionizes air particles to complete the circuit. The heat generated can be as high as 4,000 °C (7,200 °F) — hotter than the boiling points of several metals and certainly hot enough to ignite a victims clothing. A form of explosion dissipates excess energy from the arc. In addition, a high-current arc can produce a pressure wave blast in excess of 1,000 pounds per square inch (6,900 kPa) of pressure. This can throw the victim and cause severe injuries. Flash burn. Flash burns are caused by electrical arcs that pass over the skin. The intense heat and light of an arc flash can cause severe burns in a fraction of a second. Although the burns can cover a large area of skin, they are largely superficial and the tissues beneath the skin are generally undamaged and unaffected. This typically occurs when the frequency of the AC current is significantly higher than the 50 or 60 Hz used in land-based electrical distribution systems (such as in aircraft). Flame burn. Flame burns are caused by contact to objects that were ignited by an electrical source when associated with flash and arc burns. Oral burns. This is caused by biting or sucking on electrical cords, and it most commonly happens to children. Electric current typically passes from one side of the childs mouth to the other, possibly causing deformity. Pathophysiology Four electrical factors determine the severity of the damage caused by electrical burns: voltage, current, resistance, and frequency. The severity of the burn also depends on the pathway the current takes through the body. Generally, the pathway of the current will follow the course of the least resistant tissues: firstly blood vessels, nerves, and muscle, then skin, tendon, fat, and bone. Most commonly, electric injuries primarily damage the outer limbs, but more critical portions of the body may be affected as well causing severe complications.As the body comes into contact with an electrical source, it becomes part of the electrical circuit. As such, the current has a point of entry and an exit at two different points on the body. The point of entry tends to be depressed and leathery whereas the exit wound is typically more extensive and explosive. It is hard to accurately diagnose an electrical burn because only the entry and exit wounds are visible and the internal damage is not. Prevention Basic electrical safety The following are some examples of unsafe practices which could lead to electric injury (this list is not exhaustive.): Using electrical appliances while wet (showering, bathing, etc.) as plumbing is often connected to electrical ground, and wet skin loses much of its resistance. Exception for newer quality appliances intended for the bathroom when not simultaneously showering, bathing, being in a path of water going to plumbing, or touching bare concrete or sheet metal. Standing on a dry carpet or rug is ideal. All power mains outlets should have a wall cover to avoid accidentally touching the electrified sides between the wall and outlet. This is especially important for children, as their small fingers can easily reach into this gap along the sides. Using AC electrical appliances around bathtubs, swimming pools, hot tubs, etc. with the risk that the appliance may fall into the water and cause electrocution. Only battery-operated devices are safe. Failure to use child safety plugs in all outlets, and keeping children away from electrical cords. Adjusting prongs of an electrical cord that are too wide or narrow them with your fingertips while simultaneously plugging the cord into the power mains. The power plug used in the UK and some Commonwealth countries provides limited protection (Type G, with the lower half of the live prongs insulated), but all others do not. Not following manufacturer safety instructions for electrical appliances. This includes not using and immediately unplugging any appliance with a damaged electrical cord. If this cannot be done safely (i.e. damage is too close to the plug), the circuit breaker should be turned off beforehand. Touching metallic areas of an AC electrical appliance while also simultaneously touching faucets, water pipes, another metallic AC appliance, or being even partly immersed in water (including wet feet). This could ground the body through metal or water, with the risk that a faulty appliance is electrically "hot" on its outside cover or chassis. Not installing Ground Fault Circuit Interrupter (GFCI) outlets or circuit breakers in all areas with plumbing, bare concrete flooring, exposed to the elements, or outdoors by a qualified electrician. (Many newer homes already have these devices pre-installed.) Running an extension cord from non-GFCI areas such as bedrooms and hallways defeats this safety feature. Oral burns (above) cannot be prevented by GFCI. At poolside, not having a non-metallic fiberglass pole or net on hand to pull someone to safety in case the pool water is electrified, and the victim is still conscious. Furthermore, to not know where the circuit breakers for the pool are located. Failure to install a "feed-through" type GFCI to all electrical devices that are an integral part of a Swimming pool, or not testing it weekly. This is a particular concern due to the use of electric lights and pumps where persons are immersed in water. The GFCI has the typical "test" and "reset" buttons, but no plug-in outlets. A 12-volt system is safer, though not foolproof, as it is ultimately connected to the 120/240 volt power mains. Most electrocutions come from incorrectly grounded or bonded lights. This can send electric current through a pool light even if it is not turned on. Using an ordinary vacuum cleaner in wet or damp areas. Only a "wet vac" is suitable for this purpose. Overfilling its collection container is also unsafe. Not double checking polarity before doing a jump start, or attempting a jump on a frozen battery. Although 12-volt batteries used in vehicles are at a safe voltage, a short circuit can still cause various types of burns and an explosion. Failure to replace high-risk appliances of decades past with new ones (hand-held corded electric drills, blow dryers, etc.) Not inquiring about the voltage when traveling abroad for those residing in the Americas, Japan, and Taiwan (countries with 110-125 volts). This includes inter-American travel, as a few countries commonly use 220-240 volts. A matching electrical socket (power mains) does not necessarily mean the voltage is the same as ones home country. The doubling of voltage results in a very dangerous four-fold increase in power and heat. Not checking that dual-voltage small appliances have been adjusted correctly for 220-240 volts is also unsafe. Going near or under a downed power line, even if theres no direct contact with the wire. Also, not remaining inside your vehicle and waiting for rescue should a power line fall on it. See also Lightning safety Treatment First aid An electrically burned patient should not be touched or treated until the source of electricity has been removed. Electrical injuries often extend beyond burns and include cardiac arrhythmia, such as ventricular fibrillation. First aid treatments include assessment of consciousness of the victim, evaluation of pulse and circulation, and treatment of burns. Hospitalization Typically, an electrical burn patient has a lower affected body surface area than other burn patients, yet complication risks are much higher due to internal injury. Often, the damaged internal tissue demands hospitalization. If not treated, this damaged tissue can cause complications (such as gaseous gangrene from dead tissue or loss of blood flow to limbs) and the damaged body parts may need to be amputated. Repeated removal of the damaged tissue and extensive rehabilitation are common, while limb amputation rates for victims who experience direct electrical contact can be as high as 75%. Burn treatment for severe wounds may require skin grafting, debridement, excision of dead tissue, and repair of damaged organs. Rehabilitation Electrical burning has an effect on most vital body functions and is accompanied by several other electrical related injuries: Damage to the veins and arteries which can cause ischaemic necrosis. Involuntary contraction of muscles due to electrical interference which can cause bone fractures and dislocations. Interference with the electrical conductivity of organs such as the heart and nerves. This can lead to seizures, lung injury due to severe central nervous system damage, and cardiac arrest. Forceful propulsion of the body, producing such injuries as spinal and limb fractures.These injuries must be treated in addition to the burns themselves. In very rare instances, a high voltage electric shock can cause cataracts in the lens of the eyes, and detachment of the retina. This may be delayed for some days or weeks after the initial injury. See also Electric shock Electrocution == References ==

Schizophrenia

Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdrawal, decreased emotional expression, and apathy. Symptoms typically develop gradually, begin during young adulthood, and in many cases never become resolved. There is no objective diagnostic test; diagnosis is based on observed behavior, a history that includes the persons reported experiences, and reports of others familiar with the person. To be diagnosed with schizophrenia, symptoms and functional impairment need to be present for six months (DSM-5) or one month (ICD-11). Many people with schizophrenia have other mental disorders, especially substance use disorders, depressive disorders, anxiety disorders, and obsessive–compulsive disorder.About 0.3% to 0.7% of people are diagnosed with schizophrenia during their lifetime. In 2017, there were an estimated 1.1 million new cases and in 2022 a total of 24 million cases globally. Males are more often affected and on average have an earlier onset. The causes of schizophrenia include genetic and environmental factors. Genetic factors include a variety of common and rare genetic variants. Possible environmental factors include being raised in a city, cannabis use during adolescence, infections, the ages of a persons mother or father, and poor nutrition during pregnancy.About half of those diagnosed with schizophrenia will have a significant improvement over the long term with no further relapses, and a small proportion of these will recover completely. The other half will have a lifelong impairment. In severe cases people may be admitted to hospitals. Social problems such as long-term unemployment, poverty, homelessness, exploitation, and victimization are commonly correlated with schizophrenia. Compared to the general population, people with schizophrenia have a higher suicide rate (about 5% overall) and more physical health problems, leading to an average decrease in life expectancy by 20 to 28 years. In 2015, an estimated 17,000 deaths were linked to schizophrenia.The mainstay of treatment is antipsychotic medication, along with counseling, job training, and social rehabilitation. Up to a third of people do not respond to initial antipsychotics, in which case clozapine may be used. In a network comparative meta-analysis of 15 antipsychotic drugs, clozapine was significantly more effective than all other drugs, although clozapines heavily multimodal action may cause more side effects. In situations where doctors judge that there is a risk of harm to self or others, they may impose short involuntary hospitalization. Long-term hospitalization is used on a small number of people with severe schizophrenia. In some countries where supportive services are limited or unavailable, long-term hospital stays are more common. Signs and symptoms Schizophrenia is a mental disorder characterized by significant alterations in perception, thoughts, mood, and behavior. Symptoms are described in terms of positive, negative, and cognitive symptoms. The positive symptoms of schizophrenia are the same for any psychosis and are sometimes referred to as psychotic symptoms. These may be present in any of the different psychoses, and are often transient making early diagnosis of schizophrenia problematic. Psychosis noted for the first time in a person who is later diagnosed with schizophrenia is referred to as a first-episode psychosis (FEP). Positive symptoms Positive symptoms are those symptoms that are not normally experienced, but are present in people during a psychotic episode in schizophrenia. They include delusions, hallucinations, and disorganized thoughts and speech, typically regarded as manifestations of psychosis. Hallucinations occur at some point in the lifetimes of 80% of those with schizophrenia and most commonly involve the sense of hearing (most often hearing voices) but can sometimes involve any of the other senses of taste, sight, smell, and touch. The frequency of hallucinations involving multiple senses is double the rate of those involving only one sense. They are also typically related to the content of the delusional theme. Delusions are bizarre or persecutory in nature. Distortions of self-experience such as feeling as if ones thoughts or feelings are not really ones own, to believing that thoughts are being inserted into ones mind, sometimes termed passivity phenomena, are also common. Thought disorders can include thought blocking, and disorganized speech. Positive symptoms generally respond well to medication, and become reduced over the course of the illness, perhaps related to the age-related decline in dopamine activity. Negative symptoms Negative symptoms are deficits of normal emotional responses, or of other thought processes. The five recognized domains of negative symptoms are: blunted affect – showing flat expressions or little emotion; alogia – a poverty of speech; anhedonia – an inability to feel pleasure; asociality – the lack of desire to form relationships, and avolition – a lack of motivation and apathy. Avolition and anhedonia are seen as motivational deficits resulting from impaired reward processing. Reward is the main driver of motivation and this is mostly mediated by dopamine. It has been suggested that negative symptoms are multidimensional and they have been categorised into two subdomains of apathy or lack of motivation, and diminished expression. Apathy includes avolition, anhedonia, and social withdrawal; diminished expression includes blunt affect, and alogia. Sometimes diminished expression is treated as both verbal and non-verbal.Apathy accounts for around 50 percent of the most often found negative symptoms and affects functional outcome and subsequent quality of life. Apathy is related to disrupted cognitive processing affecting memory and planning including goal-directed behaviour. The two subdomains have suggested a need for separate treatment approaches. A lack of distress – relating to a reduced experience of depression and anxiety is another noted negative symptom. A distinction is often made between those negative symptoms that are inherent to schizophrenia, termed primary; and those that result from positive symptoms, from the side effects of antipsychotics, substance use disorder, and social deprivation – termed secondary negative symptoms. Negative symptoms are less responsive to medication and the most difficult to treat. However, if properly assessed, secondary negative symptoms are amenable to treatment.Scales for specifically assessing the presence of negative symptoms, and for measuring their severity, and their changes have been introduced since the earlier scales such as the PANNS that deals with all types of symptoms. These scales are the Clinical Assessment Interview for Negative Symptoms (CAINS), and the Brief Negative Symptom Scale (BNSS) also known as second-generation scales. In 2020, ten years after its introduction, a cross-cultural study of the use of BNSS found valid and reliable psychometric evidence for the five-domain structure cross-culturally. The BNSS is designed to assess both the presence and severity and change of negative symptoms of the five recognized domains, and the additional item of reduced normal distress. BNSS can register changes in negative symptoms concerning psychosocial and pharmacological intervention trials. BNSS has also been used to study a proposed non-D2 treatment called SEP-363856. Findings supported the favouring of five domains over the two-dimensional proposition. Cognitive symptoms An estimated 70% of those with schizophrenia have cognitive deficits, and these are most pronounced in early onset and late-onset illness. These are often evident long before the onset of illness in the prodromal stage, and may be present in early adolescence, or childhood. They are a core feature but not considered to be core symptoms, as are positive and negative symptoms. However, their presence and degree of dysfunction is taken as a better indicator of functionality than the presentation of core symptoms. Cognitive deficits become worse at first episode psychosis but then return to baseline, and remain fairly stable over the course of the illness.The deficits in cognition are seen to drive the negative psychosocial outcome in schizophrenia, and are claimed to equate to a possible reduction in IQ from the norm of 100 to 70–85. Cognitive deficits may be of neurocognition (nonsocial) or of social cognition. Neurocognition is the ability to receive and remember information, and includes verbal fluency, memory, reasoning, problem solving, speed of processing, and auditory and visual perception. Verbal memory and attention are seen to be the most affected. Verbal memory impairment is associated with a decreased level of semantic processing (relating meaning to words). Another memory impairment is that of episodic memory. An impairment in visual perception that is consistently found in schizophrenia is that of visual backward masking. Visual processing impairments include an inability to perceive complex visual illusions. Social cognition is concerned with the mental operations needed to interpret, and understand the self and others in the social world. This is also an associated impairment, and facial emotion perception is often found to be difficult. Facial perception is critical for ordinary social interaction. Cognitive impairments do not usually respond to antipsychotics, and there are a number of interventions that are used to try to improve them; cognitive remediation therapy is of particular help.Neurological soft signs of clumsiness and loss of fine motor movement are often found in schizophrenia, which may resolve with effective treatment of FEP. Onset Onset typically occurs between the late teens and early 30s, with the peak incidence occurring in males in the early to mid twenties, and in females in the late twenties. Onset before the age of 17 is known as early-onset, and before the age of 13, as can sometimes occur, is known as childhood schizophrenia or very early-onset. Onset can occur between the ages of 40 and 60, known as late-onset schizophrenia. Onset over the age of 60, which may be difficult to differentiate as schizophrenia, is known as very-late-onset schizophrenia-like psychosis. Late onset has shown that a higher rate of females are affected; they have less severe symptoms and need lower doses of antipsychotics. The tendency for earlier onset in males is later seen to be balanced by a post-menopausal increase in the development in females. Estrogen produced pre-menopause has a dampening effect on dopamine receptors but its protection can be overridden by a genetic overload. There has been a dramatic increase in the numbers of older adults with schizophrenia.Onset may happen suddenly or may occur after the slow and gradual development of a number of signs and symptoms, a period known as the prodromal stage. Up to 75% of those with schizophrenia go through a prodromal stage. The negative and cognitive symptoms in the prodrome stage can precede FEP (first episode psychosis) by many months and up to five years. The period from FEP and treatment is known as the duration of untreated psychosis (DUP) which is seen to be a factor in functional outcome. The prodromal stage is the high-risk stage for the development of psychosis. Since the progression to first episode psychosis is not inevitable, an alternative term is often preferred of at risk mental state. Cognitive dysfunction at an early age impacts a young persons usual cognitive development. Recognition and early intervention at the prodromal stage would minimize the associated disruption to educational and social development and has been the focus of many studies. Risk factors Schizophrenia is described as a neurodevelopmental disorder with no precise boundary, or single cause, and is thought to develop from gene–environment interactions with involved vulnerability factors. The interactions of these risk factors are complex, as numerous and diverse insults from conception to adulthood can be involved. A genetic predisposition on its own, without interacting environmental factors, will not give rise to the development of schizophrenia. The genetic component means that prenatal brain development is disturbed, and environmental influence affects the postnatal development of the brain. Evidence suggests that genetically susceptible children are more likely to be vulnerable to the effects of environmental risk factors. Genetic Estimates of the heritability of schizophrenia are between 70% and 80%, which implies that 70% to 80% of the individual differences in risk to schizophrenia is associated with genetics. These estimates vary because of the difficulty in separating genetic and environmental influences, and their accuracy has been queried. The greatest risk factor for developing schizophrenia is having a first-degree relative with the disease (risk is 6.5%); more than 40% of identical twins of those with schizophrenia are also affected. If one parent is affected the risk is about 13% and if both are affected the risk is nearly 50%. However, the DSM-5 indicates that most people with schizophrenia have no family history of psychosis. Results of candidate gene studies of schizophrenia have generally failed to find consistent associations, and the genetic loci identified by genome-wide association studies explain only a small fraction of the variation in the disease.Many genes are known to be involved in schizophrenia, each with small effect and unknown transmission and expression. The summation of these effect sizes into a polygenic risk score can explain at least 7% of the variability in liability for schizophrenia. Around 5% of cases of schizophrenia are understood to be at least partially attributable to rare copy number variations (CNVs); these structural variations are associated with known genomic disorders involving deletions at 22q11.2 (DiGeorge syndrome) and 17q12 (17q12 microdeletion syndrome), duplications at 16p11.2 (most frequently found) and deletions at 15q11.2 (Burnside–Butler syndrome). Some of these CNVs increase the risk of developing schizophrenia by as much as 20-fold, and are frequently comorbid with autism and intellectual disabilities.The genes CRHR1 and CRHBP are associated with the severity of suicidal behavior. These genes code for stress response proteins needed in the control of the HPA axis, and their interaction can affect this axis. Response to stress can cause lasting changes in the function of the HPA axis possibly disrupting the negative feedback mechanism, homeostasis, and the regulation of emotion leading to altered behaviors.The question of how schizophrenia could be primarily genetically influenced, given that people with schizophrenia have lower fertility rates, is a paradox. It is expected that genetic variants that increase the risk of schizophrenia would be selected against due to their negative effects on reproductive fitness. A number of potential explanations have been proposed, including that alleles associated with schizophrenia risk confers a fitness advantage in unaffected individuals. While some evidence has not supported this idea, others propose that a large number of alleles each contributing a small amount can persist.A meta-analysis found that oxidative DNA damage was significantly increased in schizophrenia. Environmental Environmental factors, each associated with a slight risk of developing schizophrenia in later life include oxygen deprivation, infection, prenatal maternal stress, and malnutrition in the mother during prenatal development. A risk is associated with maternal obesity, in increasing oxidative stress, and dysregulating the dopamine and serotonin pathways. Both maternal stress and infection have been demonstrated to alter fetal neurodevelopment through an increase of pro-inflammatory cytokines. There is a slighter risk associated with being born in the winter or spring possibly due to vitamin D deficiency or a prenatal viral infection. Other infections during pregnancy or around the time of birth that have been linked to an increased risk include infections by Toxoplasma gondii and Chlamydia. The increased risk is about five to eight percent. Viral infections of the brain during childhood are also linked to a risk of schizophrenia during adulthood.Adverse childhood experiences (ACEs), severe forms of which are classed as childhood trauma, range from being bullied or abused, to the death of a parent. Many adverse childhood experiences can cause toxic stress and increase the risk of psychosis. Chronic trauma can promote lasting inflammatory dysregulation throughout the nervous system. It is suggested that early stress may contribute to the development of schizophrenia through these alterations in the immune system. Schizophrenia was the last diagnosis to benefit from the link made between ACEs and adult mental health outcomes.Living in an urban environment during childhood or as an adult has consistently been found to increase the risk of schizophrenia by a factor of two, even after taking into account drug use, ethnic group, and size of social group. A possible link between the urban environment and pollution has been suggested to be the cause of the elevated risk of schizophrenia. Other risk factors include social isolation, immigration related to social adversity and racial discrimination, family dysfunction, unemployment, and poor housing conditions. Having a father older than 40 years, or parents younger than 20 years are also associated with schizophrenia. Substance use About half of those with schizophrenia use recreational drugs, including cannabis, tobacco, and alcohol excessively. Use of stimulants such as amphetamine and cocaine can lead to a temporary stimulant psychosis, which presents very similarly to schizophrenia. Rarely, alcohol use can also result in a similar alcohol-related psychosis. Drugs may also be used as coping mechanisms by people who have schizophrenia, to deal with depression, anxiety, boredom, and loneliness. The use of cannabis and tobacco are not associated with the development of cognitive deficits, and sometimes a reverse relationship is found where their use improves these symptoms. However, substance use disorders are associated with an increased risk of suicide, and a poor response to treatment.Cannabis use may be a contributory factor in the development of schizophrenia, potentially increasing the risk of the disease in those who are already at risk. The increased risk may require the presence of certain genes within an individual. Its use is associated with doubling the rate. Mechanism The mechanisms of schizophrenia are unknown, and a number of models have been put forward to explain the link between altered brain function and schizophrenia.The prevailing model of schizophrenia is that of a neurodevelopmental disorder, and the underlying changes that occur before symptoms become evident are seen as arising from the interaction between genes and the environment. Extensive studies support this model. Maternal infections, malnutrition and complications during pregnancy and childbirth are known risk factors for the development of schizophrenia, which usually emerges between the ages of 18–25, a period that overlaps with certain stages of neurodevelopment. Gene-environment interactions lead to deficits in the neural circuitry that affect sensory and cognitive functions.The common dopamine and glutamate models proposed are not mutually exclusive; each is seen to have a role in the neurobiology of schizophrenia. The most common model put forward was the dopamine hypothesis of schizophrenia, which attributes psychosis to the minds faulty interpretation of the misfiring of dopaminergic neurons. This has been directly related to the symptoms of delusions and hallucinations. Abnormal dopamine signaling has been implicated in schizophrenia based on the usefulness of medications that affect the dopamine receptor and the observation that dopamine levels are increased during acute psychosis. A decrease in D1 receptors in the dorsolateral prefrontal cortex may also be responsible for deficits in working memory.The glutamate hypothesis of schizophrenia links alterations between glutamatergic neurotransmission and the neural oscillations that affect connections between the thalamus and the cortex. Studies have shown that a reduced expression of a glutamate receptor – NMDA receptor, and glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with schizophrenia. Post-mortem studies consistently find that a subset of these neurons fail to express GAD67 (GAD1), in addition to abnormalities in brain morphometry. The subsets of interneurons that are abnormal in schizophrenia are responsible for the synchronizing of neural ensembles needed during working memory tasks. These give the neural oscillations produced as gamma waves that have a frequency of between 30 and 80 hertz. Both working memory tasks and gamma waves are impaired in schizophrenia, which may reflect abnormal interneuron functionality. An important process that may be disrupted in neurodevelopment is astrogenesis – the formation of astrocytes. Astrocytes are crucial in contributing to the formation and maintenance of neural circuits and it is believed that disruption in this role can result in a number of neurodevelopmental disorders including schizophrenia. Evidence suggests that reduced numbers of astrocytes in deeper cortical layers are assocociated with a diminished expression of EAAT2, a glutamate transporter in astrocytes; supporting the glutamate hypothesis.Deficits in executive functions, such as planning, inhibition, and working memory, are pervasive in schizophrenia. Although these functions are separable, their dysfunction in schizophrenia may reflect an underlying deficit in the ability to represent goal related information in working memory, and to utilize this to direct cognition and behavior. These impairments have been linked to a number of neuroimaging and neuropathological abnormalities. For example, functional neuroimaging studies report evidence of reduced neural processing efficiency, whereby the dorsolateral prefrontal cortex is activated to a greater degree to achieve a certain level of performance relative to controls on working memory tasks. These abnormalities may be linked to the consistent post-mortem finding of reduced neuropil, evidenced by increased pyramidal cell density and reduced dendritic spine density. These cellular and functional abnormalities may also be reflected in structural neuroimaging studies that find reduced grey matter volume in association with deficits in working memory tasks.Positive symptoms have been linked to cortical thinning in the superior temporal gyrus. Severity of negative symptoms has been linked to reduced thickness in the left medial orbitofrontal cortex. Anhedonia, traditionally defined as a reduced capacity to experience pleasure, is frequently reported in schizophrenia. However, a large body of evidence suggests that hedonic responses are intact in schizophrenia, and that what is reported to be anhedonia is a reflection of dysfunction in other processes related to reward. Overall, a failure of reward prediction is thought to lead to impairment in the generation of cognition and behavior required to obtain rewards, despite normal hedonic responses.Another theory links abnormal brain lateralization to the development of being left-handed which is significantly more common in those with schizophrenia. This abnormal development of hemispheric asymmetry is noted in schizophrenia. Studies have concluded that the link is a true and verifiable effect that may reflect a genetic link between lateralization and schizophrenia.Bayesian models of brain functioning have been utilized to link abnormalities in cellular functioning to symptoms. Both hallucinations and delusions have been suggested to reflect improper encoding of prior expectations, thereby causing expectation to excessively influence sensory perception and the formation of beliefs. In approved models of circuits that mediate predictive coding, reduced NMDA receptor activation, could in theory result in the positive symptoms of delusions and hallucinations. Diagnosis Criteria Schizophrenia is diagnosed based on criteria in either the Diagnostic and Statistical Manual of Mental Disorders (DSM) published by the American Psychiatric Association or the International Statistical Classification of Diseases and Related Health Problems (ICD) published by the World Health Organization (WHO). These criteria use the self-reported experiences of the person and reported abnormalities in behavior, followed by a psychiatric assessment. The mental status examination is an important part of the assessment. An established tool for assessing the severity of positive and negative symptoms is the Positive and Negative Syndrome Scale (PANSS). This has been seen to have shortcomings relating to negative symptoms, and other scales – the Clinical Assessment Interview for Negative Symptoms (CAINS), and the Brief Negative Symptoms Scale (BNSS) have been introduced. The DSM-5, published in 2013, gives a Scale to Assess the Severity of Symptom Dimensions outlining eight dimensions of symptoms.DSM-5 states that to be diagnosed with schizophrenia, two diagnostic criteria have to be met over the period of one month, with a significant impact on social or occupational functioning for at least six months. One of the symptoms needs to be either delusions, hallucinations, or disorganized speech. A second symptom could be one of the negative symptoms, or severely disorganized or catatonic behaviour. A different diagnosis of schizophreniform disorder can be made before the six months needed for the diagnosis of schizophrenia.In Australia the guideline for diagnosis is for six months or more with symptoms severe enough to affect ordinary functioning. In the UK diagnosis is based on having the symptoms for most of the time for one month, with symptoms that significantly affect the ability to work, study, or to carry on ordinary daily living, and with other similar conditions ruled out.The ICD criteria are typically used in European countries; the DSM criteria are used predominantly in the United States and Canada, and are prevailing in research studies. In practice, agreement between the two systems is high. The current proposal for the ICD-11 criteria for schizophrenia recommends adding self-disorder as a symptom.A major unresolved difference between the two diagnostic systems is that of the requirement in DSM of an impaired functional outcome. WHO for ICD argues that not all people with schizophrenia have functional deficits and so these are not specific for the diagnosis. Comorbidities Many people with schizophrenia may have one or more other mental disorders, such as panic disorder, obsessive–compulsive disorder, or substance use disorder. These are separate disorders that require treatment. When comorbid with schizophrenia, substance use disorder and antisocial personality disorder both increase the risk for violence. Comorbid substance use disorder also increases risk for suicide.Sleep disorders often co-occur with schizophrenia, and may be an early sign of relapse. Sleep disorders are linked with positive symptoms such as disorganized thinking and can adversely affect cortical plasticity and cognition. The consolidation of memories is disrupted in sleep disorders. They are associated with severity of illness, a poor prognosis, and poor quality of life. Sleep onset and maintenance insomnia is a common symptom, regardless of whether treatment has been received or not. Genetic variations have been found associated with these conditions involving the circadian rhythm, dopamine and histamine metabolism, and signal transduction. Limited positive evidence has been found for the use of acupuncture as an add-on. Differential diagnosis To make a diagnosis of schizophrenia other possible causes of psychosis need to be excluded.: 858  Psychotic symptoms lasting less than a month may be diagnosed as brief psychotic disorder, or as schizophreniform disorder. Psychosis is noted in Other specified schizophrenia spectrum and other psychotic disorders as a DSM-5 category. Schizoaffective disorder is diagnosed if symptoms of mood disorder are substantially present alongside psychotic symptoms. Psychosis that results from a general medical condition or substance is termed secondary psychosis.Psychotic symptoms may be present in several other conditions, including bipolar disorder, borderline personality disorder, substance intoxication, substance-induced psychosis, and a number of drug withdrawal syndromes. Non-bizarre delusions are also present in delusional disorder, and social withdrawal in social anxiety disorder, avoidant personality disorder and schizotypal personality disorder. Schizotypal personality disorder has symptoms that are similar but less severe than those of schizophrenia. Schizophrenia occurs along with obsessive–compulsive disorder (OCD) considerably more often than could be explained by chance, although it can be difficult to distinguish obsessions that occur in OCD from the delusions of schizophrenia. There can be considerable overlap with the symptoms of post-traumatic stress disorder.A more general medical and neurological examination may be needed to rule out medical illnesses which may rarely produce psychotic schizophrenia-like symptoms, such as metabolic disturbance, systemic infection, syphilis, HIV-associated neurocognitive disorder, epilepsy, limbic encephalitis, and brain lesions. Stroke, multiple sclerosis, hyperthyroidism, hypothyroidism, and dementias such as Alzheimers disease, Huntingtons disease, frontotemporal dementia, and the Lewy body dementias may also be associated with schizophrenia-like psychotic symptoms. It may be necessary to rule out a delirium, which can be distinguished by visual hallucinations, acute onset and fluctuating level of consciousness, and indicates an underlying medical illness. Investigations are not generally repeated for relapse unless there is a specific medical indication or possible adverse effects from antipsychotic medication. In children hallucinations must be separated from typical childhood fantasies. It is difficult to distinguish childhood schizophrenia from autism. Prevention Prevention of schizophrenia is difficult as there are no reliable markers for the later development of the disorder. It is unclear as of 2011 whether treating patients in the prodrome phase of schizophrenia provides benefits.: 43  There is a discrepancy between the growth in the implementation of early intervention programmes for psychosis and the underlying empirical evidence.: 44 There is some evidence as of 2009 that early intervention in those with first-episode psychosis may improve short-term outcomes, but there is little benefit from these measures after five years. Cognitive behavioral therapy may reduce the risk of psychosis in those at high risk after a year and is recommended in this group, by the National Institute for Health and Care Excellence (NICE). Another preventive measure is to avoid drugs that have been associated with development of the disorder, including cannabis, cocaine, and amphetamines.Antipsychotics are prescribed following a first-episode psychosis, and following remission a preventive maintenance use is continued to avoid relapse. However, it is recognized that some people do recover following a single episode and that long-term use of antipsychotics will not be needed but there is no way of identifying this group. Management The primary treatment of schizophrenia is the use of antipsychotic medications, often in combination with psychosocial interventions and social supports. Community support services including drop-in centers, visits by members of a community mental health team, supported employment, and support groups are common. The time between the onset of psychotic symptoms to being given treatment – the duration of untreated psychosis (DUP) – is associated with a poorer outcome in both the short term and the long term.Voluntary or involuntary admission to hospital may be imposed by doctors and courts who deem a person to be having a severe episode. In the UK, large mental hospitals termed asylums began to be closed down in the 1950s with the advent of antipsychotics, and with an awareness of the negative impact of long-term hospital stays on recovery. This process was known as deinstitutionalization, and community and supportive services were developed in order to support this change. Many other countries followed suit with the US starting in the 60s. There still remain a smaller group of people who do not improve enough to be discharged. In some countries that lack the necessary supportive and social services, long-term hospital stays are more usual. Medication The first-line treatment for schizophrenia is an antipsychotic. The first-generation antipsychotics, now called typical antipsychotics, are dopamine antagonists that block D2 receptors, and affect the neurotransmission of dopamine. Those brought out later, the second-generation antipsychotics known as atypical antipsychotics, can also have effect on another neurotransmitter, serotonin. Antipsychotics can reduce the symptoms of anxiety within hours of their use but for other symptoms they may take several days or weeks to reach their full effect. They have little effect on negative and cognitive symptoms, which may be helped by additional psychotherapies and medications. There is no single antipsychotic suitable for first-line treatment for everyone, as responses and tolerances vary between people. Stopping medication may be considered after a single psychotic episode where there has been a full recovery with no symptoms for twelve months. Repeated relapses worsen the long-term outlook and the risk of relapse following a second episode is high, and long-term treatment is usually recommended.About half of those with schizophrenia will respond favourably to antipsychotics, and have a good return of functioning. However, positive symptoms persist in up to a third of people. Following two trials of different antipsychotics over six weeks, that also prove ineffective, they will be classed as having treatment resistant schizophrenia (TRS), and clozapine will be offered. Clozapine is of benefit to around half of this group although it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people.About 30 to 50 percent of people with schizophrenia do not accept that they have an illness or comply with their recommended treatment. For those who are unwilling or unable to take medication regularly, long-acting injections of antipsychotics may be used, which reduce the risk of relapse to a greater degree than oral medications. When used in combination with psychosocial interventions, they may improve long-term adherence to treatment. Adverse effects Extrapyramidal symptoms, including akathisia, are associated with all commercially available antipsychotic to varying degrees.: 566  There is little evidence that second generation antipsychotics have reduced levels of extrapyramidical symptoms compared to typical antipsychotics.: 566  Tardive dyskinesia can occur due to long-term use of antipsychotics, developing after months or years of use. The antipsychotic clozapine is also associated with thromboembolism (including pulmonary embolism), myocarditis, and cardiomyopathy. Psychosocial interventions A number of psychosocial interventions that include several types of psychotherapy may be useful in the treatment of schizophrenia such as: family therapy, group therapy, cognitive remediation therapy (CRT), cognitive behavioral therapy (CBT), and metacognitive training. Skills training, and help with substance use, and weight management – often needed as a side effect of an antipsychotic – are also offered. In the US, interventions for first episode psychosis have been brought together in an overall approach known as coordinated speciality care (CSC) and also includes support for education. In the UK care across all phases is a similar approach that covers many of the treatment guidelines recommended. The aim is to reduce the number of relapses and stays in hospital.Other support services for education, employment, and housing are usually offered. For people with severe schizophrenia, and discharged from a stay in hospital, these services are often brought together in an integrated approach to offer support in the community away from the hospital setting. In addition to medicine management, housing, and finances, assistance is given for more routine matters such as help with shopping and using public transport. This approach is known as assertive community treatment (ACT) and has been shown to achieve positive results in symptoms, social functioning and quality of life. Another more intense approach is known as intensive care management (ICM). ICM is a stage further than ACT and emphasises support of high intensity in smaller caseloads, (less than twenty). This approach is to provide long-term care in the community. Studies show that ICM improves many of the relevant outcomes including social functioning.Some studies have shown little evidence for the effectiveness of CBT in either reducing symptoms or preventing relapse. However, other studies have found that CBT does improve overall psychotic symptoms (when in use with medication) and it has been recommended in Canada, but has been seen to have no effect on social function, relapse, or quality of life. In the UK it is recommended as an add-on therapy in the treatment of schizophrenia. Arts therapies are seen to improve negative symptoms in some people, and are recommended by NICE in the UK. This approach is criticised as having not been well-researched, and arts therapies are not recommended in Australian guidelines for example. Peer support, in which people with personal experience of schizophrenia, provide help to each other, is of unclear benefit. Other Exercise including aerobic exercise has been shown to improve positive and negative symptoms, cognition, working memory, and improve quality of life. Exercise has also been shown to increase the volume of the hippocampus in those with schizophrenia. A decrease in hippocampal volume is one of the factors linked to the development of the disease. However, there still remains the problem of increasing motivation for, and maintaining participation in physical activity. Supervised sessions are recommended. In the UK healthy eating advice is offered alongside exercise programs.An inadequate diet is often found in schizophrenia, and associated vitamin deficiencies including those of folate, and vitamin D are linked to the risk factors for the development of schizophrenia and for early death including heart disease. Those with schizophrenia possibly have the worst diet of all the mental disorders. Lower levels of folate and vitamin D have been noted as significantly lower in first episode psychosis. The use of supplemental folate is recommended. A zinc deficiency has also been noted. Vitamin B12 is also often deficient and this is linked to worse symptoms. Supplementation with B vitamins has been shown to significantly improve symptoms, and to put in reverse some of the cognitive deficits. It is also suggested that the noted dysfunction in gut microbiota might benefit from the use of probiotics. Prognosis Schizophrenia has great human and economic costs. It decreases life expectancy by between 20 and 28 years. This is primarily because of its association with heart disease, diabetes, obesity, poor diet, a sedentary lifestyle, and smoking, with an increased rate of suicide playing a lesser role. Side effects of antipsychotics may also increase the risk.Almost 40% of those with schizophrenia die from complications of cardiovascular disease which is seen to be increasingly associated. An underlying factor of sudden cardiac death may be Brugada syndrome (BrS) – BrS mutations that overlap with those linked with schizophrenia are the calcium channel mutations. BrS may also be drug-induced from certain antipsychotics and antidepressants. Primary polydipsia, or excessive fluid intake, is relatively common in people with chronic schizophrenia. This may lead to hyponatremia which can be life-threatening. Antipsychotics can lead to a dry mouth, but there are several other factors that may contribute to the disorder; it may reduce life expectancy by 13 per cent. Barriers to improving the mortality rate in schizophrenia are poverty, overlooking the symptoms of other illnesses, stress, stigma, and medication side effects.Schizophrenia is a major cause of disability. In 2016, it was classed as the 12th most disabling condition. Approximately 75% of people with schizophrenia have ongoing disability with relapses. Some people do recover completely and others function well in society. Most people with schizophrenia live independently with community support. About 85% are unemployed. In people with a first episode of psychosis in schizophrenia a good long-term outcome occurs in 31%, an intermediate outcome in 42% and a poor outcome in 31%. Males are affected more often than females, and have a worse outcome. Studies showing that outcomes for schizophrenia appear better in the developing than the developed world have been questioned. Social problems, such as long-term unemployment, poverty, homelessness, exploitation, stigmatization and victimization are common consequences, and lead to social exclusion.There is a higher than average suicide rate associated with schizophrenia estimated at 5% to 6%, most often occurring in the period following onset or first hospital admission. Several times more (20 to 40%) attempt suicide at least once. There are a variety of risk factors, including male gender, depression, a high IQ, heavy smoking, and substance use. Repeated relapse is linked to an increased risk of suicidal behavior. The use of clozapine can reduce the risk of suicide, and of aggression.A strong association between schizophrenia and tobacco smoking has been shown in worldwide studies. Smoking is especially high in those diagnosed with schizophrenia, with estimates ranging from 80 to 90% being regular smokers, as compared to 20% of the general population. Those who smoke tend to smoke heavily, and additionally smoke cigarettes with high nicotine content. Some propose that this is in an effort to improve symptoms. Among people with schizophrenia use of cannabis is also common.Schizophrenia leads to an increased risk of dementia. Violence Most people with schizophrenia are not aggressive, and are more likely to be victims of violence rather than perpetrators. People with schizophrenia are commonly exploited and victimized by violent crime as part of a broader dynamic of social exclusion. People diagnosed with schizophrenia are also subject to forced drug injections, seclusion, and restraint at high rates.The risk of violence by people with schizophrenia is small. There are minor subgroups where the risk is high. This risk is usually associated with a comorbid disorder such as a substance use disorder – in particular alcohol, or with antisocial personality disorder. Substance use disorder is strongly linked, and other risk factors are linked to deficits in cognition and social cognition including facial perception and insight that are in part included in theory of mind impairments. Poor cognitive functioning, decision-making, and facial perception may contribute to making a wrong judgement of a situation that could result in an inappropriate response such as violence. These associated risk factors are also present in antisocial personality disorder which when present as a comorbid disorder greatly increases the risk of violence. Epidemiology In 2017, the Global Burden of Disease Study estimated there were 1.1 million new cases; in 2022 the World Health Organization (WHO) reported a total of 24 million cases globally. Schizophrenia affects around 0.3–0.7% of people at some point in their life. In areas of conflict this figure can rise to between 4.0 and 6.5%. It occurs 1.4 times more frequently in males than females and typically appears earlier in men.Worldwide, schizophrenia is the most common psychotic disorder. The frequency of schizophrenia varies across the world, within countries, and at the local and neighborhood level; this variation in prevalence between studies over time, across geographical locations, and by gender is as high as fivefold.Schizophrenia causes approximately one percent of worldwide disability adjusted life years and resulted in 17,000 deaths in 2015.In 2000, WHO found the percentage of people affected and the number of new cases that develop each year is roughly similar around the world, with age-standardized prevalence per 100,000 ranging from 343 in Africa to 544 in Japan and Oceania for men, and from 378 in Africa to 527 in Southeastern Europe for women. History Conceptual development Accounts of a schizophrenia-like syndrome are rare in records before the 19th century; the earliest case reports were in 1797 and 1809. Dementia praecox, meaning premature dementia, was used by German psychiatrist Heinrich Schüle in 1886, and then in 1891 by Arnold Pick in a case report of hebephrenia. In 1893 Emil Kraepelin used the term in making a distinction, known as the Kraepelinian dichotomy, between the two psychoses – dementia praecox, and manic depression (now called bipolar disorder). When it became evident that the disorder was not a degenerative dementia, it was renamed schizophrenia by Eugen Bleuler in 1908.The word schizophrenia translates as splitting of the mind and is Modern Latin from the Greek words schizein (σχίζειν, to split) and phrēn, (φρήν, mind) Its use was intended to describe the separation of function between personality, thinking, memory, and perception.In the early 20th century, the psychiatrist Kurt Schneider categorized the psychotic symptoms of schizophrenia into two groups – hallucinations and delusions. The hallucinations were listed as specific to auditory and the delusions included thought disorders. These were seen as important symptoms, termed first-rank. The most common first-rank symptom was found to belong to thought disorders. In 2013 the first-rank symptoms were excluded from the DSM-5 criteria; while they may not be useful in diagnosing schizophrenia, they can assist in differential diagnosis.Subtypes of schizophrenia – classified as paranoid, disorganized, catatonic, undifferentiated, and residual – were difficult to distinguish and are no longer recognized as separate conditions by DSM-5 (2013) or ICD-11. Breadth of diagnosis Before the 1960s, nonviolent petty criminals and women were sometimes diagnosed with schizophrenia, categorizing the latter as ill for not performing their duties within patriarchy as wives and mothers. In the mid-to-late 1960s, black men were categorized as "hostile and aggressive" and diagnosed as schizophrenic at much higher rates, their civil rights and Black Power activism labeled as delusions.In the early 1970s in the US, the diagnostic model for schizophrenia was broad and clinically based using DSM II. Schizophrenia was diagnosed far more in the US than in Europe which used the ICD-9 criteria. The US model was criticised for failing to demarcate clearly those people with a mental illness. In 1980 DSM III was published and showed a shift in focus from the clinically based biopsychosocial model to a reason-based medical model. DSM IV brought an increased focus on an evidence-based medical model. Historical treatment In the 1930s a number of shock procedures which induced seizures (convulsions) or comas were used to treat schizophrenia. Insulin shock involved injecting large doses of insulin to induce comas, which in turn produced hypoglycemia and convulsions. The use of electricity to induce seizures was in use as electroconvulsive therapy (ECT) by 1938.Psychosurgery, including the lobotomy and frontal lobotomy – carried out from the 1930s until the 1970s in the United States, and until the 1980s in France – are recognized as a human rights abuse. In the mid-1950s the first typical antipsychotic, chlorpromazine, was introduced, followed in the 1970s by the first atypical antipsychotic, clozapine. Political abuse From the 1960s until 1989, psychiatrists in the USSR and Eastern Bloc diagnosed thousands of people with sluggish schizophrenia, without signs of psychosis, based on "the assumption that symptoms would later appear". Now discredited, the diagnosis provided a convenient way to confine political dissidents. Society and culture In 2002, the term for schizophrenia in Japan was changed from seishin-bunretsu-byō (精神分裂病, lit. mind-split disease) to tōgō-shitchō-shō (統合失調症, lit. integration–dysregulation syndrome) to reduce stigma. The new name, also interpreted as "integration disorder", was inspired by the biopsychosocial model. A similar change was made in South Korea in 2012 to attunement disorder.In the United States, the annual cost of schizophrenia – including direct costs (outpatient, inpatient, drugs, and long-term care) and non-healthcare costs (law enforcement, reduced workplace productivity, and unemployment) – was estimated at $62.7 billion for the year 2002. In the UK the cost in 2016 was put at £11.8 billion per year with a third of that figure directly attributable to the cost of hospital, social care and treatment. Cultural depictions The book A Beautiful Mind chronicled the life of John Forbes Nash who had been diagnosed with schizophrenia and won the Nobel Memorial Prize in Economic Sciences. The book was made into a film with the same name; an earlier documentary film was A Brilliant Madness. In 1964 a case study of three males diagnosed with schizophrenia who each had the delusional belief that they were Jesus Christ was published as The Three Christs of Ypsilanti; a film with the title Three Christs was released in 2020.Media coverage reinforces public perception of an association between schizophrenia and violence; in film, people with schizophrenia are highly likely to be portrayed as a danger to others. In the UK guidelines for reporting conditions and award campaigns have shown a reduction in negative reporting since 2013. Research directions A 2015 Cochrane review found unclear evidence of benefit from brain stimulation techniques to treat the positive symptoms of schizophrenia, in particular auditory verbal hallucinations (AVHs). Most studies focus on transcranial direct-current stimulation (tDCM), and repetitive transcranial magnetic stimulation (rTMS). Techniques based on focused ultrasound for deep brain stimulation could provide insight for the treatment of AVHs.The study of potential biomarkers that would help in diagnosis and treatment of schizophrenia is an active area of research as of 2020. Possible biomarkers include markers of inflammation, neuroimaging, brain-derived neurotrophic factor (BDNF), and speech analysis. Some markers such as C-reactive protein are useful in detecting levels of inflammation implicated in some psychiatric disorders but they are not disorder-specific. Other inflammatory cytokines are found to be elevated in first episode psychosis and acute relapse that are normalized after treatment with antipsychotics, and these may be considered as state markers. Deficits in sleep spindles in schizophrenia may serve as a marker of an impaired thalamocortical circuit, and a mechanism for memory impairment. MicroRNAs are highly influential in early neuronal development, and their disruption is implicated in several CNS disorders; circulating microRNAs (cimiRNAs) are found in body fluids such as blood and cerebrospinal fluid, and changes in their levels are seen to relate to changes in microRNA levels in specific regions of brain tissue. These studies suggest that cimiRNAs have the potential to be early and accurate biomarkers in a number of disorders including schizophrenia. Explanatory notes References External links Schizophrenia at Curlie

Tietze syndrome

Tietze syndrome is a benign inflammation of one or more of the costal cartilages. It was first described in 1921 by German surgeon Alexander Tietze and was subsequently named after him. The condition is characterized by tenderness and painful swelling of the anterior (front) chest wall at the costochondral (rib to cartilage), sternocostal (cartilage to sternum), or sternoclavicular (clavicle to sternum) junctions. Tietze syndrome affects the true ribs and has a predilection for the 2nd and 3rd ribs, commonly affecting only a single joint. In environments such as the emergency department, an estimated 20-50% of non-cardiac chest pain is due to a musculoskeletal cause. Despite musculoskeletal conditions such as Tietze syndrome being a common reason for visits to the emergency room, they are frequently misdiagnosed as angina pectoris, pleurisy, and other serious cardiopulmonary conditions due to similar presentation. Though Tietze syndrome can be misdiagnosed, life-threatening conditions with similar symptoms such as myocardial infarction (heart attack) should be ruled out prior to diagnosis of other conditions. Tietze syndrome is often confused with costochondritis. Tietze syndrome is differentiated from costochondritis by swelling of the costal cartilages, which does not appear in costochondritis. Additionally, costochondritis affects the 2nd to 5th ribs while Tietze syndrome typically affects the 2nd or 3rd rib. Presentation Tietze syndrome typically presents unilaterally at a single joint of the anterior chest wall, with 70% of patients having tenderness and swelling on only one side, usually at the 2nd or 3rd rib. Research has described the condition to be both sudden and gradual, varying by the individual. Pain and swelling from Tietze syndrome are typically chronic and intermittent and can last from a few days to several weeks.The most common symptom of Tietze syndrome is pain, primarily in the chest, but can also radiate to the shoulder and arm. The pain has been described as aching, gripping, neuralgic, sharp, dull, and even described as "gas pains". The symptoms of Tietze syndrome have been reported to be exacerbated by sneezing, coughing, deep inhalation, and overall physical exertion. Tenderness and swelling of the affected joint are important symptoms of Tietze syndrome and differentiate the condition from costochondritis. It has also been suggested that discomfort can be further aggravated due to restricted shoulder and chest movement. Cause The true etiology of Tietze syndrome has not been established, though several theories have been proposed. One popular theory is based on observations that many patients begin developing symptoms following a respiratory infection and dry cough, with one study finding 51 out of 65 patients contracted Tietze syndrome after either a cough or respiratory infection. Thus, it has been hypothesized that the repetitive mild trauma of a severe cough from a respiratory infection may produce small tears in the ligament called microtrauma, causing Tietze syndrome. However, this theory is disputed as it does not account for symptoms such as the onset of attacks while at rest as well as the fact that swelling sometimes develops before a cough. The respiratory infection has also been observed accompanying rheumatoid arthritis which, coupled with leukocytosis, neutrophilia, c-reactive protein (CRP), and elevated erythrocyte sedimentation rate (ESR), suggest an infectious and rheumatoid factor, though the evidence is conflicting. Many theories such as malnutrition, chest trauma, and tuberculosis, were thought to be among the potential causes but have since been disproven or left unsupported. Diagnosis Diagnosis for Tietze syndrome is primarily a clinical one, though some studies suggest the use of radiologic imaging. Musculoskeletal conditions are estimated to account for 20-50% of non-cardiac related chest pain in the emergency department. Ruling out other conditions, especially potentially life-threatening ones such as myocardial infarction (heart attack) and angina pectoris, is extremely important as they can present similarly to Tietze syndrome. These can usually be ruled out with diagnostic tools such as an electrocardiogram and a physical examination showing reproducible chest wall tenderness, . After eliminating other possible conditions, physical examination is considered the most accurate tool in diagnosing Tietze syndrome. Physical examination consists of gentle pressure to the chest wall with a single finger to identify the location of the discomfort. Swelling and tenderness upon palpation at one or more of the costochondral, sternocostal, or sternoclavicular joints, is a distinctive trait of Tietze syndrome and is considered a positive diagnosis when found.There are some pathological features that can be observed with Tietze syndrome, including degeneration of the costal cartilage, increase in vascularity, and hypertrophic changes (enlarged cells). However, these features can only be identified from a biopsy. Some studies have begun exploring and defining the use of radiographic imaging for diagnosing Tietze syndrome. This includes computed tomography (CT), magnetic resonance imaging (MRI), bone scintigraphy, and ultrasound, though these are only case studies and the methods described have yet to be thoroughly investigated. Methods such as plain radiographs, better known as an x-ray, are helpful in the exclusion of other conditions, but not in the diagnosis of Tietze syndrome. Some researchers believe that ultrasound is superior to other available imaging methods, as it can visualize the increased volume, swelling, and structural changes of the costal cartilage. Differential diagnosis The symptoms of Tietze syndrome can display as a wide variety of conditions, making it difficult to diagnose, especially to physicians unaware of the condition. Due to its presentation, Tietze syndrome can be misdiagnosed as a number of conditions, including myocardial infarction (heart attack), angina pectoris, and neoplasms.Costochondritis is most commonly confused with Tietze syndrome, as they have similar symptoms and can both affect the costochondral and sternocostal joints. Costochondritis is considered a more common condition and is not associated with any swelling to the affected joints, which is the defining distinction between the two. Tietze syndrome commonly affects the 2nd or 3rd rib and typically occurs among a younger age group, while costochondritis affects the 2nd to 5th ribs and has been found to occur in older individuals, usually over the age of 40. In addition, ultrasound can diagnose Tietze syndrome, whereas costochondritis relies heavily on physical examination and medical history.Another condition that can be confused for Tietze syndrome and costochondritis is slipping rib syndrome (SRS). All three conditions are associated with chest pain as well as inflammation of the costal cartilage. Unlike both costochondritis and Tietze syndrome, which affect some of the true ribs (1st to 7th), SRS affects the false ribs (8th to 10th). SRS is characterized by the partial dislocation, or subluxation, of the joints between the costal cartilages. This causes inflammation, irritated intercostal nerves, and straining of the intercostal muscles. SRS can cause abdominal and back pain, which costochondritis does not. Tietze syndrome and SRS can both present with radiating pain to the shoulder and arm, and both conditions can be diagnosed with ultrasound, though SRS requires a more complex dynamic ultrasound.The vast differential diagnosis also includes: Pleural diseases including pleurisy, pneumonia, pulmonary embolism, and pneumothorax. Rheumatic disorders such as rheumatoid arthritis, ankylosing spondylitis, and rheumatic fever. Arthritis of the costal cartilages, including rheumatoid arthritis, septic arthritis (pyogenic), monoarthritis, and psoriatic arthritis. Neoplasms, both benign and malignant (cancerous), including chondroma, osteochondroma, multiple myeloma, osteosarcoma, Hodgkin lymphoma, and carcinoma. Nerve pain, specifically intercostal neuritis and intercostal neuropathy. Aortic dissection, a serious condition involving a tear in the bodys largest artery. Treatment Tietze syndrome is considered to be a self-limiting condition that usually resolves within a few months with rest. Management for Tietze syndrome usually consists of analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, aspirin, acetaminophen (paracetamol), and naproxen. Other methods of management include manual therapy and local heat application. These are intended to relieve pain and are not expected to treat or cure Tietze syndrome as the condition is expected to resolve on its own. Intercostal nerve block A nerve block can be utilized in cases where symptom management is not satisfactory in relieving pain. This is usually a nerve-blocking injection that consists of a combination of steroids such as hydrocortisone, and anesthetics such as lidocaine and procaine, which is typically administered under ultrasound guidance. One study used a combination of triamcinolone hexacetonide and 2% lidocaine in 9 patients and after a week, found an average 82% decrease in size of the affected costal cartilage when assessing with ultrasound as well as a significant improvement of symptoms clinically. However, the long-term effectiveness of the injection is disputed, with multiple researchers describing recurrence of symptoms and repetitive injections. Surgical intervention In refractory cases of Tietze syndrome, where the condition is resistant to other conservative treatment options, surgery is considered. Surgery is uncommon for cases of Tietze syndrome, as many describe Tietze syndrome as manageable under less invasive options. The use of surgery in this context refers to the resection of the affected costal cartilages and some of the surrounding areas. Some surgeons have resected cartilage matching the symptoms of Tietze syndrome under the assumption the cartilage was tubercular. One study describes a case in which surgeons resected a large amount of cartilage, including minutely hypertrophied tissue, as a previous resection failed to relieve symptoms which is believed to be due to improperly resected margins. There is limited literature on surgical treatment of this disease, and overall research on the treatment of severe, chronic forms of Tietze syndrome. History Tietze syndrome was named after and first described in 1921 by German surgeon Alexander Tietze. Tietze first cited 4 cases in Germany of painful swelling where he originally believed the condition was as a result of tuberculosis or wartime malnutrition. References == External links ==

Amyloidosis

Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weight loss, shortness of breath, palpitations, and feeling faint with standing. In AL amyloidosis, specific indicators can include enlargement of the tongue and periorbital purpura. In wild-type ATTR amyloidosis, non-cardiac symptoms include: bilateral carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture, small fiber neuropathy, and autonomic dysfunction.There are about 36 different types of amyloidosis, each due to a specific protein misfolding. Within these 36 proteins, 19 are grouped into localized forms, 14 are grouped as systemic forms, and 3 proteins can identify as either. These proteins can become irregular due to genetic effects, as well as through acquired environmental factors. The four most common types of systemic amyloidosis are light chain (AL), inflammation (AA), dialysis-related (Aβ2M), and hereditary and old age (ATTR and familial amyloid polyneuropathy).Diagnosis may be suspected when protein is found in the urine, organ enlargement is present, or problems are found with multiple peripheral nerves and it is unclear why. Diagnosis is confirmed by tissue biopsy. Due to the variable presentation, a diagnosis can often take some time to reach.Treatment is geared towards decreasing the amount of the involved protein. This may sometimes be achieved by determining and treating the underlying cause. AL amyloidosis occurs in about 3–13 per million people per year and AA amyloidosis in about 2 per million people per year. The usual age of onset of these two types is 55 to 60 years old. Without treatment, life expectancy is between six months and four years. In the developed world about 1 per 1,000 people die annually from systemic amyloidosis. Amyloidosis has been described since at least 1639. Signs and symptoms The presentation of amyloidosis is broad and depends on the site of amyloid accumulation. The kidney and heart are the most common organs involved. Kidneys Amyloid deposition in the kidney often involve the glomerular capillaries and mesangial regions, affecting the organs ability to filter and excrete waste and retain plasma protein. This can lead to high levels of protein in the urine (proteinuria) and nephrotic syndrome. Several types of amyloidosis, including the AL and AA types, are associated with nephrotic syndrome. Approximately 20% and 40-60% of people with AL and AA amyloidosis respectively progress to end-stage kidney disease requiring dialysis. Heart Amyloid deposition in the heart can cause both diastolic and systolic heart failure. EKG changes may be present, showing low voltage and conduction abnormalities like atrioventricular block or sinus node dysfunction. On echocardiography, the heart shows a restrictive filling pattern, with normal to mildly reduced systolic function. AA amyloidosis usually spares the heart. Cardiac amyloidosis can present with symptoms of heart failure including shortness of breath, fatigue, and edema. As cardiac amyloidosis progresses, the amyloid deposition can affect the hearts ability to pump and fill blood as well as its ability to maintain normal rhythm, which leads to worsening heart function and decline in peoples quality of life. Nervous system People with amyloidosis do not get central nervous system involvement but can develop sensory and autonomic neuropathies. Sensory neuropathy develops in a symmetrical pattern and progresses in a distal to proximal manner. Autonomic neuropathy can present as orthostatic hypotension but may manifest more gradually with nonspecific gastrointestinal symptoms like constipation, nausea, or early satiety.Neuropathic presentation can depend on the etiology of amyloidosis. People with amyloidosis may experience dysfunction in various organ systems depending on the location and extent of nervous system involvement. For example, peripheral neuropathy can cause erectile dysfunction, incontinence and constipation, pupillary dysfunction, and sensory loss depending on the distribution of amyloidosis along different peripheral nerves. Amyloidosis of the central nervous system can have more severe and systemic presentations that may include life-threatening arrhythmias, cardiac failure, malnutrition, infection, or death. Gastrointestinal and accessory organs Accumulation of amyloid proteins in the gastrointestinal system may be caused by a wide range of amyloid disorders and have different presentations depending on the degree of organ involvement. Potential symptoms include weight loss, diarrhea, abdominal pain, heartburn (gastrointestinal reflux), and GI bleeding. Amyloidosis may also affect accessory digestive organs including the liver, and may present with jaundice, fatty stool, anorexia, fluid buildup in the abdomen, and spleen enlargement.Accumulation of amyloid proteins in the liver can lead to elevations in serum aminotransferases and alkaline phosphatase, two biomarkers of liver injury, which is seen in about one third of people. Liver enlargement is common. In contrast, spleen enlargement is rare, occurring in 5% of people. Splenic dysfunction, leading to the presence of Howell-Jolly bodies on blood smear, occurs in 24% of people with amyloidosis. Malabsorption is seen in 8.5% of AL amyloidosis and 2.4% of AA amyloidosis. One suggested mechanism for the observed malabsorption is that amyloid deposits in the tips of intestinal villi (fingerlike projections that increase the intestinal area available for absorption of food), begin to erode the functionality of the villi, presenting a sprue-like picture. Glands Both the thyroid and adrenal glands can be infiltrated. It is estimated that 10–20% of people with amyloidosis have hypothyroidism. Adrenal infiltration may be harder to appreciate given that its symptoms of orthostatic hypotension and low blood sodium concentration may be attributed to autonomic neuropathy and heart failure."Amyloid deposits occur in the pancreas of people who also have diabetes mellitus, although it is not known if this is functionally important. The major component of pancreatic amyloid is a 37-amino acid residue peptide known as islet amyloid polypeptide or amylin. This is stored with insulin in secretory granules in B cells and is co secreted with insulin." (Rang and Dales Pharmacology, 2015.) Musculoskeletal system Amyloid proteins deposit most commonly inside the knee, followed by hands, wrists, elbow, hip, and ankle, causing joint pain. In males with advanced age (>80 years), there is significant risk of wild-type transthyretin amyloid deposition in synovial tissue of knee joint, but predominantly in old age deposition of wild type transthyretin is seen in cardiac ventricles. ATTR deposits have been found in ligamentum flavum of patients that underwent surgery for lumbar spinal stenosis.In beta 2-microglobulin amyloidosis, males have high risk of getting carpal tunnel syndrome. Aβ2MG amyloidosis (Hemodialysis associated amyloidosis) tends to deposit in synovial tissue, causing chronic inflammation of the synovial tissue in knee, hip, shoulder and interphalangeal joints. Amyloid light chains deposition in shoulder joint causes enlarged shoulders, also known as "shoulder pad sign". Amyloid light chain depositions can also cause bilateral symmetric polyarthritis.The deposition of amyloid proteins in the bone marrow without causing plasma cell dyscrasias is called amyloidoma. It is commonly found in cervical, lumbar, and sacral vertebrae. Those affected may be presented with bone pain due to bone lysis, lumbar paraparesis, and a variety of neurological symptoms. Vertebral fractures are also common. Eyes A rare development is amyloid purpura, a susceptibility to bleeding with bruising around the eyes, termed "raccoon-eyes". Amyloid purpura is caused by amyloid deposition in the blood vessels and reduced activity of thrombin and factor X, two clotting proteins that lose their function after binding with amyloid. Oral cavity Amyloid deposits in tissue can cause enlargement of structures. Twenty percent of people with AL amyloidosis have an enlarged tongue, that can lead to obstructive sleep apnea, difficulty swallowing, and altered taste. Tongue enlargement does not occur in ATTR or AA amyloidosis. Deposition of amyloid in the throat can cause hoarseness. Pathogenesis Amyloidoses can be considered protein misfolding diseases. The vast majority of proteins that have been found to form amyloid deposits are secreted proteins, so the misfolding and formation of amyloid occurs outside cells, in the extracellular space. Of the 37 proteins so far identified as being vulnerable to amyloid formation, only four are cytosolic. Most amyloid-forming proteins are relatively small, but otherwise there is currently no evidence of structural or functional similarities among proteins known to form disease-associated amyloids. One third of amyloid disease is hereditary, in which case there is normally an early age of onset. Half of amyloid-related diseases are sporadic and have a late age of onset – in these cases, the protein aggregation may be associated with aging-related decline in protein regulation. Rarely, some medical treatments are associated with amyloid disease.Amyloid-forming proteins aggregate into distinctive fibrillar forms with a beta-sheet structure. The beta-sheet form of amyloid is proteolysis-resistant, meaning it can not be degraded or broken down. As a result, amyloid deposits into the bodys extracellular space. The process of forming amyloid fibrils is thought to have intermediate oligomeric forms. Both the oligomers and amyloid fibrils can be toxic to cells and can interfere with proper organ function. The relative significance of different aggregation species may depend on the protein involved and the organ system affected. Diagnosis Diagnosis of amyloidosis generally requires tissue biopsy. The biopsy is assessed for evidence of characteristic amyloid deposits. The tissue is treated with various stains. The most useful stain in the diagnosis of amyloid is Congo red, which, combined with polarized light, makes the amyloid proteins appear apple-green on microscopy. Also, thioflavin T stain may be used. A number of imaging techniques such as a DPD scan or SAP scan are also in use.A sample of tissue can be biopsied or obtained directly from the affected internal organ, but the first-line site of biopsy is subcutaneous abdominal fat, known as a "fat pad biopsy", due to its ease of acquisition. An abdominal fat biopsy is not completely sensitive and may result in false negatives, which means a negative result does not exclude the diagnosis of amyloidosis. However, direct biopsy of the affected organ may still be unnecessary as other less invasive methods of biopsy can also be used, including rectal mucosa, salivary gland, lip, or bone marrow biopsy which can achieve a diagnosis in up to 85% of people.In the amyloid deposition of the joints, there will be a decreased signal in both T1 and T2 weighted MRI images. In amyloidoma, there will be low T1 signal with gadolinium injection and low T2 signal.The type of the amyloid protein can be determined in various ways: the detection of abnormal proteins in the bloodstream (on protein electrophoresis or light chain determination); binding of particular antibodies to the amyloid found in the tissue (immunohistochemistry); or extraction of the protein and identification of its individual amino acids. Immunohistochemistry can identify AA amyloidosis the majority of the time, but can miss many cases of AL amyloidosis. Laser microdissection with mass spectrometry is the most reliable method of identifying the different forms of amyloidosis.AL was previously considered the most common form of amyloidosis, and a diagnosis often begins with a search for plasma cell dyscrasia, memory B cells producing aberrant immunoglobulins or portions of immunoglobulins. Immunofixation electrophoresis of urine or serum is positive in 90% of people with AL amyloidosis. Immunofixation electrophoresis is more sensitive than regular electrophoresis but may not be available in all centers. Alternatively immunohistochemical staining of a bone marrow biopsy looking for dominant plasma cells can be sought in people with a high clinical suspicion for AL amyloidosis but negative electrophoresis.ATTR is now considered to be the most common form of amyloidosis, and no longer considered as a rare disease. It may be either age related in wild-type ATTR (ATTRv) or familial transthyretin-associated amyloidosis, is suspected in people with family history of idiopathic neuropathies or heart failure who lack evidence of plasma cell dyscrasias. ATTR can be identified using isoelectric focusing which separates mutated forms of transthyretin. Findings can be corroborated by genetic testing to look for specific known mutations in transthyretin that predispose to amyloidosis.AA is suspected on clinical grounds in individuals with longstanding infections or inflammatory diseases. AA can be identified by immunohistochemistry staining. Classification Historical classification systems were based on clinical factors. Until the early 1970s, the idea of a single amyloid substance predominated. Various descriptive classification systems were proposed based on the organ distribution of amyloid deposits and clinical findings. Most classification systems included primary (i.e., idiopathic) amyloidosis, in which no associated clinical condition was identified, and secondary amyloidosis (i.e., secondary to chronic inflammatory conditions). Some classification systems included myeloma-associated, familial, and localized amyloidosis. The modern era of amyloidosis classification began in the late 1960s with the development of methods to make amyloid fibrils soluble. These methods permitted scientists to study the chemical properties of amyloids. Descriptive terms such as primary amyloidosis, secondary amyloidosis, and others (e.g., senile amyloidosis), which are not based on cause, provide little useful information and are no longer recommended. The modern classification of amyloid disease tends to use an abbreviation of the protein that makes the majority of deposits, prefixed with the letter A. For example, amyloidosis caused by transthyretin is termed "ATTR". Deposition patterns vary between people but are almost always composed of just one amyloidogenic protein. Deposition can be systemic (affecting many different organ systems) or organ-specific. Many amyloidoses are inherited, due to mutations in the precursor protein.Other forms are due to different diseases causing overabundant or abnormal protein production – such as with overproduction of immunoglobulin light chains (termed AL amyloidosis), or with continuous overproduction of acute phase proteins in chronic inflammation (which can lead to AA amyloidosis).About 60 amyloid proteins have been identified so far. Of those, at least 36 have been associated with a human disease.All amyloid fibril proteins start with the letter "A" followed by the protein suffix (and any applicable specification). See below for a list of amyloid fibril proteins which have been found in humans: Alternative An older clinical method of classification refers to amyloidoses as systemic or localised: Systemic amyloidoses affect more than one body organ or system. Examples are AL, AA and Aβ2m. Localised amyloidoses affect only one body organ or tissue type. Examples are Aβ, IAPP, Atrial natriuretic factor (in isolated atrial amyloidosis), and Calcitonin (in medullary carcinoma of the thyroid)Another classification is primary or secondary. Primary amyloidoses arise from a disease with disordered immune cell function, such as multiple myeloma or other immunocyte dyscrasias. Secondary (reactive) amyloidoses occur as a complication of some other chronic inflammatory or tissue-destroying disease. Examples are reactive systemic amyloidosis and secondary cutaneous amyloidosis.Additionally, based on the tissues in which it is deposited, it is divided into mesenchymal (organs derived from mesoderm) or parenchymal (organs derived from ectoderm or endoderm). Treatment Treatment depends on the type of amyloidosis that is present. Treatment with high dose melphalan, a chemotherapy agent, followed by stem cell transplantation has shown promise in early studies and is recommended for stage I and II AL amyloidosis. However, only 20–25% of people are eligible for stem cell transplant. Chemotherapy treatment including cyclophosphamide-bortezomib-dexamethasone is currently the recommended treatment option for people with AL Amyloidosis not eligible for transplant.In AA, symptoms may improve if the underlying condition is treated. In people who have inflammation caused by AA amyloidosis, tumour necrosis factor (TNF)-alpha inhibitors such as infliximab and etanercept are used for an average duration of 20 months. If TNF-alpha inhibitors are not effective, Interleukin-1 inhibitors (e.g. anakinra, canakinumab, rilonacept) and interleukin-6 inhibitors (e.g. tocilizumab) may be considered.Management of ATTR amyloidosis will depend on its classification as wild type or variant. Both may be treated with tafamidis, a low toxicity oral agent that prevents destabilization of correctly folded protein. Studies showed tafamidis reduced mortality and hospitalization due to heart failure. Previously, for variant ATTR amyloidosis, liver transplant was the only effective treatment. New therapies include diflunisal, inotersen, and patisiran. Diflunisal binds to misfolded mutant TTR protein to prevent its buildup, like how tafamidis works. Low-certainty evidence indicates that it mitigates worsening of peripheral neuropathy and disability from disease progression.Inotersen blocks gene expression of both wild-type and mutant TTR, reducing amyloid precursor. Moderate-certainty evidence suggests that it mitigates worsening of peripheral neuropathy. Long-term efficacy and safety of inotersen use in people with mutant TTR-related amyloidosis is still be evaluated in a phase-III clinical trial as of 2021. Both diflunisal and inotersen may also mitigate declines in quality-of-life, though the evidence for this effect is unclear. For people with cardiac ATTR the effect of inotersen use is inconclusive and requires further investigation. In 2018, inotersen was approved by the European Medicines Agency to treat polyneuropathy in adults with hereditary transthyretin amyloidosis. It has since been approved for use in Canada, the European Union and in the USA.Patisiran functions similarly to inotersen. Moderate-certainty evidence suggests that patisiran mitigates worsening of peripheral neuropathy and disability from disease progression. Additionally, low-certainty evidence suggests that patisiran mitigates decreases in quality-of-life and slightly reduces the rate of adverse events versus placebo. There is no evidence of an effect on mortality rate. A review of early data from use of patisiran in people with variant cardiac ATTR suggests that it may reduce mortality and hospitalization, however this is still being investigated and requires further investigation. In 2018, patisiran was not recommended by NICE in the UK for hereditary transthyretin-related amyloidosis. As of July 2019 further review however is occurring. It was approved for this use in the United States, however.The roles of inotersen and patisiran in cardiac ATTR amyloidosis are still being investigated.In 2021, in a clinical trial using the CRISPR gene-editing technique, several participants had an "80% to 96% drop in TTR levels, on par or better than the average of 81%" who were given patisiran.Vutrisiran was approved by the U.S. Food and Drug Administration (FDA) in June 2022, for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. Support groups People affected by amyloidosis are supported by organizations, including the Amyloidosis Research Consortium, Amyloidosis Foundation, Amyloidosis Support Groups, and Amyloidosis Australia. Prognosis Prognosis varies with the type of amyloidosis and the affected organ system. Prognosis for untreated AL cardiac amyloidosis is poor, with a median survival of six months. More specifically, AL amyloidosis can be classified as stage I, II or III based on cardiac biomarkers like Nt-proBNP and cardiac troponin. Survival diminishes with increasing stage, however recent advancements in treatments have improved median survival rates for stages I, II, and III, to 91.2, 60, and 7 months respectively.Outcomes in a person with AA amyloidosis depend on the underlying disease, organ(s) affected, and correlate with the concentration of serum amyloid A protein.People with ATTR, mutant ATTR and wild-type ATTR have a better prognosis when compared to people with AL and may survive for over a decade. Survival time is not associated with gender or age, however, some measures of reduced heart function are associated with a shorter survival time.Senile systemic amyloidosis was determined to be the primary cause of death for 70% of people over 110 who have been autopsied. Epidemiology Amyloidosis has a combined estimated prevalence of 30 per 100,000 persons with the three most common forms being AL, ATTR, and AA. The median age at diagnosis is 64.AL has the highest incidence at approximately 12 cases per million persons per year and an estimated prevalence of 30,000 to 45,000 cases in the US and European Union.AA amyloidoses is the most common form in developing countries and can complicate longstanding infections with tuberculosis, osteomyelitis, and bronchiectesis. AA amyloidosis is caused by an increase in extracellular deposition of serum amyloid A (SAA) protein. SAA protein levels can rise in both direct and indirect manners, through infection, inflammation, and malignancies. The most common causes of AA amyloidosis in the West are rheumatoid arthritis, inflammatory bowel disease, psoriasis, and familial Mediterranean fever.People undergoing long-term hemodialysis (14–15 years) can develop amyloidosis from accumulation of light chains of the HLA 1 complex which is normally filtered out by the kidneys.Wild-type transthyretin (ATTR) amyloidosis is found in a quarter of elderly at postmortem. ATTR is found in 13-19% of people experiencing heart failure with preserved ejection fraction, making it a very common form of systemic amyloidosis. Research Treatments for ATTR-related neuropathy include TTR-specific oligonucleotides in the form of small interfering RNA (patisiran) or antisense inotersen, the former having recently received FDA approval. Research into treatments for ATTR amyloidosis have compared liver transplantation, oral drugs that stabilize the misfolding protein (including tafamidis and diflunisal), and newer therapeutic agents still being investigated (including patisiran). Based on available research, liver transplant remains the most effective treatment option for advanced ATTR amyloidosis, protein stabilizing drugs may slow disease progression but were insufficient to justify delay of liver transplant, and newer agents such as patisiran require additional studies. See also Peptide synthesis Proteopathy References External links Amyloidosis at Curlie

Social anxiety disorder

Social anxiety disorder (SAD), also known as social phobia, is an anxiety disorder characterized by sentiments of fear and anxiety in social situations, causing considerable distress and impaired ability to function in at least some aspects of daily life.: 15  These fears can be triggered by perceived or actual scrutiny from others. Individuals with social anxiety disorder fear negative evaluations from other people. Physical symptoms often include excessive blushing, excess sweating, trembling, palpitations, and nausea. Stammering may be present, along with rapid speech. Panic attacks can also occur under intense fear and discomfort. Some affected individuals may use alcohol or other drugs to reduce fears and inhibitions at social events. It is common for those with social phobia to self-medicate in this fashion, especially if they are undiagnosed, untreated, or both; this can lead to alcohol use disorder, eating disorders or other kinds of substance use disorders. SAD is sometimes referred to as an illness of lost opportunities where "individuals make major life choices to accommodate their illness". According to ICD-10 guidelines, the main diagnostic criteria of social phobia are fear of being the focus of attention, or fear of behaving in a way that will be embarrassing or humiliating, avoidance and anxiety symptoms. Standardized rating scales can be used to screen for social anxiety disorder and measure the severity of anxiety. The first line of treatment for social anxiety disorder is cognitive behavioral therapy (CBT). Medications such as SSRIs are effective for social phobia, especially paroxetine. CBT is effective in treating this disorder, whether delivered individually or in a group setting. The cognitive and behavioral components seek to change thought patterns and physical reactions to anxiety-inducing situations. The attention given to social anxiety disorder has significantly increased since 1999 with the approval and marketing of drugs for its treatment. Prescribed medications include several classes of antidepressants: selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs). Other commonly used medications include beta blockers and benzodiazepines. History Literary descriptions of shyness can be traced back to the days of Hippocrates around 400 B.C. Hippocrates described someone who "through bashfulness, suspicion, and timorousness, will not be seen abroad; loves darkness as life and cannot endure the light or to sit in lightsome places; his hat still in his eyes, he will neither see, nor be seen by his good will. He dare not come in company for fear he should be misused, disgraced, overshoot himself in gesture or speeches, or be sick; he thinks every man observes him."The first mention of the psychiatric term "social phobia" (phobie des situations sociales) was made in the early 1900s. Psychologists used the term "social neurosis" to describe extremely shy patients in the 1930s. After extensive work by Joseph Wolpe on systematic desensitization, research on phobias and their treatment grew. The idea that social phobia was a separate entity from other phobias came from the British psychiatrist Isaac Marks in the 1960s. This was accepted by the American Psychiatric Association and was first officially included in the third edition of the Diagnostic and Statistical Manual of Mental Disorders. The definition of the phobia was revised in 1989 to allow comorbidity with avoidant personality disorder and introduced generalized social phobia. Social phobia had been largely ignored prior to 1985.After a call to action by psychiatrist Michael Liebowitz and clinical psychologist Richard Heimberg, there was an increase in attention to and research on the disorder. The DSM-IV gave social phobia the alternative name "social anxiety disorder". Research on the psychology and sociology of everyday social anxiety continued. Cognitive Behavioural models and therapies were developed for social anxiety disorder. In the 1990s, paroxetine became the first prescription drug in the U.S. approved to treat social anxiety disorder, with others following. Signs and symptoms The 10th version of the International Classification of Diseases (ICD-10) classifies social anxiety as a mental and behavioral disorder. Cognitive aspects In cognitive models of social anxiety disorder, those with social phobias experience dread over how they will present to others. They may feel overly self-conscious, pay high self-attention after the activity, or have high performance standards for themselves. According to the social psychology theory of self-presentation, an affected person attempts to create a well-mannered impression towards others but believes they are unable to do so. Many times, before the potentially anxiety-provoking social situation, they may deliberately review what could go wrong and how to deal with each unexpected case. After the event, they may have the perception that they performed unsatisfactorily. Consequently, they will perceive anything that may have possibly been abnormal as embarrassing. These thoughts may extend for weeks or longer. Cognitive distortions are a hallmark and are learned about in CBT (cognitive-behavioral therapy). Thoughts are often self-defeating and inaccurate. Those with social phobia tend to interpret neutral or ambiguous conversations with a negative outlook and many studies suggest that socially anxious individuals remember more negative memories than those less distressed.An example of an instance may be that of an employee presenting to their co-workers. During the presentation, the person may stutter a word, upon which they may worry that other people significantly noticed and think that their perceptions of them as a presenter have been tarnished. This cognitive thought propels further anxiety which compounds further stuttering, sweating, and, potentially, a panic attack. Behavioural aspects Social anxiety disorder is a persistent fear of one or more situations in which the person is exposed to possible scrutiny by others and fears that they may do something or act in a way that will be humiliating or embarrassing. It exceeds normal "shyness" as it leads to excessive social avoidance and substantial social or occupational impairment. Feared activities may include almost any type of social interaction, especially small groups, dating, parties, talking to strangers, restaurants, interviews, etc. Those who have social anxiety disorder fear being judged by others in society. In particular, individuals with social anxiety are nervous in the presence of people with authority and feel uncomfortable during physical examinations. People who have this disorder may behave a certain way or say something and then feel embarrassed or humiliated after. As a result, they often choose to isolate themselves from society to avoid such situations. They may also feel uncomfortable meeting people they do not know and act distant when they are with large groups of people. In some cases, they may show evidence of this disorder by avoiding eye contact, or blushing when someone is talking to them.According to psychologist B. F. Skinner, phobias are controlled by escape and avoidance behaviors. For instance, a student may leave the room when talking in front of the class (escape) and refrain from doing verbal presentations because of the previously encountered anxiety attack (avoid). Major avoidance behaviors could include an almost pathological or compulsive lying behavior to preserve self-image and avoid judgment in front of others. Minor avoidance behaviors are exposed when a person avoids eye contact and crosses his/her arms to conceal recognizable shaking. A fight-or-flight response is then triggered in such events. Physiological aspects Physiological effects, similar to those in other anxiety disorders, are present in social phobias. In adults, it may cause tears as well as excessive sweating, nausea, difficulty breathing, shaking, and palpitations as a result of the fight-or-flight response. The walk disturbance (where a person is so worried about how they walk that they may lose balance) may appear, especially when passing a group of people. Blushing is commonly exhibited by individuals with social phobia. These visible symptoms further reinforce the anxiety in the presence of others. A 2006 study found that the area of the brain called the amygdala, part of the limbic system, is hyperactive when patients are shown threatening faces or confronted with frightening situations. They found that patients with more severe social phobia showed a correlation with increased response in their amygdalae. People with SAD may avoid looking at other people, and even their surroundings, to a greater extent than their peers, possibly to decrease the risk of eye contact, which can be interpreted as a nonverbal signal of openness to social interaction. Social aspects People with SAD avoid situations that most people consider "normal". They may have a hard time understanding how others can handle these situations so easily. People with SAD avoid all or most social situations and hide from others, which can affect their personal relationships. Social phobia can completely remove people from social situations due to the irrational fear of these situations. People with SAD may be addicted to social media networks, have sleep deprivation, and feel good when they avoid human interactions. SAD can also lead to low self-esteem, negative thoughts, major depressive disorder, sensitivity to criticism, and poor social skills that dont improve. People with SAD experience anxiety in a variety of social situations, from important, meaningful encounters, to everyday trivial ones. These people may feel more nervous in job interviews, dates, interactions with authority, or at work. Comorbidity SAD shows a high degree of co-occurrence with other psychiatric disorders. In fact, a population-based study found that 66% of those with SAD had one or more additional mental health disorders. SAD often occurs alongside low self-esteem and most commonly clinical depression, perhaps due to a lack of personal relationships and long periods of isolation related to social avoidance. Clinical depression is 1.49 to 3.5 times more likely to occur in those with SAD. Research also indicates that the presence of certain social fears (e.g., avoidance of participating in small groups, avoidance of going to a party) are more likely to trigger comorbid depressive symptoms than other social fears, and thus deserve a very careful audit during clinical assessment among patients with SAD.Anxiety disorders other than SAD are also very common in patients with SAD, in particular generalized anxiety disorder. Avoidant personality disorder is likewise highly correlated with SAD, with comorbidity rates ranging from 25% to 89%.To try to reduce their anxiety and alleviate depression, people with social phobia may use alcohol or other drugs, which can lead to substance use disorders. It is estimated that one-fifth of patients with social anxiety disorder also have alcohol use disorder. However, some research suggests SAD is unrelated to, or even protective against alcohol-related problems. Those who have both alcohol use disorder and social anxiety disorder are more likely to avoid group-based treatments and to relapse compared to people who do not have this combination. Causes Research into the causes of social anxiety and social phobia is wide-ranging, encompassing multiple perspectives from neuroscience to sociology. Scientists have yet to pinpoint the exact causes. Studies suggest that genetics can play a part in combination with environmental factors. Social phobia is not caused by other mental disorders or substance use. Generally, social anxiety begins at a specific point in an individuals life. This will develop over time as the person struggles to recover. Eventually, mild social awkwardness can develop into symptoms of social anxiety or phobia. Passive social media usage may cause social anxiety in some people. Genetics It has been shown that there is a two to a threefold greater risk of having social phobia if a first-degree relative also has the disorder. This could be due to genetics and/or due to children acquiring social fears and avoidance through processes of observational learning or parental psychosocial education. Studies of identical twins brought up (via adoption) in different families have indicated that, if one twin developed social anxiety disorder, then the other was between 30 percent and 50 percent more likely than average to also develop the disorder. To some extent, this "heritability" may not be specific – for example, studies have found that if a parent has any kind of anxiety disorder or clinical depression, then a child is somewhat more likely to develop an anxiety disorder or social phobia. Studies suggest that parents of those with social anxiety disorder tend to be more socially isolated themselves (Bruch and Heimberg, 1994; Caster et al., 1999), and shyness in adoptive parents is significantly correlated with shyness in adopted children (Daniels and Plomin, 1985). Growing up with overprotective and hypercritical parents has also been associated with social anxiety disorder. Adolescents who were rated as having an insecure (anxious-ambivalent) attachment with their mother as infants were twice as likely to develop anxiety disorders by late adolescence, including social phobia.A related line of research has investigated behavioural inhibition in infants – early signs of an inhibited and introspective or fearful nature. Studies have shown that around 10–15 percent of individuals show this early temperament, which appears to be partly due to genetics. Some continue to show this trait into adolescence and adulthood and appear to be more likely to develop a social anxiety disorder. Social experiences A previous negative social experience can be a trigger to social phobia, perhaps particularly for individuals high in "interpersonal sensitivity". For around half of those diagnosed with social anxiety disorder, a specific traumatic or humiliating social event appears to be associated with the onset or worsening of the disorder; this kind of event appears to be particularly related to specific social phobia, for example, regarding public speaking (Stemberg et al., 1995). As well as direct experiences, observing or hearing about the socially negative experiences of others (e.g. a faux pas committed by someone), or verbal warnings of social problems and dangers, may also make the development of a social anxiety disorder more likely. Social anxiety disorder may be caused by the longer-term effects of not fitting in, or being bullied, rejected, or ignored. Shy adolescents or avoidant adults have emphasized unpleasant experiences with peers or childhood bullying or harassment. In one study, popularity was found to be negatively correlated with social anxiety, and children who were neglected by their peers reported higher social anxiety and fear of negative evaluation than other categories of children. Socially phobic children appear less likely to receive positive reactions from peers, and anxious or inhibited children may isolate themselves. Cultural influences Cultural factors that have been related to social anxiety disorder include a societys attitude towards shyness and avoidance, affecting the ability to form relationships or access employment or education, and shame. One study found that the effects of parenting are different depending on the culture: American children appear more likely to develop social anxiety disorder if their parents emphasize the importance of others opinions and use shame as a disciplinary strategy (Leung et al., 1994), but this association was not found for Chinese/Chinese-American children. In China, research has indicated that shy-inhibited children are more accepted than their peers and more likely to be considered for leadership and considered competent, in contrast to the findings in Western countries. Purely demographic variables may also play a role. Problems in developing social skills, or social fluency, may be a cause of some social anxiety disorder, through either inability or lack of confidence to interact socially and gain positive reactions and acceptance from others. The studies have been mixed, however, with some studies not finding significant problems in social skills while others have. What does seem clear is that the socially anxious perceive their own social skills to be low. It may be that the increasing need for sophisticated social skills in forming relationships or careers, and an emphasis on assertiveness and competitiveness, is making social anxiety problems more common, at least among the middle classes. An interpersonal or media emphasis on normal or attractive personal characteristics has also been argued to fuel perfectionism and feelings of inferiority or insecurity regarding negative evaluation from others. The need for social acceptance or social standing has been elaborated in other lines of research relating to social anxiety. Substance-induced While alcohol initially relieves social phobia, excessive alcohol misuse can worsen social phobia symptoms and cause panic disorder to develop or worsen during alcohol intoxication and especially during alcohol withdrawal syndrome. This effect is not unique to alcohol but can also occur with long-term use of drugs that have a similar mechanism of action to alcohol such as the benzodiazepines which are sometimes prescribed as tranquillisers. Benzodiazepines possess anti-anxiety properties and can be useful for the short-term treatment of severe anxiety. Like the anticonvulsants, they tend to be mild and well-tolerated, although there is a risk of habit-forming. Benzodiazepines are usually administered orally for the treatment of anxiety; however, occasionally lorazepam or diazepam may be given intravenously for the treatment of panic attacks.The World Council of Anxiety does not recommend benzodiazepines for the long-term treatment of anxiety due to a range of problems associated with long-term use including tolerance, psychomotor impairment, cognitive and memory impairments, physical dependence and a benzodiazepine withdrawal syndrome upon discontinuation of benzodiazepines. Despite increasing focus on the use of antidepressants and other agents for the treatment of anxiety, benzodiazepines have remained a mainstay of anxiolytic pharmacotherapy due to their robust efficacy, rapid onset of therapeutic effect, and generally favorable side effect profile. Treatment patterns for psychotropic drugs appear to have remained stable over the past decade, with benzodiazepines being the most commonly used medication for panic disorder.Many people who are addicted to alcohol or prescribed benzodiazepines when it is explained to them they have a choice between ongoing ill mental health or quitting and recovering from their symptoms decide on quitting alcohol or their benzodiazepines. Symptoms may temporarily worsen however, during alcohol withdrawal or benzodiazepine withdrawal. Psychological factors Research has indicated the role of core or unconditional negative beliefs (e.g. "I am inept") and conditional beliefs nearer to the surface (e.g. "If I show myself, I will be rejected"). They are thought to develop based on personality and adverse experiences and to be activated when the person feels under threat. Recent research has also highlighted that conditional beliefs may also be at play (e.g., "If people see Im anxious, theyll think that Im weak").A secondary factor is self-concealment which involves concealing the expression of ones anxiety or its underlying beliefs. One line of work has focused more specifically on the key role of self-presentational concerns. The resulting anxiety states are seen as interfering with social performance and the ability to concentrate on interaction, which in turn creates more social problems, which strengthens the negative schema. Also highlighted has been a high focus on and worry about anxiety symptoms themselves and how they might appear to others. A similar model emphasizes the development of a distorted mental representation of the self and overestimates of the likelihood and consequences of negative evaluation, and of the performance standards that others have. Such cognitive-behavioral models consider the role of negatively biased memories of the past and the processes of rumination after an event, and fearful anticipation before it. Studies have also highlighted the role of subtle avoidance and defensive factors, and shown how attempts to avoid feared negative evaluations or use of safety behaviors (Clark & Wells, 1995) can make social interaction more difficult and the anxiety worse in the long run. This work has been influential in the development of Cognitive Behavioral Therapy for social anxiety disorder, which has been shown to have efficacy. Mechanisms There are many studies investigating neural bases of social anxiety disorder. Although the exact neural mechanisms have not been found yet, there is evidence relating social anxiety disorder to imbalance in some neurochemicals and hyperactivity in some brain areas. Neurotransmitters Sociability is closely tied to dopaminergic neurotransmission. In a 2011 study, a direct relation between social status of volunteers and binding affinity of dopamine D2/3 receptors in the striatum was found. Other research shows that the binding affinity of dopamine D2 receptors in the striatum of people with social anxiety is lower than in controls. Some other research shows an abnormality in dopamine transporter density in the striatum of those with social anxiety. However, some researchers have been unable to replicate previous findings of evidence of dopamine abnormality in social anxiety disorder. Studies have shown high prevalence of social anxiety in Parkinsons disease and schizophrenia. In a recent study, social phobia was diagnosed in 50% of Parkinsons disease patients. Other researchers have found social phobia symptoms in patients treated with dopamine antagonists like haloperidol, emphasizing the role of dopamine neurotransmission in social anxiety disorder.Some evidence points to the possibility that social anxiety disorder involves reduced serotonin receptor binding. A recent study reports increased serotonin transporter binding in psychotropic medication-naive patients with generalized social anxiety disorder. Although there is little evidence of abnormality in serotonin neurotransmission, the limited efficacy of medications which affect serotonin levels may indicate the role of this pathway. Paroxetine, sertraline and fluvoxamine are three SSRIs that have been approved by the FDA to treat social anxiety disorder. Some researchers believe that SSRIs decrease the activity of the amygdala. There is also increasing focus on other candidate transmitters, e.g. norepinephrine and glutamate, which may be over-active in social anxiety disorder, and the inhibitory transmitter GABA, which may be under-active in the thalamus. Brain areas The amygdala is part of the limbic system which is related to fear cognition and emotional learning. Individuals with social anxiety disorder have been found to have a hypersensitive amygdala; for example in relation to social threat cues (e.g. perceived negative evaluation by another person), angry or hostile faces, and while waiting to give a speech. Recent research has also indicated that another area of the brain, the anterior cingulate cortex, which was already known to be involved in the experience of physical pain, also appears to be involved in the experience of social pain, for example perceiving group exclusion. Recent research also highlighted the potent role of the prefrontal cortex, especially its dorsolateral part, in the maintenance of cognitive biases involved in SAD. A 2007 meta-analysis also found that individuals with social anxiety had hyperactivation in the amygdala and insula areas which are frequently associated with fear and negative emotional processing. Diagnosis ICD-10 defines social phobia as fear of scrutiny by other people leading to avoidance of social situations. The anxiety symptoms may present as a complaint of blushing, hand tremor, nausea, or urgency of micturition. Symptoms may progress to panic attacks.Standardized rating scales such as the Social Phobia Inventory, the SPAI-B, Liebowitz Social Anxiety Scale, and the Social Interaction Anxiety Scale can be used to screen for social anxiety disorder and measure the severity of anxiety. DSM-V Diagnosis DSM-5 defines Social Anxiety Disorder as a marked, or intense, fear or anxiety of social situations in which the individual may be scrutinized by others.DSM-5 Diagnostic Criteria with Diagnostic Features: Marked fear or anxiety about one or more social situations in which the individual is exposed to possible scrutiny by others. Examples include social interactions (e.g., having a conversation, meeting unfamiliar people), being observed (e.g., eating or drinking), and performing in front of others (e.g., giving a speech). Note: In children, the anxiety must occur in peer settings and not just during interactions with adults. The individual fears that he or she will act in a way or show anxiety symptoms that will be negatively evaluated (i.e., will be humiliating or embarrassing: will lead to rejection or offend others). When exposed to such social situations, the individual fears that he or she will be negatively evaluated. The individual is concerned that he or she will be judged as anxious, weak, crazy, stupid, boring, intimidating, dirty, or unlikable. The individual fears that he or she will act or appear in a certain way or show anxiety symptoms, such as blushing, trembling, sweating, stumbling over ones words, or staring, that will be negatively evaluated by others. The social situations almost always provoke fear or anxiety. Thus, an individual who becomes anxious only occasionally in the social situation(s) would not be diagnosed with social anxiety disorder. Note: In children, the fear or anxiety may be expressed by crying, tantrums, freezing, clinging, shrinking, or failing to speak in social situations. The social situations are avoided. Alternatively, the situations are endured with intense fear or anxiety. The fear or anxiety is out of proportion to the actual threat posed by the social situation and to the sociocultural context. The fear or anxiety is judged to be out of proportion to the actual risk of being negatively evaluated or to the consequences of such negative evaluation. Sometimes, the anxiety may not be judged to be excessive, because it is related to an actual danger (e.g., being bullied or tormented by others). However, individuals with social anxiety disorder often overestimate the negative consequences of social situations, and thus the judgment of being out of proportion is made by the clinician. The fear, anxiety, or avoidance is persistent, typically lasting for 6 months or more. This duration threshold helps distinguish the disorder from transient social fears that are common, particularly among children and in the community. However, the duration criterion should be used as a general guide, with allowance for some degree of flexibility. The fear, anxiety, or avoidance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. The fear, anxiety, and avoidance must interfere significantly with the individuals normal routine, occupational or academic functioning, or social activities or relationships, or must cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. For example, an individual who is afraid to speak in public would not receive a diagnosis of social anxiety disorder if this activity is not routinely encountered on the job or in classroom work, and if the individual is not significantly distressed about it. However, if the individual avoids, or is passed over for, the job or education he or she really wants because of social anxiety symptoms criterion is met. The fear, anxiety, or avoidance is not attributable to the physiological effects of a substance (e.g., an addictive substance, a medication) or another medical condition. The fear, anxiety, or avoidance is not better explained by the symptoms of another mental disorder, such as panic disorder, body dysmorphic disorder, or autism spectrum disorder. If another medical condition (e.g., Parkinson disease, obesity, disfigurement from burns or injury) is present, the fear, anxiety, or avoidance is clearly unrelated or is excessive.If the fear is restricted to speaking or performing in public it is performance only social anxiety disorder. Differential diagnosis The DSM-IV criteria stated that an individual cannot receive a diagnosis of social anxiety disorder if their symptoms are better accounted for by one of the autism spectrum disorders such as autism and Asperger syndrome.Because of its close relationship and overlapping symptoms, treating people with social phobia may help understand the underlying connections to other mental disorders. Social anxiety disorder is often linked to bipolar disorder and attention deficit hyperactivity disorder (ADHD) and some believe that they share an underlying cyclothymic-anxious-sensitive disposition. The co-occurrence of ADHD and social phobia is very high, especially when SCT symptoms are present. Prevention Prevention of anxiety disorders is one focus of research. Use of CBT and related techniques may decrease the number of children with social anxiety disorder following completion of prevention programs. Treatment Psychotherapies The first-line treatment for social anxiety disorder is cognitive behavioral therapy (CBT) with medications such as selective serotonin reuptake inhibitors (SSRIs) used only in those who are not interested in therapy.: 191  Self-help based on principles of CBT is a second-line treatment.: 191 There is some emerging evidence for the use of acceptance and commitment therapy (ACT) in the treatment of social anxiety disorder. ACT is considered an offshoot of traditional CBT and emphasizes accepting unpleasant symptoms rather than fighting against them, as well as psychological flexibility – the ability to adapt to changing situational demands, to shift ones perspective, and to balance competing desires. ACT may be useful as a second line treatment for this disorder in situations where CBT is ineffective or refused.Some studies have suggested social skills training (SST) can help with social anxiety. Examples of social skills focused on during SST for social anxiety disorder include: initiating conversations, establishing friendships, interacting with members of the preferred sex, constructing a speech and assertiveness skills. However, it is not clear whether specific social skills techniques and training are required, rather than just support with general social functioning and exposure to social situations.There is some evidence that expressive therapies (e.g. painting, drawing or musical therapy) can be effective for treating social anxiety disorder in certain contexts. A 2019 study, for example, found that art therapy produced an "increase in subjective quality of life (both with large effects) and an improvement in accessibility of emotion regulation strategies" in adult women with anxiety. Both VAGA and the American Art Therapy Association run specific workshops for social anxiety disorder. Given the evidence that social anxiety disorder may predict subsequent development of other psychiatric disorders such as depression, early diagnosis and treatment is important. Social anxiety disorder remains under-recognized in primary care practice, with patients often presenting for treatment only after the onset of complications such as clinical depression or substance use disorders. Medications SSRIs Selective serotonin reuptake inhibitors (SSRIs), a class of antidepressants, are the first choice of medication for generalized social phobia but a second-line treatment.: 191  Compared to older forms of medication, there is less risk of tolerability and drug dependency associated with SSRIs.Paroxetine and paroxetine CR, Sertraline, Escitalopram, Venlafaxine XR and Fluvoxamine CR (luvox CR) are all approved for SAD and are all effective for it, especially paroxetine. All SSRIs are somewhat effective for social anxiety except fluoxetine which was equivalent to placebo in all clinical trials. Paroxetine was able to change personality and significantly increase extraversion.In a 1995 double-blind, placebo-controlled trial, the SSRI paroxetine was shown to result in clinically meaningful improvement in 55% of patients with generalized social anxiety disorder, compared with 23.9% of those taking placebo. An October 2004 study yielded similar results. Patients were treated with either fluoxetine, psychotherapy, or a placebo. The first four sets saw improvement in 50.8 to 54.2 percent of the patients. Of those assigned to receive only a placebo, 31.7% achieved a rating of 1 or 2 on the Clinical Global Impression-Improvement scale. Those who sought both therapy and medication did not see a boost in improvement. In double-blind, placebo-controlled trials other SSRIs like fluvoxamine, escitalopram and sertraline showed reduction of social anxiety symptoms, including anxiety, sensitivity to rejection and hostility.Citalopram also appears to be effective.General side-effects are common during the first weeks while the body adjusts to the drug. Symptoms may include headaches, nausea, insomnia and changes in sexual behavior. Treatment safety during pregnancy has not been established. In late 2004 much media attention was given to a proposed link between SSRI use and suicidality [a term that encompasses suicidal ideation and attempts at suicide as well as suicide]. For this reason, [although evidential causality between SSRI use and actual suicide has not been demonstrated] the use of SSRIs in pediatric cases of depression is now recognized by the Food and Drug Administration as warranting a cautionary statement to the parents of children who may be prescribed SSRIs by a family doctor. Recent studies have shown no increase in rates of suicide. These tests, however, represent those diagnosed with depression, not necessarily with social anxiety disorder. In addition, studies show that more socially phobic patients treated with anti-depressant medication develop hypomania than non-phobic controls. The hypomania can be seen as the medication creating a new problem. Other drugs Other prescription drugs are also used, if other methods are not effective. Before the introduction of SSRIs, monoamine oxidase inhibitors (MAOIs) such as phenelzine were frequently used in the treatment of social anxiety. Evidence continues to indicate that MAOIs are effective in the treatment and management of social anxiety disorder and they are still used, but generally only as a last resort medication, owing to concerns about dietary restrictions, possible adverse drug interactions and a recommendation of multiple doses per day. A newer type of this medication, reversible inhibitors of monoamine oxidase subtype A (RIMAs) such as the drug moclobemide, bind reversibly to the MAO-A enzyme, greatly reducing the risk of hypertensive crisis with dietary tyramine intake. However, RIMAs have been found to be less efficacious for social anxiety disorder than irreversible MAOIs like phenelzine.Benzodiazepines are an alternative to SSRIs. These drugs recommended usage is for short-term relief, meaning a limited time frame of over a year, of severe, disabling anxiety. Although benzodiazepines are still sometimes prescribed for long-term everyday use in some countries, there is concern over the development of drug tolerance, dependency and misuse. It has been recommended that benzodiazepines be considered only for individuals who fail to respond to other medications. Benzodiazepines augment the action of GABA, the major inhibitory neurotransmitter in the brain; effects usually begin to appear within minutes or hours. In most patients, tolerance rapidly develops to the sedative effects of benzodiazepines, but not to the anxiolytic effects. Long-term use of a benzodiazepine may result in physical dependence, and abrupt discontinuation of the drug should be avoided due to high potential for withdrawal symptoms (including tremor, insomnia, and in rare cases, seizures). A gradual tapering of the dose of clonazepam (a decrease of 0.25 mg every 2 weeks), however, is well tolerated by patients with social anxiety disorder. Benzodiazepines are not recommended as monotherapy for patients who have major depression in addition to social anxiety disorder and should be avoided in patients with a history of substance use.Certain anticonvulsant drugs such as gabapentin are effective in social anxiety disorder and may be a possible treatment alternative to benzodiazepines.Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine have shown similar effectiveness to the SSRIs. In Japan, Milnacipran is used in the treatment of Taijin kyofusho, a Japanese variant of social anxiety disorder. The atypical antidepressants mirtazapine and bupropion have been studied for the treatment of social anxiety disorder, and rendered mixed results.Some people with a form of social phobia called performance phobia have been helped by beta-blockers, which are more commonly used to control high blood pressure. Taken in low doses, they control the physical manifestation of anxiety and can be taken before a public performance. A novel treatment approach has recently been developed as a result of translational research. It has been shown that a combination of acute dosing of d-cycloserine (DCS) with exposure therapy facilitates the effects of exposure therapy of social phobia. DCS is an old antibiotic medication used for treating tuberculosis and does not have any anxiolytic properties per se. However, it acts as an agonist at the glutamatergic N-methyl-D-aspartate (NMDA) receptor site, which is important for learning and memory.Kava-kava has also attracted attention as a possible treatment, although safety concerns exist. Epidemiology Social anxiety disorder is known to appear at an early age in most cases. Fifty percent of those who develop this disorder have developed it by the age of 11, and 80% have developed it by age 20. This early age of onset may lead to people with social anxiety disorder being particularly vulnerable to depressive illnesses, substance use, and other psychological conflicts.When prevalence estimates were based on the examination of psychiatric clinic samples, social anxiety disorder was thought to be a relatively rare disorder. The opposite was found to be true; social anxiety was common, but many were afraid to seek psychiatric help, leading to an underrecognition of the problem.The National Comorbidity Survey of over 8,000 American correspondents in 1994 revealed 12-month and lifetime prevalence rates of 7.9 percent and 13.3 percent, respectively; this makes it the third most prevalent psychiatric disorder after depression and alcohol use disorder, and the most common of the anxiety disorders. According to US epidemiological data from the National Institute of Mental Health, social phobia affects 15 million adult Americans in any given year. Estimates vary within 2 percent and 7 percent of the U.S. adult population.The mean onset of social phobia is 10 to 13 years. Onset after age 25 is rare and is typically preceded by panic disorder or major depression. Social anxiety disorder occurs more often in females than males. The prevalence of social phobia appears to be increasing among white, married, and well-educated individuals. As a group, those with generalized social phobia are less likely to graduate from high school and are more likely to rely on government financial assistance or have poverty-level salaries. Surveys carried out in 2002 show the youth of England, Scotland, and Wales have a prevalence rate of 0.4 percent, 1.8 percent, and 0.6 percent, respectively. In Canada, the prevalence of self-reported social anxiety for Nova Scotians older than 14 years was 4.2 percent in June 2004 with women (4.6 percent) reporting more than men (3.8 percent). In Australia, social phobia is the 8th and 5th leading disease or illness for males and females between 15 and 24 years of age as of 2003. Because of the difficulty in separating social phobia from poor social skills or shyness, some studies have a large range of prevalence. The table also shows higher prevalence in Sweden. Terminology It has also been referred to as anthropophobia, meaning "fear of humans", from Greek: άνθρωπος, ánthropos, "human" and φόβος, phóbos, "fear". Other names have included interpersonal relation phobia. A specific Japanese cultural form is known as taijin kyofusho. See also Alexithymia Agoraphobia Asociality Highly sensitive person Impostor syndrome Obsessive-compulsive disorder Phobia Scopophobia Selective mutism Social inhibition Social rejection References Further reading Belzer K. D.; McKee M. B.; Liebowitz M. R. (2005). "Social Anxiety Disorder: Current Perspectives on Diagnosis and Treatment". Primary Psychiatry. 12 (11): 40–53. Archived from the original on 2012-05-12. Retrieved 2006-06-21. Beidel, D. C., & Turner, S. M. (2007). Shy children, phobic adults: Nature and treatment of social anxiety disorders (2nd ed.) (pp. 11–46). Washington, DC US: American Psychological Association. doi:10.1037/11533-001 Berent, Jonathan, with Amy Lemley (1993). Beyond Shyness: How to Conquer Social Anxieties. New York: Simon & Schuster. ISBN 0-671-74137-3. Boyle, L.E. (2018) "The (un)habitual geographies of Social Anxiety Disorder", Social Science and Medicine, DsocOI:10.1016/j.socscimed.2018.03.002 Bruch M. A. (1989). "Familial and developmental antecedents of social phobia: Issues and findings". Clinical Psychology Review. 9: 37–47. doi:10.1016/0272-7358(89)90045-7. Burns, D. D. (1999). Feeling Good: the new mood therapy (Rev. ed.). New York: Avon. ISBN 0-380-81033-6. Crozier, W. R., & Alden, L. E. (2001). International Handbook of Social Anxiety: Concepts, Research, and Interventions Relating to the Self and Shyness. New York: John Wiley & Sons, Ltd. ISBN 0-471-49129-2. Hales, R. E., & Yudofsky, S. C. (Eds.). (2003). Social phobia. In Textbook of Clinical Psychiatry (4th ed., pp. 572–580). Washington, D.C.: American Psychiatric Publishing. Marteinsdottir I.; Svensson A.; Svedberg M.; Anderberg U.; von Knorring L. (2007). "The role of life events in social phobia". Nordic Journal of Psychiatry. 61 (3): 207–212. doi:10.1080/08039480701352546. PMID 17523033. S2CID 11620169. External links Social Anxiety (including self-help links) at Curlie Support Group Providers for Social anxiety disorder at Curlie

Laryngeal papillomatosis

Laryngeal papillomatosis, also known as recurrent respiratory papillomatosis (RRP) or glottal papillomatosis, is a rare medical condition in which benign tumors (papilloma) form along the aerodigestive tract. There are two variants based on the age of onset: juvenile and adult laryngeal papillomatosis. The tumors are caused by human papillomavirus (HPV) infection of the throat. The tumors may lead to narrowing of the airway, which may cause vocal changes or airway obstruction. Laryngeal papillomatosis is initially diagnosed through indirect laryngoscopy upon observation of growths on the larynx and can be confirmed through a biopsy. Treatment for laryngeal papillomatosis aims to remove the papillomas and limit their recurrence. Due to the recurrent nature of the virus, repeated treatments usually are needed. Laryngeal papillomatosis is primarily treated surgically, though supplemental nonsurgical and/or medical treatments may be considered in some cases. The evolution of laryngeal papillomatosis is highly variable. Though total recovery may be observed, it is often persistent despite treatment. The number of new cases of laryngeal papillomatosis cases is approximately 4.3 cases per 100,000 children and 1.8 cases per 100,000 adults annually. Signs and symptoms A common symptom of laryngeal papillomatosis is a change in voice quality. More specifically, hoarseness is observed. As a consequence of the narrowing of the laryngeal or tracheal parts of the airway, shortness of breath, chronic cough and stridor (i.e. noisy breathing which can sound like a whistle or a snore), can be present. As the disease progresses, occurrence of secondary symptoms such as dysphagia, pneumonia, acute respiratory distress syndrome, failure to thrive, and recurrent upper respiratory infections can be diagnosed. The risk of laryngeal papillomatosis spreading to the lungs is higher in the juvenile-onset than the adult-onset. In children, symptoms are usually more severe and often mistaken for manifestations of other diseases such as asthma, croup or bronchitis. Therefore, diagnosis is usually delayed. Cause Laryngeal papillomatosis is caused by human papillomavirus (HPV) infection, most frequently types 6 and 11 although genotypes 16, 18, 31, and 33 have also been implicated. HPV-11 is associated with more aggressive forms of papillomatosis, which may involve more distal parts of the tracheobronchial tree. The mode of viral inoculation is hypothesized to vary according to age of disease onset. The presence of HPV in the respiratory tract does not necessarily result in the development of laryngeal papillomatosis. Other factors that could be involved include immunodeficiency or other similar infections. For example, laryngeal papillomatosis may become more aggressive due to the presence of certain viruses (e.g., herpes simplex virus, Epstein–Barr virus).The disease occurs in two forms, juvenile and adult papillomatosis, based on whether it develops before or after 20 years of age. The juvenile form is generally transmitted through contact with a mothers infected vaginal canal during childbirth. Less is known about transmission in the adult form of this disease, though oral sex has been implicated as a potential mode of transmission. However, it is uncertain whether oral sex would directly transmit the virus or activate the dormant virus that was transmitted at childbirth.In general, physicians are unsure why only certain people who have been exposed to the HPV types implicated in the disease develop laryngeal papillomatosis. In the case of the juvenile form of the disease, the likelihood of a child born of an infected mother developing laryngeal papillomatosis is low (between 1 in 231 to 1 in 400), even if the mothers infection is active. Risk factors for a higher likelihood of transmission at childbirth include the first birth, vaginal birth, and teenaged mother.Three major risk factors affect the acquisition of the juvenile variant. These include: Birth history (e.g., increased time spent in vaginal delivery) and the presence of HPV in the vaginal canal. It is important to note that it is still uncertain whether caesarean delivery is a protective factor. Genotype of the HPV (e.g., HPV-11) Individual factors (e.g., being younger when diagnosed, which may be due to a less developed immune system). Diagnosis Laryngeal papillomatosis can be diagnosed through visualization of the lesions using one of several indirect laryngoscopy procedures. In indirect laryngoscopy, the tongue is pulled forward and a laryngeal mirror or a rigid scope is passed through the mouth to examine the larynx. Another variation of indirect laryngoscopy involves passing a flexible scope, known as a fiberscope or endoscope, through the nose and into the throat to visualize the larynx from above. This procedure is also called flexible fiberoptic laryngoscopy.The appearance of papillomas has been described as multiple or rarely, single, white growths with a lumpy texture similar to cauliflower. Papillomas usually present in the larynx, especially on the vocal folds and in the space above the vocal folds called the ventricles. They can spread to other parts of the larynx and throughout the aerodigestive tract, from the mouth to the lower respiratory tract. Spread to regions beyond the larynx is more common in children than adults. Growths tend to be located at normal junctions in squamous and ciliated epithelium or at tissue junctions arising from injury.A confirmatory diagnosis of laryngeal papillomatosis can only be obtained through a biopsy, involving microscopic examination and HPV testing of a sample of the growth. Biopsy samples are collected under general anesthesia, either through direct laryngoscopy or fiberoptic bronchoscopy. Prevention Little is known in terms of effective means of prevention, if the mother is infected with HPV. (HPV vaccination can prevent these infections in the mother, and thereby eliminate the possibility of the virus infecting the baby.) Due to the low likelihood of transmission even from an infected mother, it is not recommended to expose the mother and child to the additional risks of caesarean section to prevent the transmission of this disease during vaginal childbirth. Opting for a caesarean section does not guarantee that transmission will not still occur. Treatment As of 2014 there was no permanent cure for laryngeal papillomatosis, and treatment options aimed to remove and limit the recurrence of the papillomas. Repeated treatments are often needed because of the recurrent nature of the virus, especially for children, as the juvenile form of laryngeal papillomatosis often triggers more aggressive relapses than the adult form. Between recurrences, voice therapy may be used to restore or maintain the persons voice function. Surgery The first line of treatment is surgery to remove papillomas. Typically performed using a laryngeal endoscopy, surgery can protect intact tissues and the individuals voice, as well as ensure that the airway remains unobstructed by the disease. However, surgery does not prevent recurrences, and can lead to a number of serious complications. Laser technology, and carbon dioxide laser surgery in particular, has been used since the 1970s for the removal of papillomas; however, laser surgery is not without its risks, and has been associated with a higher occurrence of respiratory tract burns, stenosis, severe laryngeal scarring, and tracheoesophagyeal fistulae. Tracheotomies are offered for the most aggressive cases, where multiple debulking surgery failures have led to airways being compromised. The tracheotomies use breathing tubes to reroute air around the affected area, thereby restoring the persons breathing function. Although this intervention is usually temporary, some people must use the tube indefinitely. This method should be avoided if at all possible, since the breathing tube may serve as a conduit for spread of the disease as far down as the tracheobronchial tree.A microdebrider is a tool that can suction tissue into a blade, which then cuts the tissue. Microdebriders are gradually replacing laser technology as the treatment of choice for laryngeal papillomatosis, due to their ability to selectively suction papillomas while relatively sparing unaffected tissue. In addition to the lower risk of complications, microdebrider surgery also is reportedly less expensive, less time-consuming, and more likely to give the person a better voice quality than the traditional laser surgery approaches. Nonsurgical adjuvant treatment For about 20% of people, surgery is not sufficient to control their laryngeal papillomatosis, and additional nonsurgical and/or medical treatments are necessary. As of 2015, these treatments alone are not sufficient to cure laryngeal papillomatosis, and can only be considered supplemental to surgery. Some varieties of nonsurgical treatments include interferon, antiviral drugs (especially cidofovir, but also ribavirin and acyclovir), and photodynamic therapy. The monoclonal antibody against Vascular Endothelial Growth Factor (VEGF), Bevacizumab has shown promising result as an adjuvant therapy in the management of recurrent respiratory papillomatosis.Although vaccines are normally used to prevent infections from happening, HPV vaccines can be used therapeutically (after the infection has occurred). For most patients, the HPV vaccine significantly increases the length of time needed between surgeries. Prognosis The evolution of laryngeal papillomatosis is highly unpredictable and is characterized by modulation of its severity and variable rate of progression across individuals. While instances of total recovery are observed, the condition is often persistent and lesions can reappear even after treatment. Factors that might affect the clinical course of the condition include: the HPV genotype, the age at onset, the elapsed time between the diagnosis and first treatment in addition to previous medical procedures. Other factors, albeit controversial, such as smoking or the presence of gastroesophageal reflux disease might also play a role in the progression of the disease.The papillomas can travel past the larynx and infect extralaryngeal sites. In more aggressive cases, infection of the lungs can occur with progressive airway obstruction. Although rare (less than 1% of people with laryngeal papillomatosis), transformation from a benign form to a malignant form is also observed. Death can result from these complications (morbidity rate is around 1–2%). Epidemiology Laryngeal papillomatosis is a rare disease with a bimodal distribution based on age of incidence. The incidence, or number of new cases, of laryngeal papillomatosis cases is at approximately 4.3 cases per 100 000 children and 1.8 cases per 100 000 adults annually. The incidence of laryngeal papillomatosis in children peaks before the age of 5, though the term juvenile papillomatosis refers to all cases occurring before the age of 20. The incidence of adult laryngeal papillomatosis, which has an onset after the age of 20, peaks between the ages of 20 and 40. While there are no gender differences in the incidence of laryngeal papillomatosis in children, adult laryngeal papillomatosis occurs more frequently in males than in females. The incidence of laryngeal papillomatosis also varies according to factors such as socioeconomic status, such that higher rates are observed in groups having a lower socioeconomic status. Costs Because of its relative commonness and the cost of treatments, more money is spent on treating RRP than on any other benign airway tumor. Research As of 2015 use of the measles-mumps-rubella vaccine to reduce rate of recurrences had been investigated, but had not yielded significant results. See also List of cutaneous conditions References == External links ==

Herpes simplex keratitis

Herpetic simplex keratitis is a form of keratitis caused by recurrent herpes simplex virus (HSV) infection in the cornea.It begins with infection of epithelial cells on the surface of the eye and retrograde infection of nerves serving the cornea. Primary infection typically presents as swelling of the conjunctiva and eyelids (blepharoconjunctivitis), accompanied by small white itchy lesions on the corneal surface. The effect of the lesions varies, from minor damage to the epithelium (superficial punctate keratitis), to more serious consequences such as the formation of dendritic ulcers. Infection is unilateral, affecting one eye at a time. Additional symptoms include dull pain deep inside the eye, mild to acute dryness, and sinusitis. Most primary infections resolve spontaneously in a few weeks. Healing can be aided by the use of oral and topical antivirals. Subsequent recurrences may be more severe, with infected epithelial cells showing larger dendritic ulceration, and lesions forming white plaques. The epithelial layer is sloughed off as the dendritic ulcer grows, and mild inflammation (iritis) may occur in the underlying stroma of iris. Sensation loss occurs in lesional areas, producing generalised corneal anaesthesia with repeated recurrences. Recurrence can be accompanied by chronic dry eye, low grade intermittent conjunctivitis, or chronic unexplained sinusitis. Following persistent infection the concentration of viral DNA reaches a critical limit. Antibody responses against the viral antigen expression in the stroma can trigger a massive immune response in the eye. The response may result in the destruction of the corneal stroma, resulting in loss of vision due to opacification of the cornea. This is known as immune-mediated stromal keratitis. HSV infection is very common in humans. It has been estimated that one third of the world population have recurrent infection. Keratitis caused by HSV is the most common cause of cornea-derived blindness in developed nations. Therefore, HSV infections are a large and worldwide public health problem. The global incidence (rate of new disease) of herpes keratitis is roughly 1.5 million, including 40,000 new cases of severe monocular visual impairment or blindness each year. Signs and symptoms Primary infection Primary infection most commonly manifests as blepharoconjunctivitis i.e. infection of lids and conjunctiva that heals without scarring. Lid vesicles and conjunctivitis are seen in primary infection. Corneal involvement is rarely seen in primary infection. Recurrent eye infection Recurrent herpes of the eye is caused by reactivation of the virus in a latently infected sensory ganglion, transport of the virus down the nerve axon to sensory nerve endings, and subsequent infection of ocular surface. The following classification of herpes simplex keratitis is important for understanding this disease: Dendritic ulcer (Epithelial keratitis) This classic herpetic lesion consists of a linear branching corneal ulcer (dendritic ulcer). During eye exam the defect is examined after staining with fluorescein dye. The underlying cornea has minimal inflammation. Patients with epithelial keratitis complain of foreign-body sensation, light sensitivity, redness and blurred vision. Focal or diffuse reduction in corneal sensation develops following recurrent epithelial keratitis. In immune deficient patients or with the use of corticosteroids the ulcer may become large and in these cases it is called geographic ulcer. Disciform keratitis (Endothelial keratitis) Endothelial keratitis manifests a central endothelitis in a disc-shaped manner. Longstanding corneal edema leads to permanent scarring and is the major cause of decreased vision associated with HSV. Localized endothelitis (localized inflammation of corneal endothelial layer) is the cause of disciform keratitis. Other forms Metaherpetic ulcer : is not due to live virus, results from inability of the corneal surface to heal. Necrotizing keratitis Keratouveitis : is usually granulomatous uveitis with large keratic precipitates on the corneal endothelium. Cause HSV is a double-stranded DNA virus that has icosahedral capsid. HSV-1 infections are found more commonly in the oral area and HSV-2 in the genital area. Ocular herpes simplex is usually caused by HSV-1. Diagnosis A specific clinical diagnosis of HSV as the cause of dendritic keratitis can usually be made by ophthalmologists and optometrists based on the presence of characteristic clinical features. Diagnostic testing is seldom needed because of its classic clinical features and is not useful in stromal keratitis as there is usually no live virus. Laboratory tests are indicated in complicated cases when the clinical diagnosis is uncertain and in all cases of suspected neonatal herpes infection: Corneal smears or impression cytology specimens can be analyzed by culture, antigen detection, or fluorescent antibody testing. Tzanck smear, i.e.Papanicolaou staining of corneal smears, show multinucleated giant cells and intranuclear inclusion bodies, however, the test is low in sensitivity and specificity. DNA testing is rapid, sensitive and specific. However, its high cost limits its use to research centers. Demonstration of HSV is possible with viral culture. Serologic tests may show a rising antibody titer during primary infection but are of no diagnostic assistance during recurrent episodes. Treatment Treatment of herpes of the eye is different based on its presentation: epithelial keratitis is caused by live virus while stromal disease is an immune response and metaherpetic ulcer results from inability of the corneal epithelium to heal: Epithelial keratitis Epithelial keratitis is treated with topical antivirals, which are very effective with low incidence of resistance. Treatment of the disease with topical antivirals generally should be continued for 10–14 days. Aciclovir ophthalmic ointment and Trifluridine eye drops have similar effectiveness but are more effective than Idoxuridine and Vidarabine eye drops. Oral acyclovir is as effective as topical antivirals for treating epithelial keratitis, and it has the advantage of no eye surface toxicity. For this reason, oral therapy is preferred by some ophthalmologists. Ganciclovir and brivudine treatments were found to be equally as effective as acyclovir in a systematic review.Valacyclovir, a pro-drug of acyclovir likely to be just as effective for ocular disease, can cause thrombotic thrombocytopenic purpura/Hemolytic-uremic syndrome in severely immunocompromised patients such as those with AIDS; thus, it must be used with caution if the immune status is unknown. Topical corticosteroids are contraindicated in the presence of active herpetic epithelial keratitis; patients with this disease who are using systemic corticosteroids for other indications should be treated aggressively with systemic antiviral therapy. The effect of interferon with an antiviral agent or an antiviral agent with debridement needs further assessment. Stromal keratitis Herpetic stromal keratitis is treated initially with prednisolone drops every 2 hours accompanied by a prophylactic antiviral drug: either topical antiviral or an oral agent such as acyclovir or valacyclovir. The prednisolone drops are tapered every 1–2 weeks depending on the degree of clinical improvement. Topical antiviral medications are not absorbed by the cornea through an intact epithelium, but orally administered acyclovir penetrates an intact cornea and anterior chamber. In this context, oral acyclovir might benefit the deep corneal inflammation of disciform keratitis. Metaherpetic ulcer Treatment includes artificial tears and eye lubricants, stopping toxic medications, performing punctal occlusion, bandage contact lens and amniotic membrane transplant. These measures intend to improve corneal epithelial healing. Antiviral medication may reduce the risk of HSV keratitis recurring in people having a graft due to HSV infection and may improve the chances of graft survival. References == External links ==

Congenital hypofibrinogenemia

Congenital hypofibrinogenemia is a rare disorder in which one of the three genes responsible for producing fibrinogen, a critical blood clotting factor, is unable to make a functional fibrinogen glycoprotein because of an inherited mutation. In consequence, liver cells, the normal site of fibrinogen production, make small amounts of this critical coagulation protein, blood levels of fibrinogen are low, and individuals with the disorder may develop a coagulopathy, i.e. a diathesis or propensity to experience episodes of abnormal bleeding. However, individuals with congenital hypofibringenemia may also have episodes of abnormal blood clot formation, i.e. thrombosis. This seemingly paradoxical propensity to develop thrombosis in a disorder causing a decrease in a critical protein for blood clotting may be due to the function of fibrin (the split product of fibrinogen that is the basis for forming blood clots) to promote the lysis or disintegration of blood clots. Lower levels of fibrin may reduce the lysis of early fibrin strand depositions and thereby allow these depositions to develop into clots.Congenital hypofibrinogenemia must be distinguished from: a) congenital afibrinogenemia, a rare disorder in which blood fibrinogen levels are either exceedingly low or undetectable due to mutations in both fibrinogen genes; b) congenital hypodysfibrinogenemia, a rare disorder in which one or more genetic mutations cause low levels of blood fibrinogen, at least some of which is dysfunctional and thereby contributes to excessive bleeding; and c) acquired hypofibrinogenemia, a non-hereditary disorder in which blood fibrinogen levels are low because of e.g. severe liver disease or because of excessive fibrinogen consumption resulting from, e.g. disseminated intravascular coagulation.Certain gene mutations causing congenital hypfibrinogenemia disrupt the ability of liver cells to secrete fibrinogen. In these instances, the un-mutated gene maintains blood fibrinogen at reduce levels but the mutated gene produces a fibrinogen that accumulates in liver cells sometimes to such extents that it becomes toxic. In the latter cases, liver disease may ensue in a syndrome termed fibrinogen storage disease. Signs and symptoms Individuals with congenital hypfibringenemia often lack any symptoms are detected by routine lab testing of fibrinogen or when tested for it because close relatives have symptomatic hypofibrinogenemia. Indeed, studies indicate that, among family members with the identical congenital hypofibrinogenemia mutation, some never exhibit symptoms and those that are symptomatic develop symptoms only as adults. No liver disease Individuals with this disorder are usually less symptomatic than patients with other fibrinogen disorders because their fibrinogen levels are generally sufficient to prevent spontaneous bleeding. Those with particularly low blood fibrinogen levels (<0.5 gram/liter) may develop serious bleeding spontaneously and many with the disorder do so following trauma or surgery. Depending on their fibrinogen levels, women with the disorder may also bleed excessively during delivery and the postpartum period; in rare cases, they may have an increased risk of suffering miscarriages. Individuals with the disorder also experience thrombotic events which may include blockage of large arteries in relatively young patients who have high levels of cardiovascular risk factors. The thrombi which form in these individuals are unstable, tend to embolize, and may therefore lead to thromboembolic events such as pulmonary embolism. Both bleeding and thrombotic events can occur at separate times or even concurrently in the same individual with the disorder. Fibrinogen storage disease All individuals with mutations causing fibrinogen storage disease have low blood fibrinogen levels but usually lack severe bleeding episodes, thrombotic episodes or liver disease. Individuals that do have fibrinogen storage disease often come to attention either because they have close relatives with the disease, are found to be hypofibrinogenmic during routing testing, or exhibit clinical (e.g. jaundice) or laboratory (e.g. elevated blood levels of liver enzymes) evidence of liver disease. Unlike other forms of congenital hypofibrinogenemia, a relatively high percentage of individuals with fibrinogen storage disease have been diagnosed in children of very young age. Pathophysiology Fibrinogen is made and secreted into the blood by liver hepatocytes. The final secreted protein is composed of two trimers each of which is composed of three polypeptide chains, Aα (also termed α) encoded by the FGA gene, Bβ (also termed β) encoded by the FGB gene, and γ encoded by the FGG gene. All three genes are located on the long or "p" arm of human chromosome 4 (at positions 4q31.3, 4q31.3, and 4q32.1, respectively). The genes are ordered FGB, FGA, and FGG and are transcribed into messenger RNA in tight synchrony. The messenger RNAs associate with the endoplasmic reticulum, translated into polypeptides, and enter the endoplasmaic reticulum where they assembled together. The assembled protein is passes to the Golgi apparatus where it is glycosylated, hydroxylated, sulfated, and phosphorylated to form the mature fibrinogen glycoprotein that is secreted into the blood. Congenital hypfibrinogenemia results from inherited mutations in one of the three fibrinogen chains that results in the disruption of fibrinogen synthesis, assembly, stability, processing through the endoplasmic reticulum-Golgi apparatus pathway, and/or secretion into the blood.There are >25 fibrinogen mutations that have been associated with hypofibrinogenemia. The following Table lists examples of those mutations which cause hypofibrinogenemia that is not associated with liver injury. The Table gives: a) each mutated proteins trivial name; b) the gene mutated (i.e. FGA, FGB, or FGG), its mutation site (i.e. numbered nucleotide in the gene beginning with the initial nucleotide base at the (start codon) of genomic DNA (as indicated by the "g." notation), and name of the nucleotides (i.e. C, T, A, G) at these sites before>after the mutation; and c) the name of the altered fibrinogen peptide (Aα, Bβ, or λ), the numbered position(s) of the amino acid changed by the mutation in the circulating peptide of the mutated fibrinogen, and the identity of the amino acids before-after the mutation using standard three letter abbreviations. In the Table, fs indicates a mutation that causes a Translational frameshift and consequently a premature stop codon (designated by "X") mutation and translation of a shortened fibrinogen chain, del is a deletion, and ins is an insertion. As of 2016, there have been six mutations discovered to be associated with the accumulation of the mutated fibrinogen in the endoplasmic reticulum and consequential development of liver injury that may lead to liver cirrhosis, i.e. fibrinogen storage disease. Other fibrinogen mutations have also lead to their accumulation in the endoplasmic reticulum but have not been associated with liver injury perhaps because these fibrinogens are less toxic to the liver than those that cause liver injury. The following Table lists these 6 mutations. Note that all of these 6 mutations occur in the FGG gene, that all the mutations are missense mutations except for the deletion mutation of fibrinogen Anger, and that the Table reports the gene mutation site as found in cloned (as notated by "c.") rather than genomic DNA. Fibrinogen Aguadilla is the most common mutation known to cause fibrinogen storage disease. The abbreviations in this Table are defined in the previous Table. Diagnosis The diagnosis of hypofibrinogenemia is indicated in individuals who have low levels (<1.5 gram/liter) of plasma fibrinogen as determined by both immunological (e.g. immunoelectrophoresis and (i.e. able to be clotted) methods. The ratio of immunological to functional fibrinogen masses should be ~1.0 as assayed with partial thromboplastin time, activated partial thromboplastin time, thrombin time, and reptilase time tests. These tests are used to distinguish hypofibrinogenemia from hypodysfibrinogenemia, a typically more severe disorder in which plasma fibrinogen levels are low and this fibrinogen includes at least in part dysfunctional fibrinogen. Immunological/functional fibrinogen ratios for the plasma of individuals with hypodysfibrinogenemia for all the cited tests are usually <0.7. Where available, further analyses are recommended; these include analyses of the fibrinogen genes and protein chains for mutations and specialized studies of individuals in vitro induced blood clots for stability and susceptibility to lyses.The diagnosis of fibrin storage disease requires liver biopsy and the finding of immunologically detectable fibrinogen inclusion bodies in hepatocytes. Treatment No symptoms Recommended treatment of asymptomatic congenital hypofibrinogenemia depends in part on the expectations of developing bleeding and/or thrombotic complications as indicated by the personal history of the affected individual and family members. Where possible, determination of the exact mutation causing the disorder and the propensity of this mutation type to develop these complications may be helpful. Individuals with fibrinogen levels >1.0 gram/liter typically do not develop bleeding or thrombosis episodes. Individuals with fibrinogen levels of 0.5-1.0 grams/liter require fibrinogen supplementation preferably with a plasma-derived fibrinogen concentrate to maintain fibrinogen levels of >1 gram/liter prior to major surgery. Individuals with fibrinogen levels of <0.5 gram/liter require fibrinogen supplementation to maintain fibrinogen levels of a) >1 to 2 gram/liter at the end of pregnancy and during the postpartum period; b) > 1 gram/liter prior to major surgery; c) > 0.5 to 1 gram/liter during the first two trimesters of pregnancy; and d) >0.5 gram/liter prior to minor surgery. Tranexamic acid may be used in place of fibrinogen supplementation as prophylactic treatment prior to minor surgery and to treat minor bleeding episodes. Symptoms Individuals with hypofibrinogenemia who have a history of excessive bleeding should be treated at a center specialized in treating hemophilia and avoid all medications that interfere with normal platelet function. During bleeding episodes, treatment with fibrinogen concentrates or, if unavailable infusion of fresh frozen plasma and/or cryoprecipitate (a fibrinogen-rich plasma fraction) to maintain fibrinogen activity levels >1 gram/liter.Individuals with hypofibrinogenemia who experience episodic thrombosis should also be treated at a center specialized in treating hemophilia. Standard recommendations for these individuals are that they use antithrombotic agents and be instructed on antithrombotic behavioral methods in high risk situations (e.g. long car rides and air flights). Acute venous thrombosis episodes should be treated with low molecular weight heparin for a time that depends on personal and family history of thrombosis events. Prophylactic treatment prior to minor surgery should avoid fibrinogen supplementation and use anticoagulation measures; prior to major surgery, fibrinogen supplementation should be used only if serious bleeding occurs; otherwise, prophylactic anticoagulation measures are recommended. Fibrin storage disease There are too few cases of fibrinogen storage disease to establish optimal treatments for the liver diseases. Management of the disorder has been based on general recommendations for patients with liver disease, particularly Alpha 1 antitrypsin deficiency-associated liver disease. In the latter disease, autophagy, the pathway that cells use to dispose of dysfunctional or excessively stored components including proteins, has been targeted using autophagy-enhancing drugs, e.g. carbamazepine, vitamin E, and ursodeoxycholic acid. These drugs have been tested in individual patients with fibrin storage disease with some success in reducing evidence of liver injure, i.e. reduction in blood liver enzyme levels. These and other autophagy-enhancing drugs are suggested to be further studied in fibrinogen storage disease. References == External links ==

Esophagogastric junction outflow obstruction

Esophagogastric junction outflow obstruction (EGJOO) is an esophageal motility disorder characterized by increased pressure where the esophagus connects to the stomach at the lower esophageal sphincter. EGJOO is diagnosed by esophageal manometry. However, EGJOO has a variety of etiologies; evaluating the cause of obstruction with additional testing, such as upper endoscopy, computed tomography (CT imaging), or endoscopic ultrasound may be necessary. When possible, treatment of EGJOO should be directed at the cause of obstruction. When no cause for obstruction is found (functional EGJOO), observation alone may be considered if symptoms are minimal. Functional EGJOO with significant or refractor symptoms may be treated with pneumatic dilation, per-oral endoscopic myotomy (POEM), or botulinum toxin injection. Types EGJOO may be broadly categorized into 4 subgroups: mechanical, functional, medication-related, and artifact. Signs and symptoms In some cases, EGJOO may cause no symptoms, and the manometry findings are identified during an evaluation prior to anti-reflux surgery. In other cases, EGJOO may be identified after an evaluation for esophageal symptoms. The most common symptoms are dysphagia (50-75%, typical reflux (29-67%), atypical reflux (21-36%), chest pain (16-46%), abdominal pain (43%) or regurgitation (38%). One study suggested about 5% of individuals have no symptoms. Causes Several causes for EGJOO exist. Etiologies include early achalasia, mechanical processes (eosinophilic esophagitis, hiatal hernia, strictures, etc.), esophageal wall thickness (fibrosis, cancer, etc.), compression by nearby blood vessels (external vascular compression), obesity, opioid medication effect, or anatomic abnormalities. The findings associated with EGJOO may be falsely abnormal due to measurement errors. Diagnosis EGJOO is diagnosed using esophageal manometry. High resolution esophageal manometry will show elevated pressure at the LES with normal peristalsis. The LES pressure is evaluated immediately following a swallow, when the sphincter should relax. The overall LES pressure after a swallow is represented by the integrated relaxation pressure (IRP). If the IRP is abnormally elevated (>15 mmHg), this indicates an obstruction is present. Normal peristalsis with an obstruction at the esophagogastric junction (elevated IRP) is consistent with EGJOO.Upper endoscopy is used to evaluate for mechanical causes of obstruction. Endoscopic findings may include a hiatal hernia, esophagitis, strictures, tumors, or masses. Increased pressure at the LES over time may result in an epiphrenic diverticulum. Further evaluation for mechanical causes of obstruction may include CT scans, MRI, or endoscopic ultrasound.Several additional tests may be used to further evaluate EGJOO. Further evaluation of esophageal motor function may be accomplished with functional lumen imaging probe (FLIP). Although not widely available, FLIP may help assess esophageal wall stiffness and compliance. FLIP may help identify individuals with EGJOO who are likely to benefit from therapeutic procedures.Timed barium esophagram can help distinguish EGJOO from untreated achalasia. Treatment Treatment primarily consists of addressing the underlying cause of EGJOO. For example, gastroesophageal reflux disease (GERD) with reflux esophagitis is treated with proton pump inhibitors. Esophageal rings or strictures may be treated with esophageal dilation. Simple observation may be considered, especially if symptoms are minimal or absent. If symptoms are severe or persistent, peroral endoscopic myotomy (POEM) may be offered.Pneumatic dilation may be used for persistent symptoms in the absence of identified causes of mechanical obstruction. Botulinum toxin may be considered, especially for individuals who are unlikely to tolerate surgery. Prognosis The prognosis for EGJOO depends on the etiology of obstruction. In the absence of anatomic or mechanical causes, such as cancer, outcomes are generally favorable. Individuals with minimal or no symptoms often experience resolution of the EGJOO, even without treatment. Epidemiology The overall prevalence of EGJOO is unclear. The prevalence of EGJOO among all patients undergoing high resolution manometry was up to 10 percent. The diagnostic criteria were later adjusted to distinguish relevant (symptomatic) EGJOO from isolated manometric findings of EGJOO without symptoms.Individuals diagnosed with EGJOO based on Chicago 3.0 classification have an average age of 56–57 years. EGJOO more commonly affects women (51-88%). The average BMI is between 25 and 30. == References ==

Viral encephalitis

Viral encephalitis is inflammation of the brain parenchyma, called encephalitis, by a virus. The different forms of viral encephalitis are called viral encephalitides. It is the most common type of encephalitis and often occurs with viral meningitis. Encephalitic viruses first cause infection and replicate outside of the central nervous system (CNS), most reaching the CNS through the circulatory system and a minority from nerve endings toward the CNS. Once in the brain, the virus and the hosts inflammatory response disrupt neural function, leading to illness and complications, many of which frequently are neurological in nature, such as impaired motor skills and altered behavior. Viral encephalitis can be diagnosed based on the individuals symptoms, personal history, such as travel history, and different clinical tests such as histology, medical imaging, and lumbar punctures. A differential diagnosis can also be done to rule out other causes of the encephalitis. Many encephalitic viruses often have characteristic symptoms of infection, helping to aid diagnosis. Treatment is usually supportive in nature while also providing antiviral drug therapy. The primary exception to this is herpes simplex encephalitis, which is treatable with acyclovir. Prognosis is good for most individuals who are infected by an encephalitic virus but is poor among those who develop severe symptoms, including viral encephalitis. Long-term complications of viral encephalitis typically relate to neurological damage, such as experiencing seizures, memory loss, and intellectual impairment. Encephalitic viruses are typically transmitted either from person-to-person or are arthropod-borne viruses, called arboviruses. The young and the elderly are at the highest risk of viral encephalitis. Many cases of viral encephalitis are not identified either because of lack of testing or mild illness, and serological surveys indicate that asymptomatic infections are common. Various ways of preventing viral encephalitis exist, such as vaccines that are either in standard vaccination programs or which are recommended when living in or visiting certain regions, and various measures aimed at preventing mosquito, sandfly, and tick bites in order to prevent arbovirus infection. Etiology Many viruses are capable of causing encephalitis during infection, including: Transmission Encephalitic viruses vary in their manner of transmission. Some are transmitted from person-to-person, whereas others are transmitted by animals, especially bites from arthropods such as mosquitos, sandflies, and ticks, such viruses being called arboviruses. An example of person-to-person transmission is the herpes simplex virus, which is transmitted by means of intimate physical contact. An example of arboviral transmission is the West Nile virus, which usually is incidentally transmitted to people from the bites of Culex mosquitos, especially Culex pipiens. Pathogenesis Viruses that cause viral encephalitis first infect the body and replicate outside of the central nervous system (CNS). Thereafter, most reach the spinal cord and brain via the circulatory system. Exceptions to this include herpesviruses and the rabies virus, which travel from nerve endings to the CNS. Once in the brain, the virus and the hosts inflammatory response disrupt neural cell function, including causing fluid buildup in the brain, vascular congestion, and bleeding. Widespread presence of white blood cells and microglia in the CNS is common as a response to CNS infection. For some forms of viral encephalitis, such as Eastern equine encephalitis and Japanese encephalitis, there may be a significant amount of necrosis of nerve cells. Following encephalitis caused by arboviruses, calcification may occur in the CNS, especially among children. Herpes simplex encephalitis tends to produce necrotic lesions in the CNS. Diagnosis Examination If viral encephalitis is suspected, then questions can be asked about the individuals history and physical examination can be performed. Important aspects of ones history include immune status, exposure to animals, including insects, travel history, vaccination history, geography, and time of year. Symptoms usually occur acutely, and the most common symptoms of infection are fever, headache, altered mental status, sensitivity to light, stiff neck and back, vomiting, confusion, and, in severe cases, seizures, paralysis, and coma. Neuropsychiatric features such as behavioral changes, hallucinations, or cognitive decline are frequent. Severe symptoms are most common among infants and the elderly. Most infections are asymptomatic, lacking symptoms, whereas most symptomatic cases are mild illnesses.Virus-specific symptoms may also exist or tests may indicate one virus. Specific examples include: Enterovirus 71 may cause tremors, twitching, impaired balance and coordination, fluid accumulation in the lungs, and cranial nerve palsies. Epstein-Barr virus encephalitis is usually accompanied by enlargement of the lymph nodes and enlargement of the spleen Herpes zoster encephalitis may be accompanied by rash and skin vesicles, and because it involves the frontal lobe and temporal lobe, is often characterized by psychiatric features, memory deficits, and loss of language faculties. Many arboviral encephalitides, such as Japanese encephalitis, primarily affect the basal ganglia, sometimes causing motor symptoms such as involuntary movements and movements similar to those observed in Parkinsons disease. Nipah virus may produce brainstem and cerebellar signs, hypertension, and segmental myoclonus, or twitching of a group of connected muscles. Zika virus characteristically may cause microcephaly among newborn children if a pregnant woman is infected. Histology The brain histology of viral encephalitis shows dead neurons with nuclear dissolution and elevated eosinophil count, called hypereosinophilia, within cells cytoplasm when viewed with an optical microscope. Because encephalitis is an inflammatory response, inflammatory cells situated near blood vessels, such as microglia, macrophages, and lymphocytes, are visible. Virions within neurons are visible via electron microscopes. Clinical evaluation Neuroimaging and lumbar puncture (LP) are both essential methods of diagnosing viral encephalitis. Computed tomography (CT) or magnetic resonance imaging (MRI) help identify increased intracranial pressure and the risk of uncal herniation before performing an LP. Cerebrospinal fluid (CSF), if analyzed, should be analyzed for opening pressure, cell counts, glucose, protein, and IgG and IgM antibodies. CSF testing should also include polymerase chain reaction (PCR) testing for herpes simplex viruses 1 and 2 and enteroviruses. About 10% of patients have normal CSF results. Additional testing, such as serology for various arboviruses and HIV testing, may also be performed based on the individuals history and symptoms. Brain biopsy and body fluid specimen cultures and PCR may also be useful in some cases. Electroencephalography (EEG) is abnormal in more than 80% of viral encephalitis cases, including those who are experiencing seizures, and may need to be monitored continuously to identify non-convulsive status. Lack of testing resources may prevent accurate diagnosis.Test results specific to certain viruses include: For herpes simplex virus encephalitis, a CT scan may show low-density lesions in the temporal lobe. These lesions usually appear 3 to 5 days after the start of the infection. Japanese encephalitis often has distinct EEG patterns, including diffuse delta activity with spikes, diffuse continuous delta activity, and alpha coma activity. Differential diagnosis A broad differential diagnosis can be performed that looks at many potential causes of the encephalitis, infectious and noninfectious. Potential alternatives to viral encephalitis include malignancy, autoimmune or paraneoplastic diseases such as anti-NMDA receptor encephalitis, a brain abscess, tuberculosis or drug-induced delirium, exposure to certain drugs or toxins, neurosyphilis, vascular disease, metabolic disease, or encephalitis from infection caused by a bacterium, fungus, protozoan, or parasitic worm. In children, differential diagnosis may not be able to distinguish between viral encephalitis and immune-mediated inflammatory CNS diseases, such as acute disseminated encephalomyelitis, as well as immune-mediated encephalitis, so other diagnostic methods may need to be used. Treatment Treatment of viral encephalitis is primarily supportive with intravenous antiviral therapy due to there being no specific medical therapy for most viral infections involving the central nervous system. Individuals may require intensive care for frequent neurological exams or respiratory support, and treatment for electrolyte disturbance, autonomic disregulation, and renal and hepatic dysfunction, as well as for seizures and non-compulsive status epilepticus.A very specific exception is herpes simplex virus (HSV) encephalitis, which can be treated with acyclovir for 2 to 3 weeks if it is provided early enough. Acyclovir significant decreases morbidity and mortality of HSV encephalitis and limits the long-term behavioral and cognitive impairments that occur with illness. As such, and because HSV is the most common cause of viral encephalitis, acyclovir is often administered as soon as possible to all patients suspected of having viral encephalitis even if the exact viral origin is not yet known. Viral resistance to acyclovir rarely occurs, primarily among the immunocompromised, in which case foscarnet should be used. Although not as effective, nucleoside analogs are used for other herpesviruses as well, such as acyclovir, with possible adjunctive corticosteroids for immunocompetent individuals, for varicella-zoster virus encephalitis and a combination of ganciclovir and foscarnet for cytomegalovirus encephalitis.Serial intracranial pressure (ICP) is important to monitor as elevated ICP is associated with poor prognosis. Elevated ICP can be relieved with steroids and mannitol, though there is limited data of the efficacy of such treatment with regards to viral encephalitis. Seizures can be managed with valproic acid or phenytoin. Status epilepticus may required benzodiazepines. Antipsychotic drugs may be needed for a short time period if behavior alternations are present. Given the possibility of complications developing from viral encephalitis, an interdisciplinary team consisting of the clinicians, therapists, rehabilitation specialists, and speech therapists is important in order to help patients. Prognosis If treated, most individuals recover from viral encephalitis without long-term problems related to the illness. Mortality rates vary for those who do not receive treatment, for example being about 70% for herpes encephalitis but low for the La Crosse virus. Individuals who remain symptomatic after initial infection may have difficulty concentrating, behavior or speech disorders, or memory loss. Rarely, individuals may remain in a persistent vegetative state. The most common long-term complication of viral encephalitis is seizures that may occur in 10% to 20% of patients over several decades. These seizures are resistant to medical therapy. However, individuals who have unilateral mesial temporal lobe seizures after viral encephalitis have good results following neurosurgery. Prognoses related to specific viruses include: For Eastern equine encephalitis, some children may experience seizures, severe intellectual disability, and various forms of paralysis. For Japanese encephalitis, extrapyramidal symptoms relating to motor function may remain. For St. Louis encephalitis, low blood sodium level and excess, unsuppressable release of antidiuretic hormone For Western equine encephalitis, some children may experience seizures and behavioral changes. For pregnant women infected with Zika virus, the newborn child may have microcephaly.Other potential complications following viral encephalitis include: Encephalopathy Flaccid paralysis Impaired intelligence Low blood sodium level Mononeuropathy Mood and behavioral changes Residual neurological deficits Epidemiology While the etiology of many cases of encephalitis is unknown, viruses account for about 70% of confirmed encephalitis cases, with the herpes simplex virus being the most common cause at about 50% of encephalitis cases. The incidence of viral encephalitis is about 3.5 to 7.5 per 100,000 people, with the highest incidence among the young and the elderly. Viral encephalitis caused by some viruses, such as the measles virus and the mumps virus, has become less common due to widespread vaccination. For others, such as Epstein-Barr virus and cytomegalovirus, incidence has increased due to the increased prevalence of AIDS, organ transplantation, and chemotherapy, which have increased the number of immunocompromised people who have weakened immune systems or who are susceptible to opportunistic infections. Time of the year, geography, and animal, including insect, exposure are also important. For example, arbovirus infections are seasonal and cause viral encephalitis at the highest rate during the summer and early fall when mosquitos are most active. Similarly, those who live in warm, humid climates where there are more mosquitos are more likely to experience viral encephalitis. Prevention As many encephalitic viruses are transmitted by mosquitos, many prevention efforts revolve around preventing mosquito bites. In areas where such arboviruses are widespread, people should use protective clothing and should sleep under a mosquito net. Removing containers of stagnant water and spraying insecticides can be beneficial. Activities that increase the likelihood of tick bites should be avoided. Vaccines against some arboviruses that cause viral encephalitis exist, such as those against Eastern equine encephalitis, Western equine encephalitis, and Venezuelan equine encephalitis. Although these vaccines are not perfectly effective, they are recommended for people who live in or travel to high-risk areas. Some vaccines that are included in standard vaccination programs, such as the MMR vaccine, which prevents measles, mumps, and rubella, are also capable of preventing viral encephalitis. See also List of central nervous system infections References == External links ==

Respiratory acidosis

Respiratory acidosis is a state in which decreased ventilation (hypoventilation) increases the concentration of carbon dioxide in the blood and decreases the bloods pH (a condition generally called acidosis). Carbon dioxide is produced continuously as the bodys cells respire, and this CO2 will accumulate rapidly if the lungs do not adequately expel it through alveolar ventilation. Alveolar hypoventilation thus leads to an increased PaCO2 (a condition called hypercapnia). The increase in PaCO2 in turn decreases the HCO3−/PaCO2 ratio and decreases pH. Types Respiratory acidosis can be acute or chronic. In acute respiratory acidosis, the PaCO2 is elevated above the upper limit of the reference range (over 6.3 kPa or 45 mm Hg) with an accompanying acidemia (pH <7.36). In chronic respiratory acidosis, the PaCO2 is elevated above the upper limit of the reference range, with a normal blood pH (7.35 to 7.45) or near-normal pH secondary to renal compensation and an elevated serum bicarbonate (HCO3− >30 mEq/L). Causes Acute Acute respiratory acidosis occurs when an abrupt failure of ventilation occurs. This failure in ventilation may be caused by depression of the central respiratory center by cerebral disease or drugs, inability to ventilate adequately due to neuromuscular disease (e.g., myasthenia gravis, amyotrophic lateral sclerosis, Guillain–Barré syndrome, muscular dystrophy), or airway obstruction related to asthma or chronic obstructive pulmonary disease (COPD) exacerbation. Chronic Chronic respiratory acidosis may be secondary to many disorders, including COPD. Hypoventilation in COPD involves multiple mechanisms, including decreased responsiveness to hypoxia and hypercapnia, increased ventilation-perfusion mismatch leading to increased dead space ventilation, and decreased diaphragm function secondary to fatigue and hyperinflation. Chronic respiratory acidosis also may be secondary to obesity hypoventilation syndrome (i.e., Pickwickian syndrome), neuromuscular disorders such as amyotrophic lateral sclerosis, and severe restrictive ventilatory defects as observed in interstitial lung disease and thoracic deformities. Lung diseases that primarily cause abnormality in alveolar gas exchange usually do not cause hypoventilation but tend to cause stimulation of ventilation and hypocapnia secondary to hypoxia. Hypercapnia only occurs if severe disease or respiratory muscle fatigue occurs. Physiological response Mechanism Metabolism rapidly generates a large quantity of volatile acid (H2CO3) and nonvolatile acid. The metabolism of fats and carbohydrates leads to the formation of a large amount of CO2. The CO2 combines with H2O to form carbonic acid (H2CO3). The lungs normally excrete the volatile fraction through ventilation, and acid accumulation does not occur. A significant alteration in ventilation that affects elimination of CO2 can cause a respiratory acid-base disorder. The PaCO2 is maintained within a range of 35–45 mm Hg in normal states. Alveolar ventilation is under the control of the respiratory center, which is located in the pons and the medulla. Ventilation is influenced and regulated by chemoreceptors for PaCO2, PaO2, and pH located in the brainstem, and in the aortic and carotid bodies as well as by neural impulses from lung stretch receptors and impulses from the cerebral cortex. Failure of ventilation quickly increases the PaCO2. In acute respiratory acidosis, compensation occurs in 2 steps. The initial response is cellular buffering (plasma protein buffers) that occurs over minutes to hours. Cellular buffering elevates plasma bicarbonate (HCO3−) only slightly, approximately 1 mEq/L for each 10-mm Hg increase in PaCO2. The second step is renal compensation that occurs over 3–5 days. With renal compensation, renal excretion of carbonic acid is increased and bicarbonate reabsorption is increased. For instance, PEPCK is upregulated in renal proximal tubule brush border cells, in order to secrete more NH3 and thus to produce more HCO3−. Estimated changes In renal compensation, plasma bicarbonate rises 3.5 mEq/L for each increase of 10 mm Hg in PaCO2. The expected change in serum bicarbonate concentration in respiratory acidosis can be estimated as follows: Acute respiratory acidosis: HCO3− increases 1 mEq/L for each 10 mm Hg rise in PaCO2. Chronic respiratory acidosis: HCO3− rises 3.5 mEq/L for each 10 mm Hg rise in PaCO2.The expected change in pH with respiratory acidosis can be estimated with the following equations: Acute respiratory acidosis: Change in pH = 0.08 X ((40 − PaCO2)/10) Chronic respiratory acidosis: Change in pH = 0.03 X ((40 − PaCO2)/10)Respiratory acidosis does not have a great effect on electrolyte levels. Some small effects occur on calcium and potassium levels. Acidosis decreases binding of calcium to albumin and tends to increase serum ionized calcium levels. In addition, acidemia causes an extracellular shift of potassium, but respiratory acidosis rarely causes clinically significant hyperkalemia. Diagnosis Diagnoses can be done by doing an ABG (Arterial Blood Gas) laboratory study, with a pH <7.35 and a PaCO2 >45 mmHg in an acute setting. Patients with COPD and other Chronic respiratory diseases will sometimes display higher numbers of PaCO2 with HCO3- >30 and normal pH. Terminology Acidosis refers to disorders that lower cell/tissue pH to < 7.35. Acidemia refers to an arterial pH < 7.36. See also References External links Nosek, Thomas M. "Section 7/7ch12/7ch12p43". Essentials of Human Physiology. Archived from the original on 2016-03-24.

Krabbe disease

Krabbe disease (KD) (also known as globoid cell leukodystrophy or galactosylceramide lipidosis) is a rare and often fatal lysosomal storage disease that results in progressive damage to the nervous system. KD involves dysfunctional metabolism of sphingolipids and is inherited in an autosomal recessive pattern. The disease is named after the Danish neurologist Knud Krabbe (1885–1961). Signs and symptoms Symptoms in asymptomatic infantile-onset (<12 months after birth) and later-onset Krabbe disease present themselves differently. Of individuals with infantile-onset Krabbe disease, 85–90% display progressive neurologic deterioration in infancy and death before the age of two. Symptoms include irritability, fevers, limb stiffness, seizures, feeding difficulties (like GERD), vomiting, staring episodes, and slowing of mental and motor development. In the first stages of the disease, doctors often mistake the symptoms for those of cerebral palsy. Other symptoms include muscle weakness, spasticity, deafness, optic atrophy, optic nerve enlargement, blindness, paralysis, and difficulty when swallowing. Prolonged weight loss may also occur.10–15% of individuals with later-onset Krabbe disease have a much slower disease progression. These individuals may also display symptoms such as esotropia, slurred speech, and slow development or loss of motor milestones. Causes Krabbe disease is caused by mutations in the GALC gene located on chromosome 14 (14q31), which is inherited in an autosomal recessive manner. Mutations in the GALC gene cause a deficiency of an enzyme called galactosylceramidase. In rare cases, it may be caused by a lack of active saposin A (a derivative of prosaposin).The buildup of unmetabolized lipids adversely affects the growth of the nerves protective myelin sheath (the covering that insulates many nerves) resulting in demyelination and severe progressive degeneration of motor skills. As part of a group of disorders known as leukodystrophies, Krabbe disease results from the imperfect growth and development of myelin.Galactosylceramidase deficiency also results in a buildup of a glycosphingolipid called psychosine, which is toxic to oligodendrocytes, a type of non-neuronal cell found in the nervous system, collectively termed neuroglia. Diagnosis There are a few ways to help pinpoint the presence of Krabbe disease. Newborn screening for Krabbe disease includes assaying dried blood cells for GALC enzyme activity and molecular analysis for evidence of GALC enzyme mutations. Infants displaying low enzyme activity and/or enzyme mutations should be referred for additional diagnostic testing and neurological examination. 0-5% GALC enzyme activity is observed in all symptomatic individuals with Krabbe disease. High concentration of psychosine in dried blood spots may also be identified as a marker for Krabbe disease. A 2011 study discovered that individuals with Krabbe disease, more so in later-onset individuals, tend to have an abnormal increase in CSF protein concentration.The disease may be diagnosed by its characteristic grouping of certain cells (multinucleated globoid cells), nerve demyelination and degeneration, and destruction of brain cells. Special stains for myelin (e.g., luxol fast blue) may be used to aid diagnosis. New York, Missouri and Kentucky include Krabbe in the newborn screening panel. Indiana will start screening in 2020. Parents of newborns with a diagnosis of Krabbe disease can access online community support and resources below. Treatment Although there is no known cure for Krabbe disease, bone marrow transplantation or hematopoietic stem cell transplantation (HSCT) has been shown to benefit cases early in the course of the disease. Generally, treatment for the disorder is symptomatic and supportive. Physical therapy may help maintain or increase muscle tone and circulation.A 15-year study on the developmental outcomes of children with Krabbe disease who underwent HSCT in the first seven weeks after birth found that patients have a better prognosis for both lifespan and functionality, with a slower progression of the disease. Even symptomatic individuals with later-onset Krabbe disease may benefit from HSCT if diagnosed early enough. Umbilical-cord blood is typically used as the source for the transplant stem cells. Clinical trials for gene therapy are currently enrolling patients. Management Symptom management can be particularly difficult for individuals with infantile onset, as symptoms tend to progress rapidly. Because there is no treatment for Krabbe disease, management of the condition is typically supportive and aimed at alleviating symptoms. Frequent evaluation is encouraged in order to anticipate the onset of, and preparation for, certain symptoms. Physical therapy can help to alleviate motor difficulties and increase strength, mobility, and flexibility.Gastrostomy tubes are used to circumvent feeding difficulties and prevent aspiration. A simultaneous gastrostomy tube insertion and Nissen fundoplication procedure is commonly performed to prevent the need for a secondary surgical procedure. Individuals with Krabbe disease with severe motor deficits tend to be more susceptible to overfeeding, as they require less calorie consumption and thus consume fewer calories than what caretakers may expect. There is also evidence that routine vaccines may accelerate disease progression; many individuals with Krabbe disease tend to not follow traditional vaccination procedures. Prognosis In infantile Krabbe disease, death usually occurs in early childhood. A 2011 study found one-, two-, and three-year survival rates of 60%, 26%, and 14%, respectively, with a few surviving longer. Patients with late-onset Krabbe disease tend to have a slower progression of the disease and live significantly longer. Epidemiology This disease does not only impact humans, but other animals such as monkeys, mice, and dogs have been observed to develop Krabbe disease as well. While certain gene deletions are more frequent than others, novel mutations resulting in Krabbe disease have been discovered worldwide. Most commonly, the underlying cause of the disease is a deletion of a GALC gene, which causes a deficiency in the GALC enzyme. This is the circumstance in 80% of patients who have European and Mexican origins. The mortality rate of early infantile Krabbe disease is 90% before the age of two. Later onset of symptoms is associated with longer life expectancy, with older children generally surviving two to seven years after the initial diagnosis.Krabbe disease occurs in about one in 100,000 births. Because the disease is genetic, incidence rates vary widely from population to population. The incidence rate is extremely low in Japan, with between 5 and 10 cases per 1,000,000 live births. In the United States, Krabbe disease occurs in approximately 1 out of every 100,000 live births. Scandinavian countries report incidence rates of one in 50,000 births. In certain communities Krabbe disease is much more frequent, such as the Druze community in Israel, which has an incidence rate of 6 out of every 1,000 live births. This higher rate is thought to be due in part to a high frequency of consanguineous marriages. Almost 35% of all Druze marriages were found to be between first-cousin familial relations. There have been no reported cases of Krabbe disease among the Jewish community.Time of onset also varies in frequency by location. Early infantile Krabbe Disease is the most common form of the disease overall, but Nordic communities tend to have even higher rates of early infantile onset Krabbe disease, while Southern European countries have higher incidences of late-onset cases. It is difficult to estimate the incidence of adult-onset Krabbe disease, due to discrepancies in classifying cases late-onset versus adult-onset. Society and culture Former Buffalo Bills quarterback Jim Kelly has been a leader in gaining recognition and research funding for Krabbe disease following the diagnosis of his son, Hunter, in 1997. Hunter Kelly died of the disease on August 5, 2005, at the age of eight. They created Hunters Hope - a foundation that seeks to advance Newborn Screening, research and treatments, and provides support to families of leukodystrophy children.Family advocacy is a critical part of advancing newborn screening, and many Krabbe families have made significant advocacy progress in their states.As an example, Cove Ellis is a child from Georgia, United States who was diagnosed with the disease in early 2016. Ellis family, along with her community, has worked to raise awareness of the disease and helped pass "Coves Law", which provides parents the option to have prenatal screening for the disease, which can, potentially, save the child from the morbidity and mortality of Krabbe disease. Other animals Krabbe disease is found in mice may also be found in cats and in dogs, particularly the West Highland White Terriers and Cairn Terriers. See also Maria Luisa Escolar The Myelin Project The Stennis Foundation KrabbeConnect The Legacy of Angels Foundation Hunters Hope Foundation References This article incorporates public domain text from the United States National Library of Medicine and the National Institute of Neurological Disorders and Stroke. External links GeneReviews/NCBI/NIH/UW entry on Krabbe disease OMIM entries on Krabbe disease

Nystagmus

Nystagmus is a condition of involuntary (or voluntary, in some cases) eye movement. Infants can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in reduced or limited vision. Due to the involuntary movement of the eye, it has been called "dancing eyes".In normal eyesight, while the head rotates about an axis, distant visual images are sustained by rotating eyes in the opposite direction of the respective axis. The semicircular canals in the vestibule of the ear sense angular acceleration, and send signals to the nuclei for eye movement in the brain. From here, a signal is relayed to the extraocular muscles to allow ones gaze to fix on an object as the head moves. Nystagmus occurs when the semicircular canals are stimulated (e.g., by means of the caloric test, or by disease) while the head is stationary. The direction of ocular movement is related to the semicircular canal that is being stimulated.There are two key forms of nystagmus: pathological and physiological, with variations within each type. Nystagmus may be caused by congenital disorder or sleep deprivation, acquired or central nervous system disorders, toxicity, pharmaceutical drugs, alcohol, or rotational movement. Previously considered untreatable, in recent years several drugs have been identified for treatment of nystagmus. Nystagmus is also occasionally associated with vertigo. Causes The cause of pathological nystagmus may be congenital, idiopathic, or secondary to a pre-existing neurological disorder. It also may be induced temporarily by disorientation (such as on roller coaster rides or when a person has been spinning in circles) or by some drugs (alcohol, lidocaine, and other central nervous system depressants, inhalant drugs, stimulants, psychedelics, and dissociative drugs). Early-onset nystagmus Early-onset nystagmus occurs more frequently than acquired nystagmus. It can be insular or accompany other disorders (such as micro-ophthalmic anomalies or Down syndrome). Early-onset nystagmus itself is usually mild and non-progressive. The affected persons are usually unaware of their spontaneous eye movements, but vision can be impaired depending on the severity of the eye movements. Types of early-onset nystagmus include the following, along with some of their causes: Infantile: Albinism Aniridia Bilateral congenital cataract Bilateral optic nerve hypoplasia Idiopathic Lebers congenital amaurosis Optic nerve or macular disease Persistent tunica vasculosa lentis Rod monochromatism Visual-motor syndrome of functional monophthalmus Latent nystagmus Noonan syndrome Nystagmus blockage syndromeX-linked infantile nystagmus is associated with mutations of the gene FRMD7, which is located on the X chromosome.Infantile nystagmus is also associated with two X-linked eye diseases known as complete congenital stationary night blindness (CSNB) and incomplete CSNB (iCSNB or CSNB-2), which are caused by mutations of one of two genes located on the X chromosome. In CSNB, mutations are found in NYX (nyctalopin). CSNB-2 involves mutations of CACNA1F, a voltage-gated calcium channel that, when mutated, does not conduct ions. Acquired nystagmus Nystagmus that occurs later in childhood or in adulthood is called acquired nystagmus. The cause is often unknown, or idiopathic, and thus referred to as idiopathic nystagmus. Other common causes include diseases and disorders of the central nervous system, metabolic disorders and alcohol and drug toxicity. In the elderly, stroke is the most common cause. General diseases and conditions Some of the diseases that present nystagmus as a pathological sign or symptom are as follows: Aniridia Benign paroxysmal positional vertigo Toxicity or intoxication, metabolic disorders and combination Sources of toxicity that could lead to nystagmus: Thiamine deficiency Risk factors for thiamine deficiency, or beri beri, in turn include a diet of mostly white rice, as well as alcoholism, dialysis, chronic diarrhea, and taking high doses of diuretics. Rarely it may be due to a genetic condition that results in difficulties absorbing thiamine found in food. Wernicke encephalopathy and Korsakoff syndrome are forms of dry beriberi. Central nervous system (CNS) diseases and disorders Central nervous system disorders such as with a cerebellar problem, the nystagmus can be in any direction including horizontal. Purely vertical nystagmus usually originates in the central nervous system, but it is also an adverse effect commonly seen in high phenytoin toxicity. Other causes of toxicity that may result in nystagmus include: Other causes Non-physiological Trochlear nerve malfunction Vestibular Pathology (Ménières disease, SCDS (superior canal dehiscence syndrome), BPPV, Labyrinthitis) Exposure to strong magnetic fields (as in MRI machines) Long-term lack of light, called miners nystagmus after 19th-century coal miners who developed nystagmus from working in the dark. A slightly different form of nystagmus may be produced voluntarily by some people. Diagnosis Nystagmus is highly noticeable but rarely recognized. Nystagmus can be clinically investigated by using a number of non-invasive standard tests. The simplest one is the caloric reflex test, in which one ear canal is irrigated with warm or cold water or air. The temperature gradient provokes the stimulation of the horizontal semicircular canal and the consequent nystagmus. Nystagmus is often very commonly present with Chiari malformation. The resulting movement of the eyes may be recorded and quantified by a special device called an electronystagmograph (ENG), a form of electrooculography (an electrical method of measuring eye movements using external electrodes), or an even less invasive device called a videonystagmograph (VNG), a form of video-oculography (VOG) (a video-based method of measuring eye movements using external small cameras built into head masks), administered by an audiologist. Special swinging chairs with electrical controls can be used to induce rotatory nystagmus.Over the past forty years, objective eye-movement-recording techniques have been applied to the study of nystagmus, and the results have led to greater accuracy of measurement and understanding of the condition. Orthoptists may also use an optokinetic drum, or electrooculography or Frenzel goggles to assess a patients eye movements. Nystagmus can be caused by subsequent foveation of moving objects, pathology, sustained rotation or substance use. Nystagmus is not to be confused with other superficially similar-appearing disorders of eye movements (saccadic oscillations) such as opsoclonus or ocular flutter that are composed purely of fast-phase (saccadic) eye movements, while nystagmus is characterized by the combination of a smooth pursuit, which usually acts to take the eye off the point of focus, interspersed with the saccadic movement that serves to bring the eye back on target. Without the use of objective recording techniques, it may be very difficult to distinguish among these conditions. In medicine, the presence of nystagmus can be benign, or it can indicate an underlying visual or neurological problem. Pathologic nystagmus Pathological nystagmus is characterized by "excessive drifts of stationary retinal images that degrades vision and may produce illusory motion of the seen world: oscillopsia (an exception is congenital nystagmus)".When nystagmus occurs without fulfilling its normal function, it is pathologic (deviating from the healthy or normal condition). Pathological nystagmus is the result of damage to one or more components of the vestibular system, including the semicircular canals, otolith organs, and the vestibulocerebellum.Pathological nystagmus generally causes a degree of vision impairment, although the severity of such impairment varies widely. Also, many blind people have nystagmus, which is one reason that some wear dark glasses. Variations Central nystagmus occurs as a result of either normal or abnormal processes not related to the vestibular organ. For example, lesions of the midbrain or cerebellum can result in up- and down-beat nystagmus. Gaze induced nystagmus occurs or is exacerbated as a result of changing ones gaze toward or away from a particular side which has an affected central apparatus. Peripheral nystagmus occurs as a result of either normal or diseased functional states of the vestibular system and may combine a rotational component with vertical or horizontal eye movements and may be spontaneous, positional, or evoked. Positional nystagmus occurs when a persons head is in a specific position. An example of disease state in which this occurs is Benign paroxysmal positional vertigo (BPPV). Post rotational nystagmus occurs after an imbalance is created between a normal side and a diseased side by stimulation of the vestibular system by rapid shaking or rotation of the head. Spontaneous nystagmus is nystagmus that occurs randomly, regardless of the position of the patients head. Physiological nystagmus Physiological nystagmus is a form of involuntary eye movement that is part of the vestibulo-ocular reflex (VOR), characterized by alternating smooth pursuit in one direction and saccadic movement in the other direction. Variations The direction of nystagmus is defined by the direction of its quick phase (e.g. a right-beating nystagmus is characterized by a rightward-moving quick phase, and a left-beating nystagmus by a leftward-moving quick phase). The oscillations may occur in the vertical, horizontal or torsional planes, or in any combination. The resulting nystagmus is often named as a gross description of the movement, e.g. downbeat nystagmus, upbeat nystagmus, seesaw nystagmus, periodic alternating nystagmus. These descriptive names can be misleading, however, as many were assigned historically, solely on the basis of subjective clinical examination, which is not sufficient to determine the eyes true trajectory. Optokinetic (syn. opticokinetic) nystagmus: a nystagmus induced by looking at moving visual stimuli, such as moving horizontal or vertical lines, and/or stripes. For example, if one fixates on a stripe of a rotating drum with alternating black and white, the gaze retreats to fixate on a new stripe as the drum moves. This is first a rotation with the same angular velocity, then returns in a saccade in the opposite direction. The process proceeds indefinitely. This is optokinetic nystagmus, and is a source for understanding the fixation reflex. Postrotatory nystagmus: if one spins in a chair continuously and stops suddenly, the fast phase of nystagmus is in the opposite direction of rotation, known as the "post-rotatory nystagmus", while slow phase is in the direction of rotation. Treatment Congenital nystagmus has long been viewed as untreatable, but medications have been discovered in recent years that show promise in some patients. In 1980, researchers discovered that a drug called baclofen could stop periodic alternating nystagmus. Subsequently, gabapentin, an anticonvulsant, led to improvement in about half the patients who took it. Other drugs found to be effective against nystagmus in some patients include memantine, levetiracetam, 3,4-diaminopyridine (available in the US to eligible patients with downbeat nystagmus at no cost under an expanded access program), 4-aminopyridine, and acetazolamide. Several therapeutic approaches, such as contact lenses, drugs, surgery, and low vision rehabilitation have also been proposed. For example, it has been proposed that mini-telescopic eyeglasses suppress nystagmus.Surgical treatment of congenital nystagmus is aimed at improving head posture, simulating artificial divergence, or weakening the horizontal recti muscles. Clinical trials of a surgery to treat nystagmus (known as tenotomy) concluded in 2001. Tenotomy is now being performed regularly at numerous centres around the world. The surgery aims to reduce the eye oscillations, which in turn tends to improve visual acuity.Acupuncture tests have produced conflicting evidence on its beneficial effects on the symptoms of nystagmus. Benefits have been seen in treatments in which acupuncture points of the neck were used, specifically points on the sternocleidomastoid muscle. Benefits of acupuncture for treatment of nystagmus include a reduction in frequency and decreased slow phase velocities, which led to an increase in foveation duration periods both during and after treatment. By the standards of evidence-based medicine, the quality of these studies is poor (for example, Ishikawas study had sample size of six subjects, was unblinded, and lacked proper controls), and given high quality studies showing that acupuncture has no effect beyond placebo, the results of these studies have to be considered clinically irrelevant until higher quality studies are performed. Physical or occupational therapy is also used to treat nystagmus. Treatment consists of learning strategies to compensate for the impaired system.A Cochrane Review on interventions for eye movement disorders due to acquired brain injury, updated in June 2017, identified three studies of pharmacological interventions for acquired nystagmus but concluded that these studies provided insufficient evidence to guide treatment choices. Epidemiology Nystagmus is a relatively common clinical condition, affecting one in several thousand people. A survey conducted in Oxfordshire, United Kingdom found that by the age of two, one in every 670 children had manifested nystagmus. Authors of another study in the United Kingdom estimated an incidence of 24 in 10,000 (c. 0.240%), noting an apparently higher rate amongst white Europeans than in individuals of Asian origin. Law enforcement In the United States, testing for horizontal gaze nystagmus is one of a battery of field sobriety tests used by police officers to determine whether a suspect is driving under the influence of alcohol. The test involves observation of the suspects pupil as it follows a moving object, noting lack of smooth pursuit, distinct and sustained nystagmus at maximum deviation, and the onset of nystagmus prior to 45 degrees.The horizontal gaze nystagmus test has been highly criticized and major errors in the testing methodology and analysis found. However, the validity of the horizontal gaze nystagmus test for use as a field sobriety test for persons with a blood alcohol level between 0.04 and 0.08 is supported by peer reviewed studies and has been found to be a more accurate indication of blood alcohol content than other standard field sobriety tests. See also Bruns nystagmus Myoclonus Oscillopsia Opsoclonus Optokinetic nystagmus Explanatory notes == References ==

Kawasaki disease

Kawasaki disease is a syndrome of unknown cause that results in a fever and mainly affects children under 5 years of age. It is a form of vasculitis, where blood vessels become inflamed throughout the body. The fever typically lasts for more than five days and is not affected by usual medications. Other common symptoms include large lymph nodes in the neck, a rash in the genital area, lips, palms, or soles of the feet, and red eyes. Within three weeks of the onset, the skin from the hands and feet may peel, after which recovery typically occurs. In some children, coronary artery aneurysms form in the heart.While the specific cause is unknown, it is thought to result from an excessive immune system response to an infection in children who are genetically predisposed. It does not spread between people. Diagnosis is usually based on a persons signs and symptoms. Other tests such as an ultrasound of the heart and blood tests may support the diagnosis. Diagnosis must take into account many other conditions that may present similar features, including scarlet fever and juvenile rheumatoid arthritis. An emerging Kawasaki-like disease temporally associated with COVID-19 appears to be a distinct syndrome.Typically, initial treatment of Kawasaki disease consists of high doses of aspirin and immunoglobulin. Usually, with treatment, fever resolves within 24 hours and full recovery occurs. If the coronary arteries are involved, ongoing treatment or surgery may occasionally be required. Without treatment, coronary artery aneurysms occur in up to 25% and about 1% die. With treatment, the risk of death is reduced to 0.17%. People who have had coronary artery aneurysms after Kawasaki disease require lifelong cardiological monitoring by specialized teams.Kawasaki disease is rare. It affects between 8 and 67 per 100,000 people under the age of five except in Japan, where it affects 124 per 100,000. Boys are more commonly affected than girls. The disorder is named after Japanese pediatrician Tomisaku Kawasaki, who first described it in 1967. Signs and symptoms Kawasaki disease often begins with a high and persistent fever that is not very responsive to normal treatment with paracetamol (acetaminophen) or ibuprofen. This is the most prominent symptom of Kawasaki disease, and is a characteristic sign that the disease is in its acute phase; the fever normally presents as a high (above 39–40 °C) and remittent, and is followed by extreme irritability. Recently, it is reported to be present in patients with atypical or incomplete Kawasaki disease; nevertheless, it is not present in 100% of cases.The first day of fever is considered the first day of the illness, and its duration is typically one to two weeks; in the absence of treatment, it may extend for three to four weeks. Prolonged fever is associated with a higher incidence of cardiac involvement. It responds partially to antipyretic drugs and does not cease with the introduction of antibiotics. However, when appropriate therapy is started – intravenous immunoglobulin and aspirin – the fever subsides after two days.Bilateral conjunctival inflammation has been reported to be the most common symptom after fever. It typically involves the bulbar conjunctivae, is not accompanied by suppuration, and is not painful. This usually begins shortly after the onset of fever during the acute stage of the disease. Anterior uveitis may be present under slit-lamp examination. Iritis can occur, too. Keratic precipitates are another eye manifestation (detectable by a slit lamp, but are usually too small to be seen by the unaided eye).Kawasaki disease also presents with a set of mouth symptoms, the most characteristic of which are a red tongue, swollen lips with vertical cracking, and bleeding. The mucosa of the mouth and throat may be bright red, and the tongue may have a typical "strawberry tongue" appearance (marked redness with prominent gustative papillae). These mouth symptoms are caused by necrotizing microvasculitis with fibrinoid necrosis.Cervical lymphadenopathy is seen in 50% to 75% of children, whereas the other features are estimated to occur in 90%, but sometimes it can be the dominant presenting symptom. According to the diagnostic criteria, at least one impaired lymph node ≥ 15 mm in diameter should be involved. Affected lymph nodes are painless or minimally painful, nonfluctuant, and nonsuppurative; erythema of the neighboring skin may occur. Children with fever and neck adenitis who do not respond to antibiotics should have Kawasaki disease considered as part of the differential diagnoses. In the acute phase of the disease, changes in the peripheral extremities can include erythema of the palms and soles, which is often striking with sharp demarcation and often accompanied by painful, brawny edema of the dorsa of the hands or feet, so affected children frequently refuse to hold objects in their hands or to bear weight on their feet. Later, during the convalescent or the subacute phase, desquamation of the fingers and toes usually begins in the periungual region within two to three weeks after the onset of fever and may extend to include the palms and soles. Around 11% of children affected by the disease may continue skin-peeling for many years. One to two months after the onset of fever, deep transverse grooves across the nails may develop (Beaus lines), and occasionally nails are shed.The most common skin manifestation is a diffuse macular-papular erythematous rash, which is quite nonspecific. The rash varies over time and is characteristically located on the trunk; it may further spread to involve the face, extremities, and perineum. Many other forms of cutaneous lesions have been reported; they may include scarlatiniform, papular, urticariform, multiform-like erythema, and purpuric lesions; even micropustules were reported. It can be polymorphic, not itchy, and normally observed up to the fifth day of fever. However, it is never bullous or vesicular.In the acute stage of Kawasaki disease, systemic inflammatory changes are evident in many organs. Joint pain (arthralgia) and swelling, frequently symmetrical, and arthritis can also occur. Myocarditis, diarrhea, pericarditis, valvulitis, aseptic meningitis, pneumonitis, lymphadenitis, and hepatitis may be present and are manifested by the presence of inflammatory cells in the affected tissues. If left untreated, some symptoms will eventually relent, but coronary artery aneurysms will not improve, resulting in a significant risk of death or disability due to myocardial infarction. If treated quickly, this risk can be mostly avoided and the course of illness cut short. Other reported nonspecific symptoms include cough, rhinorrhea, sputum, vomiting, headache, and seizure.The course of the disease can be divided into three clinical phases. The acute febrile phase, which usually lasts for one to two weeks, is characterized by fever, conjunctival injection, erythema of the oral mucosa, erythema and swelling of the hands and feet, rash, cervical adenopathy, aseptic meningitis, diarrhea, and hepatic dysfunction. Myocarditis is common during this time, and a pericardial effusion may be present. Coronary arteritis may be present, but aneurysms are generally not yet visible by echocardiography. The subacute phase begins when fever, rash, and lymphadenopathy resolve at about one to two weeks after the onset of fever, but irritability, anorexia, and conjunctival injection persist. Desquamation of the fingers and toes and thrombocytosis are seen during this stage, which generally lasts until about four weeks after the onset of fever. Coronary artery aneurysms usually develop during this time, and the risk for sudden death is highest. The convalescent stage begins when all clinical signs of illness have disappeared, and continues until the sedimentation rate returns to normal, usually at six to eight weeks after the onset of illness.Adult onset of Kawasaki disease is rare. The presentation differs between adults and children: in particular, it seems that adults more often have cervical lymphadenopathy, hepatitis, and arthralgia.Some children, especially young infants, have atypical presentations without the classic set of symptoms. Such presentations are associated with a higher risk of cardiac artery aneurysms. Cardiac Heart complications are the most important aspect of Kawasaki disease, which is the leading cause of heart disease acquired in childhood in the United States and Japan. In developed nations, it appears to have replaced acute rheumatic fever as the most common cause of acquired heart disease in children. Coronary artery aneurysms occur as a sequela of the vasculitis in 20–25% of untreated children. It is first detected at a mean of 10 days of illness and the peak frequency of coronary artery dilation or aneurysms occurs within four weeks of onset. Aneurysms are classified into small (internal diameter of vessel wall <5 mm), medium (diameter ranging from 5–8 mm), and giant (diameter > 8 mm). Saccular and fusiform aneurysms usually develop between 18 and 25 days after the onset of illness.Even when treated with high-dose IVIG regimens within the first 10 days of illness, 5% of children with Kawasaki disease develop at the least transient coronary artery dilation and 1% develop giant aneurysms. Death can occur either due to myocardial infarction secondary to blood clot formation in a coronary artery aneurysm or to rupture of a large coronary artery aneurysm. Death is most common two to 12 weeks after the onset of illness.Many risk factors predicting coronary artery aneurysms have been identified, including persistent fever after IVIG therapy, low hemoglobin concentrations, low albumin concentrations, high white-blood-cell count, high band count, high CRP concentrations, male sex, and age less than one year. Coronary artery lesions resulting from Kawasaki disease change dynamically with time. Resolution one to two years after the onset of the disease has been observed in half of vessels with coronary aneurysms. Narrowing of the coronary artery, which occurs as a result of the healing process of the vessel wall, often leads to significant obstruction of the blood vessel and the heart not receiving enough blood and oxygen. This can eventually lead to heart muscle tissue death, i.e., myocardial infarction (MI).MI caused by thrombotic occlusion in an aneurysmal, stenotic, or both aneurysmal and stenotic coronary artery is the main cause of death from Kawasaki disease. The highest risk of MI occurs in the first year after the onset of the disease. MI in children presents with different symptoms from those in adults. The main symptoms were shock, unrest, vomiting, and abdominal pain; chest pain was most common in older children. Most of these children had the attack occurring during sleep or at rest, and around one-third of attacks were asymptomatic.Valvular insufficiencies, particularly of mitral or tricuspid valves, are often observed in the acute phase of Kawasaki disease due to inflammation of the heart valve or inflammation of the heart muscle-induced myocardial dysfunction, regardless of coronary involvement. These lesions mostly disappear with the resolution of acute illness, but a very small group of the lesions persist and progress. There is also late-onset aortic or mitral insufficiency caused by thickening or deformation of fibrosed valves, with the timing ranging from several months to years after the onset of Kawasaki disease. Some of these lesions require valve replacement. Other Other Kawasaki disease complications have been described, such as aneurysm of other arteries: aortic aneurysm, with a higher number of reported cases involving the abdominal aorta, axillary artery aneurysm, brachiocephalic artery aneurysm, aneurysm of iliac and femoral arteries, and renal artery aneurysm. Other vascular complications can occur such as increased wall thickness and decreased distensibility of carotid arteries, aorta, and brachioradial artery. This change in the vascular tone is secondary to endothelial dysfunction. In addition, children with Kawasaki disease, with or without coronary artery complications, may have a more adverse cardiovascular risk profile, such as high blood pressure, obesity, and abnormal serum lipid profile.Gastrointestinal complications in Kawasaki disease are similar to those observed in Henoch–Schönlein purpura, such as: intestinal obstruction, colon swelling, intestinal ischemia, intestinal pseudo-obstruction, and acute abdomen.Eye changes associated with the disease have been described since the 1980s, being found as uveitis, iridocyclitis, conjunctival hemorrhage, optic neuritis, amaurosis, and ocular artery obstruction. It can also be found as necrotizing vasculitis, progressing into peripheral gangrene.The neurological complications per central nervous system lesions are increasingly reported. The neurological complications found are meningoencephalitis, subdural effusion, cerebral hypoperfusion, cerebral ischemia and infarct, cerebellar infarction, manifesting with seizures, chorea, hemiplegia, mental confusion, lethargy and coma, or even a cerebral infarction with no neurological manifestations. Other neurological complications from cranial nerve involvement are reported as ataxia, facial palsy, and sensorineural hearing loss. Behavioral changes are thought to be caused by localised cerebral hypoperfusion, can include attention deficits, learning deficits, emotional disorders (emotional lability, fear of night, and night terrors), and internalization problems (anxious, depressive or aggressive behavior). Causes The specific cause of Kawasaki disease is unknown. A plausible explanation is that it may be caused by an infection that triggers an inappropriate immunologic cascade in a small number of genetically predisposed children. The pathogenesis is complex and incompletely understood. Various explanations exist. (See #Classification) Circumstantial evidence points to an infectious cause. Since recurrences are unusual in Kawasaki disease, it is thought that the trigger is more likely to be represented by a single pathogen, rather than a range of viral or bacterial agents. Various candidates have been implicated, including upper respiratory tract infection by some novel RNA virus. Despite intensive search, no single pathogen has been identified. There has been debate as to whether the infectious agent might be a superantigen (i.e. one commonly associated with excessive immune system activation). Current consensus favors an excessive immunologic response to a conventional antigen which usually provides future protection. Research points to an unidentified ubiquitous virus, possibly one that enters through the respiratory tract.Seasonal trends in the appearance of new cases of Kawasaki disease have been linked to tropospheric wind patterns, which suggests wind-borne transport of something capable of triggering an immunologic cascade when inhaled by genetically susceptible children. Winds blowing from central Asia correlate with numbers of new cases of Kawasaki disease in Japan, Hawaii, and San Diego. These associations are themselves modulated by seasonal and interannual events in the El Niño–Southern Oscillation in winds and sea surface temperatures over the tropical eastern Pacific Ocean. Efforts have been made to identify a possible pathogen in air-filters flown at altitude above Japan. One source has been suggested in northeastern China. Genetics Genetic susceptibility is suggested by increased incidence among children of Japanese descent around the world, and also among close and extended family members of affected people. Genetic factors are also thought to influence development of coronary artery aneurysms and response to treatment. The exact genetic contribution remains unknown. Genome-wide association studies and studies of individual candidate genes have together helped identify specific single nucleotide polymorphisms (SNPs), mostly found in genes with immune regulatory functions. The associated genes and their levels of expression appear to vary among different ethnic groups, both with Asian and non-Asian backgrounds.SNPs in FCGR2A, CASP3, BLK, ITPKC, CD40 and ORAI1 have all been linked to susceptibility, prognosis, and risk of developing coronary artery aneurysms. Various other possible susceptibility genes have been proposed, including polymorphisms in the HLA region, but their significance is disputed. Genetic susceptibility to Kawasaki disease appears complex. Gene–gene interactions also seem to affect susceptibility and prognosis. At an epigenetic level, altered DNA methylation has been proposed as an early mechanistic factor during the acute phase of the disease. Diagnosis Since no specific laboratory test exists for Kawasaki disease, diagnosis must be based on clinical signs and symptoms, together with laboratory findings. Timely diagnosis requires careful history-taking and thorough physical examination. Establishing the diagnosis is difficult, especially early in the course of the illness, and frequently children are not diagnosed until they have seen several health-care providers. Many other serious illnesses can cause similar symptoms, and must be considered in the differential diagnosis, including scarlet fever, toxic shock syndrome, juvenile idiopathic arthritis, and childhood mercury poisoning (infantile acrodynia).Classically, five days of fever plus four of five diagnostic criteria must be met to establish the diagnosis. The criteria are: erythema of the lips or oral cavity or cracking of the lips rash on the trunk swelling or erythema of the hands or feet red eyes (conjunctival injection) swollen lymph node in the neck of at least 15 mmMany children, especially infants, eventually diagnosed with Kawasaki disease, do not exhibit all of the above criteria. In fact, many experts now recommend treating for Kawasaki disease even if only three days of fever have passed and at least three diagnostic criteria are present, especially if other tests reveal abnormalities consistent with Kawasaki disease. In addition, the diagnosis can be made purely by the detection of coronary artery aneurysms in the proper clinical setting. Investigations A physical examination will demonstrate many of the features listed above. Blood tests Complete blood count may reveal normocytic anemia and eventually thrombocytosis. Erythrocyte sedimentation rate will be elevated. C-reactive protein will be elevated. Liver function tests may show evidence of hepatic inflammation and low serum albumin levels.Other optional tests include: Electrocardiogram may show evidence of ventricular dysfunction or, occasionally, arrhythmia due to myocarditis. Echocardiogram may show subtle coronary artery changes or, later, true aneurysms. Ultrasound or computerized tomography may show hydrops (enlargement) of the gallbladder. Urinalysis may show white blood cells and protein in the urine (pyuria and proteinuria) without evidence of bacterial growth. Lumbar puncture may show evidence of aseptic meningitis. Angiography was historically used to detect coronary artery aneurysms, and remains the gold standard for their detection, but is rarely used today unless coronary artery aneurysms have already been detected by echocardiography.Biopsy is rarely performed, as it is not necessary for diagnosis. Subtypes Based on clinical findings, a diagnostic distinction may be made between the classic / typical presentation of Kawasaki disease and incomplete / atypical presentation of a "suspected" form of the disease. Regarding incomplete / atypical presentation, American Heart Association guidelines state that Kawasaki disease "should be considered in the differential diagnosis of prolonged unexplained fever in childhood associated with any of the principal clinical features of the disease, and the diagnosis can be considered confirmed when coronary artery aneurysms are identified in such patients by echocardiography."A further distinction between incomplete and atypical subtypes may also be made in the presence of non-typical symptoms. Case definition For study purposes, including vaccine safety monitoring, an international case definition has been proposed to categorize definite (i.e. complete/incomplete), probable and possible cases of Kawasaki disease. Differential diagnosis The broadness of the differential diagnosis is a challenge to timely diagnosis of Kawasaki disease. Infectious and noninfectious conditions requiring consideration include: measles and other viral infections (e.g. adenovirus, enterovirus); staphylococcal and streptococcal toxin-mediated diseases such as scarlet fever and toxic shock syndrome; drug hypersensitivity reactions (including Stevens Johnson syndrome); systemic onset juvenile idiopathic arthritis; Rocky Mountain spotted fever or other rickettsial infections; and leptospirosis. Infectious conditions that can mimic Kawasaki disease include periorbital cellulitis, peritonsillar abscess, retropharyngeal abscess, cervical lymphadenitis, parvovirus B19, mononucleosis, rheumatic fever, meningitis, staphylococcal scalded skin syndrome, toxic epidermal necrolysis, and Lyme disease. Kawasaki-like disease temporally associated with COVID-19 In 2020, reports of a Kawasaki-like disease following exposure to SARS-CoV-2, the virus responsible for COVID-19, emerged in the US and Europe. The World Health Organization is examining possible links with COVID-19. This emerging condition was named paediatric multisystem inflammatory syndrome by the Royal College of Paediatrics and Child Health, and multisystem inflammatory syndrome in children by the Centers for Disease Control and Prevention. Guidance for diagnosis and reporting of cases has been issued by these organizations. Classification Debate has occurred about whether Kawasaki disease should be viewed as a characteristic immune response to some infectious pathogen, as an autoimmune process, or as an autoinflammatory disease (i.e. involving innate rather than adaptive immune pathways). Overall, immunological research suggests that Kawasaki disease is associated with a response to a conventional antigen (rather than a superantigen) that involves both activation of the innate immune system and also features of an adaptive immune response. Identification of the exact nature of the immune process involved in Kawasaki disease could help guide research aimed at improving clinical management.Inflammation, or vasculitis, of the arteries and veins occurs throughout the body, usually caused by increased production of the cells of the immune system to a pathogen, or autoimmunity. Systemic vasculitides may be classified according to the type of cells involved in the proliferation, as well as the specific type of tissue damage occurring within the vein or arterial walls. Under this classification scheme for systemic vasculitis, Kawasaki disease is considered to be a necrotizing vasculitis (also called necrotizing angiitis), which may be identified histologically by the occurrence of necrosis (tissue death), fibrosis, and proliferation of cells associated with inflammation in the inner layer of the vascular wall.Other diseases involving necrotizing vasculitis include polyarteritis nodosa, granulomatosis with polyangiitis, Henoch–Schönlein purpura, and eosinophilic granulomatosis with polyangiitis.Kawasaki disease may be further classified as a medium-sized vessel vasculitis, affecting medium- and small-sized blood vessels, such as the smaller cutaneous vasculature (veins and arteries in the skin) that range from 50 to 100 µm in diameter. Kawasaki disease is also considered to be a primary childhood vasculitis, a disorder associated with vasculitis that mainly affects children under the age of 18. A recent, consensus-based evaluation of vasculitides occurring primarily in children resulted in a classification scheme for these disorders, to distinguish them and suggest a more concrete set of diagnostic criteria for each. Within this classification of childhood vasculitides, Kawasaki disease is, again, a predominantly medium-sized vessel vasculitis.It can also be classed as an autoimmune form of vasculitis. It is not associated with anti-neutrophil cytoplasmic antibodies, unlike other vasculitic disorders associated with them (such as granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis). This form of categorization is relevant for appropriate treatment. Treatment Children with Kawasaki disease should be hospitalized and cared for by a physician who has experience with this disease. In an academic medical center, care is often shared between pediatric cardiology, pediatric rheumatology, and pediatric infectious disease specialists (although no specific infectious agent has yet been identified). To prevent damage to coronary arteries, treatment should be started immediately following the diagnosis.Intravenous immunoglobulin (IVIG) is the standard treatment for Kawasaki disease and is administered in high doses with marked improvement usually noted within 24 hours. If the fever does not respond, an additional dose may be considered. In rare cases, a third dose may be given. IVIG is most useful within the first seven days of fever onset, to prevent coronary artery aneurysm. IVIG given within the first 10 days of the disease reduces the risk of damage to the coronary arteries in children, without serious adverse effects.Salicylate therapy, particularly aspirin, remains an important part of the treatment (though questioned by some) but salicylates alone are not as effective as IVIG. There is limited evidence to indicate whether children should continue to receive salicylate as part of their treatment. Aspirin therapy is started at high doses until the fever subsides, and then is continued at a low dose when the patient returns home, usually for two months to prevent blood clots from forming. Except for Kawasaki disease and a few other indications, aspirin is otherwise normally not recommended for children due to its association with Reye syndrome. Because children with Kawasaki disease will be taking aspirin for up to several months, vaccination against varicella and influenza is required, as these infections are most likely to cause Reye syndrome.High-dose aspirin is associated with anemia and does not confer benefit to disease outcomes.About 15-20% of children following the initial IVIG infusion show persistent or recurrent fever and are classified as IVIG-resistant. While the use of TNF alpha blockers (TNF-α) may reduce treatment resistance and the infusion reaction after treatment initiation, further research is needed. Due to the potential involvement of the upregulated calcium-nuclear factor of activated T cells pathway in the development of the disease, a 2019 study found that the combination of ciclosporin and IVIG infusion can suppress coronary artery abnormalities. Further research is needed to determine which patients would respond best to this treatment.Corticosteroids have also been used, especially when other treatments fail or symptoms recur, but in a randomized controlled trial, the addition of corticosteroid to immune globulin and aspirin did not improve outcome. Additionally, corticosteroid use in the setting of Kawasaki disease is associated with increased risk of coronary artery aneurysm, so its use is generally contraindicated in this setting. In cases of Kawasaki disease refractory to IVIG, cyclophosphamide and plasma exchange have been investigated as possible treatments, with variable outcomes. However, a Cochrane review published in 2017 (updated in 2022) found that, in children, the use of corticosteroids in the acute phase of KD was associated with improved coronary artery abnormalities, shorter hospital stays, a decreased duration of clinical symptoms, and reduced inflammatory marker levels. Patient populations based in Asia, people with higher risk scores, and those receiving longer steroid treatment may have greater benefit from steroid use. Prognosis With early treatment, rapid recovery from the acute symptoms can be expected, and the risk of coronary artery aneurysms is greatly reduced. Untreated, the acute symptoms of Kawasaki disease are self-limited (i.e. the patient will recover eventually), but the risk of coronary artery involvement is much greater, even many years later. Many cases of myocardial infarction in young adults have now been attributed to Kawasaki disease that went undiagnosed during childhood. Overall, about 2% of patients die from complications of coronary vasculitis.Laboratory evidence of increased inflammation combined with demographic features (male sex, age less than six months or greater than eight years) and incomplete response to IVIG therapy create a profile of a high-risk patient with Kawasaki disease. The likelihood that an aneurysm will resolve appears to be determined in large measure by its initial size, in which the smaller aneurysms have a greater likelihood of regression. Other factors are positively associated with the regression of aneurysms, including being younger than a year old at the onset of Kawasaki disease, fusiform rather than saccular aneurysm morphology, and an aneurysm location in a distal coronary segment. The highest rate of progression to stenosis occurs among those who develop large aneurysms. The worst prognosis occurs in children with giant aneurysms. This severe outcome may require further treatment such as percutaneous transluminal angioplasty, coronary artery stenting, bypass grafting, and even cardiac transplantation.A relapse of symptoms may occur soon after initial treatment with IVIG. This usually requires rehospitalization and retreatment. Treatment with IVIG can cause allergic and nonallergic acute reactions, aseptic meningitis, fluid overload, and rarely, other serious reactions. Overall, life-threatening complications resulting from therapy for Kawasaki disease are exceedingly rare, especially compared with the risk of nontreatment. Evidence indicates Kawasaki disease produces altered lipid metabolism that persists beyond the clinical resolution of the disease.Rarely, recurrence can occur in Kawasaki disease with or without treatment. Epidemiology Kawasaki disease affects boys more than girls, with people of Asian ethnicity, particularly Japanese people. The higher incidence in Asian populations is thought to be linked to genetic susceptibility. Incidence rates vary between countries. Currently, Kawasaki disease is the most commonly diagnosed pediatric vasculitis in the world. By far, the highest incidence of Kawasaki disease occurs in Japan, with the most recent study placing the attack rate at 218.6 per 100,000 children less than five years of age (about one in 450 children). At this present attack rate, more than one in 150 children in Japan will develop Kawasaki disease during their lifetimes.However, its incidence in the United States is increasing. Kawasaki disease is predominantly a disease of young children, with 80% of patients younger than five years of age. About 2,000–4,000 cases are identified in the U.S. each year (9 to 19 per 100,000 children younger than five years of age). In the continental United States, Kawasaki disease is more common during the winter and early spring, boys with the disease outnumber girls by ≈1.5–1.7:1, and 76% of affected children are less than years of age.In the United Kingdom, prior to 2000, it was diagnosed in fewer than one in every 25,000 people per year. Incidence of the disease doubled from 1991 to 2000, however, with four cases per 100,000 children in 1991 compared with a rise of eight cases per 100,000 in 2000. By 2017, this figure had risen to 12 in 100,000 people with 419 diagnosed cases of Kawasaki disease in the United Kingdom.In Japan, the rate is 240 in every 100,000 people.Coronary artery aneurysms due to Kawasaki disease are believed to account for 5% of acute coronary syndrome cases in adults under 40 years of age. History The disease was first reported by Tomisaku Kawasaki in a four-year-old child with a rash and fever at the Red Cross Hospital in Tokyo in January 1961, and he later published a report on 50 similar cases. Later, Kawasaki and colleagues were persuaded of definite cardiac involvement when they studied and reported 23 cases, of which 11 (48%) patients had abnormalities detected by an electrocardiogram. In 1974, the first description of this disorder was published in the English-language literature. In 1976, Melish et al. described the same illness in 16 children in Hawaii. Melish and Kawasaki had independently developed the same diagnostic criteria for the disorder, which are still used today to make the diagnosis of classic Kawasaki disease. Dr. Kawasaki died on June 5, 2020, at the age of 95.A question was raised whether the disease only started during the period between 1960 and 1970, but later a preserved heart of a seven-year-old boy who died in 1870 was examined and showed three aneurysms of the coronary arteries with clots, as well as pathologic changes consistent with Kawasaki disease. Kawasaki disease is now recognized worldwide. Why cases began to emerge across all continents around the 1960s and 1970s is unclear. Possible explanations could include confusion with other diseases such as scarlet fever, and easier recognition stemming from modern healthcare factors such as the widespread use of antibiotics. In particular, old pathological descriptions from Western countries of infantile polyarteritis nodosa coincide with reports of fatal cases of Kawasaki disease.In the United States and other developed nations, Kawasaki disease appears to have replaced acute rheumatic fever as the most common cause of acquired heart disease in children. References == External links ==

Neutropenia

Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria, bacterial fragments and immunoglobulin-bound viruses in the blood. People with neutropenia are more susceptible to bacterial infections and, without prompt medical attention, the condition may become life-threatening (neutropenic sepsis).Neutropenia can be divided into congenital and acquired, with severe congenital neutropenia (SCN) and cyclic neutropenia (CyN) being autosomal dominant and mostly caused by heterozygous mutations in the ELANE gene (neutrophil elastase). Neutropenia can be acute (temporary) or chronic (long lasting). The term is sometimes used interchangeably with "leukopenia" ("deficit in the number of white blood cells").Decreased production of neutrophils is associated with deficiencies of vitamin B12 and folic acid, aplastic anemia, tumors, drugs, metabolic disease, nutritional deficiency and immune mechanisms. In general, the most common oral manifestations of neutropenia include ulcer, gingivitis, and periodontitis. Agranulocytosis can be presented as whitish or greyish necrotic ulcer in oral cavity, without any sign of inflammation. Acquired agranulocytosis is much more common than the congenital form. The common causes of acquired agranulocytosis including drugs (non-steroidal anti-inflammatory drugs, antiepileptics, antithyroid and antibiotics) and viral infection. Agranulocytosis has a mortality rate of 7–10%. To manage this, the application of granulocyte colony stimulating factor (G-CSF) or granulocyte transfusion and the use of broad-spectrum antibiotics to protect against bacterial infections are recommended. Signs and symptoms Signs and symptoms of neutropenia include fever, painful swallowing, gingival pain, skin abscesses, and otitis. These symptoms may exist because individuals with neutropenia often have infection.Children may show signs of irritability and poor feeding. Additionally, hypotension has also been observed in individuals who have this condition. Causes The causes of neutropenia can be divided between problems that are transient and those that are chronic. Causes can be divided into these groups: Severe bacterial infections, especially in people with underlying hematological diseases or alcoholism, can deplete neutrophil reserves and lead to neutropenia. Gram-positive bacteria are present in 60–70% of bacterial infections. There are serious concerns regarding antibiotic-resistant organisms. These would include as methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE).Nutritional deficiencies, such as deficiency in vitamin B12, folate, copper or protein-calorie malnutrition are associated with chronic neutropenia. However, nutritional deficiencies are usually associated with decreases in other cell lines (multiple cytopenia or pancytopenia) rather than isolated neutropenia.Other causes of congenital neutropenia are Shwachman–Diamond syndrome, Cyclic neutropenia, bone marrow failure syndromes, cartilage–hair hypoplasia, reticular dysgenesis, and Barth syndrome. Viruses that infect neutrophil progenitors can also be the cause of neutropenia. Viruses identified that have an effect on neutrophils are rubella and cytomegalovirus. Though the body can manufacture a normal level of neutrophils, in some cases the destruction of excessive numbers of neutrophils can lead to neutropenia. These are: Pathophysiology The pathophysiology of neutropenia can be divided into congenital and acquired. The congenital neutropenia (severe and cyclic type) is autosomal dominant, with mutations in the ELA2 gene (neutrophil elastase) as the most common genetic reason for this condition. Acquired neutropenia (immune-associated neutropenia) is due to anti-neutrophil antibodies that target neutrophil-specific antigens, ultimately altering neutrophil function. Furthermore, emerging research suggests neutropenia without an identifiable etiology (idiopathic neutropenia) may be the result of a low-grade, chronic inflammatory process with an abnormal excessive production of myelosuppressive cytokines in a study conducted in the island of Crete.Neutropenia fever can complicate the treatment of cancers. Observations of children noted that fungal infections are more likely to develop in those with neutropenia. Mortality increases during cancer treatments if neutropenia is also present. Congenital neutropenia is determined by blood neutrophil counts (absolute neutrophil counts or ANC) < 0.5 × 109/L and recurrent bacterial infections beginning very early in childhood. Congenital neutropenia is related to alloimmunization, sepsis, maternal hypertension, twin-to-twin transfusion syndrome, and Rh hemolytic disease. Diagnosis Neutropenia can be the result of a variety of consequences, including from certain types of drugs, environmental toxins, vitamin deficiencies, metabolic abnormalities, as well as cancer or infections. Neutropenia itself is a rare entity, but can be clinically common in oncology and immunocompromised individuals as a result of chemotherapy (drug-induced neutropenia). Additionally, acute neutropenia can be commonly seen from people recovering from a viral infection or in a post-viral state. Meanwhile, several subtypes of neutropenia exist which are rarer and chronic, including acquired (idiopathic) neutropenia, cyclic neutropenia, autoimmune neutropenia, and congenital neutropenia.Neutropenia that is developed in response to chemotherapy typically becomes evident in seven to fourteen days after treatment, this period is known as the Nadir. Conditions that indicate the presence of neutropenic fever are implanted devices; leukemia induction; the compromise of mucosal, mucociliary and cutaneous barriers; a rapid decline in absolute neutrophil count, duration of neutropenia >7–10 days, and other illnesses that exist in the patient.Signs of infection can be subtle. Fevers are a common and early observation. Sometimes overlooked is the presence of hypothermia, which can be present in sepsis. Physical examination and accessing the history and physical examination is focused on sites of infection. Indwelling line sites, areas of skin breakdown, sinuses, nasopharynx, bronchi and lungs, alimentary tract, and skin are assessed.The diagnosis of neutropenia is done via the low neutrophil count detection on a complete blood count. Generally, other investigations are required to arrive at the right diagnosis. When the diagnosis is uncertain, or serious causes are suspected, bone marrow biopsy may be necessary. A bone marrow biopsy can identify abnormalities in myelopoesis contributing to neutropenia such as the stage of arrest in the development of myeloid progenitor cells. Bone marrow biopsies can also be used to monitor the development of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in patients with chronic neutropenia (especially in those with severe congenital neutropenia (SCN) which carries a higher risk of MDS and AML)). Other investigations commonly performed: serial neutrophil counts for suspected cyclic neutropenia, tests for antineutrophil antibodies, autoantibody screen (and investigations for systemic lupus erythematosus), vitamin B12 and folate assays. Rectal examinations are usually not performed due to the increased risk of introducing bacteria into the blood stream and the possible development of rectal abscesses. Classification Generally accepted reference range for absolute neutrophil count (ANC) in adults is 1500 to 8000 cells per microliter (µl) of blood. Three general guidelines are used to classify the severity of neutropenia based on the ANC (expressed below in cells/µl): Mild neutropenia (1000 <= ANC < 1500): minimal risk of infection Moderate neutropenia (500 <= ANC < 1000): moderate risk of infection Severe neutropenia (ANC < 500): severe risk of infection.Each of these are either derived from laboratory tests or via the formula below: ANC = ( % n e u t r o p h i l s + % b a n d s ) × ( W B C ) ( 100 ) {\displaystyle (\%neutrophils+\%bands)\times (WBC) \over (100)} Treatment A fever, when combined with profound neutropenia (febrile neutropenia), is considered a medical emergency and requires broad spectrum antibiotics. An absolute neutrophil count less than 200 is also considered a medical emergency and almost always requires hospital admission and initiation of broad spectrum antibiotics with selection of specific antibiotics based on local resistance patterns.Precautions to avoid opportunistic infections in those with chronic neutropenia include maintaining proper soap and water hand hygiene, good dental hygiene and avoiding highly contaminated sources that may contain a large fungal reservoirs such as mulch, construction sites and bird or other animal waste.Neutropenia can be treated with the hematopoietic growth factor granulocyte-colony stimulating factor (G-CSF). These are cytokines that are present naturally in the body. The factors promote neutrophil recovery following anticancer therapy or in chronic neutropenia. Recombinant G-CSF factor preparations, such as filgrastim can be effective in people with congenital forms of neutropenia including severe congenital neutropenia and cyclic neutropenia; the amount needed (dosage) to stabilize the neutrophil count varies considerably (depending on the individuals condition). Guidelines for neutropenia regarding diet are currently being studied. Those who have chronic neutropenia and fail to respond to G-CSF or who have an increased risk of developing MDS or AML (due to increased dosage requirements of G-CSF or having abnormal precursor cells in the bone marrow) often require hematopoietic stem cell transplantation as a treatment.Most cases of neonatal neutropenia are temporary. Antibiotic prophylaxis is not recommended because of the possibility of encouraging the development of multidrug-resistant bacterial strains.These are cytokines that are present naturally in the body. The factors promote neutrophil recovery following anticancer therapy.The administration of intravenous immunoglobulins (IVIGs) has had some success in treating neutropenias of alloimmune and autoimmune origins with a response rate of about 50%. Blood transfusions have not been effective.Patients with neutropenia caused by cancer treatment can be given antifungal drugs. A Cochrane review found that lipid formulations of amphotericin B had fewer side effects than conventional amphotericin B, though it is not clear whether there are particular advantages over conventional amphotericin B if given under optimal circumstances. Another Cochrane review was not able to detect a difference in effect between amphotericin B and fluconazole because available trial data analysed results in a way that disfavoured amphotericin B. Trilaciclib, a CDK4/6 inhibitor, administered approximately thirty minutes before chemotherapy, has been shown in three clinical trials to significantly reduce the occurrence of chemotherapy-induced neutropenia and the associated need for interventions such as the administration of G-CSFs. The drug is currently under review by the FDA for use in small cell lung cancer with a decision expected by February 15, 2021. Prognosis If left untreated, people with fever and absolute neutrophil count <500 have a mortality of up to 70% within 24 hours. The prognosis of neutropenia depends on the cause. Antibiotic agents have improved the prognosis for individuals with severe neutropenia. Neutropenic fever in individuals treated for cancer has a mortality of 4–30%. Epidemiology Neutropenia is usually detected shortly after birth, affecting 6% to 8% of all newborns in neonatal intensive care units (NICUs). Out of the approximately 600,000 neonates annually treated in NICUs in the United States, 48,000 may be diagnosed as neutropenic. The incidence of neutropenia is greater in premature infants. Six to fifty-eight percent of preterm neonates are diagnosed with this auto-immune disease. The incidence of neutropenia correlates with decreasing birth weight. The disorder is seen up to 38% in infants that weigh less than 1000g, 13% in infants weighing less than 2500g, and 3% of term infants weighing more than 2500 g. Neutropenia is often temporary, affecting most newborns in only first few days after birth. In others, it becomes more severe and chronic indicating a deficiency in innate immunity.Furthermore, the prevalence of chronic neutropenia in the general public is rare. In a study conducted in Denmark, over 370,000 people were assessed for the presence of neutropenia. Results published demonstrated only 1% of those evaluated were neutropenic, and were commonly seen in those with HIV, viral infections, acute leukemias, and myelodysplastic syndromes. The study concluded the presence of neutropenia is an ominous sign that warrants further investigation and follow-up. See also Pancytopenia Thrombocytopenia References == External links ==

Orofacial granulomatosis

Orofacial granulomatosis (OFG) is a condition characterized by persistent enlargement of the soft tissues of the mouth, lips and the area around the mouth on the face, causing in most cases extreme pain. The mechanism of the enlargement is granulomatous inflammation. The underlying cause of the condition is not completely understood, and there is disagreement as to how it relates to Crohns disease and sarcoidosis. Signs and symptoms Signs and symptoms may include: Persistent or recurrent enlargement of the lips, causing them to protrude. If recurrent, the interval during which the lips are enlarged may be weeks or months. The enlargement can cause midline fissuring of the lip ("median cheilitis") or angular cheilitis (sores at the corner of the mouth). The swelling is non-pitting (c.f. pitting edema) and feels soft or rubbery on palpation. The mucous membrane of the lip may be erythematous (red) and granular. One or both lips may be affected. Oral ulceration (mouth ulcers) which may be aphthous like, or be more chronic and deep with raised margins. Alternatively, lesions similar to pyostomatitis vegetans may occur in OFG, but this is uncommon. "Full width" gingivitis (compare with marginal gingivitis). Gingival enlargement (swelling of the gums). Fissured tongue (grooves in the tongue). Enlargement of the mucous membrane of the mouth, which may be associated with cobblestoning and mucosal tags (similar lesions often occur on the intestinal mucosa in Crohn disease). Enlargement of the perioral and periorbital soft tissues (the tissues of the face around the mouth and the eyes). The facial skin may be dry, exfoliative (flaking) or erythematous. Cervical lymphadenopathy (enlarged lymph nodes in the neck). Facial palsy (weakness and altered sensation of the face).The enlargement of the tissues of the mouth, lips and face seen in OFG is painless. Melkersson–Rosenthal syndrome is where OFG occurs with fissured tongue and paralysis of the facial nerve. The cause of the facial paralysis is thought to be caused by the formation of granulomas in the facial nerve, which supplies the muscles of facial expression. Causes The cause of the condition is unknown. The disease is characterized by non-caseating granulomatous inflammation. That is, the granulomas do not undergo the caseating ("cheese-like") necrosis typical of the granulomas of tuberculosis. There is disagreement as to whether OFG represents an early form of Crohn disease or sarcoidosis, or whether it is a distinct, but similar clinical entity. Crohn disease can affect any part of gastrointestinal tract, from mouth to anus. When it involves the mouth alone, some authors refer to this as "oral Crohn disease", distinguishing it from OFG, and others suggest that OFG is the same condition as Crohn disease when it presents in the oral cavity. OFG may represent a delayed hypersensitivity reaction, but the causative antigen(s) is not identified or varies form one individual to the next. Suspected sources of antigens include metals, e.g. cobalt, or additives and preservatives in foods, including benzoates, benzoic acid, cinnamaldehyde, metabisulfates, butylated hydroxyanisole, dodecyl gallate, tartrazine, or menthol, Examples of foods which may contain these substances include margarine, cinnamon, eggs, chocolate or peppermint oil.Some suggest that infection with atypical mycobacteria could be involved, (paratuberculosis), and that OFG is a reaction to mycobacterial stress protein mSP65 acting as an antigen.In response to an antigen, a chronic, submucosal, T cell mediated inflammatory response occurs, which involves cytokines (e.g. tumor necrosis factor alpha), protease-activated receptors, matrix metalloproteinases and cyclooxygenases. The granulomas in OFG form in the lamina propria, and may form adjacent to or within lymphatic vessels. This is thought to cause obstruction of lymphatic drainage and lymphedema which is manifest as swelling clinically.There may be a genetic predisposition to the condition. People who develop OFG often have a history of atopy, such as childhood asthma or eczema. Diagnosis The diagnosis is usually made by tissue biopsy, however this cannot reliably distinguish between the granulomas of OFG and those of Crohn disease or sarcoidosis. Other causes of granulomatous inflammation are ruled out, such as sarcoidosis, Crohn disease, allergic or foreign body reactions and mycobacterial infections. Classification OFG could be classified as a type of cheilitis (lip inflammation), hence the alternative names for the condition using the word cheilitis, and a granulomatous condition. Treatment Anti-tumour necrosis factor α drugs (e.g. infliximab) Dietary restriction of a particular suspected or proven antigen may be involved in the management of OFG, such as cinnamon or benzoate-free diets. Epidemiology OFG is uncommon, but the incidence is increasing. The disease usually presents in adolescence or young adulthood. It may occur in either sex, but males are slightly more commonly affected. History OFG was first described in 1985. References == External links ==

Dyschromatosis universalis hereditaria

Dyschromatosis universalis hereditaria is a rare genodermatosis characterized by reticulate hyper- and hypo- pigmentated macules in a generalized distribution.: 856 Both autosomal dominant and recessive inheritance have been reported with the disorder.It has been associated with mutations in genes SASH1 and ABCB6. References External links Dyschromatosis universalis hereditaria: Two cases, Dermatology Online Journal.

Chronic progressive external ophthalmoplegia

Chronic progressive external ophthalmoplegia (CPEO) is a type of eye disorder characterized by slowly progressive inability to move the eyes and eyebrows. It is often the only feature of mitochondrial disease, in which case the term CPEO may be given as the diagnosis. In other people suffering from mitochondrial disease, CPEO occurs as part of a syndrome involving more than one part of the body, such as Kearns–Sayre syndrome. Occasionally CPEO may be caused by conditions other than mitochondrial diseases. Signs and symptoms CPEO is a rare disease that may affect those of all ages, but typically manifests in the young adult years. CPEO is the most common manifestation of mitochondrial myopathy, occurring in an estimated two-thirds of all cases of mitochondrial myopathy. Patients typically present with ptosis (drooping eyelids). Other diseases like Graves disease, myasthenia gravis and glioma that may cause an external ophthalmoplegia must be ruled out. CPEO itself CPEO is a slowly progressing disease. It may begin at any age and progresses over a period of 5–15 years. The first presenting symptom of ptosis is often unnoticed by the patient until the lids droop to the point of producing a visual field defect. Often, patients will tilt the head backwards to adjust for the slowly progressing ptosis of the lids. In addition, as the ptosis becomes complete, the patients will use the frontalis (forehead) muscle to help elevate the lids. The ptosis is typically bilateral but may be unilateral for a period of months to years before the fellow lid becomes involved.Ophthalmoplegia (the inability or difficulty to move the eye) is usually symmetrical, therefore, patients are not affected by diplopia (double vision). The progressive ophthalmoplegia is often unnoticed till decreased ocular motility limits peripheral vision. Often someone else will point out the ocular disturbance to the patient. Patients will move their heads to adjust for the loss of peripheral vision caused by inability to abduct or adduct the eye. All directions of gaze are affected; however, downward gaze appears to be best spared. This is in contrast to progressive supranuclear palsy (PSP), which typically affects vertical gaze and spares horizontal gaze.Mitochondrial retinopathy has been described in CPEO which presents with a spectrum of distinct retinal phenotypes. This includes mild, focal pigmentary abnormalities on funduscopy and widespread granular pigmented fundus alterations. Mild, asymptomatic retinopathy might be underreported; severe retinopathy may be associated with significant vision loss. Occurring alongside CPEO Weakness of extraocular muscle groups including, the orbicularis oculi muscle as well as facial and limb muscles may be present in up to 25% of patients with CPEO. As a result of the orbicularis oculi weakness, patients may suffer from exposure keratopathy (damage to cornea) from the inability to close the eyes tightly. Frontalis muscle weakness may exacerbate the ptotic lids with the inability to compensate for the ptosis. Facial muscles may be involved which lead to atrophy of facial muscle groups producing a thin, expressionless face with some having difficulty with chewing. Neck, shoulder and extremity weakness with atrophy may affect some patients and can be mild or severe.Mild visual impairment was seen in 95% of patients that were evaluated using the Visual Function Index (VF-14).The ciliary muscles that control the lens shape and the iris muscles are often unaffected by CPEO.Additional symptoms are variable, and may include exercise intolerance, cataracts, hearing loss, sensory axonal neuropathy, ataxia, clinical depression, hypogonadism, and parkinsonism.Kearns–Sayre syndrome is characterized by onset before 15 years of age of CPEO, heart block and pigmentary retinopathy. Genetics Mitochondrial DNA which is transmitted from the mother, encodes proteins that are critical to the respiratory chain required to produce adenosine triphosphate (ATP). Deletions or mutations to segments of mtDNA lead to defective function of oxidative phosphorylation. This may be made evident in highly oxidative tissues like skeletal muscle and heart tissue. However, extraocular muscles contain a volume of mitochondria that is several times greater than any other muscle group. As such, this results in the preferential ocular symptoms of CPEO.Multiple mtDNA abnormalities exist which cause CPEO. One mutation is located in a conserved region of mitochondrial tRNA at nucleotide 3243 in which there is an A to G nucleotide transition. This mutation is associated with both CPEO and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). A common deletion found in one-third of CPEO patients is a 4,977 base pair segment found between a 13 base pair repeat.The mtDNA that is affected maybe a single or multiple point deletion, with associated nuclear DNA deletions. One study showed that mtDNA deletion seen in CPEO patients also had an associated nuclear DNA deletion of the Twinkle gene which encodes specific mitochondrial protein; Twinkle.Whether a tissue is affected is correlated with the amount of oxidative demands in relation to the amount of mtDNA deletion.In most cases, PEO occurs due to a sporadic deletion or duplication within the mitochondrial DNA. However, transmission from the mother to the progeny appears only in few cases. Both autosomal dominant and autosomal recessive inheritance can occur, autosomal recessive inheritance being more severe. Dominant and recessive forms of PEO can be caused by genetic mutations in the ANT1, POLG, POLG2 and PEO1 genes. Diagnosis It is important to differentiate CPEO from other pathologies that may cause an ophthalmoplegia. There are specific therapies used for these pathologies.CPEO is diagnosed via muscle biopsy. On examination of muscle fibers stained with Gömöri trichrome stain, one can see an accumulation of enlarged mitochondria. This produces a dark red staining of the muscle fibers given the name "ragged red fibers". While ragged red fibers are seen in normal aging, amounts in excess of normal aging give a diagnosis of a mitochondrial myopathy. Polymerase chain reaction (PCR) from a sample of blood or muscle tissue can determine a mutation of the mtDNA.Elevated acetylcholine receptor antibody level which is typically seen in myasthenia gravis has been seen in certain patients of mitochondrial associated ophthalmoplegia. It is important to have a dilated eye exam to determine if there is pigmentary retinopathy that may signify Kearns–Sayre syndrome which is associated with cardiac abnormalities.MRI may be helpful in the diagnosis, in one study volumes of medial rectus, lateral rectus, and inferior rectus muscles in CPEO were not smaller than normal (in contrast to the profound atrophy typical of neurogenic paralysis). Although volumes of the superior rectus muscle-levator complex and superior oblique were significantly reduced. Treatment There is currently no defined treatment to ameliorate the muscle weakness of CPEO. Treatments used to treat other pathologies causing ophthalmoplegia has not been shown to be effective. Experimental treatment with tetracycline has been used to improve ocular motility in one patient. Coenzyme Q10 has also been used to treat this condition. However, most neuro-ophthalmologists do not ascribe to any treatment.Ptosis associated with CPEO may be corrected with surgery to raise the lids, however due to weakness of the orbicularis oculi muscles, care must be taken not to raise the lids in excess causing an inability to close the lids. This results in an exposure keratopathy. Therefore, rarely should lid surgery be performed and only by a neuro-ophthalmologist familiar with the disease.The most common strabismus finding is large angle exotropia which can be treated by maximal bilateral eye surgery, but due to the progressive nature of the disease, strabismus may recur. Those that have diplopia as a result of asymmetric ophthalmoplegia may be corrected with prisms or with surgery to create a better alignment of the eyes. See also Ophthalmoparesis References Further reading https://web.archive.org/web/20060925130130/http://journals.tubitak.gov.tr/medical/issues/sag-04-34-3/sag-34-3-9-0401-8.pdf == External links ==

Pericarditis

Pericarditis is inflammation of the pericardium, the fibrous sac surrounding the heart. Symptoms typically include sudden onset of sharp chest pain, which may also be felt in the shoulders, neck, or back. The pain is typically less severe when sitting up and more severe when lying down or breathing deeply. Other symptoms of pericarditis can include fever, weakness, palpitations, and shortness of breath. The onset of symptoms can occasionally be gradual rather than sudden.The cause of pericarditis often remains unknown but is believed to be most often due to a viral infection. Other causes include bacterial infections such as tuberculosis, uremic pericarditis, heart attack, cancer, autoimmune disorders, and chest trauma. Diagnosis is based on the presence of chest pain, a pericardial rub, specific electrocardiogram (ECG) changes, and fluid around the heart. A heart attack may produce similar symptoms to pericarditis.Treatment in most cases is with NSAIDs and possibly the anti-inflammatory medication colchicine. Steroids may be used if these are not appropriate. Symptoms usually improve in a few days to weeks but can occasionally last months. Complications can include cardiac tamponade, myocarditis, and constrictive pericarditis. Pericarditis is an uncommon cause of chest pain. About 3 per 10,000 people are affected per year. Those most commonly affected are males between the ages of 20 and 50. Up to 30% of those affected have more than one episode. Signs and symptoms Substernal or left precordial pleuritic chest pain with radiation to the trapezius ridge (the bottom portion of scapula on the back) is the characteristic pain of pericarditis. The pain is usually relieved by sitting up or bending forward, and worsened by lying down (both recumbent and supine positions) or by inspiration (taking a breath in). The pain may resemble that of angina but differs in that pericarditis pain changes with body position, where heart attack pain is generally constant and pressure-like. Other symptoms of pericarditis may include dry cough, fever, fatigue, and anxiety.Due to its similarity to the pain of myocardial infarction (heart attack), pericarditis can be misdiagnosed as a heart attack. Acute myocardial infarction can also cause pericarditis, but the presenting symptoms often differ enough to warrant diagnosis. The following table organizes the clinical presentation of pericarditis differential to myocardial infarction: Physical examinations The classic sign of pericarditis is a friction rub heard with a stethoscope on the cardiovascular examination, usually on the lower left sternal border. Other physical signs include a person in distress, positional chest pain, diaphoresis (excessive sweating); possibility of heart failure in form of pericardial tamponade causing pulsus paradoxus, and the Becks triad of low blood pressure (due to decreased cardiac output), distant (muffled) heart sounds, and distension of the jugular vein (JVD). Complications Pericarditis can progress to pericardial effusion and eventually cardiac tamponade. This can be seen in people who are experiencing the classic signs of pericarditis but then show signs of relief, and progress to show signs of cardiac tamponade which include decreased alertness and lethargy, pulsus paradoxus (decrease of at least 10 mmHg of the systolic blood pressure upon inspiration), low blood pressure (due to decreased cardiac index), (jugular vein distention from right sided heart failure and fluid overload), distant heart sounds on auscultation, and equilibration of all the diastolic blood pressures on cardiac catheterization due to the constriction of the pericardium by the fluid.In such cases of cardiac tamponade, EKG or Holter monitor will then depict electrical alternans indicating wobbling of the heart in the fluid filled pericardium, and the capillary refill might decrease, as well as severe vascular collapse and altered mental status due to hypoperfusion of body organs by a heart that can not pump out blood effectively.The diagnosis of tamponade can be confirmed with trans-thoracic echocardiography (TTE), which should show a large pericardial effusion and diastolic collapse of the right ventricle and right atrium. Chest X-ray usually shows an enlarged cardiac silhouette ("water bottle" appearance) and clear lungs. Pulmonary congestion is typically not seen because equalization of diastolic pressures constrains the pulmonary capillary wedge pressure to the intra-pericardial pressure (and all other diastolic pressures). Causes Infectious Pericarditis may be caused by viral, bacterial, or fungal infection. In the developed world, viruses are believed to be the cause of about 85% of cases. In the developing world tuberculosis is a common cause but it is rare in the developed world. Viral causes include coxsackievirus, herpesvirus, mumps virus, and HIV among others.Pneumococcus or tuberculous pericarditis are the most common bacterial forms. Anaerobic bacteria can also be a rare cause. Fungal pericarditis is usually due to histoplasmosis, or in immunocompromised hosts Aspergillus, Candida, and Coccidioides. The most common cause of pericarditis worldwide is infectious pericarditis with tuberculosis. Other Idiopathic: No identifiable cause found after routine testing. Autoimmune disease: systemic lupus erythematosus, rheumatic fever, IgG4-related disease Myocardial infarction Dresslers syndrome) Peri-Myocardial Infarction Pericarditis Trauma to the heart Uremia (uremic pericarditis) Cancer Side effect of some medications, e.g. isoniazid, cyclosporine, hydralazine, warfarin, and heparin Radiation induced Aortic dissection Postpericardiotomy syndrome—such as after CABG surgery Vaccines-such as smallpox and Covid-19 Vaccines in rare yet documented instances. Diagnosis Laboratory test Laboratory values can show increased urea (BUN), or increased blood creatinine in cases of uremic pericarditis. Generally, however, laboratory values are normal, but if there is a concurrent myocardial infarction (heart attack) or great stress to the heart, laboratory values may show increased cardiac markers like Troponin (I, T), CK-MB, Myoglobin, and LDH1 (lactase dehydrogenase isotype 1).The preferred initial diagnostic testing is the ECG, which may demonstrate a 12-lead electrocardiogram with diffuse, non-specific, concave ("saddle-shaped"), ST-segment elevations in all leads except aVR and V1 and PR-segment depression possible in any lead except aVR; sinus tachycardia, and low-voltage QRS complexes can also be seen if there is subsymptomatic levels of pericardial effusion. The PR depression is often seen early in the process as the thin atria are affected more easily than the ventricles by the inflammatory process of the pericardium.Since the mid-19th century, retrospective diagnosis of pericarditis has been made upon the finding of adhesions of the pericardium.When pericarditis is diagnosed clinically, the underlying cause is often never known; it may be discovered in only 16–22 percent of people with acute pericarditis. Imaging On MRI T2-weighted spin-echo images, inflamed pericardium will show high signal intensity. Late gadolinium contrast will show uptake of contrast by the inflamed pericardium. Normal pericardium will not show any contrast enhancement. Classification Pericarditis can be classified according to the composition of the fluid that accumulates around the heart.Types of pericarditis include the following: serous purulent fibrinous caseous hemorrhagic Acute vs. chronic Depending on the time of presentation and duration, pericarditis is divided into "acute" and "chronic" forms. Acute pericarditis is more common than chronic pericarditis, and can occur as a complication of infections, immunologic conditions, or even as a result of a heart attack (myocardial infarction), as Dresslers syndrome. Chronic pericarditis however is less common, a form of which is constrictive pericarditis. The following is the clinical classification of acute vs. chronic: Clinically: Acute (<6 weeks), Subacute (6 weeks to 6 months) and Chronic (>6 months) Treatment The treatment in viral or idiopathic pericarditis is with aspirin, or non-steroidal anti-inflammatory drugs (NSAIDs such as ibuprofen). Colchicine may be added to the above as it decreases the risk of further episodes of pericarditis.Severe cases may require one or more of the following: antibiotics to treat tuberculosis or other bacterial causes steroids are used in acute pericarditis but are not favored because they increase the chance of recurrent pericarditis pericardiocentesis to treat a large pericardial effusion causing tamponadeRecurrent pericarditis resistant to colchicine and anti-inflammatory steroids may benefit from a number of medicines that affect the action of interleukin 1; they cannot be taken in tablet form. These are anakinra, canakinumab and rilonacept. Rilonacept has been specifically approved as an orphan drug for use in this situation. Azathioprine has also been used.Surgical removal of the pericardium, pericardiectomy, may be used in severe cases and where the pericarditis is causing constriction, impairing cardiac function. It is less effective if the pericarditis is a consequence of trauma, in elderly patients, and if the procedure is done incompletely. It carries a risk of death between 5 and 10%. Epidemiology About 30% of people with viral pericarditis or pericarditis of an unknown cause have one or several recurrent episodes. See also Myopericarditis Viral cardiomyopathy References External links Pericarditis — National Library of Medicine Pericarditis — National Heart Lung Blood Institute

Synovial chondromatosis

Synovial chondromatosis is a locally aggressive bone tumor of the cartilaginous type. It consists of several hyaline cartilaginous nodules and has the potential of becoming cancerous. Signs and symptoms People usually complain of pain in one joint, which persists for months, or even years, does not ease with exercise, steroid injection or heat treatment, shows nothing on X-ray, but shows a definite restriction of movement. There are 3 defined stages to this disease: early: no loose bodies but active synovial disease; transitional: active synovial disease, and loose bodies; late: loose bodies but no synovial disease;In the early stages of the disease it is often confused with tendinitis and/or arthritis. Once it reaches transitional the loose bodies become apparent with X-ray in greater than 70% of cases, with MRI often showing where xray fails. In experienced hands, ultrasound is also useful for the diagnosis.Rare and little known, with currently no known cure, the disease gradually forms blisters in the thin flexible membrane of the synovium, which calcify and enlarge. These nodules eventually break free and float around the joint space becoming larger – these add to the discomfort and stiffness of the joint. The affected tissue will show up as a semi-solid mass in an MRI scan, final diagnosis is usually confirmed by taking a biopsy. The disease generally affects only one of the larger weight bearing joints (hip, ankle, knee) – although the elbow, and wrist can also be affected. It rarely involves the temporomandibular joint (TMJ) and most publications are case reports.Synovial chondromatosis occurs twice as commonly in males as females and usually in their forties. However, online communities for synovial chondromatosis patients have yielded a stark contrast, with equal representation from both genders and members diagnosed as young as late teenage/early 20s. Familial synovial chondromatosis with dwarfism introduces characteristics of dwarfism. Cause The exact underlying cause of synovial chondromatosis is unknown. Some evidence suggests trauma may play a role in its development as it mainly presents in weight-bearing joints. Infection has also been considered as a contributing factor. The condition is not inherited.Synovial chondromatosis can reportedly occur as either a primary or secondary form. Primary synovial chondromatosis, which is more rare, occurs spontaneously and does not appear to relate to any pre-existing conditions. Secondary synovial chondromatosis is the more common form and often occurs when there is pre-existent osteoarthritis, rheumatoid arthritis, osteonecrosis, osteochondritis dissecans, neuropathic osteoarthropathy (which often occurs in diabetic individuals), tuberculosis, or osteochondral fractures (torn cartilage covering the end of a bone in a joint) in the affected individual. Diagnosis Diagnosis is by medical imaging; X-ray, CT scan and MRI. For diagnosis of the TMJ, Cone beam computed tomography (CBCT) can also be useful. Treatment Treatment is frequently by means of removal of the loose bodies and of a partial or full synovectomy (removal of the synovium) Full synovectomy is a moderately major operation and involves completely exposing the joint and removing the affected tissue. Partial synovectomy is normally done arthroscopically. Synovectomies are normally carried out by shaving the lining of the knee but there are other ways of achieving this by either freezing the synovium or by the use of radiation treatment. The need for further procedures is greater than 25% although normally the frequency of the required removal of loose bodies is reduced by the previous synovectomy. There have been documented cases of malignant transformation however this is rare. Whilst the condition can be described as a ‘benign growth’ it seldom affects more than one joint, and does not usually affect surrounding tissue. Names It is also known as Reichels syndrome or Reichel-Jones-Henderson syndrome, named after Friedrich Paul Reichel, Hugh Toland Jones and Melvin Starkey Henderson. References External links Patient story at The Washington Post

Lacunar stroke

Lacunar stroke or lacunar cerebral infarct (LACI) is the most common type of ischemic stroke, resulting from the occlusion of small penetrating arteries that provide blood to the brains deep structures. Patients who present with symptoms of a lacunar stroke, but who have not yet had diagnostic imaging performed, may be described as having lacunar stroke syndrome (LACS). Much of the current knowledge of lacunar strokes comes from C. Miller Fishers cadaver dissections of post-mortem stroke patients. He observed "lacunae" (empty spaces) in the deep brain structures after occlusion of 200–800 μm penetrating arteries and connected them with five classic syndromes. These syndromes are still noted today, though lacunar infarcts are diagnosed based on clinical judgment and radiologic imaging. Signs and symptoms Each of the five classical lacunar syndromes has a relatively distinct symptom complex. Symptoms may occur suddenly, progressively, or in a fluctuating (e.g., the capsular warning syndrome) manner. Occasionally, cortical infarcts and intracranial hemorrhages can mimic lacunar infarcts, but true cortical signs (aphasia, visuospatial neglect, gaze deviation, and visual field defects) are always absent in lacunar strokes. The classic syndromes are as follows: Silent lacunar infarction A silent lacunar infarction (SLI) is one type of silent stroke which usually shows no identifiable outward symptoms, and is thus termed "silent." Because stroke is a clinical diagnosis (that is, it is defined by clinical symptoms), there is debate about whether SLI are considered to be strokes, even though the pathophysiology is presumably the same. Individuals who have a SLI are often completely unaware they have had a stroke. This type of stroke often causes lesions in the surrounding brain tissue that are visibly detected via neuroimaging techniques such as MRI and computed axial tomography (CT scan). Silent strokes, including silent lacunar infarctions, have been shown to be much more common than previously thought, with an estimated prevalence rate of eleven million per year in the United States. Approximately 10% of these silent strokes are silent lacunar infarctions. While dubbed "silent" due to the immediate lack of classic stroke symptoms, SLIs can cause damage to the surrounding brain tissue and can affect various aspects of a persons mood, personality, and cognitive functioning. A SLI or any type of silent stroke places an individual at greater risk for future major stroke. Pathophysiology According to Koffler et al., lacunes are derived from an "occlusion of a single deep penetrating artery that arises directly from the constituents of the circle of Willis, cerebellar arteries, and basilar artery". Other lesions that are associated with lacunes appear in the "deep nuclei of the brain (37% putamen, 14% thalamus, and 10% caudate) as well as the pons (16%) or the posterior limb of the internal capsule (10%)". These lesions are less common within other brain regions such as the cerebellum, cerebral white matter and anterior limb of the internal capsule.The two proposed mechanisms are microatheroma and lipohyalinosis. At the beginning, lipohyalinosis was thought to be the main small vessel pathology, but microatheroma now is thought to be the most common mechanism of arterial occlusion (or stenosis). Occasionally, atheroma in the parent artery blocks the orifice of the penetrating artery (luminal atheroma), or atheroma involves the origin of the penetrating artery (junctional atheroma). Alternatively, hypoperfusion is believed to be the mechanism when there is stenosis of the penetrating artery. When no evidence of small vessel disease is found on histologic examination, an embolic cause is assumed, either artery-to-artery embolism or cardioembolism. In one recent series, 25% of patients with clinical radiologically defined lacunes had a potential cardiac cause for their strokes. More recent advances have also suggested these mechanisms may play a combined role in the aetiology of lacunar infarction. The most current theory indicates endothelial dysfunction and increased permeability of the blood-brain barrier first allow leakage of blood contents, promoting gliosis and white matter hyper-intensities on magnetic resonance imaging. Moreover, focal narrowing of brain vessels and impairment of their ability to dilate in response to various stimuli may lead to a decreased cerebral blood flow and ultimately lacunar stroke.Advanced age, chronic hypertension, smoking and diabetes mellitus are risk factors. It is unclear whether there is an association with alcohol consumption, elevated cholesterol, or history of prior stroke. Lacunar strokes may result from carotid artery pathology or microemboli from the heart as in atrial fibrillation. Patients often recover well, but if there is enough white matter disease from lacunar pathology, one can see a subcortical dementia such as Binswanger disease. Treatment and prognosis Typically, tissue plasminogen activator may be administered within 3 to 4.5 hours of stroke onset if the patient is without contraindications (i.e. a bleeding diathesis such as recent major surgery or cancer with brain metastases). High dose aspirin can be given within 48 hours. For long term prevention of recurrence, medical regimens are typically aimed towards correcting the underlying risk factors for lacunar infarcts such as hypertension, diabetes mellitus and cigarette smoking. Anticoagulants such as heparin and warfarin have shown no benefit over aspirin with regards to five-year survival.Patients who have lacunar strokes have a greater chance of surviving beyond thirty days (96%) than those with other types of stroke (85%), and better survival beyond a year (87% versus 65-70%). Between 70% and 80% are functionally independent at 1 year, compared with fewer than 50% otherwise.Occupational therapy and physical therapy interventions are used in the rehabilitation of lacunar stroke. A physiotherapy program will improve joint range of motion of the paretic limb using passive range of motion exercises. When increases in activity are tolerated, and stability improvements are made, patients will progress from rolling to side-lying, to standing (with progressions to prone, quadruped, bridging, long-sitting and kneeling for example) and learn to transfer safely (from their bed to a chair or from a wheel chair to a car for example). Assistance and ambulation aids are used as required as the patient begins walking and lessened as function increases. Furthermore, splints and braces can be used to support limbs and joints to prevent or treat complications such as contractures and spasticity. The rehabilitation healthcare team should also educate the patient and their family on common stroke symptoms and how to manage an onset of stroke. Continuing follow-up with a physician is essential so that the physician may monitor medication dosage and risk factors. Epidemiology It is estimated that lacunar infarcts account for 25% of all ischemic strokes, with an annual incidence of approximately 15 per 100,000 people. They may be more frequent in men and in people of African, Mexican, and Hong Kong Chinese descent. References == External links ==

Toxic epidermal necrolysis

Toxic epidermal necrolysis (TEN) is a type of severe skin reaction. Together with Stevens–Johnson syndrome (SJS) it forms a spectrum of disease, with TEN being more severe. Early symptoms include fever and flu-like symptoms. A few days later the skin begins to blister and peel forming painful raw areas. Mucous membranes, such as the mouth, are also typically involved. Complications include dehydration, sepsis, pneumonia, and multiple organ failure.The most common cause is certain medications such as lamotrigine, carbamazepine, allopurinol, sulfonamide antibiotics, and nevirapine. Other causes can include infections such as Mycoplasma pneumoniae and cytomegalovirus or the cause may remain unknown. Risk factors include HIV/AIDS and systemic lupus erythematosus. Diagnosis is based on a skin biopsy and involvement of more than 30% of the skin. TEN is a type of severe cutaneous adverse reactions (SCARs), together with SJS, a SJS/TEN, and drug reaction with eosinophilia and systemic symptoms. It is called SJS when less than 10% of the skin is involved and an intermediate form with 10 to 30% involvement. Erythema multiforme (EM) is generally considered a separate condition.Treatment typically takes place in hospital such as in a burn unit or intensive care unit. Efforts include stopping the cause, pain medication, and antihistamines. Antibiotics, intravenous immunoglobulins, and corticosteroids may also be used. Treatments do not typically change the course of the underlying disease. Together with SJS it affects 1 to 2 persons per million per year. It is more common in females than males. Typical onset is over the age of 40. Skin usually regrows over two to three weeks; however, recovery can take months and most are left with chronic problems. Signs and symptoms Prodrome TEN ultimately results in extensive skin involvement with redness, necrosis, and detachment of the top (epidermal) layer of the skin and mucosa. Before these severe findings develop, people often have a flu-like prodrome, with a cough, runny nose, fever, decreased appetite and malaise. A history of drug exposure exists on average 14 days (ranging from 1–4 weeks) prior to the onset of symptoms, but may result as early as 48 hours if it is a reexposure. Skin findings Initial skin findings include red-purple, dusky, flat spots known as macules that start on the trunk and spread out from there. These skin lesions then transform into large blisters. The affected skin can then become necrotic or sag from the body and peel off in great swaths. Mucosal findings Nearly all people with TEN have oral, eye and genital involvement as well. Painful crusts and erosions may develop on any mucosal surface. The mouth becomes blistered and eroded, making eating difficult and sometimes necessitating feeding through a nasogastric tube through the nose or a gastric tube directly into the stomach. The eyes can become swollen, crusted, and ulcerated, leading to potential blindness. The most common problem with the eyes is severe conjunctivitis. Complications Those who survive the acute phase of TEN often develop long-term complications affecting the skin and eyes. Skin manifestations can include scarring, eruptive melanocytic nevi, vulvovaginal stenosis, and dyspareunia. The epithelium of the trachea, bronchi, or gastrointestinal tract may be involved in SJS and TEN. Ocular symptoms are the most common complication in TEN, experienced by 20–79% of those with TEN, even by those who do not experience immediate ocular manifestations. These can include dry eyes, photophobia, symblepharon, corneal scarring or xerosis, subconjunctival fibrosis, trichiasis, decreased visual acuity, and blindness. Cause Drug reactions have been reported to cause 80–95% of TEN cases.The drugs most often implicated in TEN are: antibiotics sulfonamides (sulfamethoxazole, sulfadiazine, sulfapyridine) beta-lactams (cephalosporins, penicillins, carbapenems) nonsteroidal anti-inflammatory drugs allopurinol antimetabolites (methotrexate) antiretroviral drugs (nevirapine) corticosteroids anxiolytics (chlormezanone) anticonvulsants (phenobarbital, phenytoin, carbamazepine, lamotrigine, and valproic acid).TEN has also been reported to result from infection with Mycoplasma pneumoniae or dengue virus. Contrast agents used in imaging studies as well as transplantation of bone marrow or organs have also been linked to TEN development. HIV HIV-positive individuals have 1000 times the risk of developing SJS/TEN compared to the general population. The reason for this increased risk is not clear. Genetics Certain genetic factors are associated with increased risk of TEN. For example, certain HLA-types such as, HLA-B*1502, HLA-A*3101, HLA-B*5801, and HLA‐B*57:01 have been seen to be linked with TEN development when exposed to specific drugs. Pathogenesis The immune systems role in the precise pathogenesis of TEN remains unclear. It appears that a certain type of immune cell (cytotoxic CD8+ T cell) is primarily responsible for keratinocyte death and subsequent skin detachment. Keratinocytes are the cells found lower in the epidermis and specialize in holding the surrounding skin cells together. It is theorized that CD8+ immune cells become overactive by stimulation from drugs or drug metabolites. CD8+ T cells then mediate keratinocyte cell death through release of a number of molecules, including perforin, granzyme B, and granulysin. Other agents, including tumor necrosis factor alpha and Fas ligand, also appear to be involved in TEN pathogenesis. Diagnosis The diagnosis of TEN is based on both clinical and histologic findings. Early TEN can resemble non-specific drug reactions, so clinicians should maintain a high index of suspicion for TEN. The presence of oral, ocular, and/or genital mucositis is helpful diagnostically, as these findings are present in nearly all patients with TEN. The Nikolsky sign (a separation of the papillary dermis from the basal layer upon gentle lateral pressure) and the Asboe-Hansen sign (a lateral extension of bullae with pressure) are also helpful diagnostic signs found in patients with TEN.Given the significant morbidity and mortality from TEN, as well as improvement in outcome from prompt treatment, there is significant interest in the discovery of serum biomarkers for early diagnosis of TEN. Serum granulysin and serum high-mobility group protein B1 (HMGB1) are among a few of the markers being investigated which have shown promise in early research. Histology Definitive diagnosis of TEN often requires biopsy confirmation. Histologically, early TEN shows scattered necrotic keratinocytes. In more advanced TEN, full thickness epidermal necrosis is visualized, with a subepidermal split, and scant inflammatory infiltrate in the papillary dermis. Epidermal necrosis found on histology is a sensitive but nonspecific finding for TEN. Differential diagnosis Staphylococcal scalded skin syndrome Drug-induced linear immunoglobulin A dermatosis Acute graft versus host disease Acute generalized exanthematous pustulosis Erythroderma Drug reaction with eosinophilia and systemic symptoms aka DRESS A generalized morbilliform eruption Treatment The primary treatment of TEN is discontinuation of the causative factor(s), usually an offending drug, early referral and management in burn units or intensive care units, supportive management, and nutritional support.Current literature does not convincingly support use of any adjuvant systemic therapy. Initial interest in Intravenous immunoglobulin (IVIG) came from research showing that IVIG could inhibit Fas-FasL mediated keratinocyte apoptosis in vitro. Unfortunately, research studies reveal conflicting support for use of IVIG in treatment of TEN. Ability to draw more generalized conclusions from research to date has been limited by lack of controlled trials, and inconsistency in study design in terms of disease severity, IVIG dose, and timing of IVIG administration. Larger, high quality trials are needed to assess the actual benefit of IVIG in TEN. Numerous other adjuvant therapies have been tried in TEN including, corticosteroids, ciclosporin, cyclophosphamide, plasmapheresis, pentoxifylline, acetylcysteine, ulinastatin, infliximab, and granulocyte colony-stimulating factors (if TEN associated-leukopenia exists). There is mixed evidence for use of corticosteroids and scant evidence for the other therapies. A meta-analysis from 2002 concluded that there is no reliable evidence for the treatment of TEN. Thalidomide did not show any benefit and was associated with increased mortality compared with placebo. Prognosis The mortality for toxic epidermal necrolysis is 25–30%. People with SJS or TEN caused by a medication have a better prognosis the earlier the causative medication is withdrawn. Loss of the skin leaves patients vulnerable to infections from fungi and bacteria, and can result in sepsis, the leading cause of death in the disease. Death is caused either by infection or by respiratory distress which is either due to pneumonia or damage to the linings of the airway. Microscopic analysis of tissue (especially the degree of dermal mononuclear inflammation and the degree of inflammation in general) can play a role in determining the prognosis of individual cases. Severity score The "Severity of Illness Score for Toxic Epidermal Necrolysis" (SCORTEN) is a scoring system developed to assess the severity of TEN and predict mortality in patients with acute TEN.One point is given for each of the following factors: age >40 heart rate >120 beats/minute carrying diagnosis of cancer separation of epidermis on more than ten percent of body surface area (BSA) on day 1. Blood Urea Nitrogen >28 mg/dL Glucose >252 mg/dL (14 mmol/L) Bicarbonate <20mEq/L Score 0–1: 3.2% mortality 2: 12.2% mortality 3: 35.3% mortality 4: 58.3% mortality ≥5: 90% mortalityOf note, this scoring system is most valuable when used on the first and third day of hospitalization, and it may underestimate mortality in patients with respiratory symptoms. References External links 18-203e. at Merck Manual of Diagnosis and Therapy Home Edition DermNetNZ

Pneumonia

Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severity of the condition is variable.Pneumonia is usually caused by infection with viruses or bacteria, and less commonly by other microorganisms. Identifying the responsible pathogen can be difficult. Diagnosis is often based on symptoms and physical examination. Chest X-rays, blood tests, and culture of the sputum may help confirm the diagnosis. The disease may be classified by where it was acquired, such as community- or hospital-acquired or healthcare-associated pneumonia.Risk factors for pneumonia include cystic fibrosis, chronic obstructive pulmonary disease (COPD), sickle cell disease, asthma, diabetes, heart failure, a history of smoking, a poor ability to cough (such as following a stroke), and a weak immune system.Vaccines to prevent certain types of pneumonia (such as those caused by Streptococcus pneumoniae bacteria, linked to influenza, or linked to COVID-19) are available. Other methods of prevention include hand washing to prevent infection, not smoking, and social distancing.Treatment depends on the underlying cause. Pneumonia believed to be due to bacteria is treated with antibiotics. If the pneumonia is severe, the affected person is generally hospitalized. Oxygen therapy may be used if oxygen levels are low.Each year, pneumonia affects about 450 million people globally (7% of the population) and results in about 4 million deaths. With the introduction of antibiotics and vaccines in the 20th century, survival has greatly improved. Nevertheless, pneumonia remains a leading cause of death in developing countries, and also among the very old, the very young, and the chronically ill. Pneumonia often shortens the period of suffering among those already close to death and has thus been called "the old mans friend". Signs and symptoms People with infectious pneumonia often have a productive cough, fever accompanied by shaking chills, shortness of breath, sharp or stabbing chest pain during deep breaths, and an increased rate of breathing. In elderly people, confusion may be the most prominent sign.The typical signs and symptoms in children under five are fever, cough, and fast or difficult breathing. Fever is not very specific, as it occurs in many other common illnesses and may be absent in those with severe disease, malnutrition or in the elderly. In addition, a cough is frequently absent in children less than 2 months old. More severe signs and symptoms in children may include blue-tinged skin, unwillingness to drink, convulsions, ongoing vomiting, extremes of temperature, or a decreased level of consciousness.Bacterial and viral cases of pneumonia usually result in similar symptoms. Some causes are associated with classic, but non-specific, clinical characteristics. Pneumonia caused by Legionella may occur with abdominal pain, diarrhea, or confusion. Pneumonia caused by Streptococcus pneumoniae is associated with rusty colored sputum. Pneumonia caused by Klebsiella may have bloody sputum often described as "currant jelly". Bloody sputum (known as hemoptysis) may also occur with tuberculosis, Gram-negative pneumonia, lung abscesses and more commonly acute bronchitis. Pneumonia caused by Mycoplasma pneumoniae may occur in association with swelling of the lymph nodes in the neck, joint pain, or a middle ear infection. Viral pneumonia presents more commonly with wheezing than bacterial pneumonia. Pneumonia was historically divided into "typical" and "atypical" based on the belief that the presentation predicted the underlying cause. However, evidence has not supported this distinction, therefore it is no longer emphasized. Cause Pneumonia is due to infections caused primarily by bacteria or viruses and less commonly by fungi and parasites. Although more than 100 strains of infectious agents have been identified, only a few are responsible for the majority of cases. Mixed infections with both viruses and bacteria may occur in roughly 45% of infections in children and 15% of infections in adults. A causative agent may not be isolated in about half of cases despite careful testing. In an active population-based surveillance for community-acquired pneumonia requiring hospitalization in five hospitals in Chicago and Nashville from January 2010 through June 2012, 2259 patients were identified who had radiographic evidence of pneumonia and specimens that could be tested for the responsible pathogen. Most patients (62%) had no detectable pathogens in their sample, and unexpectedly, respiratory viruses were detected more frequently than bacteria. Specifically, 23% had one or more viruses, 11% had one or more bacteria, 3% had both bacterial and viral pathogens, and 1% had a fungal or mycobacterial infection. "The most common pathogens were human rhinovirus (in 9% of patients), influenza virus (in 6%), and Streptococcus pneumoniae (in 5%)."The term pneumonia is sometimes more broadly applied to any condition resulting in inflammation of the lungs (caused for example by autoimmune diseases, chemical burns or drug reactions); however, this inflammation is more accurately referred to as pneumonitis.Factors that predispose to pneumonia include smoking, immunodeficiency, alcoholism, chronic obstructive pulmonary disease, sickle cell disease (SCD), asthma, chronic kidney disease, liver disease, and biological aging. Additional risks in children include not being breastfed, exposure to cigarette smoke and other air pollution, malnutrition, and poverty. The use of acid-suppressing medications – such as proton-pump inhibitors or H2 blockers – is associated with an increased risk of pneumonia. Approximately 10% of people who require mechanical ventilation develop ventilator-associated pneumonia, and people with a gastric feeding tube have an increased risk of developing aspiration pneumonia. For people with certain variants of the FER gene, the risk of death is reduced in sepsis caused by pneumonia. However, for those with TLR6 variants, the risk of getting Legionnaires disease is increased. Bacteria Bacteria are the most common cause of community-acquired pneumonia (CAP), with Streptococcus pneumoniae isolated in nearly 50% of cases. Other commonly isolated bacteria include Haemophilus influenzae in 20%, Chlamydophila pneumoniae in 13%, and Mycoplasma pneumoniae in 3% of cases; Staphylococcus aureus; Moraxella catarrhalis; and Legionella pneumophila. A number of drug-resistant versions of the above infections are becoming more common, including drug-resistant Streptococcus pneumoniae (DRSP) and methicillin-resistant Staphylococcus aureus (MRSA).The spreading of organisms is facilitated by certain risk factors. Alcoholism is associated with Streptococcus pneumoniae, anaerobic organisms, and Mycobacterium tuberculosis; smoking facilitates the effects of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Legionella pneumophila. Exposure to birds is associated with Chlamydia psittaci; farm animals with Coxiella burnetti; aspiration of stomach contents with anaerobic organisms; and cystic fibrosis with Pseudomonas aeruginosa and Staphylococcus aureus. Streptococcus pneumoniae is more common in the winter, and it should be suspected in persons aspirating a large number of anaerobic organisms. Viruses In adults, viruses account for about one third of pneumonia cases, and in children for about 15% of them. Commonly implicated agents include rhinoviruses, coronaviruses, influenza virus, respiratory syncytial virus (RSV), adenovirus, and parainfluenza. Herpes simplex virus rarely causes pneumonia, except in groups such as newborns, persons with cancer, transplant recipients, and people with significant burns. After organ transplantation or in otherwise immunocompromised persons, there are high rates of cytomegalovirus pneumonia. Those with viral infections may be secondarily infected with the bacteria Streptococcus pneumoniae, Staphylococcus aureus, or Haemophilus influenzae, particularly when other health problems are present. Different viruses predominate at different times of the year; during flu season, for example, influenza may account for more than half of all viral cases. Outbreaks of other viruses also occur occasionally, including hantaviruses and coronaviruses. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can also result in pneumonia. Fungi Fungal pneumonia is uncommon, but occurs more commonly in individuals with weakened immune systems due to AIDS, immunosuppressive drugs, or other medical problems. It is most often caused by Histoplasma capsulatum, Blastomyces, Cryptococcus neoformans, Pneumocystis jiroveci (pneumocystis pneumonia, or PCP), and Coccidioides immitis. Histoplasmosis is most common in the Mississippi River basin, and coccidioidomycosis is most common in the Southwestern United States. The number of cases of fungal pneumonia has been increasing in the latter half of the 20th century due to increasing travel and rates of immunosuppression in the population. For people infected with HIV/AIDS, PCP is a common opportunistic infection. Parasites A variety of parasites can affect the lungs, including Toxoplasma gondii, Strongyloides stercoralis, Ascaris lumbricoides, and Plasmodium malariae. These organisms typically enter the body through direct contact with the skin, ingestion, or via an insect vector. Except for Paragonimus westermani, most parasites do not specifically affect the lungs but involve the lungs secondarily to other sites. Some parasites, in particular those belonging to the Ascaris and Strongyloides genera, stimulate a strong eosinophilic reaction, which may result in eosinophilic pneumonia. In other infections, such as malaria, lung involvement is due primarily to cytokine-induced systemic inflammation. In the developed world, these infections are most common in people returning from travel or in immigrants. Around the world, parasitic pneumonia is most common in the immunodeficient. Noninfectious Idiopathic interstitial pneumonia or noninfectious pneumonia is a class of diffuse lung diseases. They include diffuse alveolar damage, organizing pneumonia, nonspecific interstitial pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis interstitial lung disease, and usual interstitial pneumonia. Lipoid pneumonia is another rare cause due to lipids entering the lung. These lipids can either be inhaled or spread to the lungs from elsewhere in the body. Mechanisms Pneumonia frequently starts as an upper respiratory tract infection that moves into the lower respiratory tract. It is a type of pneumonitis (lung inflammation). The normal flora of the upper airway give protection by competing with pathogens for nutrients. In the lower airways, reflexes of the glottis, actions of complement proteins and immunoglobulins are important for protection. Microaspiration of contaminated secretions can infect the lower airways and cause pneumonia. The progress of pneumonia is determined by the virulence of the organism; the amount of organism required to start an infection; and the bodys immune response against the infection. Bacterial Most bacteria enter the lungs via small aspirations of organisms residing in the throat or nose. Half of normal people have these small aspirations during sleep. While the throat always contains bacteria, potentially infectious ones reside there only at certain times and under certain conditions. A minority of types of bacteria such as Mycobacterium tuberculosis and Legionella pneumophila reach the lungs via contaminated airborne droplets. Bacteria can also spread via the blood. Once in the lungs, bacteria may invade the spaces between cells and between alveoli, where the macrophages and neutrophils (defensive white blood cells) attempt to inactivate the bacteria. The neutrophils also release cytokines, causing a general activation of the immune system. This leads to the fever, chills, and fatigue common in bacterial pneumonia. The neutrophils, bacteria, and fluid from surrounding blood vessels fill the alveoli, resulting in the consolidation seen on chest X-ray. Viral Viruses may reach the lung by a number of different routes. Respiratory syncytial virus is typically contracted when people touch contaminated objects and then touch their eyes or nose. Other viral infections occur when contaminated airborne droplets are inhaled through the nose or mouth. Once in the upper airway, the viruses may make their way into the lungs, where they invade the cells lining the airways, alveoli, or lung parenchyma. Some viruses such as measles and herpes simplex may reach the lungs via the blood. The invasion of the lungs may lead to varying degrees of cell death. When the immune system responds to the infection, even more lung damage may occur. Primarily white blood cells, mainly mononuclear cells, generate the inflammation. As well as damaging the lungs, many viruses simultaneously affect other organs and thus disrupt other body functions. Viruses also make the body more susceptible to bacterial infections; in this way, bacterial pneumonia can occur at the same time as viral pneumonia. Diagnosis Pneumonia is typically diagnosed based on a combination of physical signs and often a chest X-ray. In adults with normal vital signs and a normal lung examination, the diagnosis is unlikely. However, the underlying cause can be difficult to confirm, as there is no definitive test able to distinguish between bacterial and non-bacterial cause. The overall impression of a physician appears to be at least as good as decision rules for making or excluding the diagnosis. Diagnosis in children The World Health Organization has defined pneumonia in children clinically based on either a cough or difficulty breathing and a rapid respiratory rate, chest indrawing, or a decreased level of consciousness. A rapid respiratory rate is defined as greater than 60 breaths per minute in children under 2 months old, greater than 50 breaths per minute in children 2 months to 1 year old, or greater than 40 breaths per minute in children 1 to 5 years old.In children, low oxygen levels and lower chest indrawing are more sensitive than hearing chest crackles with a stethoscope or increased respiratory rate. Grunting and nasal flaring may be other useful signs in children less than five years old.Lack of wheezing is an indicator of Mycoplasma pneumoniae in children with pneumonia, but as an indicator it is not accurate enough to decide whether or not macrolide treatment should be used. The presence of chest pain in children with pneumonia doubles the probability of Mycoplasma pneumoniae. Diagnosis in adults In general, in adults, investigations are not needed in mild cases. There is a very low risk of pneumonia if all vital signs and auscultation are normal. C-reactive protein (CRP) may help support the diagnosis. For those with CRP less than 20 mg/L without convincing evidence of pneumonia, antibiotics are not recommended.Procalcitonin may help determine the cause and support decisions about who should receive antibiotics. Antibiotics are encouraged if the procalcitonin level reaches 0.25 μg/L, strongly encouraged if it reaches 0.5 μg/L, and strongly discouraged if the level is below 0.10 μg/L. In people requiring hospitalization, pulse oximetry, chest radiography and blood tests – including a complete blood count, serum electrolytes, C-reactive protein level, and possibly liver function tests – are recommended.The diagnosis of influenza-like illness can be made based on the signs and symptoms; however, confirmation of an influenza infection requires testing. Thus, treatment is frequently based on the presence of influenza in the community or a rapid influenza test. Physical exam Physical examination may sometimes reveal low blood pressure, high heart rate, or low oxygen saturation. The respiratory rate may be faster than normal, and this may occur a day or two before other signs. Examination of the chest may be normal, but it may show decreased expansion on the affected side. Harsh breath sounds from the larger airways that are transmitted through the inflamed lung are termed bronchial breathing and are heard on auscultation with a stethoscope. Crackles (rales) may be heard over the affected area during inspiration. Percussion may be dulled over the affected lung, and increased, rather than decreased, vocal resonance distinguishes pneumonia from a pleural effusion. Imaging A chest radiograph is frequently used in diagnosis. In people with mild disease, imaging is needed only in those with potential complications, those not having improved with treatment, or those in which the cause is uncertain. If a person is sufficiently sick to require hospitalization, a chest radiograph is recommended. Findings do not always match the severity of disease and do not reliably separate between bacterial and viral infection.X-ray presentations of pneumonia may be classified as lobar pneumonia, bronchopneumonia, lobular pneumonia, and interstitial pneumonia. Bacterial, community-acquired pneumonia classically show lung consolidation of one lung segmental lobe, which is known as lobar pneumonia. However, findings may vary, and other patterns are common in other types of pneumonia. Aspiration pneumonia may present with bilateral opacities primarily in the bases of the lungs and on the right side. Radiographs of viral pneumonia may appear normal, appear hyper-inflated, have bilateral patchy areas, or present similar to bacterial pneumonia with lobar consolidation. Radiologic findings may not be present in the early stages of the disease, especially in the presence of dehydration, or may be difficult to interpret in the obese or those with a history of lung disease. Complications such as pleural effusion may also be found on chest radiographs. Laterolateral chest radiographs can increase the diagnostic accuracy of lung consolidation and pleural effusion.A CT scan can give additional information in indeterminate cases. CT scans can also provide more details in those with an unclear chest radiograph (for example occult pneumonia in chronic obstructive pulmonary disease) and can exclude pulmonary embolism and fungal pneumonia and detect lung abscess in those who are not responding to treatments. However, CT scans are more expensive, have a higher dose of radiation, and cannot be done at bedside.Lung ultrasound may also be useful in helping to make the diagnosis. Ultrasound is radiation free and can be done at bedside. However, ultrasound requires specific skills to operate the machine and interpret the findings. It may be more accurate than chest X-ray. Microbiology In people managed in the community, determining the causative agent is not cost-effective and typically does not alter management. For people who do not respond to treatment, sputum culture should be considered, and culture for Mycobacterium tuberculosis should be carried out in persons with a chronic productive cough. Microbiological evaluation is also indicated in severe pneumonia, alcoholism, asplenia, immunosuppression, HIV infection, and those being empirically treated for MRSA of pseudomonas. Although positive blood culture and pleural fluid culture definitively establish the diagnosis of the type of micro-organism involved, a positive sputum culture has to be interpreted with care for the possibility of colonisation of respiratory tract. Testing for other specific organisms may be recommended during outbreaks, for public health reasons. In those hospitalized for severe disease, both sputum and blood cultures are recommended, as well as testing the urine for antigens to Legionella and Streptococcus. Viral infections, can be confirmed via detection of either the virus or its antigens with culture or polymerase chain reaction (PCR), among other techniques. Mycoplasma, Legionella, Streptococcus, and Chlamydia can also be detected using PCR techniques on bronchoalveolar lavage and nasopharyngeal swab. The causative agent is determined in only 15% of cases with routine microbiological tests. Classification Pneumonitis refers to lung inflammation; pneumonia refers to pneumonitis, usually due to infection but sometimes non-infectious, that has the additional feature of pulmonary consolidation. Pneumonia is most commonly classified by where or how it was acquired: community-acquired, aspiration, healthcare-associated, hospital-acquired, and ventilator-associated pneumonia. It may also be classified by the area of the lung affected: lobar pneumonia, bronchial pneumonia and acute interstitial pneumonia; or by the causative organism. Pneumonia in children may additionally be classified based on signs and symptoms as non-severe, severe, or very severe.The setting in which pneumonia develops is important to treatment, as it correlates to which pathogens are likely suspects, which mechanisms are likely, which antibiotics are likely to work or fail, and which complications can be expected based on the persons health status. Community Community-acquired pneumonia (CAP) is acquired in the community, outside of health care facilities. Compared with healthcare-associated pneumonia, it is less likely to involve multidrug-resistant bacteria. Although the latter are no longer rare in CAP, they are still less likely. Healthcare Health care–associated pneumonia (HCAP) is an infection associated with recent exposure to the health care system, including hospitals, outpatient clinics, nursing homes, dialysis centers, chemotherapy treatment, or home care. HCAP is sometimes called MCAP (medical care–associated pneumonia). People may become infected with pneumonia in a hospital; this is defined as pneumonia not present at the time of admission (symptoms must start at least 48 hours after admission). It is likely to involve hospital-acquired infections, with higher risk of multidrug-resistant pathogens. People in a hospital often have other medical conditions, which may make them more susceptible to pathogens in the hospital. Ventilator-associated pneumonia occurs in people breathing with the help of mechanical ventilation. Ventilator-associated pneumonia is specifically defined as pneumonia that arises more than 48 to 72 hours after endotracheal intubation. Differential diagnosis Several diseases can present with similar signs and symptoms to pneumonia, such as: chronic obstructive pulmonary disease, asthma, pulmonary edema, bronchiectasis, lung cancer, and pulmonary emboli. Unlike pneumonia, asthma and COPD typically present with wheezing, pulmonary edema presents with an abnormal electrocardiogram, cancer and bronchiectasis present with a cough of longer duration, and pulmonary emboli present with acute onset sharp chest pain and shortness of breath. Mild pneumonia should be differentiated from upper respiratory tract infection (URTI). Severe pneumonia should be differentiated from acute heart failure. Pulmonary infiltrates that resolved after giving mechanical ventilation should point to heart failure and atelectasis rather than pneumonia. For recurrent pneumonia, underlying lung cancer, metastasis, tuberculosis, a foreign bodies, immunosuppression, and hypersensitivity should be suspected. Prevention Prevention includes vaccination, environmental measures, and appropriate treatment of other health problems. It is believed that, if appropriate preventive measures were instituted globally, mortality among children could be reduced by 400,000; and, if proper treatment were universally available, childhood deaths could be decreased by another 600,000. Vaccination Vaccination prevents against certain bacterial and viral pneumonias both in children and adults. Influenza vaccines are modestly effective at preventing symptoms of influenza, The Center for Disease Control and Prevention (CDC) recommends yearly influenza vaccination for every person 6 months and older. Immunizing health care workers decreases the risk of viral pneumonia among their patients.Vaccinations against Haemophilus influenzae and Streptococcus pneumoniae have good evidence to support their use. There is strong evidence for vaccinating children under the age of 2 against Streptococcus pneumoniae (pneumococcal conjugate vaccine). Vaccinating children against Streptococcus pneumoniae has led to a decreased rate of these infections in adults, because many adults acquire infections from children. A Streptococcus pneumoniae vaccine is available for adults, and has been found to decrease the risk of invasive pneumococcal disease by 74%, but there is insufficient evidence to suggest using the pneumococcal vaccine to prevent pneumonia or death in the general adult population. The CDC recommends that young children and adults over the age of 65 receive the pneumococcal vaccine, as well as older children or younger adults who have an increased risk of getting pneumococcal disease. The pneumococcal vaccine has been shown to reduce the risk of community acquired pneumonia in people with chronic obstructive pulmonary disease, but does not reduce mortality or the risk of hospitalization for people with this condition. People with COPD are recommended by a number of guidelines to have a pneumococcal vaccination. Other vaccines for which there is support for a protective effect against pneumonia include pertussis, varicella, and measles. Medications When influenza outbreaks occur, medications such as amantadine or rimantadine may help prevent the condition, but they are associated with side effects. Zanamivir or oseltamivir decrease the chance that people who are exposed to the virus will develop symptoms; however, it is recommended that potential side effects are taken into account. Other Smoking cessation and reducing indoor air pollution, such as that from cooking indoors with wood, crop residues or dung, are both recommended. Smoking appears to be the single biggest risk factor for pneumococcal pneumonia in otherwise-healthy adults. Hand hygiene and coughing into ones sleeve may also be effective preventative measures. Wearing surgical masks by the sick may also prevent illness.Appropriately treating underlying illnesses (such as HIV/AIDS, diabetes mellitus, and malnutrition) can decrease the risk of pneumonia. In children less than 6 months of age, exclusive breast feeding reduces both the risk and severity of disease. In people with HIV/AIDS and a CD4 count of less than 200 cells/uL the antibiotic trimethoprim/sulfamethoxazole decreases the risk of Pneumocystis pneumonia and is also useful for prevention in those that are immunocompromised but do not have HIV.Testing pregnant women for Group B Streptococcus and Chlamydia trachomatis, and administering antibiotic treatment, if needed, reduces rates of pneumonia in infants; preventive measures for HIV transmission from mother to child may also be efficient. Suctioning the mouth and throat of infants with meconium-stained amniotic fluid has not been found to reduce the rate of aspiration pneumonia and may cause potential harm, thus this practice is not recommended in the majority of situations. In the frail elderly good oral health care may lower the risk of aspiration pneumonia. Zinc supplementation in children 2 months to five years old appears to reduce rates of pneumonia.For people with low levels of vitamin C in their diet or blood, taking vitamin C supplements may be suggested to decrease the risk of pneumonia, although there is no strong evidence of benefit. There is insufficient evidence to recommend that the general population take vitamin C to prevent or treat pneumonia.For adults and children in the hospital who require a respirator, there is no strong evidence indicating a difference between heat and moisture exchangers and heated humidifiers for preventing pneumonia. There is no good evidence that one approach to mouth care is better than others in preventing nursing home acquired pneumonia. There is tentative evidence that laying flat on the back compared to semi-raised increases pneumonia risks in people who are intubated. Management Antibiotics by mouth, rest, simple analgesics, and fluids usually suffice for complete resolution. However, those with other medical conditions, the elderly, or those with significant trouble breathing may require more advanced care. If the symptoms worsen, the pneumonia does not improve with home treatment, or complications occur, hospitalization may be required. Worldwide, approximately 7–13% of cases in children result in hospitalization, whereas in the developed world between 22 and 42% of adults with community-acquired pneumonia are admitted. The CURB-65 score is useful for determining the need for admission in adults. If the score is 0 or 1, people can typically be managed at home; if it is 2, a short hospital stay or close follow-up is needed; if it is 3–5, hospitalization is recommended. In children those with respiratory distress or oxygen saturations of less than 90% should be hospitalized. The utility of chest physiotherapy in pneumonia has not yet been determined. Over-the-counter cough medicine has not been found to be effective, nor has the use of zinc in children. There is insufficient evidence for mucolytics. There is no strong evidence to recommend that children who have non-measles related pneumonia take vitamin A supplements. Vitamin D, as of 2018 is of unclear benefit in children.Pneumonia can cause severe illness in a number of ways, and pneumonia with evidence of organ dysfunction may require intensive care unit admission for observation and specific treatment. The main impact is on the respiratory and the circulatory system. Respiratory failure not responding to normal oxygen therapy may require heated humidified high-flow therapy delivered through nasal cannulae, non-invasive ventilation, or in severe cases invasive ventilation through an endotracheal tube. Regarding circulatory problems as part of sepsis, evidence of poor blood flow or low blood pressure is initially treated with 30 ml/kg of crystalloid infused intravenously. In situations where fluids alone are ineffective, vasopressor medication may be required.For adults with moderate or severe acute respiratory distress syndrome (ARDS) undergoing mechanical ventilation, there is a reduction in mortality when people lay on their front for at least 12 hours a day. However, this increases the risk of endotracheal tube obstruction and pressure sores. Bacterial Antibiotics improve outcomes in those with bacterial pneumonia. The first dose of antibiotics should be given as soon as possible. Increased use of antibiotics, however, may lead to the development of antimicrobial resistant strains of bacteria. Antibiotic choice depends initially on the characteristics of the person affected, such as age, underlying health, and the location the infection was acquired. Antibiotic use is also associated with side effects such as nausea, diarrhea, dizziness, taste distortion, or headaches. In the UK, treatment before culture results with amoxicillin is recommended as the first line for community-acquired pneumonia, with doxycycline or clarithromycin as alternatives. In North America, amoxicillin, doxycycline, and in some areas a macrolide (such as azithromycin or erythromycin) is the first-line outpatient treatment in adults. In children with mild or moderate symptoms, amoxicillin taken by mouth is the first line. The use of fluoroquinolones in uncomplicated cases is discouraged due to concerns about side-effects and generating resistance in light of there being no greater benefit.For those who require hospitalization and caught their pneumonia in the community the use of a β-lactam such as cephazolin plus macrolide such as azithromycin is recommended. A fluoroquinolone may replace azithromycin but is less preferred. Antibiotics by mouth and by injection appear to be similarly effective in children with severe pneumonia.The duration of treatment has traditionally been seven to ten days, but increasing evidence suggests that shorter courses (3–5 days) may be effective for certain types of pneumonia and may reduce the risk of antibiotic resistance. Research in children showed that a shorter, 3-day course of amoxicillin was as effective as a longer, 7-day course for treating pneumonia in this population. For pneumonia that is associated with a ventilator caused by non-fermenting Gram-negative bacilli (NF-GNB), a shorter course of antibiotics increases the risk that the pneumonia will return. Recommendations for hospital-acquired pneumonia include third- and fourth-generation cephalosporins, carbapenems, fluoroquinolones, aminoglycosides, and vancomycin. These antibiotics are often given intravenously and used in combination. In those treated in hospital, more than 90% improve with the initial antibiotics. For people with ventilator-acquired pneumonia, the choice of antibiotic therapy will depend on the persons risk of being infected with a strain of bacteria that is multi-drug resistant. Once clinically stable, intravenous antibiotics should be switched to oral antibiotics. For those with Methicillin resistant Staphylococcus aureus (MRSA) or Legionella infections, prolonged antibiotics may be beneficial.The addition of corticosteroids to standard antibiotic treatment appears to improve outcomes, reducing death and morbidity for adults with severe community acquired pneumonia, and reducing death for adults and children with non-severe community acquired pneumonia. A 2017 review therefore recommended them in adults with severe community acquired pneumonia. A 2019 guideline however recommended against their general use, unless refractory shock was present. Side effects associated with the use of corticosteroids include high blood sugar. There is some evidence that adding corticosteroids to the standard PCP pneumonia treatment may be beneficial for people who are infected with HIV.The use of granulocyte colony stimulating factor (G-CSF) along with antibiotics does not appear to reduce mortality and routine use for treating pneumonia is not supported by evidence. Viral Neuraminidase inhibitors may be used to treat viral pneumonia caused by influenza viruses (influenza A and influenza B). No specific antiviral medications are recommended for other types of community acquired viral pneumonias including SARS coronavirus, adenovirus, hantavirus, and parainfluenza virus. Influenza A may be treated with rimantadine or amantadine, while influenza A or B may be treated with oseltamivir, zanamivir or peramivir. These are of most benefit if they are started within 48 hours of the onset of symptoms. Many strains of H5N1 influenza A, also known as avian influenza or "bird flu", have shown resistance to rimantadine and amantadine. The use of antibiotics in viral pneumonia is recommended by some experts, as it is impossible to rule out a complicating bacterial infection. The British Thoracic Society recommends that antibiotics be withheld in those with mild disease. The use of corticosteroids is controversial. Aspiration In general, aspiration pneumonitis is treated conservatively with antibiotics indicated only for aspiration pneumonia. The choice of antibiotic will depend on several factors, including the suspected causative organism and whether pneumonia was acquired in the community or developed in a hospital setting. Common options include clindamycin, a combination of a beta-lactam antibiotic and metronidazole, or an aminoglycoside.Corticosteroids are sometimes used in aspiration pneumonia, but there is limited evidence to support their effectiveness. Follow-up The British Thoracic Society recommends that a follow-up chest radiograph be taken in people with persistent symptoms, smokers, and people older than 50. American guidelines vary, from generally recommending a follow-up chest radiograph to not mentioning any follow-up. Prognosis With treatment, most types of bacterial pneumonia will stabilize in 3–6 days. It often takes a few weeks before most symptoms resolve. X-ray findings typically clear within four weeks and mortality is low (less than 1%). In the elderly or people with other lung problems, recovery may take more than 12 weeks. In persons requiring hospitalization, mortality may be as high as 10%, and in those requiring intensive care it may reach 30–50%. Pneumonia is the most common hospital-acquired infection that causes death. Before the advent of antibiotics, mortality was typically 30% in those that were hospitalized. However, for those whose lung condition deteriorates within 72 hours, the problem is usually due to sepsis. If pneumonia deteriorates after 72 hours, it could be due to nosocomial infection or excerbation of other underlying comorbidities. About 10% of those discharged from hospital are readmitted due to underlying co-morbidities such as heart, lung, or neurological disorders, or due to new onset of pneumonia.Complications may occur in particular in the elderly and those with underlying health problems. This may include, among others: empyema, lung abscess, bronchiolitis obliterans, acute respiratory distress syndrome, sepsis, and worsening of underlying health problems. Clinical prediction rules Clinical prediction rules have been developed to more objectively predict outcomes of pneumonia. These rules are often used to decide whether to hospitalize the person. Pneumonia severity index (or PSI Score) CURB-65 score, which takes into account the severity of symptoms, any underlying diseases, and age Pleural effusion, empyema, and abscess In pneumonia, a collection of fluid may form in the space that surrounds the lung. Occasionally, microorganisms will infect this fluid, causing an empyema. To distinguish an empyema from the more common simple parapneumonic effusion, the fluid may be collected with a needle (thoracentesis), and examined. If this shows evidence of empyema, complete drainage of the fluid is necessary, often requiring a drainage catheter. In severe cases of empyema, surgery may be needed. If the infected fluid is not drained, the infection may persist, because antibiotics do not penetrate well into the pleural cavity. If the fluid is sterile, it must be drained only if it is causing symptoms or remains unresolved.In rare circumstances, bacteria in the lung will form a pocket of infected fluid called a lung abscess. Lung abscesses can usually be seen with a chest X-ray but frequently require a chest CT scan to confirm the diagnosis. Abscesses typically occur in aspiration pneumonia, and often contain several types of bacteria. Long-term antibiotics are usually adequate to treat a lung abscess, but sometimes the abscess must be drained by a surgeon or radiologist. Respiratory and circulatory failure Pneumonia can cause respiratory failure by triggering acute respiratory distress syndrome (ARDS), which results from a combination of infection and inflammatory response. The lungs quickly fill with fluid and become stiff. This stiffness, combined with severe difficulties extracting oxygen due to the alveolar fluid, may require long periods of mechanical ventilation for survival. Other causes of circulatory failure are hypoxemia, inflammation, and increased coagulability.Sepsis is a potential complication of pneumonia but usually occurs in people with poor immunity or hyposplenism. The organisms most commonly involved are Streptococcus pneumoniae, Haemophilus influenzae, and Klebsiella pneumoniae. Other causes of the symptoms should be considered such as a myocardial infarction or a pulmonary embolism. Epidemiology Pneumonia is a common illness affecting approximately 450 million people a year and occurring in all parts of the world. It is a major cause of death among all age groups resulting in 4 million deaths (7% of the worlds total death) yearly. Rates are greatest in children less than five, and adults older than 75 years. It occurs about five times more frequently in the developing world than in the developed world. Viral pneumonia accounts for about 200 million cases. In the United States, as of 2009, pneumonia is the 8th leading cause of death. Children In 2008, pneumonia occurred in approximately 156 million children (151 million in the developing world and 5 million in the developed world). In 2010, it resulted in 1.3 million deaths, or 18% of all deaths in those under five years, of which 95% occurred in the developing world. Countries with the greatest burden of disease include India (43 million), China (21 million) and Pakistan (10 million). It is the leading cause of death among children in low income countries. Many of these deaths occur in the newborn period. The World Health Organization estimates that one in three newborn infant deaths is due to pneumonia. Approximately half of these deaths can be prevented, as they are caused by the bacteria for which an effective vaccine is available. In 2011, pneumonia was the most common reason for admission to the hospital after an emergency department visit in the U.S. for infants and children. History Pneumonia has been a common disease throughout human history. The word is from Greek πνεύμων (pneúmōn) meaning "lung". The symptoms were described by Hippocrates (c. 460–370 BC): "Peripneumonia, and pleuritic affections, are to be thus observed: If the fever be acute, and if there be pains on either side, or in both, and if expiration be if cough be present, and the sputa expectorated be of a blond or livid color, or likewise thin, frothy, and florid, or having any other character different from the common... When pneumonia is at its height, the case is beyond remedy if he is not purged, and it is bad if he has dyspnoea, and urine that is thin and acrid, and if sweats come out about the neck and head, for such sweats are bad, as proceeding from the suffocation, rales, and the violence of the disease which is obtaining the upper hand." However, Hippocrates referred to pneumonia as a disease "named by the ancients". He also reported the results of surgical drainage of empyemas. Maimonides (1135–1204 AD) observed: "The basic symptoms that occur in pneumonia and that are never lacking are as follows: acute fever, sticking pleuritic pain in the side, short rapid breaths, serrated pulse and cough." This clinical description is quite similar to those found in modern textbooks, and it reflected the extent of medical knowledge through the Middle Ages into the 19th century. Edwin Klebs was the first to observe bacteria in the airways of persons having died of pneumonia in 1875. Initial work identifying the two common bacterial causes, Streptococcus pneumoniae and Klebsiella pneumoniae, was performed by Carl Friedländer and Albert Fraenkel in 1882 and 1884, respectively. Friedländers initial work introduced the Gram stain, a fundamental laboratory test still used today to identify and categorize bacteria. Christian Grams paper describing the procedure in 1884 helped to differentiate the two bacteria, and showed that pneumonia could be caused by more than one microorganism. In 1887, Jaccond demonstrated pneumonia may be caused by opportunistic bacteria always present in the lung.Sir William Osler, known as "the father of modern medicine", appreciated the death and disability caused by pneumonia, describing it as the "captain of the men of death" in 1918, as it had overtaken tuberculosis as one of the leading causes of death in this time. This phrase was originally coined by John Bunyan in reference to "consumption" (tuberculosis). Osler also described pneumonia as "the old mans friend" as death was often quick and painless when there were much slower and more painful ways to die.Viral pneumonia was first described by Hobart Reimann in 1938. Reimann, Chairman of the Department of Medicine at Jefferson Medical College, had established the practice of routinely typing the pneumococcal organism in cases where pneumonia presented. Out of this work, the distinction between viral and bacterial strains was noticed.Several developments in the 1900s improved the outcome for those with pneumonia. With the advent of penicillin and other antibiotics, modern surgical techniques, and intensive care in the 20th century, mortality from pneumonia, which had approached 30%, dropped precipitously in the developed world. Vaccination of infants against Haemophilus influenzae type B began in 1988 and led to a dramatic decline in cases shortly thereafter. Vaccination against Streptococcus pneumoniae in adults began in 1977, and in children in 2000, resulting in a similar decline. Society and culture Awareness Due to the relatively low awareness of the disease, 12 November was declared as the annual World Pneumonia Day, a day for concerned citizens and policy makers to take action against the disease, in 2009. Costs The global economic cost of community-acquired pneumonia has been estimated at $17 billion annually. Other estimates are considerably higher. In 2012 the estimated aggregate costs of treating pneumonia in the United States were $20 billion; the median cost of a single pneumonia-related hospitalization is over $15,000. According to data released by the Centers for Medicare and Medicaid Services, average 2012 hospital charges for inpatient treatment of uncomplicated pneumonia in the U.S. were $24,549 and ranged as high as $124,000. The average cost of an emergency room consult for pneumonia was $943 and the average cost for medication was $66. Aggregate annual costs of treating pneumonia in Europe have been estimated at €10 billion. References Footnotes Citations Bibliography == External links ==

Sowda

Sowda is a cutaneous condition, a localized type of onchocerciasis.: 440  This is mostly seen in patients with the disease from Yemen, Saudi Arabia, East and West Africa See also Skin lesion == References ==

Leukoplakia

Oral leukoplakia is a potentially malignant disorder affecting the oral mucosa. It is defined as "essentially an oral mucosal white lesion that cannot be considered as any other definable lesion." Oral leukoplakia is a white patch or plaque that develops in the oral cavity and is strongly associated with smoking. Leukoplakia is a firmly attached white patch on a mucous membrane which is associated with increased risk of cancer. The edges of the lesion are typically abrupt and the lesion changes with time. Advanced forms may develop red patches. There are generally no other symptoms. It usually occurs within the mouth, although sometimes mucosa in other parts of the gastrointestinal tract, urinary tract, or genitals may be affected.The cause of leukoplakia is unknown. Risk factors for formation inside the mouth include smoking, chewing tobacco, excessive alcohol, and use of betel nuts. One specific type is common in HIV/AIDS. It is a precancerous lesion, a tissue alteration in which cancer is more likely to develop. The chance of cancer formation depends on the type, with between 3–15% of localized leukoplakia and 70–100% of proliferative leukoplakia developing into squamous cell carcinoma.Leukoplakia is a descriptive term that should only be applied after other possible causes are ruled out. Tissue biopsy generally shows increased keratin build up with or without abnormal cells, but is not diagnostic. Other conditions that can appear similar include yeast infections, lichen planus, and keratosis due to repeated minor trauma. The lesions from a yeast infection can typically be rubbed off while those of leukoplakia cannot.Treatment recommendations depend on features of the lesion. If abnormal cells are present or the lesion is small surgical removal is often recommended; otherwise close follow up at three to six month intervals may be sufficient. People are generally advised to stop smoking and limit the drinking of alcohol. In potentially half of cases leukoplakia will shrink with stopping smoking; however, if smoking is continued up to 66% of cases will become more white and thick. The percentage of people affected is estimated at 1–3%. Leukoplakia becomes more common with age, typically not occurring until after 30. Rates may be as high as 8% in men over the age of 70. Classification Leukoplakia could be classified as mucosal disease, and also as a premalignant condition. Although the white color in leukoplakia is a result of hyperkeratosis (or acanthosis), similarly appearing white lesions that are caused by reactive keratosis (smokers keratosis or frictional keratoses e.g. morsicatio buccarum) are not considered to be leukoplakias. Leukoplakia could also be considered according to the affected site, e.g. oral leukoplakia, leukoplakia of the urinary tract, including bladder leukoplakia or leukoplakia of the penis, vulvae, cervix or vagina. Leukoplakia may also occur in the larynx, possibly in association with gastro-esophageal reflux disease. Oropharyngeal leukoplakia is linked to the development of esophageal squamous cell carcinoma, and sometimes this is associated with tylosis, which is thickening of the skin on the palms and soles of the feet (see: Leukoplakia with tylosis and esophageal carcinoma). Dyskeratosis congenita may be associated with leukoplakia of the oral mucosa and of the anal mucosa. Mouth Within the mouth, leukoplakia is sometimes further classified according to the site involved, e.g. leukoplakia buccalis (leukoplakia of the buccal mucosa) or leukoplakia lingualis (leukoplakia of the lingual mucosa). There are two main clinical variants of oral leukoplakia, namely homogeneous leukoplakia and non-homogeneous (heterogenous) leukoplakia, which are described below. The word leukoplakia is also included within the nomenclature of other oral conditions which present as white patches, however, these are specific diagnoses that are generally considered separate from leukoplakia, with the notable exception of proliferative verrucous leukoplakia, which is a recognized sub-type of leukoplakia. Homogeneous leukoplakia Homogeneous leukoplakia (also termed "thick leukoplakia") is usually well defined white patch of uniform, flat appearance and texture, although there may be superficial irregularities. Homogeneous leukoplakia is usually slightly elevated compared to surrounding mucosa, and often has a fissured, wrinkled or corrugated surface texture, with the texture generally consistent throughout the whole lesion. This term has no implications on the size of the lesion, which may be localized or extensive. When homogeneous leukoplakia is palpated, it may feel leathery, dry, or like cracked mud. Non-homogeneous leukoplakia Non-homogeneous leukoplakia is a lesion of non-uniform appearance. The color may be predominantly white or a mixed white and red. The surface texture is irregular compared to homogeneous leukoplakia, and may be flat (papular), nodular or exophytic. "Verrucous leukoplakia" (or "verruciform leukoplakia") is a descriptive term used for thick, white, papillary lesions. Verrucous leukoplakias are usually heavily keratinized and are often seen in elderly people. Some verrucous leukoplakias may have an exophytic growth pattern, and some may slowly invade surrounding mucosa, when the term proliferative verrucous leukoplakia may be used. Non-homogeneous leukoplakias have a greater risk of cancerous changes than homogeneous leukoplakias. Proliferative verrucous leukoplakia Proliferative verrucous leukoplakia (PVL) is a recognized high risk subtype of non-homogeneous leukoplakia. It is uncommon, and usually involves the buccal mucosa and the gingiva (the gums). This condition is characterized by (usually) extensive, papillary or verrucoid keratotic plaques that tends to slowly enlarge into adjacent mucosal sites. An established PVL lesion is usually thick and exophytic (prominent), but initially it may be flat. Smoking does not seem to be as strongly related as it is to leukoplakia generally, and another dissimilarity is the preponderance for women over 50. There is a very high risk of dysplasia, transformation to squamous cell carcinoma with high mortality (PVL does not transform into verrucous carcinoma, which is a lesion with a good prognosis usually; the similarity of names does not reflect the common origin, but only the resemblance of their appearance). Erythroleukoplakia Erythroleukoplakia (also termed speckled leukoplakia, erythroleukoplasia or leukoerythroplasia) is a non-homogeneous lesion of mixed white (keratotic) and red (atrophic) color. Erythroplakia (erythroplasia) is an entirely red patch that cannot be attributed to any other cause. Erythroleukoplakia can therefore be considered a variant of either leukoplakia or erythroplakia since its appearance is midway between. Erythroleukoplakia frequently occurs on the buccal mucosa in the commissural area (just inside the cheek at the corners of the mouth) as a mixed lesion of white nodular patches on an erythematous background, although any part of the mouth may be affected. Erythroleukoplakia and erythroplakia have a higher risk of cancerous changes than homogeneous leukoplakia. Sublingual keratosis Sometimes leukoplakia of the floor of mouth or under the tongue is called sublingual keratosis,. though this is not universally accepted to be a distinct clinical entity from idiopathic leukoplakia generally, as it is distinguished from the latter by location only. Usually sublingual keratoses are bilateral and possess a parallel-corrugated, wrinkled surface texture described as "ebbing tide". Candidal leukoplakia Candidal leukoplakia is usually considered to be a largely historical synonym for a type of oral candidiasis, now more commonly termed chronic hyperplastic candidiasis, rather than a subtype of true leukoplakia. However, some sources use this term to refer to leukoplakia lesions that become colonized secondarily by Candida species, thereby distinguishing it from hyperplastic candidiasis. Oral hairy leukoplakia Oral hairy leukoplakia is a corrugated ("hairy") white lesion on the sides of the tongue caused by opportunistic infection with Epstein-Barr virus on a systemic background of immunodeficiency, almost always human immunodeficiency virus (HIV) infection. This condition is not considered to be a true idiopathic leukoplakia since the causative agent has been identified. It is one of the most common oral lesions associated with HIV infection, along with pseudomembraneous candidiasis. The appearance of the lesion often heralds the transition from HIV to acquired immunodeficiency syndrome (AIDS). Syphilitic leukoplakia This term refers to a white lesion associated with syphilis, specifically in the tertiary stage of the infection. It is not considered to be a type of idiopathic leukoplakia, since the causative agent Treponema pallidum is known. It is now rare, but when syphilis was more common, this white patch usually appeared on the top surface of the tongue and carried a high risk of cancerous changes. It is unclear if this lesion was related to the condition itself or whether it was caused by the treatments for syphilis at the time. Esophagus Leukoplakia of the esophagus is rare compared to oral leukoplakia. The relationship with esophageal cancer is unclear because the incidence of esophageal leukoplakia is so low. It usually appears as a small, nearly opaque white lesion that may resemble early esophageal squamous cell carcinoma. The histologic appearance is similar to oral leukoplakia, with hyperkeratosis and possible dysplasia. Bladder In the context of lesions of the mucous membrane lining of the bladder, leukoplakia is a historic term for a visualized white patch which histologically represents keratinization in an area of squamous metaplasia. The symptoms may include frequency, suprapubic pain (pain felt above the pubis), hematuria (blood in the urine), dysuria (difficult urination or pain during urination), urgency, and urge incontinence. The white lesion may be seen during cystoscopy, where it appears as a whitish-gray or yellow lesion, on a background of inflamed urothelium and there may be floating debris in the bladder. Leukoplakia of the bladder may undergo cancerous changes, so biopsy and long term follow up are usually indicated. Anal canal Leukoplakia of the anal canal is rare. It may extend up to the anorectal junction. On digital examination it feels hard and granular, and at proctoscopy, it appears as white plaques which may be diffuse, circumferential, or circumscribed. The histologic appearance is similar to oral leukoplakia, with hyperkeratosis and acanthosis. It may be asymptomatic, with symptoms due to other lesions such as hemorrhoids or fissures. Progression to anal stenosis has been described. The malignant potential is seemingly low, and few cases of anal carcinoma have been reported associated with anal leukoplaka. Signs and symptoms Most cases of leukoplakia cause no symptoms, but infrequently there may be discomfort or pain. The exact appearance of the lesion is variable. Leukoplakia may be white, whitish yellow or grey. The size can range from a small area to much larger lesions. The most common sites affected are the buccal mucosa, the labial mucosa and the alveolar mucosa, although any mucosal surface in the mouth may be involved. The clinical appearance, including the surface texture and color, may be homogeneous or non-homogeneous (see: classification). Some signs are generally associated with a higher risk of cancerous changes (see: prognosis). Leukoplakia may rarely be associated with esophageal carcinoma.: 805 Causes The exact underlying cause of leukoplakia is largely unknown, but it is likely multifactorial, with the main factor being the use of tobacco. Tobacco use and other suggested causes are discussed below. The mechanism of the white appearance is thickening of the keratin layer, called hyperkeratosis. The abnormal keratin appears white when it becomes hydrated by saliva, and light reflects off the surface evenly. This hides the normal pink-red color of mucosae (the result of underlying vasculature showing through the epithelium). A similar situation can be seen on areas of thick skin such as the soles of the feet or the fingers after prolonged immersion in water. Another possible mechanism is thickening of the stratum spinosum, called acanthosis. Tobacco Tobacco smoking or chewing is the most common causative factor, with more than 80% of persons with leukoplakia having a positive smoking history. Smokers are much more likely to develop leukoplakia than non-smokers. The size and number of leukoplakia lesions in an individual is also correlated with the level of smoking and how long the habit has lasted for. Other sources argue that there is no evidence for a direct causative link between smoking and oral leukoplakia. Cigarette smoking may produce a diffuse leukoplakia of the buccal mucosa, lips, tongue and rarely the floor of mouth. Reverse smoking, where the lit end of the cigarette is held in the mouth is also associated with mucosal changes. Tobacco chewing, e.g. betel leaf and areca nut, called paan, tends to produce a distinctive white patch in a buccal sulcus termed "tobacco pouch keratosis". In the majority of persons, cessation triggers shrinkage or disappearance of the lesion, usually within the first year after stopping. Alcohol Although the synergistic effect of alcohol with smoking in the development of oral cancer is beyond doubt, there is no clear evidence that alcohol is involved in the development of leukoplakia, but it does appear to have some influence. Excessive use of a high alcohol-containing mouth wash (> 25%) may cause a grey plaque to form on the buccal mucosa, but these lesions are not considered true leukoplakia. Sanguinaria Sanguinaria (Bloodroot) is a herbal extract that is included in some toothpastes and mouthwashes. Its use is strongly associated with development of leukoplakia, usually in the buccal sulcus. This type of leukoplakia has been termed "sanguinaria associated keratosis" and more than 80% of people with leukoplakia in the vestibule of the mouth have used this substance. Upon stopping contact with the causative substance, the lesions may persist for many years. Although this type of leukoplakia may show dysplasia, the potential for malignant transformation is unknown. Ultraviolet radiation Ultraviolet radiation is believed to be a factor in the development of some leukoplakia lesions of the lower lip, usually in association with actinic cheilitis. Micro-organisms Candida in its pathogenic hyphal form is occasionally seen in biopsies of idiopathic leukoplakia. It is debated whether candida infection is a primary cause of leukoplakia with or without dysplasia, or a superimposed (secondary) infection that occurs after the development of the lesion. It is known that Candida species thrive in altered tissues. Some leukoplakias with dysplasia reduce or disappear entirely following use of antifungal medication. Smoking, which as discussed above can lead to the development of leukoplakia, can also promote oral candidiasis. Candida in association with leukoplakia should not be confused with white patches which are primarily caused by candida infection, such as chronic hyperplastic candidiasis ("candidal leukoplakia").The involvement of viruses in the formation of some oral white lesions is well established, e.g. Epstein-Barr virus in oral hairy leukoplakia (which is not a true leukoplakia). Human papilloma virus (HPV), especially HPV 16 and 18, is sometimes found in areas of leukoplakia, however, since this virus can be coincidentally found on normal, healthy mucosal surfaces in the mouth, it is unknown if this virus is involved in the development of some leukoplakias. In vitro experimentation has demonstrated that HPV 16 is capable of inducing dysplastic changes in previously normal squamous epithelium. Epithelial atrophy Leukoplakia is more likely to develop in areas of epithelial atrophy. Conditions associated with mucosal atrophy include iron deficiency, some vitamin deficiencies, oral submucous fibrosis, syphilis and sideropenic dysphagia. Trauma Another very common cause of white patches in the mouth is frictional or irritational trauma leading to keratosis. Examples include nicotine stomatitis, which is keratosis in response to heat from tobacco smoking (rather than a response to the carcinogens in tobacco smoke). The risk of malignant transformation is similar to normal mucosa. Mechanical trauma, e.g. caused by a sharp edge on a denture, or a broken tooth, may cause white patches which appear very similar to leukoplakia. However, these white patches represent a normal hyperkeratotic reaction, similar to a callus on the skin, and will resolve when the cause is removed. Where there is a demonstrable cause such as mechanical or thermal trauma, the term idiopathic leukoplakia should not be used. Pathophysiology Tumor suppressor genes Tumor suppressor genes are genes involved in the regulation of normal cell turnover and apoptosis (programmed cell death). One of the most studied tumor suppressor genes is p53, which is found on the short arm of chromosome 17. Mutation of p53 can disrupt its regulatory function and lead to uncontrolled cell growth. Mutations of p53 have been demonstrated in the cells from areas of some leukoplakias, especially those with dysplasia and in individuals who smoke and drink heavily. Diagnosis Definition Leukoplakia is a diagnosis of exclusion, meaning that which lesions are included depends upon what diagnoses are currently considered acceptable. Accepted definitions of leukoplakia have changed over time and are still controversial. It is possible that the definition will be further revised as new knowledge becomes available. In 1984 an international symposium agreed upon the following definition: "a whitish patch or plaque, which cannot be characterized clinically or pathologically as any other disease, and is not associated with any physical or chemical agent except the use of tobacco." There were, however, problems and confusion in applying this definition. At a second international symposium held in 1994, it was argued that whilst tobacco was a likely causative factor in the development of leukoplakia, some white patches could be linked directly to the local effects of tobacco by virtue of their disappearance following smoking cessation, suggesting that this kind of white patch represents a reactive lesion to local tissue irritation rather than a lesion caused by carcinogens in cigarette smoke, and could be better termed to reflect this etiology, e.g. smokers keratosis. The second international symposium, therefore, revised the definition of leukoplakia to: "a predominantly white lesion of the oral mucosa that cannot be characterized as any other definable lesion." In the mouth, the current definition of oral leukoplakia adopted by the World Health Organization is "white plaques of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer". However, this definition is inconsistently applied in the medical literature, and some refer to any oral white patch as "leukoplakia".The term has been incorrectly used for white patches of any cause (rather than specifically referring to idiopathic white patches) and also to refer only to white patches which have a risk of cancerous changes. It has been suggested that leukoplakia is an unhelpful term since there is so much inconsistency surrounding its use, and some clinicians now avoid using it at all. Biopsy Tissue biopsy is usually indicated to rule out other causes of white patches and also to enable a detailed histologic examination to grade the presence of any epithelial dysplasia. This is an indicator of malignant potential and usually determines the management and recall interval. The sites of a leukoplakia lesion that are preferentially biopsied are the areas that show induration (hardening) and erythroplasia (redness), and erosive or ulcerated areas. These areas are more likely to show any dysplasia than homogeneous white areas.Brush biopsy/exfoliative cytology is an alternative to incisional biopsy, where a stiff brush is scraped against the lining of the mouth to remove a sample of cells. This is then made into a smear which can be examined microscopically. Sometimes the biopsy site can be selected with adjunct methods which aim to highlight areas of dysplasia. Toluidine blue staining, where the dye is preferentially retained by dysplastic tissue, is sometimes used, but there is high false positive rate. Other methods involve the use of luminescence, relying on either the property of normal autoflorescent molecules in mucosa such as collagen and keratin which is lost from areas of dysplasia or carcinoma under blue light or by initially staining of the mucosa with toluidine blue or dilute acetic acid and examination under white light. Histologic appearance Leukoplakia has a wide range of possible histologic appearances. The degree of hyperkeratosis, epithelial thickness (acanthosis/atrophy), dysplasia and inflammatory cell infiltration in the underlying lamina propria are variable. In mucous membranes, hyperkeratosis can be defined as "an increase in the thickness of the keratin layer of the epithelium, or the presence of such a layer in a site where none would normally be expected." In leukoplakia, the hyperkeratosis varies in thickness and may be either ortho- or para-keratosis, (depending upon whether cell nuclei are lost or retained in the superficial layers respectively), or a mixture of both in different areas of the lesion.The epithelium may show hypertrophy (e.g. acanthosis) or atrophy. Red areas within leukoplakia represent atrophic or immature epithelium which has lost the ability to keratinize. The transition between the lesion and normal surrounding mucosa may be well-demarcated, or poorly defined. Melanin, a pigment naturally produced in oral mucosa, can leak from cells and give a grey color to some leukoplakia lesions.Hyperkeratosis and altered epithelial thickness may be the only histologic features of a leukoplakia lesion, but some show dysplasia. The word "dysplasia" generally means "abnormal growth", and specifically, in the context of oral red or white lesions, refers to microscopic changes ("cellular atypia") in the mucosa that indicate a risk of malignant transformation. When dysplasia is present, there is generally an inflammatory cell infiltration in the lamina propria. The following are commonly cited as being possible features of epithelial dysplasia in leukoplakia specimens: Cellular pleomorphism, in which cells are of abnormal and different shapes. Nuclear atypia, in which the nuclei of cells varies in size, any may be increased in size relative to the cytoplasm, shape, and may stain more intensely. There may also be more prominent nucleoli. Increased number of cells seen undergoing mitosis, including both normal and abnormal mitoses. Abnormal mitosis may be abnormally located, e.g. occurring in suprabasal cells (cell layers more superficial to the basal cell layer) or of abnormal form, e.g. "tri-radiate mitoses" (a cell splitting into 3 daughter cells rather than only 2) Loss the normal organization of the epithelial layers. The distinction between the epithelial layers may be lost. Normally stratified squamous epithelium shows progressive changes in the form of cells from the basal to the superficial layers, with cells becoming more flat ("squames") towards the surface as a continuous maturation process. In dysplastic epithelium, cells may become vertically orientated rather than becoming flat towards the surface. There may be abnormal keratinization, where keratin is formed below the normal keratin layer. This can occur in individual cells or groups of cells, forming an intraepithelial keratin pearl. There may be an increase in the number of basal cells, and they may lose their cellular orientation (losing their polarity and long axis). Alteration of the normal epithelial-connective tissue architecture - the rete pegs may become "drop shaped". wider at their base than more superficially.Generally, dysplasia is subjectively graded by pathologists into mild, moderate or severe dysplasia. This requires experience as it is a difficult skill to learn. It has been shown that there is high degree of inter-observer variation and poor reproducibility in how dysplasia is graded. Severe dysplasia is synonymous with the term carcinoma in situ, denoting the presence of neoplastic cells which have not yet penetrated the basement membrane and invaded other tissues. Differential diagnosis There are many known conditions that present with a white lesion of the oral mucosa, but the majority of oral white patches have no known cause. These are termed leukoplakia once other likely possibilities have been ruled out. There are also few recognized subtypes of leukoplakia, described according to the clinical appearance of the lesion. Almost all oral white patches are usually the result of keratosis. For this reason, oral white patches are sometimes generally described as keratoses, although a minority of oral white lesions are not related to hyperkeratosis, e.g. epithelial necrosis and ulceration caused by a chemical burn (see: Oral ulceration#Chemical injury). In keratosis, the thickened keratin layer absorbs water from saliva in the mouth and appears white in comparison with normal mucosa. Normal oral mucosa is a red-pink color due to the underlying vasculature in the lamina propria showing through the thin layer of epithelium. Melanin produced in the oral mucosa also influences the color, with a darker appearance being created by higher levels of melanin in the tissues (associated with racial/physiologic pigmentation, or with disorders causing melanin overproduction such as Addisons disease). Other endogenous pigments can be overproduced to influence the color, e.g. bilirubin in hyperbilirubinemia or hemosiderin in hemochromatosis, or exogenous pigments such as heavy metals can be introduced into the mucosa, e.g. in an amalgam tattoo. Almost all white patches are benign, i.e. non-malignant. The differential diagnosis of a white lesion in the mouth can be considered according to a surgical sieve (see table).Leukoplakia cannot be rubbed off the mucosa, distinguishing it readily from white patches such as pseudomembraneous candidiasis, where a white layer can be removed to reveal an erythematous, sometimes bleeding surface underneath. The white color associated with leukoedema disappears when the mucosa is stretched. A frictional keratosis will generally be adjacent to a sharp surface such as a broken tooth or rough area on a denture and will disappear when the causative factor is removed. Some have a suggested as general rule that any lesion that does not show signs of healing within 2 weeks should be biopsied. Morsicatio buccarum and linea alba are located at the level of the occlusal plane (the level at which the teeth meet). A chemical burn has a clear history of placing an aspirin tablet (or other caustic substance such as eugenol) against the mucosa in an attempt to relieve toothache. Developmental white patches usually are present from birth or become apparent earlier in life, whilst leukoplakia generally affects middle aged or elderly people. Other causes of white patches generally require pathologic examination of a biopsy specimen to distinguish with certainty from leukoplakia. Management A systematic review found that no treatments commonly used for leukoplakia have been shown to be effective in preventing malignant transformation. Some treatments may lead to healing of leukoplakia, but do not prevent relapse of the lesion or malignant change. Regardless of the treatment used, a diagnosis of leukoplakia almost always leads to a recommendation that possible causative factors such as smoking and alcohol consumption be stopped, and also involves long term review of the lesion, to detect any malignant change early and thereby improve the prognosis significantly. Predisposing factors and review Beyond advising smoking cessation, many clinicians will employ watchful waiting rather than intervene. Recommended recall intervals vary. One suggested program is every 3 months initially, and if there is no change in the lesion, then annual recall thereafter. Some clinicians use clinical photographs of the lesion to help demonstrate any changes between visits. Watchful waiting does not rule out the possibility of repeated biopsies. If the lesion changes in appearance repeat biopsies are especially indicated. Since smoking and alcohol consumption also places individuals at higher risk of tumors occurring in the respiratory tract and pharynx, "red flag" symptoms (e.g. hemoptysis - coughing blood) often trigger medical investigation by other specialties. Surgery Surgical removal of the lesion is the first choice of treatment for many clinicians. However, the efficacy of this treatment modality cannot be assessed due to insufficient available evidence. This can be carried out by traditional surgical excision with a scalpel, with lasers, or with eletrocautery or cryotherapy. Often, if biopsy demonstrates moderate or severe dysplasia then the decision to excise them is taken more readily. Sometimes, white patches are too large to remove completely and instead they are monitored closely. Even if the lesion is completely removed, long term review is still usually indicated since leukoplakia can recur, especially if predisposing factors such as smoking are not stopped. Medications Many different topical and systemic medications have been studied, including anti-inflammatories, antimycotics (target Candida species), carotenoids (precursors to vitamin A, e.g. beta carotene), retinoids (drugs similar to vitamin A), and cytotoxics, but none have evidence that they prevent malignant transformation in an area of leukoplakia. Vitamins C and E have also been studied with regards a therapy for leukoplakia. Some of this research is carried out based upon the hypothesis that antioxidant nutrients, vitamins and cell growth suppressor proteins (e.g. p53) are antagonistic to oncogenesis. High doses of retinoids may cause toxic effects. Other treatments that have been studied include photodynamic therapy. Prognosis The annual malignant transformation rate of leukoplakia rarely exceeds 1%, i.e. the vast majority of oral leukoplakia lesions will remain benign. A number of clinical and histopathologic features are associated with varying degrees of increased risk of malignant transformation, although other sources argue that there are no universally accepted and validated factors which can reliably predict malignant change. It is also unpredictable to an extent if an area of leukoplakia will disappear, shrink or remain stable. Presence and degree of dysplasia (mild, moderate or severe/carcinoma in situ). While the degree of dysplasia has been shown to be an important predictor of malignant change, many have challenged its use due to the low predictive value from the lack of objectivity of grading dysplasia. While 10% of leukoplakia lesions show dysplasia when biopsied, as many as 18% of oral lesions undergo malignant change in the absence of dysplasia. Leukoplakia located on the floor of the mouth, the posterior and lateral tongue, and the retromolar areas (the region behind the wisdom teeth) have higher risk, whereas white patches in areas such as the top surface of the tongue and the hard palate do not have significant risk. Although these "high risk" sites are recognized, statistically, leukoplakia is more common on the buccal mucosa, alveolar mucosa, and the lower labial mucosa. Leukoplakia of the floor of the mouth and tongue accounts for over 90% of leukoplakias showing dysplasia or carcinoma on biopsy. This is thought to be due to pooling of saliva in the lower part of the mouth, exposing these areas to more carcinogens held in suspension. Red lesions (erythroplasia) and mixed red and white lesions (erythroleukoplakia/"speckled leukoplakia") have a higher risk of malignant change than homogeneous leukoplakia. Verrucous or nodular areas have a higher risk. Although smoking increases risk of malignant transformation, smoking also causes many white patches with no dysplasia. This means that statistically, white patches in non-smokers have a higher risk. Older people with white patches are at higher risk. Larger white patches are more likely to undergo malignant transformation than smaller lesions. White patches which have been present for a long period of time have a higher risk. Persons with a positive family history of cancer in the mouth. Candida infection in the presence of dysplasia has a small increased risk. A change in the appearance of the white patch, apart from a change in the color, has a higher risk. Changes in the lesion such as becoming fixed to underlying tissues, ulceration, cervical lymphadenopathy (enlargement of lymph nodes in the neck), and bone destruction may herald the appearance of malignancy. White patches present in combination with other conditions that carry a higher risk (e.g. oral submucous fibrosis), are more likely to turn malignant. Although overall, oral cancer is more common in males, females with white patches are at higher risk than men. Epidemiology The prevalence of oral leukoplakia varies around the world, but generally speaking it is not an uncommon condition. Reported prevalence estimates range from less than 1% to more than 5% in the general population. Leukoplakia is, therefore, the most common premalignant lesion that occurs in the mouth. Leukoplakia is more common in middle-aged and elderly males. The prevalence increases with increasing age. In areas of the world where smokeless tobacco use is common, there is a higher prevalence. In the Middle East region, the prevalence of leukoplakia is less than 1% (0.48%). Etymology The word leukoplakia means "white patch", and is derived from the Greek words λευκός - "white" and πλάξ - "plate". History The term leukoplakia was coined in 1861 by Karl Freiherr von Rokitansky, who used it to refer to white lesions of the urinary tract. In 1877, Schwimmer first used the term for an oral white lesion. It is now thought that this white lesion on the tongue represented syphilitic glossitis, a condition not included in the modern definitions of oral leukoplakia. Since then, the word leukoplakia has been incorporated into the names for several other oral lesions (e.g. candidal leukoplakia, now more usually termed hyperplastic candidiasis). In 1930, it was shown experimentally that leukoplakia could be induced in rabbits that were subjected to tobacco smoke for 3 minutes per day. According to one source from 1961, leukoplakia can occur on multiple different mucous membranes of the body, including in the urinary tract, rectum, vagina, uterus, vulva, paranasal sinuses, gallbladder, esophagus, eardrums, and pharynx. Generally, oral leukoplakia is the only context where the term is in common usage in modern medicine. In 1988, a case report used the term acquired dyskeratotic leukoplakia to refer to an acquired condition in a female where dyskeratotic cells were present in the epithelia of the mouth and genitalia.: 480 : 806 References == External links ==

Posterior amorphous corneal dystrophy

Posterior amorphous corneal dystrophy (PACD) is a rare form of corneal dystrophy. It is not yet linked to any chromosomal locus. The first report describing this dystrophy dates back to 1977. References == External links ==

Dawn phenomenon

The dawn phenomenon, sometimes called the dawn effect, is an observed increase in blood sugar (glucose) levels that takes place in the early-morning, often between 2 a.m. and 8 a.m. First described by Schmidt in 1981 as an increase of blood glucose or insulin demand occurring at dawn, this naturally occurring phenomenon is frequently seen among the general population and is clinically relevant for patients with diabetes as it can affect their medical management. In contrast to Chronic Somogyi rebound, the dawn phenomenon is not associated with nocturnal hypoglycemia. Physiology Although not yet completely understood, the dawn phenomenon is thought to be caused by an exaggeration of the normal physiologic hormonal processes that occur overnight. Overnight the human body sees increased levels of several hormones, most notably growth hormone and catecholamines, that lead to increased rates of glucose production and release from the liver. These hormones also inhibit the effects of insulin, leading to an overall increase in circulating blood glucose. This effect is amplified in patients with islet β-cell dysfunction such as diabetics. Notably throughout this process glucagon levels remain unchanged and the increased levels of cortisol observed overnight do not appear to be involved. Observed hyperglycemia secondary to the dawn phenomenon is often defined as an increase in blood glucose of at least >1.1mmol/L (20mg/dL) between the lowest level at night and the highest level before breakfast; however, actual ranges may vary.The physiologic process involved in causing the dawn phenomenon has been shown to occur in most people. In non-diabetic patients there is a modest increase in insulin secretion just before dawn which compensates for the increased glucose being released from the liver to prevent hyperglycemia. However, studies have shown that diabetic patients fail to compensate for this transiently increased blood glucose release, resulting in hyperglycemia. This resulting hyperglycemia is clinically relevant in diabetic patients as its lasting effects can lead to overall poor glycemic control. In Type 1 diabetics hyperglycemia due to the dawn phenomenon can persist despite adequate insulin compensation overnight, while in Type 2 diabetics the dawn phenomenon has been shown to be resistant to treatment with both oral medications and diet modifications. An "extended" dawn phenomenon has also been observed in which the abnormal increase in blood glucose levels continues after breakfast. This prolonged duration is thought to be caused by the compounding effects of absorbing and metabolizing breakfast carbohydrates during this period. Both the dawn phenomenon and its extended period have been shown to be significantly more difficult to control when a patients HbA1c is greater than 7%. Treatment Management of the dawn phenomenon varies by patient and thus should be done with regular assistance from a patients physician. Some treatment options include, but are not limited to, dietary modifications, increased exercise before breakfast and during the evening, and oral anti-hyperglycemic medications if a patients HbA1c is > 7%. Insulin pumps can also be used to provide continuous subcutaneous infusions and are regarded as the gold standard for managing the dawn phenomenon in type 1 diabetics. See also Cortisol awakening response References External links Mayo Clinic - The dawn phenomenon: What causes it? Diabetes Self Management - Dawn Phenomenon Dawn Phenomenon (Liver Dump) Spiritual and scientific benefits of waking up before Dawn

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Retinal vasculopathy with cerebral leukocencephalopathy and systemic manifestations (RVCL or RVCL-S, also previously known as retinal vasculopathy with cerebral leukodystrophy, RVCL; or cerebroretinal vasculopathy, CRV; or hereditary vascular retinopathy, HVR; or hereditary endotheliopathy, retinopathy, nephropathy, and stroke, HERNS) is an inherited condition resulting from a frameshift mutation in the C-terminal region of the TREX1 gene. This disease affects small blood vessels, leading to damage of multiple organs including but not limited to the retina and the white matter of the central nervous system. Patients with RVCL develop vision loss, brain lesions, strokes, brain atrophy, and dementia. Patients with RVCL also exhibit other organ involvement, including kidney, liver, gastrointestinal tract, thyroid, and bone disease. Symptoms of RVCL commonly begin between ages 40 and 50, although sometimes disease onset occurs earlier or later. The overall prognosis is poor, and death can sometimes occur within 5 or 10 years of the first symptoms appearing, although patients sometimes live about 20 years after initial symptoms. Clinical trials are underway, as are efforts to develop personalized medicines for patients with RVCL. Presentation For most patients, disease onset is between ages 35 and 55. Earliest onset is usually not before age 35. Late onset is usually not after age 55. RVCL affects multiple organs. All patients develop brain and eye disease, leading to disability, vision loss, and premature death. All patients with RVCL develop kidney and liver disease, with elevated alkaline phosphatase. Some patients develop bone lesions (osteonecrosis) as well as hypothyroidism. Sometimes patients also develop gastrointestinal symptoms or bleeding. RVCL is associated with progressive deterioration in visual acuity due to multifocal microvascular disease, retinal neovascularization leading, and/or glaucoma. Retinal microvascular disease is noninflammatory and resembles that of diabetic retinopathy. This leads to partial or complete vision loss. Headaches due to multiple factors including brain lesions, edema, and papilledema. Mental confusion, loss of cognitive function, loss of memory, slowing of speech and hemiparesis due to brain lesions. Some patients have Jacksonian seizures or grand mal seizures. Progressive neurologic deterioration unresponsive to systemic immunosuppression including corticosteroid therapy and chemotherapeutic agents. Autopsy typically demonstrates discrete, often confluent, foci of coagulative necrosis in the cerebral white matter, with intermittent findings of fine calcium deposition within necrotic foci. Additionally, tissues exhibit vasculopathic changes involving both arteries and veins of medium and small caliber in the cerebral white matter. There is fibrinoid necrosis of vessel walls with extravasation of fibrinoid material into adjacent parenchyma present in both necrotic and non-necrotic tissue. Vessels can exhibit obliterative fibrosis in all the layers of vessel walls, as well as perivascular, adventitial fibrosis with limited intimal thickening. In rare cases, RVCL has been associated with severe disease involving other organs outside the brain and the eye (e.g., osteonecrosis requiring joint replacement, gastrointestinal ischemia leading to bowel resection, or liver failure requiring liver transplantation). Clinical Associations Raynauds phenomenon Anemia Hypertension Normocytic anemia Normochromic anemia Gastrointestinal bleeding or telangiectasias Elevated alkaline phosphatase Chronic kidney disease Genetics RVCL is caused by mutations in the TREX1 gene. The official name of the TREX1 gene is "three prime repair exonuclease 1". The normal function of the TREX1 gene is to provide instructions for making the 3-prime repair exonuclease 1 enzyme. This enzyme is a DNA exonuclease, which means it trims molecules of DNA by removing DNA building blocks (nucleotides) from the ends of the molecules. In this way, it breaks down unneeded DNA molecules or fragments that may be generated during genetic material in preparation for cell division, DNA repair, cell death, and other processes. Changes (mutations) to the TREX1 gene can result in a range of conditions, one of which is RVCL. The mutant TREX1 protein is produced and mislocalized. Haploinsufficiency of TREX1 does not explain the disease, since the parents of patients with Aicairdi-Goutieres syndrome, a disease characterized by insufficient TREX1 activity, are completely healthy with only one functional TREX1 allele. Different mutations in the TREX1 gene have also been identified in people with disorders involving the immune system. These disorders include a chronic inflammatory disease called Aicardi-Goutieres syndrome, as well as systemic lupus erythematosus (SLE), including a rare form of SLE called chilblain lupus that mainly affects the skin. Those diseases, which are inflammatory, may have a completely distinct mechanism compared with that of RVCL. The TREX1 gene is located on chromosome 3: base pairs 48,465,519 to 48,467,644 Pathogenesis The main pathologic process centers on small blood vessels that prematurely "drop out" and disappear. The retina of the eye and white matter of the brain appear to be among the most sensitive to this pathologic process. Over a five- to ten-year period, this vasculopathy (blood vessel pathology) results in vision loss and destructive brain lesions with neurologic deficits and death. Although brain and eye disease are universally present in patients with RVCL, the disease is truly a multi-system disorder characterized by chronic kidney disease, liver disease, and frequently other manifestations including gastrointestinal disease, osteonecrosis, and hypothyroidism. Diagnosis Differential diagnosis Treatment Currently, there is no therapy that is proven to prevent the blood vessel deterioration. In 2021, Dr. Jonathan Miner of the University of Pennsylvania (Penn) in Philadelphia, and the Hospital of the University of Pennsylvania (Penn Medicine), initiated a clinical trial of crizanlizumab for RVCL. The University of Pennsylvania also sponsors RVCL patient support groups, and collaborates with the RVCL Research Center at Washington University (WashU) on clinical trials and longitudinal studies. Miner also established a large RVCL Research Center, which is conducting clinical trials, performing basic research, and developing novel personalized therapies for RVCL. This includes small molecular inhibitors (to be taken as pills) and gene therapy approaches, with the goal of fully correcting the disease-causing mutation. Developing these personalized therapies is a challenging process that will take years. History 1985–1988: CRV (Cerebral Retinal Vasculopathy) was discovered by multiple investigators including Dr. Gil Grand, Dr. John P. Atkinson, and colleagues at Washington University School of Medicine (WashU). 1988: 10 families worldwide were identified as having CRV (now known as RVCL or RVCL-S) 1991: Related disease reported, HERNS (Hereditary Endiotheliopathy with Retinopathy, Nephropathy and Stroke – UCLA 1998: Related disease reported, HRV (Hereditary Retinal Vasculopathy) – Leiden University, Netherlands 2001: Localized to Chromosome 3. 2007: The specific genetic defect in all of these families was discovered in a single gene called TREX1 on chromosome 3. 2008: Name changed to AD-RVCL Autosomal Dominant-Retinal Vasculopathy with Cerebral Leukodystrophy 2009: Testing for the disease available to persons 21 and older 2011: 20 families worldwide were identified as having CRV 2012: Obtained mouse models for further research and to test therapeutic agents 2021: At least 42 families and 200 patients worldwide are known to have RVCL (or RVCL-S).[1] 2021: Dr. Jonathan Miner of the University of Pennsylvania (Penn) initiates the second clinical trial for RVCL, in collaboration with Dr. Andria Ford of WashU. Miner also establishes an International Registry in collaboration with colleagues. References == External links ==

Thunderclap headache

A thunderclap headache is a headache that is severe and has a sudden onset. It is defined as a severe headache that takes seconds to minutes to reach maximum intensity. Although approximately 75% are attributed to "primary" headaches—headache disorder, non-specific headache, idiopathic thunderclap headache, or uncertain headache disorder—the remainder are secondary to other causes, which can include some extremely dangerous acute conditions, as well as infections and other conditions. Usually, further investigations are performed to identify the underlying cause. Signs and symptoms A headache is called "thunderclap headache" if it is severe in character and reaches maximum severity within seconds to minutes of onset. In many cases, there are no other abnormalities, but the various causes of thunderclap headaches may lead to a number of neurological symptoms. Causes Approximately 75% are attributed to "primary" headaches: headache disorder, non-specific headache, idiopathic thunderclap headache or uncertain headache disorder. The remainder are secondary to a number of conditions, including: Subarachnoid hemorrhage (10–25% of all cases of thunderclap headache) Cerebral venous sinus thrombosis Cervical artery dissection Hypertensive emergency (severely raised blood pressure) Spontaneous intracranial hypotension (unexplained low cerebrospinal fluid pressure) Stroke (headache occurs in about 25% of strokes but usually not thunderclap character) Retroclival hematoma (hematoma behind the clivus in the skull, usually due to physical trauma but sometimes spontaneous) Pituitary apoplexy (infarction or hemorrhage of the pituitary gland) Colloid cyst of the third ventricle Meningitis, sinusitis Reversible cerebral vasoconstriction syndrome (previously Call-Fleming syndrome, several subtypes) Primary cough headache, primary exertional headache, and primary sexual headacheThe most important of the secondary causes are subarachnoid hemorrhage, cerebral venous sinus thrombosis, and dissection of an artery in the neck.In subarachnoid hemorrhage, there may be syncope (transient loss of consciousness), seizures, meningism (neck pain and stiffness), visual symptoms, and vomiting. 50–70% of people with subarachnoid hemorrhage have an isolated headache without decreased level of consciousness. The headache typically persists for several days.Cerebral venous sinus thrombosis, thrombosis of the veins of the brain, usually causes a headache that reflects raised intracranial pressure and is therefore made worse by anything that makes the pressure rise further, such as coughing. In 2–10% of cases, the headache is of thunderclap character. In most cases there are other neurological abnormalities, such as seizures and weakness of part of the body, but in 15–30% the headache is the only abnormality.Carotid artery dissection and vertebral artery dissection (together cervical artery dissection), in which a tear forms inside the wall of the blood vessels that supply the brain, often causes pain on the affected side of the head or neck. The pain usually precedes other problems that are caused by impaired blood flow through the artery into the brain; these may include visual symptoms, weakness of part of the body, and other abnormalities depending on the vessel affected. Diagnosis The most important initial investigation is computed tomography of the brain, which is very sensitive for subarachnoid hemorrhage. If this is normal, a lumbar puncture is performed, as a small proportion of SAH is missed on CT and can still be detected as xanthochromia.If both investigations are normal, the specific description of the headache and the presence of other abnormalities may prompt further tests, usually involving magnetic resonance imaging (MRI). Magnetic resonance angiography (MRA) may be useful in identifying problems with the arteries (such as dissection), and magnetic resonance venography (MRV) identifies venous thrombosis. It is not usually necessary to proceed to cerebral angiography, a more precise but invasive investigation of the brains blood vessels, if MRA and MRV are normal. Epidemiology Incidence of thunderclap headache has been estimated at 43 per 100,000 people every year. Approximately 75% are attributed to "primary" headaches: headache disorder, non-specific headache, idiopathic thunderclap headache or uncertain headache disorder. The remainder is attributed to secondary causes: vascular problems, infections and various other conditions. History The importance of severe headaches in the diagnosis of subarachnoid hemorrhage has been known since the 1920s, when London neurologist Charles Symonds described the clinical syndrome. The term "thunderclap headache" was introduced in 1986 in a report by John Day and Neil Raskin, neurologists at the University of California, San Francisco, in a report of a 42-year-old woman who had experienced several sudden headaches and was found to have an aneurysm that had not ruptured. References Further reading Dodick, DW (1 January 2002). "Thunderclap headache". Journal of Neurology, Neurosurgery & Psychiatry. 72 (1): 6–11. doi:10.1136/jnnp.72.1.6. PMC 1737692. PMID 11784817. Ju, Yo-El; Schwedt, Todd (29 March 2010). "Abrupt-Onset Severe Headaches". Seminars in Neurology. 30 (2): 192–200. doi:10.1055/s-0030-1249229. PMC 3558726. PMID 20352589. Ducros, A; Bousser, MG (9 January 2013). "Thunderclap headache". BMJ. 346 (jan08 15): e8557. doi:10.1136/bmj.e8557. PMID 23303883. S2CID 2537784. == External links ==

Nutritional anemia

Anemia is a deficiency in the size or number of red blood cells or in the amount of hemoglobin they contain.This deficiency limits the exchange of O2 and CO2 between the blood and the tissue cells.Globally, young children, women, and older adults are at the highest risk of developing anemia. Anemia can be classified based on different parameters, and one classification depends on whether it is related to nutrition or not so there are two types: nutritional anemia and non-nutritional anemia. Nutritional anemia refers to anemia that can be directly attributed to nutritional disorders or deficiencies. Examples include Iron deficiency anemia and pernicious anemia. It is often discussed in a pediatric context.According to the World Health Organization, a hemoglobin concentration below 110 g/L for children under 5 years of age and pregnant women, and below 130 g/L for men indicates anemia. Hemoglobin is a blood protein that transports oxygen to the cells of the body. Without oxygen, the human body cannot undergo respiration and create Adenosine triphosphate, thereby depriving cells of energy.Nutritional anemia can be caused by a lack of iron, protein, vitamin B12, and other vitamins and minerals that are needed for the formation of hemoglobin. However, Iron deficiency anemia is the most common nutritional disorder.Signs of anemia include cyanosis, jaundice, and easy bruising. In addition, anemic patients may experience difficulties with memory and concentration, fatigue, lightheadedness, sensitivity to temperature, low energy levels, shortness of breath, and pale skin. Symptoms of severe or rapid-onset anemia are very dangerous as the body is unable to adjust to the lack of hemoglobin. This may result in shock and death. Mild and moderate anemia have symptoms that develop slowly over time.[5] If patients believe that they are at risk for or experience symptoms of anemia, they should contact their doctor. Symptoms Symptoms of nutritional anemia can include fatigue and lack of energy. However if symptoms progress, one may experience shortness of breath, rapid pulse, paleness—especially in the hands, eyelids and fingernails---, swelling of ankles, hair loss, lightheadedness, compulsive and atypical cravings, constipation, depression, muscle twitching, numbness, or burning and chest pain. Those who have nutritional anemia often show little to no symptoms. Often, symptoms can go undetected as mild forms of the anemia have only minor symptoms. Cause Internationally, anemia caused by iron deficiencies is the most common nutritional disorder. It is the only significantly prevalent nutritional deficiency disorder in industrialized countries. In poorer areas, anemia is worsened by infectious diseases such as HIV/AIDS, tuberculosis, hookworm infestation, and malaria. In developing countries, about 40% of preschool children and 50% of pregnant women are estimated to be anemic. 20% of maternal deaths can be contributed to anemia. Health consequences of anemia include poor pregnancy outcomes, impaired cognitive and physical development, increased rate of morbidity, and reduced rate of work in adults.Nutritional anemia has many different causes, each either nutritional or non-nutritional. Nutritional causes are vitamin and mineral deficiencies and non-nutritional causes include infections. The number one cause of this type of anemia, however, is iron deficiency.An insufficient intake of iron, Vitamin B12, and folic acid impairs the bone marrow function. The lack of iron within a person’s body can also stem from ulcer bacteria. These microbes live in the digestive tract and after many years cause ulcers in the lining of the stomach or small intestine. Therefore, a high percentage of patients with nutritional anemia may have a potential gastrointestinal disorder that causes chronic blood loss. This is common in immunocompromised, elderly, and diabetic people. High blood loss can also come from increased loss of blood during menstruation, childbirth, cancers of the intestines, and disorders that hinder the blood’s ability to coagulate. Medications can have adverse effects and cause nutritional anemia as well. Medications that stop the absorption of iron in the gut and cause bleeding from the gut (NSAIDs and Aspirin) can be culprits in the development of this condition. Hydrocortisones and valproic acid are also two drugs that can cause moderate bleeding from the gut. Amoxicillin and phenytoin have the ability to cause a vitamin B12 deficiency. Other common causes are thyroid disorders, lead toxicity, infectious diseases (e.g malaria), alcoholism, and vitamin E deficiency. Diagnosis Complete blood count. Acute phase reactants Serum iron studies Peripheral blood morphology Types of nutritional anemia Iron Deficiency Anemia It is the last stage of iron deficiency and it is characterized by the production of small (microcytic) erythrocytes and diminished level of circulating hemoglobin. It represents the end point of a long period of iron deprivation. Megaloblastic Anemia It reflects DNA disturbance which affects the blood cells (erythrocytes, leukocytes, platelets) and the bone marrow, and it is characterized by large and immature blood cells in the bone marrow (macrocytic anemia), mainly caused by both vitamins B9 (Folic Acid) and B12. Anemia of Protein-Energy Malnutrition As explained before, hemoglobin is a protein which means that its production requires adequate and enough intake of protein from the diet, but in case of protein-energy malnutrition, hemoglobin will not be produced sufficiently leading to anemia. As a result there is a reduction in cell mass and thus fewer RBCs are required to oxygenate the tissue ( reduced number of RBCs with a low hemoglobin). Copper Deficiency Anemia Copper and copper proteins are needed for adequate hemoglobin formation, use of iron by the developing erythrocyte (ceruloplasmin), optimal functions of the erythrocyte membrane. Ceruloplasmin (copper containing protein) is required for normal mobilization of iron from its storage sites. Thus, in a copper- deficient state; iron cannot be released à low serum iron and hemoglobin levels (even in the presence of normal iron stores). Sideroblastic Anemia It is an inherited defect of heme synthesis enzyme which results in derangement in the final pathway of heme synthesis and buildup of immature Fe- containing RBCs. It is classified as microcytic and hypochromic type of anemia and it is nutritional because it is Vitamin B6-responsive. Hemolytic Anemia A defect in RBC membranes causes oxidative damage and lysis the cells. Vitamin E has shown to be protective as it has an antioxidative function. Treatment Treatments for nutritional anemia includes replacement therapy is used to elevate the low levels of nutrients.[1] Diet improvement is a way to combat nutritional anemia and this can be done by taking dietary supplements such as iron, folate, and Vitamin B12.[2] These supplements are available over-the-counter however, a doctor may prescribe prescription medicine as needed, depending on the patient’s health needs. References == External links ==

Myopathy, X-linked, with excessive autophagy

X-linked myopathy with excessive autophagy (XMEA) is a rare childhood onset disease characterized by slow progressive vacuolation and atrophy of skeletal muscle. There is no known cardiac or intellectual involvement. Presentation The incidence of this disease is not precisely known but it is considered to be rare (< 1/106 population). It has been reported in 15 families to date mostly from Canada, Finland and France.This disease usually presents between the ages of 5 to 10 years old. The usual picture is with weakness involving the upper legs and affects activities such as running and climbing stairs. As the condition progresses, patients tend to experience weakness in their lower legs and arms. Some remain able to walk in advanced age, while others require assistance in adulthood. Genetics This disorder is inherited in a recessive X linked fashion. As a result, males are much more commonly affected than females. It is due to a mutation in VMA21 gene - the human homolog of the yeast Vma21p protein. This gene is located on the long arm of chromosome X (Xq28). It is an essential assembly chaperone of the vacuolar ATPase - the principal mammalian proton pump complex. Mutations in this gene increase lysosomal pH. This in turn reduces lysosomal degradative ability and blocks autophagy. Pathology The muscle fibers are rarely necrotic but have evidence of excessive autophagic activity and exocytosis of the phagocytosed material. They have increased variation in size and are predominantly composed of round small and hypertrophic fibers. The vacuoles are strongly reactive for dystrophin and lysosome associated membrane protein 2 (LAMP2). Membrane bound vacuoles and balls of dense material under the basal lamina are present. Deposition of the C5b-9 complement attack complex, subsarcolemmal deposition of calcium and expression of MHC1 complex also occur.On electron microscopy characteristic balls of dense material are commonly seen. The vacuoles may contain remains of mitochondria, membrane whorls and calcium apatite crystals. Diagnosis The diagnosis can be established by muscle biopsy. Investigations The serum creatinine is raised. Differential diagnosis Acid maltase deficiency Danon disease Treatment History This disorder was described in 1988 by Kalimo et al in Finland in three brothers. The same condition affected their maternal grandfather and great-uncle. References == External links ==

Cutaneous horn

Cutaneous horns, also known by the Latin name cornu cutaneum, are unusual keratinous skin tumors with the appearance of horns, or sometimes of wood or coral. Formally, this is a clinical diagnosis for a "conical projection above the surface of the skin." They are usually small and localized but can, in very rare cases, be much larger. Although often benign, they can also be malignant or premalignant. Signs and symptoms The lesion at the base of the keratin mound is benign in the majority of cases. Malignancy is present in up to 20% of cases, with squamous-cell carcinoma being the most common type. The incidence of squamous-cell carcinoma increases to 37% when the cutaneous horn is present on the penis. Tenderness at the base of the lesion often suggests the presence of a possible underlying squamous-cell carcinoma. Cause The cause of cutaneous horns is still unknown, but it is believed that exposure to radiation can trigger the condition. This is evidenced by a higher rate of cases occurring on the face and hands, areas that are often exposed to sunlight. Other cases have reported cutaneous horns arising from burn scars. As with many other wart-like skin conditions, a link to the HPV virus family, especially the HPV-2 subtype has been suggested. Diagnosis Cutaneous horn usually arises due to an underlying epidermal lesion, the most common being verruca vulgaris (wart), actinic keratosis (a potentially pre-malignant lesion of dysplastic keratinocytes), or squamous cell carcinoma (a form of skin cancer). These can look essentially identical clinically. The only reliable way to diagnose which type of lesion is present under the horn is to biopsy the lesion and have it microscopically examined by a pathologist (or dermatologist). Treatments As the horn is composed of keratin, the same material found in fingernails, the horn can usually be removed with a sterile razor. However, the underlying condition will still need to be treated. Treatments vary, but they can include surgery, radiation therapy, and chemotherapy. Notable cases Zhang Ruifang, aged 101 (as of 2010), living in Linlou Village, Henan province, China, has grown a cutaneous horn on her forehead, resembling what those who have examined her and her family call "Devils Horns." Notably, this growth has expanded to reach a total of 6 centimeters in length. Another is forming on the opposite side of her forehead. Liang Xiuzhen, aged 87 (as of 2015) living in Guiyan village in Ziyang City, Sichuan province, China, grew a 13 cm (5.1") pointed horn from her forehead, earning her the nickname "Unicorn Woman". Huang Yuanfan, aged 84 (living in Ziyuan, China). Shyam Lal Yadav, aged 74 (living in Madhya Pradesh, India). Madame Dimanche, called Widow Sunday, a French woman living in Paris in the early 19th century, grew a 24.9 cm (9.8") horn from her forehead in six years from the age of 76 before it was successfully removed by French surgeon Br. Joseph Souberbeille (1754–1846). A wax model of her head is on display at the Mütter Museum, The College of Physicians of Philadelphia, US. The Shope papilloma virus can cause rabbits to grow horns. This may have been the source of myths such as the Wolpertinger and the Jackalope. See also Wart Actinic keratosis Epidermodysplasia verruciformis List of cutaneous conditions References Further reading Matthew Moore (2007-11-12). "Tree man who grew roots may be cured". London: Daily Telegraph. Archived from the original on 2007-11-13. Retrieved 2007-11-14. "Images of cutaneous horns". DermAtlas. Archived from the original on 2003-04-19. Retrieved 2007-11-14. DiClaudio, Dennis (2006) "The Hypochondriacs Pocket Guide to Horrible Diseases You Probably Already Have", Bloomsbury Publishing, ISBN 978-1-59691-061-4 == External links ==

Lecithin cholesterol acyltransferase deficiency

Lecithin cholesterol acyltransferase deficiency is a disorder of lipoprotein metabolism. The disease has two forms: Familial LCAT deficiency, in which there is complete LCAT deficiency, and Fish-eye disease, in which there is a partial deficiency.Lecithin cholesterol acyltransferase catalyzes the formation of cholesterol esters in lipoproteins. Signs and symptoms Symptoms of the familial form include visual impairment caused by diffuse corneal opacities, target cell hemolytic anemia, and kidney failure. Less common symptoms include atherosclerosis, hepatomegaly (enlarged liver), splenomegaly (enlarged spleen), and enlarged lymph nodes.Fish-eye disease is less severe and most commonly presents with impaired vision due to corneal opacification. It rarely presents with other findings, although, atherosclerosis, hepatomegaly, splenomegaly, and lymphadenopathy can occur. Carlson and Philipson found that the disease was named so because the cornea of the eye was so opaque or cloudy with dots of cholesterol that it resembled a boiled fish.If an individual only carries one copy of the mutated gene, they typically do not show symptoms. Pathophysiology A deficiency of LCAT causes accumulation of unesterified cholesterol in certain body tissues. Cholesterol effluxes from cells as free cholesterol and is transported in HDL as esterified cholesterol. LCAT is the enzyme that esterifies the free cholesterol on HDL to cholesterol ester and allows the maturation of HDL. LCAT deficiency does not allow for HDL maturation resulting in its rapid catabolism of circulating apolipoprotein A1 and apolipoprotein A2. The remaining form of HDL resembles nascent HDL.The LCAT glycoprotein produces lysophosphatidylcholine and cholesterol ester and binds to lipoproteins after being secreted by the liver. Usually the enzyme produced is responsible for cholesterol ester formation and high density lipoprotein (HDL) metabolism, but in fish-eye disease the enzyme cannot esterify, or make the acid into an alkyl, cholesterol in HDL particles. However, there is only a partial deficiency because the enzyme remains active on the cholesterol particles in very low density lipoproteins (VLDL) and low density lipoproteins (LDL). The opaqueness of the eye is caused by the deposit of lipids onto the cornea. Diagnosis Definitive diagnosis requires LCAT gene analysis for mutation and functional activity. However, numerous lab tests may help with making a diagnosis such as complete blood count (CBC), urinalysis, blood chemistries, lipid panels, and plasma LCAT activity.Fish-eye disease is characterized by abnormalities like visual impairment, plaques of fatty material, and dense opacification. Types Both the familial type and Fish-eye disease are autosomal recessive disorders caused by mutations of the LCAT gene located on chromosome 16q22.1, which is the long (q) arm of chromosome 16 a position 22.1. Both diseases are very rare with ~70 reported cases of familial LCAT deficiency and ~30 cases of fish-eye disease. Familial LCAT Deficiency Lab Findings CBC: normochromic normocytic anemia Urinalysis: proteinuria in young adults (suggestive of kidney failure) Blood Chemistries: elevated blood urea nitrogen (BUN) and creatinine (suggestive of kidney failure) Lipid Panel: low high-density lipoprotein (HDL) < 10 mg/dL, elevated very low-density lipoprotein (VLDL) and triglycerides, high plasma unesterified cholesterol, and low plasma cholesterol ester Plasma LCAT activity: decreased (determined by decreased ability to esterify radioactive cholesterol in exogenous lipoproteins) Fish-eye Disease Lab Findings CBC: no anemia Urinalysis: no protein in the urine Blood Chemistries: normal blood urea nitrogen (BUN) and creatinine (no signs of kidney failure) Lipid Panel: low high-density lipoprotein (HDL) < 10 mg/dL, elevated very low-density lipoprotein (VLDL) and triglycerides, high plasma unesterified cholesterol in HDL particles, and low cholesterol ester in HDL particles but normal levels in low-density lipoprotein (LDL) and VLDL particles Plasma LCAT activity: decreased only in HDL particles but not LDL Genetic Findings in Fish-eye Disease Mutations in the LCAT gene, which is localized in the q21–22 region of chromosome 16, cause fish-eye disease. The mutation in the LCAT gene is homozygous for a Thr123→Ile mutation or Pro10→Leu mutation. New mutations have been identified as homozygosity for an A2205→G nucleotide substitution in exon 4 of the LCAT gene which is predicted to be the cause of an Asp131→Asn substitution. Treatment Currently, there is no specific treatment to correct the LCAT deficiency so therapy is focused on symptom relief. Corneal transplant may be considered for patients presenting with severely impaired vision caused by cholesterol corneal opacities. Dialysis may be required for patients presenting with kidney failure, and kidney transplant may be considered. Prognosis Kidney failure is the major cause of morbidity and mortality in complete LCAT deficiency, while in partial deficiency (fish eye disease) major cause of morbidity is visual impairment due to corneal opacity. These patients have low HDL cholesterol but surprisingly premature atherosclerosis is not seen. However, there are some reported cases. References == External links ==

Micropsia

Micropsia is a condition affecting human visual perception in which objects are perceived to be smaller than they actually are. Micropsia can be caused by optical factors (such as wearing glasses), by distortion of images in the eye (such as optically, via swelling of the cornea or from changes in the shape of the retina such as from retinal edema, macular degeneration, or central serous retinopathy), by changes in the brain (such as from traumatic brain injury, epilepsy, migraines, prescription drugs, and illicit drugs), and from psychological factors. Dissociative phenomena are linked with micropsia, which may be the result of brain-lateralization disturbance.Micropsia is also commonly reported when the eyes are fixating at (convergence), or focusing at (accommodation), a distance closer than that of the object in accord with Emmerts law. Specific types of micropsia include hemimicropsia, a form of micropsia that is localized to one half of the visual field and can be caused by brain lesions in one of the cerebral hemispheres. Related visual distortion conditions include macropsia, a less common condition with the reverse effect, and Alice in Wonderland syndrome, a condition that has symptoms that can include both micropsia and macropsia. Signs and symptoms Micropsia causes affected individuals to perceive objects as being smaller or more distant than they actually are.The majority of individuals with micropsia are aware that their perceptions do not mimic reality. Many can imagine the actual sizes of objects and distances between objects. It is common for patients with micropsia to be able to indicate true size and distance despite their inability to perceive objects as they actually are. One specific patient was able to indicate the dimensions of specific objects with her hands. She was also able to estimate the distances between two objects and between an object and herself. She succeeded in indicating horizontal, vertical, and 45 degree positions and did not find it difficult to search for an object in a cluttered drawer, indicating that her figure-ground discrimination was intact despite having micropsia.Individuals experiencing hemimicropsia often complain that objects in their left or right visual field appear to be shrunken or compressed. They may also have difficulty appreciating the symmetry of pictures. When drawing, patients often have a tendency to compensate for their perceptual asymmetry by drawing the left or right half of objects slightly larger than the other. In a case of one person with hemimicropsia asked to draw six symmetrical objects, the size of the picture on the left half was on average 16% larger than the corresponding right half. Diagnosis EEG testing can diagnose patients with medial temporal lobe epilepsy. Epileptiform abnormalities including spikes and sharp waves in the medial temporal lobe of the brain can diagnose this condition, which can in turn be the cause of an epileptic patients micropsia.The Amsler grid test can be used to diagnose macular degeneration. For this test, patients are asked to look at a grid, and distortions or blank spots in the patients central field of vision can be detected. A positive diagnosis of macular degeneration may account for a patients micropsia.A controlled size comparison task can be employed to evaluate objectively whether a person is experiencing hemimicropsia. For each trial, a pair of horizontally aligned circles is presented on a computer screen, and the person being tested is asked to decide which circle is larger. After a set of trials, the overall pattern of responses should display a normal distance effect where the more similar the two circles, the higher the number of errors. This test is able to effectively diagnose micropsia and confirm which hemisphere is being distorted.Due to the large range of causes that lead to micropsia, diagnosis varies among cases. Computed tomography (CT) and magnetic resonance imaging (MRI) may find lesions and hypodense areas in the temporal and occipital lobes. MRI and CT techniques are able to rule out lesions as the cause for micropsia, but are not sufficient to diagnose the most common causes. Definition Micropsia is the most common visual distortion, or dysmetropsia. It is categorized as an illusion in the positive phenomena grouping of abnormal visual distortions. Convergence-accommodative micropsia is a physiologic phenomenon in which an object appears smaller as it approaches the subject. Psychogenic micropsia can present itself in individuals with certain psychiatric disorders. Retinal micropsia is characterized by an increase in the distance between retinal photoreceptors and is associated with decreased visual acuity. Cerebral micropsia is a rare form of micropsia that can arise in children with chronic migraines. Hemimicropsia is a type of cerebral micropsia that occurs within one half of the visual field. Differential diagnosis Of all of the visual distortions, micropsia has the largest variety of causes. Migraines Micropsia can occur during the aura phase of a migraine attack, a phase that often precedes the onset of a headache and is commonly characterized by visual disturbances. Micropsia, along with hemianopsia, quadrantopsia, scotoma, phosphene, teicopsia, metamorphopsia, macropsia, teleopsia, diplopia, dischromatopsia, and hallucination disturbances, is a type of aura that occurs immediately before or during the onset of a migraine headache. The symptom usually occurs less than thirty minutes before the migraine headache begins and lasts for five to twenty minutes. Only 10-20% of children with migraine headaches experience auras. Visual auras such as micropsia are most common in children with migraines. Seizures The most frequent neurological origin of micropsia is a result of temporal lobe seizures. These seizures affect the entire visual field of the patient. More rarely, micropsia can be part of purely visual seizures. This in turn only affects one half of the visual field and is accompanied by other cerebral visual disturbances. The most common cause of seizures which produce perceptual disturbances such as micropsia and macropsia is medial temporal lobe epilepsy in which the seizures originate in the amygdala-hippocampus complex. Micropsia often occurs as an aura signalling a seizure in patients with medial temporal lobe epilepsy. Most auras last for a very short period, ranging from a few seconds to a few minutes. Drug use Micropsia can result from the action of mescaline and other hallucinogenic drugs. Although drug-induced changes in perception usually subside as the chemical leaves the body, long-term cocaine use can result in the chronic residual effect of micropsia. Micropsia can be a symptom of Hallucinogen Persisting Perception Disorder, or HPPD, in which a person can experience hallucinogenic flashbacks long after ingesting a hallucinogen. A majority of these flashbacks are visual distortions which include micropsia, and 15-80% of hallucinogen users may experience these flashbacks. Micropsia can also be a rare side effect of zolpidem, a prescription medication used to temporarily treat insomnia. Psychological factors Psychiatric patients may experience micropsia in an attempt to distance themselves from situations involving conflict. Micropsia may also be a symptom of psychological conditions in which patients visualize people as small objects as a way to control others in response to their insecurities and feelings of weakness. In some adults who experienced loneliness as children, micropsia may arise as a mirror of prior feelings of separation from people and objects. Epstein-Barr virus infection Micropsia can be caused by swelling of the cornea due to infection by the Epstein-Barr virus (EBV) and can therefore present as an initial symptom of EBV mononucleosis, a disease caused by Epstein-Barr virus infection. Retinal edema Micropsia can result from retinal edema causing a dislocation of the receptor cells. Photoreceptor misalignment seems to occur following the surgical re-attachment for macula-off rhegmatogenous retinal detachment. After surgery, patients may experience micropsia as a result of larger photoreceptor separation by edematous fluid. Macular degeneration Macular degeneration typically produces micropsia due to the swelling or bulging of the macula, an oval-shaped yellow spot near the center of the retina in the human eye. The main factors leading to this disease are age, smoking, heredity, and obesity. Some studies show that consuming spinach or collard greens five times a week cuts the risk of macular degeneration by 43%. Central serous chorioretinopathy CSCR is a disease in which a serous detachment of the neurosensory retina occurs over an area of leakage from the choriocapillaris through the retinal pigment epithelium (RPE). The most common symptoms that result from the disease are a deterioration of visual acuity and micropsia. Brain lesions Micropsia is sometimes seen in individuals with brain infarctions. The damaged side of the brain conveys size information that contradicts the size information conveyed by the other side of the brain. This causes a contradiction to arise between the true perception of an objects size and the smaller perception of the object, and micropsic bias ultimately causes the individual to experience micropsia. Lesions affecting other parts of the extracerebral visual pathways can also cause micropsia. Treatment Treatment varies for micropsia due to the large number of different causes for the condition.Treatments involving the occlusion of one eye and the use of a prism fitted over an eyeglass lens have both been shown to provide relief from micropsia.Micropsia that is induced by macular degeneration can be treated in several ways. A study called AREDS (age-related eye disease study) determined that taking dietary supplements containing high-dose antioxidants and zinc produced significant benefits with regard to disease progression. This study was the first ever to prove that dietary supplements can alter the natural progression and complications of a disease state. Laser treatments also look promising but are still in clinical stages. Epidemiology Episodes of micropsia or macropsia occur in 9% of adolescents.10-35% of those with migraines experience auras, with 88% of these patients experiencing both visual auras (which include micropsia) and neurological auras.Micropsia seems to be slightly more common in boys than in girls among children who experience migraines.Approximately 80% of temporal lobe seizures produce auras that may lead to micropsia or macropsia. They are a common feature of simple partial seizures and usually precede complex partial seizures of temporal lobe origin.Central Serous Chorioretinopathy (CSCR) which can produce micropsia predominantly affects persons between the ages of 20 and 50. Women appear to be affected more than men by a factor of almost 3 to 1. Society and culture Comparison with Alices Adventures in Wonderland Alice in Wonderland Syndrome, a neurological condition associated with both micropsia and macropsia, is named after Lewis Carrolls famous 19th century novel Alices Adventures in Wonderland. In the story, the title character, Alice, experiences numerous situations similar to those of micropsia and macropsia. Speculation has arisen that Carroll may have written the story using his own direct experience with episodes of micropsia resulting from the numerous migraines he was known to have. It has also been suggested that Carroll may have had temporal lobe epilepsy. Comparison with Gullivers Travels Micropsia has also been related to Jonathan Swifts novel Gullivers Travels. It has been referred to as "Lilliput sight" and "Lilliputian hallucination," a term coined by British physician Raoul Leroy in 1909, based on the small people that inhabited the island of Lilliput in the novel. Research Current experimental evidence focuses on the involvement of the occipitotemporal pathway in both the perceptual equivalence of objects across translations of retinal position and also across size modifications. Recent evidence points to this pathway as a mediator for an individuals perception of size. Even further, numerous cases suggest that size perception may be dissociated from other aspects of visual perception such as color and movement. However, more research is called for to correctly relate the condition to defined physiological conditions.Current research is being done on macular degeneration which could help prevent cases of micropsia. A variety of drugs that block vascular endothelial growth factors (VEGFs) are being evaluated as a treatment option. These treatments for the first time have produced actual improvements in vision, rather than simply delaying or arresting the continued loss of vision characteristic of macular degeneration. A number of surgical treatments are also being investigated for macular degeneration lesions that may not qualify for laser treatment, including macular translocation to a healthier area of the eye, displacement of submacular blood using gas, and removing membranes by surgery. See also Alice in Wonderland syndrome Convergence micropsia Dysmetropsia Macropsia References External links Medical Dictionary: Micropsia Web-Md: Migraines in Children

Primary progressive aphasia

Primary progressive aphasia (PPA) is a type of neurological syndrome in which language capabilities slowly and progressively become impaired. As with other types of aphasia, the symptoms that accompany PPA depend on what parts of the left hemisphere are significantly damaged. However, unlike most other aphasias, PPA results from continuous deterioration in brain tissue, which leads to early symptoms being far less detrimental than later symptoms. Those with PPA slowly lose the ability to speak, write, read, and generally comprehend language. Eventually, almost every patient becomes mute and completely loses the ability to understand both written and spoken language. Although it was first described as solely impairment of language capabilities while other mental functions remain intact, it is now recognized that many, if not most of those with PPA experience impairment of memory, short-term memory formation and loss of executive functions. It was first described as a distinct syndrome by M.‑Marsel Mesulam in 1982. Primary progressive aphasias have a clinical and pathological overlap with the frontotemporal lobar degeneration (FTLD) spectrum of disorders and Alzheimers disease. However, PPA is not considered synonymous to Alzheimers disease due to the fact that, unlike those affected by Alzheimers disease, those with PPA are generally able to maintain the ability to care for themselves, remain employed, and pursue interests and hobbies. Moreover, in diseases such as Alzheimers disease, Picks disease, and Creutzfeldt-Jakob disease, progressive deterioration of comprehension and production of language is just one of the many possible types of mental deterioration, such as the progressive decline of memory, motor skills, reasoning, awareness, and visuospatial skills. Causes Currently, the specific causes for PPA and other degenerative brain disease similar to PPA are unknown. Autopsies have revealed a variety of brain abnormalities in people who had PPA. These autopsies, as well as imaging techniques such as CT scans, MRI, EEG, single photon emission computed tomography (SPECT), and positron emission tomography (PET), have generally revealed abnormalities to be almost exclusively in the left hemisphere. Risk factors There have been no large epidemiological studies on the incidence and prevalence of the PPA variants. Though it most likely has been underestimated, onset of PPA has been found to occur in the sixth or seventh decade.There are no known environmental risk factors for the progressive aphasias. However, one observational, retrospective study suggested that vasectomy could be a risk factor for PPA in men. These results have yet to be replicated or demonstrated by prospective studies.PPA is not considered a hereditary disease. However, relatives of a person with any form of frontotemporal lobar degeneration, including PPA, are at slightly greater risk of developing PPA or another form of the condition. In a quarter of patients diagnosed with PPA, there is a family history of PPA or one of the other disorders in the FTLD spectrum of disorders. It has been found that genetic predisposition varies among the different PPA variants, with PNFA being more commonly familial in nature than LPA or SD.The most convincing genetic basis of PPA has been found to be a mutation in the GRN gene. Most patients with observed GRN mutations present clinical features of PNFA, but the phenotype can be atypical. Diagnosis Diagnostic criteria The following diagnosis criteria were defined by Mesulam: As opposed to having followed trauma to the brain, a patient must show an insidious onset and a gradual progression of aphasia, defined as a disorder of sentence and/or word usage, affecting the production and comprehension of speech. The disorder in question must be the only determinant on functional impairment in the activities of the patients daily living. On the basis of diagnostic procedures, the disorder in question must be unequivocally attributed to a neurodegenerative process.Whether or not PPA and other aphasias are the only source of cognitive impairment in a patient is often difficult to assess because: 1) as with other neurologically degenerative diseases, such as Alzheimers disease, there are currently no reliable non-invasive diagnostic tests for aphasias, and thus neuropsychological assessments are the only tool physicians have for diagnosing patients; and 2) aphasias often affect other, non-language portions of these neuropsychological tests, such as those specific for memory. Classification In 2011, the classification of primary progressive aphasia was updated to include three clinical variants. Patients must first be diagnosed with PPA, and then divided into variants based on speech production features, repetition, single- word and syntax comprehension, confrontation naming, semantic knowledge, and reading/spelling. In the classical Mesulam criteria for primary progressive aphasia, there are two variants: a non-fluent type progressive nonfluent aphasia (PNFA) and a fluent type semantic dementia (SD). A third variant of primary progressive aphasia, logopenic progressive aphasia (LPA) was then added, and is an atypical form of Alzheimers disease. For PNFA, The core criteria for diagnosis includes agrammatism and slow, and labored speech. Inconsistent speech sound errors are also very common, including distortions, deletions, and insertions. In terms of comprehension, there are deficits in syntax and sentence comprehension due to grammatical complexity, but single- word and object comprehension is relatively maintained. The second variant, SD, presents with deficits in single-word and object comprehension. Naming impairments can be severe, specially for low-frequency objects, and can eventually lead to a more widespread semantic memory deficiency over time. The ability to read and write can also be impaired if there are irregularities between pronunciation and spelling. However, repetition and motor speech is relatively preserved. The logopenic variant involves impairments in word retrieval, sentence repetition, and phonological paraphasias, comparable to conduction aphasia. Compared to the semantic variant, single word comprehension and naming is spared, however, sentence comprehension presents difficulty because of length and grammatical complexity. Speech will include incomplete words, hesitations preceding content words, and repetition. However, these PPA subtypes differ from similar aphasias, as these subtypes do not occur acutely following trauma to the brain, such as following a stroke, due to differing functional and structural neuroanatomical patterns of involvement and the progressive nature of the disease. Treatment Due to the progressive, continuous nature of the disease, improvement over time seldom occurs in patients with PPA as it often does in patients with aphasias caused by trauma to the brain.In terms of medical approaches to treating PPA, there are currently no drugs specifically used for patients with PPA, nor are there any specifically designed interventions for PPA. A large reason for this is the limited research that has been done on this disease. However, in some cases, patients with PPA are prescribed the same drugs Alzheimers patients are normally prescribed.The primary approach to treating PPA has been with behavioral treatment, with the hope that these methods can provide new ways for patients to communicate in order to compensate for their deteriorated abilities. Speech therapy can assist an individual with strategies to overcome difficulties. There are three very broad categories of therapy interventions for aphasia: restorative therapy approaches, compensatory therapy approaches, and social therapy approaches. Rapid and sustained improvement in speech and dementia in a patient with primary progressive aphasia utilizing off-label perispinal etanercept, an anti-TNF treatment strategy also used for Alzheimers, has been reported. A video depicting the patients improvement was published in conjunction with the print article. These findings have not been independently replicated and remain controversial. History M.-Marsel Mesulam coined the term primary progressive aphasia. See also References Further reading Amici S, Ogar J, Brambati SM, et al. (Dec 2007). "Performance in specific language tasks correlates with regional volume changes in progressive aphasia". Cognitive & Behavioral Neurology. 20 (4): 203–11. doi:10.1097/WNN.0b013e31815e6265. PMID 18091068. S2CID 18090918. Gliebus G (March 2010). "Primary progressive aphasia: clinical, imaging, and neuropathological findings". Am J Alzheimers Dis Other Demen. 25 (2): 125–7. doi:10.1177/1533317509356691. PMID 20124255. S2CID 29195502. Henry ML, Beeson PM, Alexander GE, Rapcsak SZ (February 2012). "Written language impairments in primary progressive aphasia: a reflection of damage to central semantic and phonological processes". J Cogn Neurosci. 24 (2): 261–75. doi:10.1162/jocn_a_00153. PMC 3307525. PMID 22004048. Henry ML, Gorno-Tempini ML (December 2010). "The logopenic variant of primary progressive aphasia". Current Opinion in Neurology. 23 (6): 633–7. doi:10.1097/WCO.0b013e32833fb93e. PMC 3201824. PMID 20852419. Reilly J, Rodriguez AD, Lamy M, Neils-Strunjas J (2010). "Cognition, language, and clinical pathological features of non-Alzheimers dementias: an overview". J Commun Disord. 43 (5): 438–52. doi:10.1016/j.jcomdis.2010.04.011. PMC 2922444. PMID 20493496. Rohrer JD, Knight WD, Warren JE, Fox NC, Rossor MN, Warren JD (January 2008). "Word-finding difficulty: a clinical analysis of the progressive aphasias". Brain. 131 (Pt 1): 8–38. doi:10.1093/brain/awm251. PMC 2373641. PMID 17947337. == External links ==

Coffin–Lowry syndrome

Coffin–Lowry syndrome is a genetic disorder that is X-linked dominant and which causes severe mental problems sometimes associated with abnormalities of growth, cardiac abnormalities, kyphoscoliosis, as well as auditory and visual abnormalities. Presentation Symptoms of disease are more severe in males, who are generally diagnosed in early childhood. Children with CLS display cognitive disabilities of varying severity. Additional neuromuscular features include sleep apnea, muscular spasticity, progressive loss of muscle strength and tone leading to paraplegia or partial paralysis. Affected individuals are at elevated risk of stroke. Some patients experience stimulus-induced drop attacks (SIDAs, temporary paralytic episodes without loss of consciousness), triggered by unpredictable environmental stimuli (touch, scents, sounds, etc.). SIDA episodes become more frequent as the disease progresses, and become frequent around adolescence in males. Additional clinical physical features include small, soft hands with tapered fingers. Distinct facial architecture such as a flattened nose, widely separated and downward sloping eyes, a prominent forehead, and a wide mouth with large lips are reported as coincident facial features in patients with the disorder. Some individuals experience hearing loss. Others display kyphoscoliosis (multidirectional curvature of the spine) which can lead to difficulty with breathing and/or pulmonary hypertension. Cardiorespiratory complications may arise, which is why it is recommended that CLS patients undergo regular monitoring for spinal irregularities. Physical exams, CT imaging and X-ray imaging are standard methods of assessment. Causes The syndrome is caused by mutations in the RPS6KA3 gene. This gene is located on the short arm of the X chromosome (Xp22.2). The RPS6KA3 gene makes a protein that is involved with signaling within cells. Researchers believe that this protein helps control the activity of other genes and plays an important role in the brain. The protein is involved in cell signaling pathways that are required for learning, the formation of long-term memories, and the survival of nerve cells. The protein RSK2 which is encoded by the RPS6KA3 gene is a kinase which phosphorylates some substrates like CREB and histone H3. RSK2 is involved at the distal end of the Ras/MAPK signaling pathway. Mutations in the RPS6KA3 disturb the function of the protein, but it is unclear how a lack of this protein causes the signs and symptoms of Coffin–Lowry syndrome. At this time more than 120 mutations have been found. Some people with the features of Coffin–Lowry syndrome do not have identified mutations in the RPS6KA3 gene. In these cases, the cause of the condition is unknown.This condition is inherited in an X-linked dominant pattern. A condition is considered X-linked if the gene that causes the disorder is located on the X chromosome (one of the two sex chromosomes). The inheritance is dominant if one copy of the altered gene is sufficient to cause the condition.A majority of boys with Coffin–Lowry syndrome have no history of the condition in their families. These cases are caused by new mutations in the RPS6KA3 gene (de novo mutations). A new mutation means that neither parent has the altered gene, but the affected individual could pass it on to his children. Genetics Coffin–Lowry syndrome is an X-linked disorder resulting from loss-of-function mutations in the RPS6KA3 gene, which encodes RSK2 (ribosomal S6 kinase 2). Multiple mutations have been identified in RPS6KA3 that can give rise to the disorder, including missense mutations, nonsense mutations, insertions and deletions. Individuals with CLS rarely have affected parents, suggesting that most incidents arise from de novo mutations in the germline. The lack of an inheritance pattern may be due to the fact that affected individuals are unlikely to parent children. In 20–30% of cases, however, there is a family history of disease. In these cases, the disorder is typically inherited from the maternal parent. Because RPS6KA3 is located on the X chromosome, males (who possess only one copy of the X chromosome) display more severe symptoms than females. Affected females usually possess one mutated copy of the RPS6KA3 gene and one wild type copy. Random inactivation of one copy of the X chromosome in females mitigates the impact of possessing a mutant allele. Occasionally females are born with two mutated alleles. In these cases the symptoms are as severe as in males with the disease. Cell physiology Mutations in the RPS6KA3 gene can result in expression of an RSK2 protein (ribosomal S6 kinase 2) with reduced or absent kinase function. RSK2 is a downstream component of the MAPK (mitogen-activated protein kinase) cascade that is itself a kinase. RSK2 phosphorylates cellular proteins (including histone H3, and CREB), which regulate eukaryotic gene expression. In individuals with Coffin–Lowry syndrome, phosphorylation of transcriptional regulators is reduced due to the weakened activity of RSK2 kinase activity. RSK2 is normally activated by the ERK MAP kinase. Mutated RSK2 may be deficient for activation by ERK, or its kinase activity may be reduced despite activation by ERK. The most common mutation in RPS6KA3 is an early stop codon that fails to produce a functional protein, indicating that disease etiology most likely arises from loss-of-function effects. Substitution mutations (which alter a single amino acid) have also been shown to give rise to the disease. RSK2 is highly expressed in the brain, specifically in the neocortex, hippocampus, and Purkinje cells, all of which are involved in cognitive function and behavior. There is some experimental evidence that RSK2 regulates synaptic transmission and plasticity in neuronal cell types. Diagnosis Affected individuals are often short in stature. Behavioral symptoms include aggression and depression, but these may be secondary to the emotional consequences of significant physical disabilities associated with the disorder.Coffin–Lowry patients may be affected by chewing and swallowing difficulties, for which there are diagnostic assessments. Among these are the Videofluoroscopic Swallowing Evaluation (VFSE), the Karaduman Chewing Performance Scale, and the Penetration Aspiration Scale (PAS) which is used to evaluate accidental aspiration of food particles. The Pediatric Assessment Tool (PEDI-EAT-10) also includes measurement of severity of dysphagia (difficulty in swallowing). Molecular genetic testing can be used to confirm the genetic diagnosis of Coffin–Lowry syndrome or to assess pregnancy risk in affected families.Symptoms table: Generally symptoms listed as "rare" are common in more severe cases. Imaging studies X-ray and neuroimaging studies may be helpful in confirming a diagnosis of Coffin–Lowry syndrome. Decreased ribosomal S6 kinase activity in cultured fibroblast or transformed lymphoblast cells from a male indicates Coffin–Lowry syndrome. Studies of enzyme activity can not be used to diagnose an affected female.Molecular genetic testing on a blood specimen or cells from a cheek swab is available to identify mutations in the RSK2 gene. This testing can be used to confirm but not rule out the diagnosis of Coffin–Lowry syndrome because not all affected individuals have a detectable mutation. Treatment There is no cure for Coffin–Lowry syndrome. Clinical objectives are centered on symptom management. Because stimulus-induced drop attacks (SIDAs) can result in physical harm to patients with the disorder, the use of medication to prevent or reduce the number of SIDA episodes is a safety priority. Physical precautionary measures have also been used to protect patients from injury, including the use of a helmet or a wheelchair. Because sudden excitement or fright can trigger a SIDA episode it is important to minimize exposure to startling stimuli. Medications prescribed include benzodiazepines (tranquilizers used to treat anxiety), valproate (used to manage epilepsy and bipolar disorder), and selective serotonin reuptake inhibitors (SSRIs) (used to treat major depression). When affected individuals display aggressive or destructive behavior that could harm themselves or others, the antipsychotic medication risperidone may eventually be prescribed. It is recommended that spinal development be monitored regularly by X-ray and physical exams. Echocardiograms are recommended every 5–10 years to assess cardiac function and development. Families are encouraged to receive genetic counseling in order to understand and prepare to provide care for children affected by Coffin–Lowry syndrome. Prognosis Lifespan may be significantly shortened in males with Coffin–Lowry syndrome. Patients may survive into their late twenties, but generally die young due to cardiac, respiratory, and post-operative complications. The progression of reduced cardiac functioning over time may necessitate surgical procedures to counteract mitral valve dysfunction, congenital heart disease, patent ductus arteriosus, and ventricular hypertrophy. Kyphoscoliosis may worsen over time and contribute to these pathologies. Epidemiology The prevalence of CLS is uncertain due to the rarity of the disease, but CLS is estimated to affect between 1 in 50,000 and 1 in 100,000 people. Prenatal testing is available to test for CLS of an offspring if a family member has been diagnosed with CLS. History Coffin–Lowry was first described by Grange S. Coffin (b. 1923) in 1966 and independently by Robert Brian Lowry (b. 1932) in 1971. Dr. Temtamy showed that the cases represented a single syndrome in 1975.In 1972, Peter G. Procopis and B. Turner published a case study on a family of four brothers with Coffin-Lowry Syndrome, with female relatives, specifically sisters, only possessing some mild deformities and abnormalities. In 1975, Samia Temtamy reported eight patients from three different families displaying symptoms of Coffin-Lowry Syndrome, suggesting that the disorder is more common than believed and often goes underdiagnosed. On the basis of these reports, AG Hunter, Simone Gilgenkrantz, and ID Young established Coffin-Lowry Syndrome as a novel medical diagnosis and named it for the two doctors to originally describe its clinical symptoms. Additional case studies have since expanded the original list of clinical signs and symptoms. In 2002, Helen Fryssira and RJ Simensen identified a 3 base pair deletion in the gene encoding RSK2, which was the first report of the gene responsible for Coffin-Lowry. Culture The Coffin–Lowry Syndrome Foundation acts as a clearinghouse for information on Coffin–Lowry syndrome and hosts a forum for affected families. The family matching program facilitates community building and resource sharing for recent diagnoses.The Coffin-Lowry Syndrome Foundation was created in 1991. The mission of the Foundation is to provide informational links, resources, and databases to families and patients dealing with the disease and enables them to communicate with one another. Families and patients can share their experiences and retrieve advice on the foundations online site as well as locate helpful services, telephone support, and day-to-day news on medical progress into understanding and treating those affected by Coffin-Lowry Syndrome. The symbol of the foundation is an apple, chosen for its representation of knowledge, feminine beauty, immortality, rebirth, and peace. The foundation provides a support network and source of hope for the families of patients with Coffin-Lowry Syndrome. References Sources This article incorporates public domain text from The U.S. National Library of Medicine and the National Institute of Neurological Disorders and Stroke. External links GeneReviews/UW/NIH entry on Coffin–Lowry syndrome Coffin-Lowry syndrome: MedlinePlus Genetics

Transverse nasal crease

The transverse nasal crease or groove is a usually white line between the upper two-thirds and the lower third of the human nose (slightly above the cartilage tip between the bridge and nostrils). It can occur as the result of heredity, accident, or the constant rubbing or wiping of the nose, commonly referred to as the allergic salute. Occurrence In addition to cases caused by heredity, physical injury, the transverse nasal crease is common in children and adults with chronic nasal allergies. People with allergies often use their hands to remove mucus from a runny nose or rub an itchy nose. As the hand slides upward, the tip of the nose is pressed up, thus creating the crease. Appearance The appearance of the line depends on skin pigmentation. On lighter-skinned people, the transverse nasal crease is lighter in color than the surrounding skin, and may appear white. This is due to hypopigmentation resulting from the low level of melanin present in the damaged skin. In darker-skinned people, the line may appear darker than the surrounding skin. == References ==

Aniseikonia

Aniseikonia is an ocular condition where there is a significant difference in the perceived size of images. It can occur as an overall difference between the two eyes, or as a difference in a particular meridian. If the ocular image size in both eyes are equal, the condition is known as iseikonia. Symptoms and signs Up to 7% difference in image size is well tolerated. If magnification difference becomes excessive the effect can cause diplopia, suppression, disorientation, eyestrain, headache, and dizziness and balance disorders. Asthenopic symptoms alone may occur even if image size difference is less than 7%. Causes Retinal image size is determined by many factors. The size and position of the object being viewed affects the characteristics of the light entering the system. Corrective lenses affect these characteristics and are used commonly to correct refractive error. The optics of the eye including its refractive power and axial length also play a major role in retinal image size.Aniseikonia can occur naturally or be induced by the correction of a refractive error, usually anisometropia (having significantly different refractive errors between each eye) or antimetropia (being myopic (nearsighted) in one eye and hyperopic (farsighted) in the other.) Meridional aniseikonia occurs when these refractive differences only occur in one meridian (see astigmatism). One cause of significant anisometropia and subsequent aniseikonia has been aphakia. Aphakic patients do not have a crystalline lens. The crystalline lens is often removed because of opacities called cataracts. The absence of this lens left the patient highly hyperopic (farsighted) in that eye. For some patients the removal was only performed on one eye, resulting in the anisometropia / aniseikonia. Today, this is rarely a problem because when the lens is removed in cataract surgery, an intraocular lens, or IOL is left in its place.Retinal aniseikonia occur due to forward displacement, stretching or edema of retina. Diagnosis A way to demonstrate aniseikonia is to hold a near target (e.g., a pen or a finger) approximately 6 inches directly in front of one eye. The person then closes one eye, and then the other. The person should notice that the target appears larger to the eye that it is directly in front of. When this object is viewed with both eyes, it is seen with a small amount of aniseikonia. The principles behind this demonstration are relative distance magnification (closer objects appear larger) and asymmetrical convergence (the target is not an equal distance from each eye). Treatment Optical aniseikonia due to anisometropia can be corrected by spectacles, contact lenses or refractive corneal surgeries.Spectacle correction is done by changing the optical magnification properties of the auxiliary optics (corrective lenses). The optical magnification properties of spectacle lenses can be adjusted by changing parameters like the base curve, vertex distance, and center thickness. Magnification size matched lenses that are used to correct aniseikonia are known as iseikonic lenses.Contact lenses may also provide less difference in retinal image size. Wider and better field of vision is another benefit of contact lens use. The difference in magnification can also be eliminated by a combination of contact lenses and glasses (creating a weak telescope system). The optimum design solution will depend on different parameters like cost, cosmetic implications, and if the patient can tolerate wearing a contact lens.For reducing aniseikonia, similar to contact lens correction, optical image size difference will be reduced in refractive surgeries also.Aniseikonia due to uniocular aphakia is best corrected surgically by intraocular lens implantation. Similarly retinal aniseikonia is corrected by treating causative retinal disease.Note however that before the optics can be designed, first the aniseikonia should be measured. When the image disparity is astigmatic (cylindrical) and not uniform, images can appear wider, taller, or diagonally different. When the disparity appears to vary across the visual field (field-dependent aniseikonia), as may be the case with an epiretinal membrane or retinal detachment, the aniseikonia cannot fully be corrected with traditional optical techniques like standard corrective lenses. However, partial correction often improves the patients vision comfort significantly. Etymology The word "aniseikonia" is derived from the following Greek morphemes: "an" = "not" (as in "anæmia"); "is(o)" = "equal" (as in "isobar"); "eikōn" = "image" (as in "icon"). See also Adelbert Ames, Jr. (Dartmouth Eye Institute, research in the 1930s and 1940s on aniseikonia) Anisometropia Macropsia Micropsia References Further reading Bannon, Robert E.; Neumueller, Julius; Boeder, Paul; Burian, Hermann M. (June 1970), "Aniseikonia and space perception: After 50 years", American Journal of Optometry & Archives of American Academy of Optometry, 47 (6): 423–441, doi:10.1097/00006324-197006000-00001, PMID 4912937, S2CID 37288776 Bisno, David C. (1994), Eyes in the Storm—President Hopkins Dilemma: The Dartmouth Eye Institute, Norwich, Vermont: Norwich Book Press, p. 288 External links Aniseikonia Calculator, Chadwick Optical (U.S.A.) — a magnification calculator for iseikonic prescriptions or aniseikonia.

Pulp stone

Pulp stones (also denticles or endoliths) are nodular, calcified masses appearing in either or both the coronal and root portion of the pulp organ in teeth. Pulp stones are not painful unless they impinge on nerves. They are classified: A) On the basis of structure 1) True pulp stones: formed of dentin by odontoblasts 2) False pulp stones: formed by mineralization of degenerating pulp cells, often in a concentric patternB) On the basis of location 1) Free: entirely surrounded by pulp tissue 2) Adherent: partly fused with dentin 3) Embedded: entirely surrounded by dentin Introduction Pulp stones are discrete calcifications found in the pulp chamber of the tooth which may undergo changes to become diffuse pulp calcifications such as dystrophic calcification. They are usually noticed by radiographic examination and appeared as round or ovoid radiopaque lesions. Clinically, a tooth with a pulp stone has normal appearance like any other tooth. The number of pulp stones in a single tooth may vary from 1 to 12 or more, with varying sizes from minute particles to large masses which tend to occlude the pulpal space. It is reported that pulp stones are more commonly found in the coronal region of pulp, albeit also found in the radicular pulp.It is believed that pulp stones develop around a central nidus of pulp tissue, for instance collagen fibril, ground substance and necrotic cell remnants. Initial calcification occurs around the central nidus and extends outward with regular calcified material in a concentric or radial manner. Etiology The pulp calcifications can arise due to: pulp degeneration increasing age circulatory disturbances within the pulp long standing local irritants such as dental caries, pulp-capping procedures, healed tooth fractures, tooth injury restorations and periodontal diseases orthodontic tooth movements transplantation of teeth traumaIt is shown that pulp stone occurring in adolescents is significantly associated with carious and/or restored teeth, which suggests a causative relationship of chronic pulp irritation to pulp stone formation. A defence reaction in the pulpodentinal complex may be triggered by caries and microleakage around restorations which lead to pulp calcifications. The formation of pulp stone may have a similar mechanism as the tertiary dentine formation near the irritated odontoblasts. Apart from that, with aging, the pulp decreases in size due to the deposition of secondary or tertiary dentine. This subsequently results in favourable conditions for the formation of pulpal calcifications. The other reported etiologic factors also include: idiopathic factors consumption of fluoride supplements hypervitaminosis D a possible genetic predisposition such as dentinogenesis imperfecta and dentinal dysplasia Types/classification Pulp stones can be classified based on different location and structure. Based on location, they can classified into free, embedded and adherent pulp stones. Free pulp stones are found within the pulp tissue and is the most common encounter. The size vary from 50μm in diameter to several millimetres and may occlude the entire pulp chamber. Embedded pulp stone is fully embedded in dentine and most commonly found in the apical portion of the root. Adherent pulp stones are attached to the wall of pulp space but not fully enclosed by dentine. Structurally, pulp stones can be classified as true and false pulp stones. True pulp stones are made up of dentine that is lined by odontoblast. True pulp stones are quite rare. On the other hand, false pulp stones are made up of concentric layers of mineralised tissue around blood thrombi, collagen fibres, or dying and dead cells. Histopathology Histologically, there are two types of stones: (1) stones with regular calcifications (2) stones with irregular calcifications. For regular calcification, the pulp stones are smooth, round or ovoid with concentric laminations. It is commonly found in the coronal pulp. As for irregular calcifications without laminations, pulp stones may have the shape of rods or leaves and the surface is rough. It is more common in the radicular pulp. Pulp stones with regular calcification grow in size by addition of collagen fibrils to their surface, whereas the irregular type of pulp stones are formed by calcification of pre-existing collagen fibres. Pulp stones may also form around epithelial cells such as remnants of Hertwigs epithelial root sheath. It is presumed that epithelial remnants are able to induce adjacent mesenchymal stem cells to differentiate into odontoblasts. Associations A pilot study was done with patients with cardiovascular disease (CVD) and it shows increased incidence of pulp stones in teeth with patients with CVD compared to healthy patients without CVD. There are also researchers which suggest the link between pulpal calcification and carotid artery calcification, despite not having a strong proof on this correlation. Besides cardiovascular disease, other disease such as end stage renal disease, Marfan syndrome, Ehlers-Danlos syndrome, Calcinosis universalis, tumoral calcinosis are also discovered to be in association with pulpal calcifications.Several genetic diseases such as dentin dysplasia and dentinogenesis imperfecta are also accompanied by pulpal calcifications and hence, Marfan syndrome was suspected to be in association with pulp stones due to abnormal dentin formation, leading to the increased frequency of pulpal calcifications in these individuals. Another theory suggests that individuals with Marfan syndrome have connective tissue dysplasia or vascular defects which in the case of tooth pulp, endothelial rupture of the pulp arterioles will lead to hemorrhagic areas in the pulp. It was proposed that these hemorrhagic areas in the pulp will induce mineralization within the pulp. Prevalence Pulpal calcifications can be developed throughout the life and prevalence rates from 8–9% in worldwide population had been reported in studies. It was also found that pulpal stones occurred most frequently over the fourth decade, in advancing age. Generally, pulp stones are more frequent to be found in maxillary teeth compared to mandibular teeth. A study in Australia resulted higher occurrences of pulp stones in molars as opposed to premolars, and first molars as opposed to second molars. First molars which were restored and/or with caries showed a higher incidence of pulp stones as compared to intact, unrestored first molars. Clinical implications Pulp stones generally do not have significant clinical implications as they are usually not a source of pain, discomfort or any form of pulpitis. However, when the tooth concerned will undergo endodontic treatment such as root canal treatment, presence of large pulp stones will be clinically significant.Large pulp stones in the pulp chamber might block the access to canal orifices and prevent the exploring dental instruments from passaging down the canal. In these cases, burs or even ultrasonic instrumentation can be used to remove the blocking pulp stones. During the removal process, sodium hypochlorite which has dissolving action can also be used as a synergistic effect. == References ==

Microdontia

Microdontia is a condition in which one or more teeth appear smaller than normal. In the generalized form, all teeth are involved. In the localized form, only a few teeth are involved. The most common teeth affected are the upper lateral incisors and third molars. Teeth affected by microdontia may also have abnormal shape, and the abnormal size may affect the whole tooth, or only a part of the tooth. Definition Males tend to have larger teeth than females, and tooth size also varies by race. Abnormal tooth size is defined by some as when the dimensions are more than 2 standard deviations from the average. Microdontia is when the teeth are abnormally small, and macrodontia is when the teeth are abnormally large. Classification There are 3 types of microdontia: True generalized All the teeth are smaller than the normal size. True generalized microdontia is very rare, and occurs in pituitary dwarfism. Due to decreased levels of growth hormone the teeth fail to develop to a normal size. Relative generalized All the teeth are normal size but appear smaller relative to enlarged jaws. Relative generalized microdontia may be the result of inheritance of a large jaw from one parent, and normal sized teeth from the other. Localized (focal) Localized microdontia is also termed focal, or pseudo-microdontia. A single tooth is smaller than normal. Localized microdontia is far more common than generalized microdontia, and is often associated with hypodontia (reduced number of teeth). The most commonly involved tooth in localized microdontia is the maxillary lateral incisor, which may also be shaped like an inverted cone (a "peg lateral"). Peg laterals typically occur on both sides, and have short roots. Inheritance may be involved, and the frequency of microdontia in the upper laterals is just under 1%. The second most commonly involved tooth is the maxillary third molars, and after this supernumerary teeth. Causes There are many potential factors involved. Congenital hypopituitarism Ectodermal dysplasia Down syndrome Ionizing radiation to the jaws during tooth development (odontogenesis) Chemotherapy during tooth development Marshall syndrome Rieger syndrome Focal dermal hypoplasia Silver-Russell syndrome Williams syndrome Gorlin-Chaudhry-Moss syndrome Coffin–Siris syndrome Salamon syndrome Cleft lip and palateOthers include trichorhinopharyngeal, odontotrichomelic, neuroectodermal and dermo-odontodysplasia syndromes. Treatment Unerupted microdonts may require surgical removal to prevent the formation of cysts. Erupted microdonts, peg laterals especially, may cause cosmetic concern. Such teeth may be restored to resemble normal sized teeth, typically with composite build ups or crowns. Orthodontics may be required in severe cases to close gaps between the teeth. Epidemiology Females are affected more than males, and the condition occurs in permanent (adult) teeth more than deciduous (baby teeth or milk teeth). References == External links ==

Refractory cytopenia with multilineage dysplasia

Refractory cytopenia with multilineage dysplasia is a form of myelodysplastic syndrome.It is abbreviated "RCMD". References == External links ==