<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Postpartum psychosis and can you explain it in depth? [/INST] Early in the history of medicine, it was recognized that severe mental illness sometimes started abruptly in the days after childbirth, later known as postpartum psychosis or puerperal psychosis. Gradually, it became clear that this was not a single and unique phenomenon, but a group of at least twenty distinct disorders.Psychosis implies the presence of manic symptoms, stupor or catatonia, perplexity, confusion, disorders of the will and self, delusions and/or hallucinations. Psychiatric disorders that lack these symptoms are excluded; depression, however severe, is not included, unless there are psychotic features.
Of this group of psychoses, postpartum bipolar disorder is overwhelmingly the most common in high-income nations.

Postpartum bipolar disorder
Signs and symptoms
Almost every symptom known to psychiatry occurs in these mothers – every kind of delusion including the rare delusional parasitosis, delusional misidentification syndrome, Cotard delusion, erotomania, the changeling delusion, denial of pregnancy or birth, command hallucinations, disorders of the will and self, catalepsy and other symptoms of catatonia, self-mutilation and all the severe disturbances of mood. In addition, literature from the 18th century also describes symptoms not generally recognized, such as rhyming speech, enhanced intellect, and enhanced perception.As for collections of symptoms (syndromes), about 40% have puerperal mania, with increased vitality and sociability, reduced need for sleep, rapid thinking and pressured speech, euphoria and irritability, loss of inhibition, violence, recklessness and grandiosity (including religious and expansive delusions); puerperal mania is considered to be particularly severe, with highly disorganized speech, extreme excitement and eroticism.Another 25% have an acute polymorphic (cycloid) syndrome. This is a changing clinical state, with transient delusions, fragments of other syndromes, extreme fear or ecstasy, perplexity, confusion, and motility disturbances. In the past, some experts regarded this as pathognomonic (specific) for puerperal psychosis, but this syndrome is found in other settings, not just the reproductive process, and in men. These psychoses are placed in the World Health Organizations ICD-10 under the rubric of acute and transient psychotic disorders. In general psychiatry, manic and cycloid syndromes are regarded as distinct, but, studied long-term among childbearing women, the bipolar and cycloid variants are intermingled in a bewildering variety of combinations, and, in this context, it seems best to regard them as members of the same bipolar/cycloid group. Together, the manic and cycloid variants make up about two thirds of childbearing psychoses.

Diagnosis
Postpartum bipolar disorders must be distinguished from a long list of organic psychoses that can present in the puerperium, and from other non-organic psychoses; both of these groups are described below. It is also necessary to distinguish them from other psychiatric disorders associated with childbirth, such as anxiety disorders, depression, post-traumatic stress disorder, complaining disorders and bonding disorders (emotional rejection of the infant), which occasionally cause diagnostic difficulties.
Clinical assessment requires obtaining the history from the mother herself and, because she is often severely ill, lacking in insight and unable to give a clear account of events, from at least one close relative. A social work report and, in mothers admitted to hospital, nursing observations are information sources of great value. A physical examination and laboratory investigations may disclose somatic illness complicating the obstetric events, which sometimes provokes psychosis. It is important to obtain the case records of previous episodes of mental illness, and, in patients with multiple episodes, to construct a summary of the whole course of her psychiatric history in relation to her life.
In the 10th edition of the International Classification of Diseases, published in 1992, the recommendation is to classify these cases by the form of the illness, without highlighting the postpartum state. There is, however, a category F53.1, entitled severe mental and behavioural disorders associated with the puerperium, which can be used when it is not possible to diagnose some variety of affective disorder or schizophrenia. The American Psychiatric Associations Diagnostic and Statistical Manual, whose 5th edition was published in May 2013, allows the use of a peripartum onset specifier in episodes of mania, hypomania or major depression if the symptoms occur during pregnancy or the first four weeks of the puerperium. The failure to recognize postpartum psychosis, and its complexity, is unhelpful to clinicians, epidemiologists, and other researchers.

Onset groups
Postpartum bipolar disease belongs to the bipolar spectrum, whose disorders exist in two contrasting forms – mania and depression. They are highly heritable, and affected individuals (less than 1% of the population ) have a lifelong tendency (diathesis) to develop psychotic episodes in certain circumstances. The triggers include a number of pharmaceutical agents, surgical operations, adrenal corticosteroids, seasonal changes, menstruation and childbearing. Research into puerperal mania is, therefore, not the study of a disease-in-its-own right, but an investigation into the childbearing triggers of bipolar disorder.
Psychoses triggered in the first two weeks after the birth – between the first postpartum day (or even during parturition  until about the 15th day – complicate approximately 1/1,000 pregnancies. The impression is sometimes given that this is the only trigger associated with childbearing. But there is evidence of four other triggers – late postpartum, prepartum, post-abortion  and weaning. Marcé, widely considered an authority on puerperal psychoses, claimed that they could be divided into early and late forms; the late form begins about six weeks after childbirth, associated with the return of the menses. His view is supported by the large number of cases in the literature with onset 4–13 weeks after the birth, mothers with serial 4-13 week onsets and some survey evidence. The evidence for a trigger acting in pregnancy is also based on the large number of reported cases, and particularly on the frequency of mothers experiencing two or more prepartum episodes. There is evidence, especially from surveys, of bipolar episodes triggered by abortion (miscarriage or termination). The evidence for a weaning trigger rests on 32 cases in the literature, of which 14 were recurrent. The relative frequency of these five triggers is given by the number of cases in the literature – just over half early postpartum onset, 20% each late postpartum and prepartum onset, and the rest post-abortion and weaning onset.
In addition, episodes starting after childbirth may be triggered by adrenal corticosteroids, surgical operations (such as Caesarean section) or bromocriptine as an alternative to, or in addition to, the postpartum trigger.

Course of the illness
With modern treatment, a full recovery can be expected within 6–10 weeks. After recovery from the psychosis, some mothers have depression, which can last for weeks or months. About one third have a relapse, with a return of psychotic symptoms a few weeks after recovery; these relapses are not due to a failure to comply with medication, because they were often described  before pharmaceutical treatment was discovered. A minority have a series of periodic relapses related to the menstrual cycle. Complete recovery, with a resumption of normal life and a normal mother-infant relationship is the rule.Many of these mothers experience other bipolar episodes, on the average about one every six years. Although suicide is almost unknown in an acute puerperal manic or cycloid episode, depressive episodes later in life carry an increased risk, and it is wise for mothers to maintain contact with psychiatric services in the long term.
In the event of a further pregnancy, the recurrence rate is high – in the largest series, about three quarters had a recurrence, but not always in the early puerperium; the recurrence could occur during pregnancy, or later in the postpartum period. This suggests a link between early onset and other onset groups.

Management, treatment and prevention
Pre-conception counselling
It is known that women with a personal or family history of puerperal psychosis or bipolar disorder are at risk of a puerperal episode. The highest risk of all (82%) is a combination of a previous postpartum episode and at least one earlier non-puerperal episode. There is a need to counsel women at high risk before they embark on pregnancy, especially those on prophylactic treatment. The issues include the teratogenic risk, the frequency of recurrence and the risks and benefit of various treatments during pregnancy and breast-feeding; a personal analysis should be made for each individual, and is best shared with close family members. The teratogenic risks of antipsychotic agents are small, but are higher with lithium and anti-convulsant agents. Carbamazepine, when taken in early pregnancy, has some teratogenic effects, but valproate is associated with spina bifida and other major malformations, and a foetal valproate syndrome; it is contra-indicated in women who may become pregnant. Given late in pregnancy, antipsychotic agents and lithium  can have adverse effects on the infant. Stopping mood-stabilisers has a high risk of recurrence during pregnancy.

Pre-birth planning
If a woman at high risk becomes pregnant, it is essential to convene a planning meeting. This is urgent because the diagnosis of pregnancy may be late, and the birth may be premature. The meeting should be attended by primary care, obstetric and psychiatric staff, together (if possible) with the expectant mother and her family and (if appropriate) a social worker. There are many issues – pharmaceutical treatment, antenatal care, early signs of a recurrence, the management of the puerperium, and the care and safety of the infant. It is important that the psychiatric team is notified as soon as the infant is born.

Home treatment and hospitalization
It has been recognized since the 19th century that it is optimal for a woman with puerperal psychosis to be treated at home, where she can maintain her role as homemaker and mother to her other children, and develop her relationship with the new-born. But there are many risks, and it is essential that she is monitored by a competent adult round the clock, and visited frequently by professional staff. Home treatment is a counsel of perfection and most women will be admitted to a psychiatric hospital, many as an emergency, and usually without their babies. In a few countries, especially Australia, Belgium, France, India, the Netherlands, Switzerland and the United Kingdom, special units allow the admission of both woman and infant. Conjoint admission has many advantages, but the risks to the infant of admission to a ward full of severely ill mothers should not be understated, and the high ratio of nursing staff, required to safeguard the infants, make these among the most expensive psychiatric units.

Treatment of the acute episode
These mothers require sedation with anti-psychotic (neuroleptic) agents, but are liable to extrapyramidal symptoms, including the neuroleptic malignant syndrome. Since the link with bipolar disorder was recognized (about 1970), treatment with mood-stabilizing agents, such as lithium and anti-convulsant drugs, has been employed with success. Electroconvulsive therapy has the reputation of efficacy in this disorder, and it can be given during pregnancy (avoiding the risk of pharmaceutical treatment), with due precautions. But there have been no trials, and Dutch experience has shown that almost all mothers recover quickly without it. After recovery the mother may need antidepressant treatment and/or prophylactic mood stabilizers; she will need counselling about the risk of recurrence and will often appreciate psychotherapeutic support.

Prevention
There is much evidence that lithium can at least partly prevent episodes in mothers at high risk. It is dangerous during parturition, when pressure in the pelvis can obstruct the ureters and raise blood levels. Started after the birth its adverse effects are minimal, even in breast-fed infants.

Causes
The cause of postpartum bipolar disorder breaks down into two parts – the nature of the brain anomalies that predispose to manic and depressive symptoms, and the triggers that provoke these symptoms in those with the bipolar diathesis. The genetic, anatomical and neurochemical basis of bipolar disorder is at present unknown, and is one of the most important projects in psychiatry; but is not the main concern here. The challenge and opportunity presented by the childbearing psychoses is to identify the triggers of early postpartum onset and other onset groups.
Considering that these psychoses have been known for centuries, little effort has so far been made to understand the underlying biology. Research has lagged far behind other areas of medicine and psychiatry. There is a dearth of knowledge and of theories. There is a much evidence of heritability, both from family studies and molecular genetics. Early onset cases occur more frequently in first time mothers, but this is not true of late postpartum or pregnancy onset. There are not many other predictors. Sleep deprivation has been suggested. Inhibition of steroid sulphatase caused behavioural abnormalities in mice. A recent hypothesis, supported by collateral studies, invokes the re-awakening of auto-immunity after its suppression during pregnancy, on the model of multiple sclerosis or autoimmune thyroiditis; a related hypothesis has proposed that abnormal immune system processes (regulatory T cell biology) and consequent changes in myelinogenesis may increase postpartum psychosis risk. 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. Another promising lead is based on the similarity of bipolar-cycloid puerperal and menstrual psychosis; many women have had both. Late-onset puerperal psychoses, and relapses may be linked to menstruation. Since almost all reproductive onsets occur when the menstrual cycle is released from a long period of inhibition, this may be a common factor, but it can hardly explain episodes starting in the 2nd and 3rd trimesters of pregnancy.

History
Between the 16th and 18th centuries about 50 brief reports were published; among them is the observation that these psychoses could recur, and that they occur both in breast-feeding and non-lactating women. In 1797, Osiander, an obstetrician from Tübingen, reported two cases at length – masterly descriptions which are among the treasures of medical literature. In 1819, Esquirol  conducted a survey of cases admitted to the Salpêtrière, and pioneered long-term studies. From that time, puerperal psychosis became widely known to the medical profession. In the next 200 years over 2,500 theses, articles and books were published. Among the outstanding contributions were Delays unique investigation using serial curettage  and Kendells record-linkage study comparing 8 trimesters before and 8 trimesters after the birth. In the last few years, two monographs reviewed over 2,400 works, with more than 4,000 cases of childbearing psychoses from the literature and a personal series of more than 320 cases.

Research directions
The lack of a formal diagnosis in the DSM and ICD has hindered research. Research is needed to improve the care and treatment of affected mothers, but it is of paramount importance to investigate the causes, because this can lead to long term control and elimination of the disease. The opportunities come under the heading of clinical observation, the study of the acute episode, long-term studies, epidemiology, genetics and neuroscience. In a disorder with a strong genetic element and links to the reproductive process, costly imaging, molecular-genetic and neuroendocrinological investigations will be decisive. These depend on expert laboratory methods. It is important that the clinical study is also state-of-the-art– that scientists understand the complexity of these psychoses, and the need for multiple and reliable information sources to establish the diagnosis.

Other non-organic postpartum psychoses
It is much less common to encounter other acute psychoses in the puerperium.

Psychogenic psychosis
This is the name given to a psychosis whose theme, onset and course are all related to an extremely stressful event. The psychotic symptom is usually a delusion. Over 50 cases have been described, but usually in unusual circumstances, such as abortion or adoption, or in fathers at the time of the birth of one of their children. They are occasionally seen after normal childbirth.

Paranoid and schizophrenic psychoses
These are so uncommon in the puerperium that it seems reasonable to regard them as sporadic events, not puerperal complications.

Early postpartum stupor
Brief states of stupor have rarely been described in the first few hours or days after the birth. They are similar to parturient delirium and stupor, which are among the psychiatric disorders of childbirth.

Organic postpartum psychoses
There are at least a dozen organic (neuropsychiatric) psychoses that can present in pregnancy or soon after childbirth. The clinical picture is usually delirium – a global disturbance of cognition, affecting consciousness, attention, comprehension, perception and memory – but amnesic syndromes and a mania-like state also occur. The two most recent were described in 1980 and 2010, and it is quite likely that others will be described. Organic psychoses, especially those due to infection, may be more common in nations with high parturient morbidity.

Infective delirium
The most common organic postpartum psychosis is infective delirium. This was mentioned by Hippocrates: there are 8 cases of puerperal or post-abortion sepsis among the 17 women in the 1st and 3rd books of epidemics, all complicated by delirium. In Europe and North America the foundation of the metropolitan maternity hospitals, together with instrumental deliveries and the practice of attending necropsies, led to epidemics of streptococcal puerperal fever, resulting in maternal mortality rates up to 10%. The peak was about 1870, after which antisepsis and asepsis gradually brought them under control. These severe infections were often complicated by delirium, but it was not until the nosological advances of Chaslin and Bonhöffer that they could be distinguished from other causes of postpartum psychosis. Infective delirium hardly ever starts during pregnancy, and usually begins in the first postpartum week. The onset of sepsis and delirium are closely related, and the course parallels the infection, although about 20% of patients continue to have chronic confusional states after recovery from the infection. Recurrences after another pregnancy are rare. Their frequency began to decline at the end of the 19th century, and fell steeply after the discovery of the sulphonamides. Puerperal sepsis is still common in Bangladesh, Nigeria and Zambia. Even in the United Kingdom, cases are still occasionally seen. It would be a mistake to forget this cause of puerperal psychosis.

Eclamptic and Donkin psychoses
Eclampsia is the sudden eruption of convulsions in a pregnant woman, usually around the time of delivery. It is the late complication of pre-eclamptic toxaemia (gestosis). Although its frequency in nations with excellent obstetric services has fallen below 1/500 pregnancies, it is still common in many other countries. The primary pathology is in the placenta, which secretes an anti-angiogenic factor in response to ischaemia, leading to endothelial dysfunction. In fatal cases, there are arterial lesions in many organs including the brain. This is the second most frequent organic psychosis, and the second to be described. Psychoses occur in about 5% of cases, and about 240 detailed cases have been reported. It particularly affects first time mothers. Seizures may begin before, during or after labour, but the onset of psychosis is almost always postpartum. These mothers usually experience delirium but some have manic features. The duration is remarkably short, with a median duration of 8 days. This, together with the absence of a family history and of recurrences, contrasts with puerperal bipolar/cycloid psychoses. After recovery, amnesia and sometimes retrograde memory loss may occur, as well as other permanent cerebral lesions such as dysphasia, hemiplegia or blindness.
A variant was described by Donkin . He had been trained by Simpson (one of those who first recognized the importance of albuminuria) in Edinburgh, and recognized that some cases of eclamptic psychosis occurred without seizures; this explains the interval between seizures (or coma) and psychosis, a gap that has occasionally exceeded 4 days: seizures and psychosis are two different consequences of severe gestosis. Donkin psychosis may not be rare: a British series included 13 possible cases; but clarifying its distinction from postpartum bipolar disorder requires prospective investigations in collaboration with obstetricians.

Wernicke-Korsakoff psychosis
This was described by Wernicke and Korsakoff. The pathology is damage to the core of the brain including the thalamus and mamillary bodies. Its most striking clinical feature is loss of memory, which can be permanent. It is usually found in severe alcoholics, but can also result from pernicious vomiting of pregnancy (hyperemesis gravidarum), because the requirement for thiamine is much increased in pregnancy; nearly 200 cases have been reported. The cause is vitamin B1 (thiamine) deficiency. This has been available for treatment and prevention since 1936, so the occurrence of this syndrome in pregnancy should be extinct. But these cases continue to be reported – more than 50 in this century – from all over the world, including some from countries with advanced medical services; most are due to rehydration without vitamin supplements. A pregnant woman who presents in a dehydrated state due to pernicious vomiting urgently needs thiamine, as well as intravenous fluids.

Vascular disorders
Various vascular disorders occasionally cause psychosis, especially cerebral venous thrombosis. Puerperal women are liable to thrombosis, especially thrombophlebitis of the leg and pelvic veins; aseptic thrombi can also form in the dural venous sinuses and the cerebral veins draining into them. Most patients present with headache, vomiting, seizures and focal signs such as hemiplegia or dysphasia, but a minority of cases have a psychiatric presentation. The incidence is about 1 in 1,000 births in Europe and North America, but much higher in India, where large series have been collected. Psychosis is occasionally associated with other arterial or venous lesions: epidural anaesthesia can, if the dura is punctured, lead to leakage of cerebrospinal fluid and subdural haematoma. Arterial occlusion may be due to thrombi, amniotic fragments or air embolism. Postpartum cerebral angiopathy is a transitory arterial spasm of medium caliber cerebral arteries; it was first described in cocaine and amphetamine addicts, but can also complicate ergot and bromocriptine prescribed to inhibit lactation. Subarachnoid haemorrhage can occur after miscarriage or childbirth. All these usually present with neurological symptoms, and occasionally with delirium.

Epilepsy
Women with a lifelong epileptic history are liable to psychoses during pregnancy, labour and the puerperium. Women occasionally develop epilepsy for the first time in relation to their first pregnancy, and psychotic episodes have been described. There are over 30 cases in the literature.

Hypopituitarism
Pituitary necrosis following postpartum haemorrhage (Sheehans syndrome) leads to failure and atrophy of the gonads, adrenal and thyroid. Chronic psychoses can supervene many years later, based on myxoedema, hypoglycaemia or Addisonian crisis. But these patients can also develop acute and recurrent psychoses, even as early as the puerperium.

Water intoxication
Hyponatraemia (which leads to delirium) can complicate oxytocin treatment, usually when given to induce an abortion. By 1975, 29 cases had been reported, of which three were severe or fatal.

Urea cycle disorders
Inborn errors of the Krebs-Henseleit urea cycle lead to hyperammonaemia. In carriers and heterozygotes, encephalopathy can develop in pregnancy or the puerperium. Cases have been described in carbamoyl phosphate synthetase 1, argino-succinate synthetase and ornithine carbamoyltransferase deficiency.

Anti-NMDA receptor encephalitis
The most recent form of organic childbearing psychosis to be described is encephalitis associated with antibodies to the NMDA receptor; these women often have ovarian teratomas. A Japanese review found ten reported during pregnancy and five after delivery.

Other organic psychoses with a specific link to childbearing
Sydenhams chorea, of which chorea gravidarum is a severe variant, has a number of psychiatric complications, which include psychosis. This usually develops during pregnancy, and occasionally after the birth or abortion. Its symptoms include severe hypnagogic hallucinations (hypnagogia), possibly the result of the extreme sleep disorder. This form of chorea was caused by streptococcal infections, which at present respond to antibiotics; it still occurs as a result of systemic lupus or anti-phospholipid syndromes. Only about 50 chorea psychoses have been reported, and only one this century; but it could return if the streptococcus escapes control. Alcohol withdrawal states (delirium tremens) occur in addicts whose intake has been interrupted by trauma or surgery; this can happen after childbirth. Postpartum confusional states have also been reported during withdrawal from opium and barbiturates. One would expect acquired immunodeficiency syndrome (HIV/AIDS) encephalitis to present in pregnancy or the puerperium, because it is a venereal disease that can progress rapidly; one case of AIDS encephalitis, presenting in the 28th week of gestation, has been reported from Haiti, and there may be others in countries where AIDS is rife. Anaemia is common in pregnancy and the puerperium, and folate deficiency has been linked to psychosis.

Incidental organic psychoses
The psychoses, mentioned above, all had a recognized connection with childbearing. But medical disorders with no specific link have presented with psychotic symptoms in the puerperium; in them the association seems to be fortuitous. They include neurosyphilis, encephalitis including von Economos, meningitis, cerebral tumours, thyroid disease and ischaemic heart disease.

Society and culture
Support
In the UK, a series of workshops called "Unravelling Eve" were held in 2011, where women who had experienced postpartum depression shared their stories.

Notable cases in history and fiction
Harriet Sarah, Lady Mordaunt (1848–1906), formerly Harriet Moncreiffe, was the Scottish wife of an English baronet and Member of Parliament, Sir Charles Mordaunt. She was the defendant in a sensational divorce case in which the Prince of Wales (later King Edward VII) was embroiled; after a controversial trial lasting seven days, the jury determined that Lady Mordaunt had "puerperal mania" and her husbands petition for divorce was dismissed, while Lady Mordaunt was committed to an asylum.Andrea Yates had depression and, four months after the birth of her fifth child, relapsed, with psychotic features </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Müllerian agenesis and can you explain it in depth? [/INST] Mayer-Rokitansky-Küster-Hauser syndrome (MRKH syndrome), also known as Müllerian agenesis, Müllerian aplasia, or vaginal agenesis is a congenital malformation characterized by a failure of the Müllerian duct to develop, resulting in a missing uterus and variable degrees of vaginal hypoplasia of its upper portion. Müllerian agenesis (including absence of the uterus, cervix and/or vagina) is the cause in 15% of cases of primary amenorrhoea. Because most of the vagina does not develop from the Müllerian duct, instead developing from the urogenital sinus, along with the bladder and urethra, it is present even when the Müllerian duct is completely absent. Because ovaries do not develop from the Müllerian ducts, affected people might have normal secondary sexual characteristics but are infertile due to the lack of a functional uterus. However, parenthood is possible through use of gestational surrogates.
Mayer–Rokitansky–Küster–Hauser syndrome is hypothesized to be a result of autosomal dominant inheritance with incomplete penetrance and variable expressivity, which contributes to the complexity involved in identifying of the underlying mechanisms causing the condition. Because of the variance in inheritance, penetrance and expressivity patterns, MRKH is subdivided into two types: type 1, in which only the structures developing from the Müllerian duct are affected (the upper vagina, cervix, and uterus), and type 2, where the same structures are affected, but is characterized by the additional malformations of other body systems most often including the renal and skeletal systems. MRKH type 2 includes MURCS (Müllerian Renal Cervical Somite).
The majority of MRKH syndrome cases are characterized as sporadic, but familial cases have provided evidence that, at least for some patients, MRKH is an inherited disorder. The underlying causes of MRKH syndrome is still being investigated, but several causative genes have been studied for their possible association with the syndrome. Most of these studies have served to rule-out genes as causative factors in MRKH, but thus far, only WNT4 has been associated with MRKH with hyperandrogenism.Reports of MRKH syndrome can be traced back to Hippocrates (460 B.C.–377 B.C.). The medical eponym honors August Franz Josef Karl Mayer (1787–1865), Carl Freiherr von Rokitansky (1804–1878), Hermann Küster (1879–1964) and Georges Andre Hauser (1921–2009).

Signs and symptoms
A female with this condition is hormonally normal; that is, the woman will enter puberty with development of secondary sexual characteristics including thelarche and pubarche (pubic hair). The womans karyotype will be 46,XX. At least one ovary is intact, if not both, and ovulation usually occurs. Typically, the vagina is shortened and intercourse may, in some cases, be difficult and painful. Medical examination supported by gynecologic ultrasonography demonstrates a complete or partial absence of the cervix, uterus, and vagina.If there is no uterus, a woman with MRKH cannot carry a pregnancy without intervention. It is possible for the woman to have genetic offspring by in vitro fertilization (IVF) and surrogacy. Successful uterine transplant has been performed in limited numbers of patients, resulting in several live births, but the technique is not widespread or accessible to many women.A woman with MRKH typically discovers the condition when, during puberty years, the menstrual cycle does not start (primary amenorrhoea). Some find out earlier through surgeries for other conditions, such as a hernia.

Causes
The etiology of MRKH syndrome in many cases remains elusive. However, mutations in a variety of different genes have been implicated in causing MRKH syndrome. The typical and atypical forms of the disorder are presumably caused by mutations in different genes.WNT4 (found on the short arm (p) of chromosome 1) has been clearly implicated in the atypical version of this disorder. A genetic mutation causes a leucine to proline residue substitution at amino acid position 12. This occurrence reduces the intranuclear levels of β catenin. In addition, it removes the inhibition of steroidogenic enzymes like 3β-hydroxysteriod dehydrogenase and 17α-hydroxylase. Patients therefore have androgen excess. Furthermore, without WNT4, the Müllerian duct is either deformed or absent. Female reproductive organs, such as the cervix, fallopian tubes, and much of the vagina, are hence affected.An association with 17q12 microdeletion syndrome, a deletion mutation in the long arm (q) of chromosome 17, has been reported. The gene LHX1 is located in this region and may be the cause of a number of these cases.

Diagnosis
Classification
Typical MRKH – Isolated uterovaginal aplasia/hypoplasia
Prevalence – 64%
Atypical MRKH – Uterovaginal aplasia/hypoplasia with renal malformation or uterovaginal aplasia/hypoplasia with ovarian dysfunction
Prevalence – 24%
MURCS syndrome – Uterovaginal aplasia/hypoplasia with renal malformation, skeletal malformation, and cardiac malformation
Prevalence – 12%

Treatment
A number of treatments have become available to create a functioning vagina, the first successful uterus transplantation has been done in 2021, giving fertility to the transplant recipient. Standard approaches use vaginal dilators and/or surgery to develop a functioning vagina to allow for penetrative sexual intercourse. A number of surgical approaches have been used. In the McIndoe procedure, a skin graft is applied to form an artificial vagina. After the surgery, dilators are still necessary to prevent vaginal stenosis. The Vecchietti procedure has been shown to result in a vagina that is comparable to a normal vagina in patients. In the Vecchietti procedure, a small plastic “olive” is threaded against the vaginal area, and the threads are drawn through the vaginal skin, up through the abdomen and through the navel using laparoscopic surgery. There the threads are attached to a traction device. The operation takes about 45 minutes. The traction device is then tightened daily so the olive is pulled inwards and stretches the vagina by approximately 1 cm per day, creating a vagina approximately 7 cm deep in 7 days, although it can be more than this. Another approach is the use of an autotransplant of a resected sigmoid colon using laparoscopic surgery; results are reported to be very good with the transplant becoming a functional vagina.Uterine transplantation has been performed in a number of people with MRKH, but the surgery is still in the experimental stage. Since ovaries are present, people with this condition can have genetic children through IVF with embryo transfer to a gestational carrier </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is X-linked dystonia parkinsonism and can you explain it in depth? [/INST] X-linked dystonia parkinsonism (XDP), also known as Lubag Syndrome or X-linked Dystonia of Panay, is a rare x-linked progressive movement disorder with high penetrance found almost exclusively in males from Panay, Philippines. It is characterized by dystonic movements first typically occurring in the 3rd and 4th decade of life. The dystonic movements often either coexist or develop into parkinsonism within 10 years of disease onset.

Symptoms and signs
Symptoms typically present in the 3rd or 4th decade of life, but have been seen as early as the age of 14. It presents with torsion dystonia, particularly when presenting at a younger age, which then progresses to parkinsonism with or without ongoing dystonia. Often the two symptoms coexist. The parkinsonian features of x-linked dystonia parkinsonism include festinating gait, bradykinesia, blepharospasm, and postural instability. It often lacks a resting tremor, helping to differentiate it from Parkinsons disease.

Genetics
X-linked dystonia parkinsonism is thought to result from a mutation of the TAF1 (TATA-binding protein-associated factor 1) gene at Xq13.1. It has an X-linked, recessive pattern of inheritance. Genetic analysis suggests that the responsible mutation was introduced into the ethnic groups of Panay (especially to the Hiligaynon people) over two millennia ago.

Diagnosis
Treatment
There is no cure for XDP and medical treatment offers only temporary relief. Some authors have reported benzodiazepines and anticholinergic agents in the early stages of the disease. Botulinum toxin injections have been used to relieve focal dystonia </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Postpartum thyroiditis and can you explain it in depth? [/INST] Postpartum thyroiditis refers to thyroid dysfunction occurring in the first 12 months after pregnancy and may involve hyperthyroidism, hypothyroidism or the two sequentially.  According to the National Institute of Health, postpartum thyroiditis affects about 8% of pregnancies. There are, however, different rates reported globally. This is likely due to the differing amounts of average postpartum follow times around the world, and due to humans own innate differences. For example, in Bangkok, Thailand the rate is 1.1%, but in Brazil it is 13.3%. The first phase is typically hyperthyroidism. Then, the thyroid either returns to normal or a woman develops hypothyroidism. Of those women who experience hypothyroidism associated with postpartum thyroiditis, one in five will develop permanent hypothyroidism requiring lifelong treatment.
Postpartum thyroiditis is believed to result from the modifications to the immune system necessary in pregnancy, and histologically is a subacute lymphocytic thyroiditis. The process is normally self-limiting, but when conventional antibodies are found there is a high chance of this proceeding to permanent hypothyroidism. Postpartum thyroiditis is a member of the group of thyroiditis conditions known as resolving thyroiditis.

Signs and symptoms
The initial phase of hyperthyroid symptoms occurs transiently about two to six months postpartum. Typical symptoms include irritability, nervousness, palpitations, and heat intolerance. Hormonal disturbances during this phase tend to occur with lower intensity compared with the hypothyroid phase. As a result, the hyperthyroid phase may pass undetected. The second phase of hypothyroid symptoms is also transient and can occur anytime within the three- to twelve-month period postpartum. Women in this phase experience low energy, poor memory, impaired concentration, carelessness, dry skin, cold intolerance, and general aches and pains. After one year postpartum, euthyroid function resumes. Any case with hypothyroid symptoms extending beyond one year postpartum is not considered postpartum thyroiditis.Women who test positive for thyroid antibodies may be at increased risk of developing symptoms associated with postpartum depression than women without thyroid antibodies.

Cause
During pregnancy, immunologic suppression occurs which induces tolerance to the presence of the fetus. Without this suppression, the fetus would be rejected causing miscarriage. As a result, following delivery, the immune system rebounds causing levels of thyroids antibodies to rise in susceptible women.Specifically, the immunohistological features of susceptible women are indicated by:
antibodies to thyroglobulin (TgAb)
antibodies to thyroid peroxidase (TPOAb)
increase in TPOAb subclasses IgG1-IgG3
lymphocyte infiltration and follicle formation within thyroid gland (Hashimotos thyroiditis)
T-cell changes (increased CD4:CD8 ratio)
TSH-receptor antibodies (TSH-R Abs)

Diagnosis
This condition is commonly undiagnosed by physicians due to either unfamiliarity with the disease, the subtlety of symptoms, or the attribution of the symptoms to the stresses of having a newborn. Usual screening begins with assessing the thyroid stimulating hormone (TSH) level. A suppressed TSH could represent the hyperthyroid phase, but warrants further testing to investigate for possible Graves disease. A normal TSH with persistent symptoms could represent the shift between phases and requires repeat testing 4–6 weeks later; an elevated TSH at this time could indicate the hypothyroid phase.

Treatment
For most women, the hyperthyroid phase presents with very mild symptoms or is asymptomatic; intervention is usually not required </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Argyria and can you explain it in depth? [/INST] Argyria or argyrosis is a condition caused by excessive exposure to chemical compounds of the element silver, or to silver dust. The most dramatic symptom of argyria is that the skin turns blue or blue-grey. It may take the form of generalized argyria or local argyria. Generalized argyria affects large areas over much of the visible surface of the body. Local argyria shows in limited regions of the body, such as patches of skin, parts of the mucous membrane or the conjunctiva.
The terms argyria and argyrosis have long been used interchangeably, with argyria being used more frequently. Argyrosis has been used particularly in referring to argyria of the conjunctiva, but the usage has never been consistent and cannot be relied on except where it has been explicitly specified. The term is from the Ancient Greek: ἄργυρος (argyros, silver).

Pathophysiology
In humans and other animals, chronic intake of silver products commonly leads to gradual accumulation of silver compounds in various parts of the body. As in photography (where silver is useful because of its sensitivity to light), exposure of pale or colourless silver compounds to sunlight decomposes them to silver metal or silver sulfides. Commonly these products deposit as microscopic particles in the skin, in effect a dark pigment. This condition is known as argyria or argyrosis.
Chronic intake also may lead to silver pigments depositing in other organs exposed to light, particularly the eyes. In the conjunctiva this is not generally harmful, but it also may affect the lens, leading to serious effects.
Localised argyria often results from topical use of substances containing silver, such as some kinds of eye drops. Generalized argyria results from chronically swallowing or inhaling silver compounds, either for home medicinal purposes, or as a result of working with silver or silver compounds.While silver is potentially toxic to humans at high doses, the risk of serious harm from low doses, given over a short term, is small. Silver is used in some medical appliances because of its anti-microbial nature, which stems from the oligodynamic effect. Chronic ingestion or inhalation of silver preparations (especially colloidal silver) can lead to argyria in the skin and other organs. This is not life-threatening, but is considered by most to be cosmetically undesirable.The reference dose, published by the United States Environmental Protection Agency in 1991, which represents the estimated daily exposure that is unlikely to incur an appreciable risk of deleterious effects during a lifetime, is 5 µg/(kg·d).Argyria worsens and builds up as exposure to silver continues, and does not resolve once exposure stops.

History
Since at least the mid-19th century, doctors have known that silver or silver compounds can cause some areas of the skin and other body tissues to turn grey or blue-grey.  Argyria occurs in people who ingest or inhale silver in large quantities over a long period (several months to many years). People who work in factories that manufacture silver products can also breathe in silver or its compounds. In the past, some of these workers have become argyric. However, the level of silver in the air and the length of exposure that caused argyria in these workers is not known. Historically, colloidal silver, a liquid suspension of microscopic silver particles, was also used as an internal medication to treat a variety of diseases. In the 1940s, they were overtaken by the use of pharmaceutical antibiotics, such as penicillin.

Society and culture
A prominent case involving the ingestion of colloidal silver was that of Stan Jones of Montana, a Libertarian candidate for the United States Senate in 2002 and 2006.  The peculiar coloration of his skin was featured prominently in media coverage of his unsuccessful campaign, though Jones contended that the best-known photo was "doctored". Jones promised that he was not using his silvery complexion as a gimmick. His purposeful consumption of colloidal silver was a self-prescribed measure undertaken in response to fears that the Y2K problem would make antibiotics unavailable, an event that did not occur. He is reported to have said that given the chance to go back, he would do it again. He maintains that his good health, excepting the unusual skin tone, is the result of his use of colloidal silver.In 2007, press reports described Paul Karason, an American man whose entire skin gradually turned blue after he took a homemade silver chloride colloid and used a silver salve on his face in an attempt to treat problems with his sinuses, dermatitis, acid reflux and other issues. At the time of the reports, Karason maintained his belief in silvers effectiveness and continued to take it, albeit in smaller doses. He died in 2013 of a heart attack; "a cause of death was not immediately known", but according to Jo Anna Karason, his estranged wife, "Paul Karason had suffered heart problems for years. He was a heavy smoker, despite undergoing triple bypass surgery about five years ago".Rosemary Jacobs is a prominent activist against alternative medicine. As a child, Jacobs was treated for allergies with nose drops that contained colloidal silver, and developed argyria as a result. Jacobs came to international attention after Paul Karason was on The Today Show in 2008 </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Pitted keratolysis and can you explain it in depth? [/INST] Pitted keratolysis (also known as Keratolysis plantare sulcatum, Keratoma plantare sulcatum, and Ringed keratolysis) is a bacterial skin infection of the foot. The infection is characterized by craterlike pits on the sole of the feet and toes, particularly weight bearing areas.
The infection is caused by Corynebacterium species bacteria and Kytococcus sedentarius. Excessive sweating of the feet and use of occlusive footwear provide an environment in which these bacteria thrive and therefore increase the risk of developing pitted keratolysis.The condition is fairly common, especially in the military where wet shoes/boots are worn for extended periods of time without removing/cleaning. Skin biopsy specimens are not usually utilized, as the diagnosis of pitted keratolysis is often made by visual examination and recognition of the characteristic odor. Woods lamp examination results are inconsistent. Treatment of pitted keratolysis requires the application of antibiotics to the skin such as benzoyl peroxide, clindamycin, erythromycin, fusidic acid, or mupirocin. Prevention efforts aim to keep the feet dry by using moisture-wicking shoes and socks as well as antiperspirants.

Signs and symptoms
Pitted keratolysis typically presents with white discoloration of the skin and numerous discrete, "punched-out" pitted lesions or erosions, usually located on the soles of the feet. The pits are typically 1–7 millimeters in diameter. These circular and shallow pits are characteristic of pitted keratolysis, and often overlap to produce larger areas of erosion. The appearance of this condition’s characteristic lesions becomes more pronounced when the affected area is wet or submerged in water. Occasionally these lesions present with a green or brown hue around and within the pits.These superficial erosions are found under the toes and on the soles of the feet, and especially at the pressure bearing points such as the heel. Typically, both feet are equally affected. Rarely, the condition affects the palms.

Cause
The most common cause of pitted keratolysis is Corynebacterium species. However, several other bacteria may also cause the condition, particularly Actinomyces keratolytica, Dermatophilus congolensis, Kytococcus sedentarius, and Streptomyces. Less frequently, it is due to Acinetobacter, Clostridium, Klebsiella, and Pseudomonas species.

Pathogenesis
Pitted keratolysis is associated with excessive sweating of the palms or soles (palmoplantar hyperhidrosis.) The pits seen in pitted keratolysis are caused by bacteria secreting proteinase enzymes which cause the breakdown of the keratin proteins in the stratum corneum layer of the affected skin. This results in the formation of sulfur compounds which leads to a very strong and foul foot odor. The bacteria that cause pitted keratolysis thrive in warm and humid environments. Irritation is generally minimal, though occasionally burning, itching, and soreness are experienced with pitted keratolysis.

Diagnosis
The diagnosis of pitted keratolysis is based primarily on the physical examination, with recognition of the classic pitted lesions and pungent odor. Dermoscopic examination can facilitate visualization of pits and pit walls. A Woods lamp may show coral red fluorescence, as seen in erythrasma.  However, this finding is not uniformly present, as the condition may be caused by bacteria that do not produce fluorescent pigments. Further laboratory testing is not typically required for the diagnosis. However, a potassium hydroxide preparation can help rule out the presence of a fungal infection. Imaging and biopsy are not necessary.

Differential diagnosis
Acid
Athletes foot (Tinea pedis)
Erythrasma
Hyperhidrosis

Treatment
As of 2014, there is little high-quality evidence to provide guidance and support one treatment method over another. Therefore, the optimal treatment approach for pitted keratolysis remains unclear as the condition has not been well-studied. One review suggested a treatment approach requiring modification of risk factors (e.g., keeping feet clean and dry) and treating the underlying bacterial infection. Effective antibiotic options include clindamycin, erythromycin, mupirocin, and fusidic acid. Topical clindamycin is generally preferred as the first-line choice due to lower cost and better availability </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Congenital dyserythropoietic anemia and can you explain it in depth? [/INST] Congenital dyserythropoietic anemia (CDA) is a rare blood disorder, similar to the thalassemias. CDA is one of many types of anemia, characterized by ineffective erythropoiesis, and resulting from a decrease in the number of red blood cells (RBCs) in the body and a less than normal quantity of hemoglobin in the blood. CDA may be transmitted by both parents autosomal recessively or dominantly.

Signs and symptoms
The symptoms and signs of congenital dyserythropoietic anemia are consistent with:
Tiredness (fatigue)
Weakness
Pale skin

Types
Congenital dyserythropoietic anemia has four different subtypes, CDA Type I, CDA Type II, CDA Type III, and CDA Type IV. CDA type II (CDA II) is the most frequent type of congenital dyserythropoietic anemias.

Diagnosis
The diagnosis of congenital dyserythropoietic anemia can be done via sequence analysis of the entire coding region, types I, II, III and IV ( is a relatively new form of CDA that had been found, just 4 cases have been reported) according to the genetic testing registry.

Treatment
Treatment of individuals with CDA usually consist of frequent blood transfusions, but this can vary depending on the type that the individual has.  Patients report going every 2–3 weeks for blood transfusions. In addition, they must undertake chelation therapy to survive; either deferoxamine, deferasirox, or deferiprone to eliminate the excess iron that accumulates. Removal of the spleen and gallbladder are common. Hemoglobin levels can run anywhere between 8.0 g/dl and 11.0 g/dl in untransfused patients, the amount of blood received by the patient is not as important as their baseline pre-transfusion hemoglobin level. This is true for ferritin levels and iron levels in the organs as well, it is important for patients to go regularly for transfusions in order to maximize good health, normal ferritin levels run anywhere between 24 and 336 ng/ml, hematologists generally do not begin chelation therapy until ferritin levels reach at least 1000 ng/ml. It is more important to check iron levels in the organs through MRI scans, however, than to simply get regular blood tests to check ferritin levels, which only show a trend, and do not reflect actual organ iron content.

Gene therapy
Gene therapy, as well as, bone marrow transplant are also possible treatments for the disorder, but each have their own risks at this point in time. Bone marrow transplantation is the more used method between the two, whereas researchers are still trying to definitively establish the results of gene therapy treatment. It generally requires a 10/10 HLA matched donor, however, who is usually a sibling. As most patients do not have this, they must rely on gene therapy research to potentially provide them with an alternative. CDA at both clinical and genetic aspects are part of a heterogeneous group of genetic conditions. Gene therapy is still experimental and has largely only been tested in animal models until now. This type of therapy has promise, however, as it allows for the autologous transplantation of the patients own healthy stem cells rather than requiring an outside donor, thereby bypassing any potential for graft vs. host disease (GVHD).In the United States, the FDA approved clinical trials on Beta thalassemia patients in 2012. The first study, which took place in July 2012, recruited human subjects with thalassemia major,

See also
Thalassemia
Hemoglobinopathy
List of hematologic conditions

References
Further reading
Greer, John P.; Arber, Daniel A.; Glader, Bertil; List, Alan F.; Means, Robert T.; Paraskevas, Frixos; Rodgers, George M </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is GM1 gangliosidoses and can you explain it in depth? [/INST] The GM1 gangliosidoses, usually shortened to GM1, are gangliosidoses caused by mutation in the GLB1 gene resulting in a deficiency of beta-galactosidase. The deficiency causes abnormal storage of acidic lipid materials in cells of the central and peripheral nervous systems, but particularly in the nerve cells, resulting in progressive neurodegeneration. GM1 is a rare lysosomal storage disorder with a prevalence of 1 to every 100,000 to 200,000 live births worldwide, although rates are higher in some regions.

Cause
GM1 Gangliosidoses disorders are caused by mutations in the GLB1 gene, which codes for lysosomal hydrolase, acid beta-galactosidase (β-gal). Low levels of β-gal cause an accumulation of GM1 gangliosides. They are inherited, autosomal recessive sphingolipidoses, a class of lipid storage disorders.

Diagnosis
Diagnosis of GM1 can be obtained by genetic and enzymatic testing.

Types
GM1 has three forms classified by age of onset.
Type 1: early infantile
Type 2: late infantile/juvenile
Type 3: adult

Early infantile GM1
Symptoms of early infantile GM1 (the most severe subtype, with onset shortly after birth) may include neurodegeneration, seizures, liver enlargement (hepatomegaly), spleen enlargement (splenomegaly), coarsening of facial features, skeletal irregularities, joint stiffness, distended abdomen, muscle weakness, exaggerated startle response to sound, and problems with gait.About half of affected patients develop cherry-red spots in the eye.
Children may be deaf and blind by age 1 and often die by age 3 from cardiac complications or pneumonia.
Early psychomotor deterioration: decreased activity and lethargy in the first weeks; never sit; feeding problems - failure to thrive; visual failure (nystagmus noted) by 6 months; initial hypotonia; later spasticity with pyramidal signs; secondary microcephaly develops; decerebrate rigidity by 1 year and death by age 1–2 years (due to pneumonia and respiratory failure); some have hyperacusis.
Macular cherry-red spots in 50% by 6–10 months; corneal opacities in some
Facial dysmorphology: frontal bossing, wide nasal bridge, facial edema (puffy eyelids); peripheral edema, epicanthus, long upper lip, microretrognathia, gingival hypertrophy (thick alveolar ridges), macroglossia
Hepatomegaly by 6 months and splenomegaly later; some have cardiac failure
Skeletal deformities: flexion contractures noted by 3 months; early subperiosteal bone formation (may be present at birth); diaphyseal widening later; demineralization; thoracolumbar vertebral hypoplasia and beaking at age 3–6 months; kyphoscoliosis. *Dysostosis multiplex (as in the mucopolysaccharidoses)
10–80% of peripheral lymphocytes are vacuolated; foamy histiocytes in bone marrow; visceral mucopolysaccharide storage similar to that in Hurler disease; GM1 storage in cerebral gray matter is 10-fold elevated (20–50-fold increased in viscera)
Galactose-containing oligosacchariduria and moderate keratan sulfaturia
Morquio disease Type B: Mutations with higher residual beta-galactosidase activity for the GM1 substrate than for keratan sulfate and other galactose-containing oligosaccharides have minimal neurologic involvement but severe dysostosis resembling Morquio disease type A (Mucopolysaccharidosis type 4).

Late infantile/Juvenile GM1
Onset of late infantile GM1 is typically between ages 1 and 3 years </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Hepatoblastoma and can you explain it in depth? [/INST] Hepatoblastoma is a malignant liver cancer occurring in infants and children and composed of tissue resembling fetal liver cells, mature liver cells, or bile duct cells. They usually present with an abdominal mass.  The disease is most commonly diagnosed during a childs first three years of life. Alpha-fetoprotein (AFP) levels are commonly elevated, but when AFP is not elevated at diagnosis the prognosis is poor.

Signs and symptoms
Patients are usually asymptomatic at diagnosis. As a result, disease is often advanced at diagnosis.

Pathophysiology
Hepatoblastomas originate from immature liver precursor cells, are typically unifocal, affect the right lobe of the liver more often than the left lobe, and can metastasize. They are categorized into two types: "Epithelial Type" and "Mixed Epithelial / Mesenchymal Type."Individuals with familial adenomatous polyposis (FAP), a syndrome of early-onset colonic polyps and adenocarcinoma, frequently develop hepatoblastomas </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Erythropoietic protoporphyria and can you explain it in depth? [/INST] Erythropoietic protoporphyria (or commonly called EPP) is a form of porphyria, which varies in severity and can be very painful.  It arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the red blood cells (erythrocytes), plasma, skin, and liver. The severity varies significantly from individual to individual.
A clinically similar form of porphyria, known as X-Linked dominant protoporphyria, was identified in 2008.

Presentation
EPP usually presents in childhood with the most common mode of presentation as acute photosensitivity of the skin. It affects areas exposed to the sun and tends to be intractable. A few minutes of exposure to the sun induces pruritus, erythema, swelling and pain. Longer periods of exposure may induce second degree burns. After repetitive exposure, patients may present with lichenification, hypopigmentation, hyperpigmentation and scarring of the skin.EPP usually first presents in childhood, and most often affects the face and the upper surfaces of the arms, hands, and feet and the exposed surfaces of the legs. Most patients, if the EPP is not as severe, manifest symptoms with onset of puberty when the male and female hormone levels elevate during sexual development and maintenance. More severe EPP can manifest in infancy. EPP can be triggered through exposure to sun even though the patient is behind glass. Even the UV emissions from arc welding with the use of full protective mask have been known to trigger EPP. EPP can also manifest between the ages of 3 and 6.Prolonged exposure to the sun can lead to edema of the hands, face, and feet, rarely with blistering and petechiae. Skin thickening can sometimes occur over time.People with EPP are also at increased risk to develop gallstones. One study has noted that EPP patients suffer from vitamin D deficiency.

Liver failure
Protoporphyrin accumulates to toxic levels in the liver in 5–20% of EPP patients, leading to liver failure. The spectrum of hepatobiliary disease associated with EPP is wide. It includes cholelithiasis, mild parenchymal liver disease, progressive hepatocellular disease and end-stage liver disease.A lack of diagnostic markers for liver failure makes it difficult to predict which patients may experience liver failure, and the mechanism of liver failure is poorly understood. A retrospective European study identified 31 EPP patients receiving a liver transplant between 1983 and 2008, with phototoxic reactions in 25% of patients who were unprotected by surgical light filters. The same study noted a 69% recurrence of the disease in the grafted organ. Five UK liver transplants for EPP have been identified between 1987 and 2009. Frequent liver testing is recommended in EPP patients where no effective therapy has been identified to manage liver failure to date.

Pregnancy
EPP photosensitivity symptoms are reported to lessen in some female patients during pregnancy and menstruation, although this phenomenon is not consistent, and the mechanism is not understood.

Genetics
Most cases of EPP are results of inborn errors of metabolism but the metabolic defect in some patients may be acquired. Mutation of the gene that encodes for ferrochelatase in the long arm of chromosome 18 is found in majority of the cases. Ferrochelatase (FECH) catalyzes the insertion of ferrous iron into the protoporphyrin IX ring to form heme. EPP exhibits both recessive and dominant patterns of inheritance and a high degree of allelic heterogeneity with incomplete penetrance. Most heterozygotes are asymptomatic. Symptoms do not occur unless FECH activity is less than 30% of normal, but such low levels are not present in a majority of patients.

Pathophysiology
Cells which synthesize heme are predominantly erythroblasts/reticulocytes in the bone marrow (80%) and hepatocytes (20%). Deficiency of FECH results in increased release of protoporphyrin, which binds to albumin in plasma and subsequently undergoes hepatic extraction. Normally, most protoporphyrin in hepatocytes is secreted into bile; the remainder undergoes transformation into heme. Some protoporphyrin in bile is returned to the liver as a consequence of the enterohepatic circulation; the remaining protoporphyrin in the intestine undergoes fecal excretion. Protoporphyrin is insoluble and hence unavailable for renal excretion. In EPP, subnormal biotransformation of protoporphyrin into heme results in accumulation of protoporphyrin in hepatocytes.Since FECH deficiency is associated with increased concentrations of protoporphyrin in erythrocytes, plasma, skin and liver, retention of protoporphyrin in skin predisposes to acute photosensitivity. As a result of absorption of ultraviolet and visible light (peak sensitivity at 400 nm, with lesser peaks between 500-625 nm) by protoporphyrin in plasma and erythrocytes when blood circulates through the dermal vessels, free radicals are formed, erythrocytes become unstable and injury to the skin is induced.A significant increase in the hepatobiliary excretion of protoporphyrin can damage the liver through both cholestatic phenomena and oxidative stress - predisposing to hepatobiliary disease of varying degrees of severity

Diagnosis
EPP is generally suspected by the presence of acute photosensitivity of the skin and can be confirmed by detection of a plasmatic fluorescence peak at 634 nm. It is also useful to find increased levels of protoporphyrin in feces and the demonstration of an excess of free protoporphyrin in erythrocytes.Screening for FECH mutation on one allele or aminolevulinic acid synthase 2 gain-of-function mutation in selected family members may be useful, especially in genetic counseling.
Liver biopsy confirms hepatic disease in EPP by the presence of protoporphyrin deposits in the hepatocytes that can be observed as a brown pigment within the biliary canaliculi and the portal macrophages. Macroscopically, the cirrhotic liver can have a black color due to protoporphyrin deposits. Using polarized light the characteristic Maltese cross shape of birefringent crystalline pigment deposits is found. The examination of liver tissue under a Wood’s lamp reveals a red fluorescence due to protoporphyrin. Liver biopsy is not helpful for estimation of prognosis of liver disease.

Treatment
There is no cure for this disorder; however, symptoms can usually be managed by limiting exposure to daytime sun and some types of artificial lighting.  Most types of artificial lighting emit light in the problematic wavelengths, with fluorescent lighting being the worst offender.  Color temperature can be a good indicator of what light is most detrimental, as the higher the color temperature, the more violet light (380–450 nm) is emitted.  Incandescent and LED lighting in the soft white range (2700–3000 K) produce the least problematic light.  Additionally, selecting lower wattage bulbs can reduce the overall output of light.
Since the photosensitivity results from light in the visible spectrum, most sunscreens are of little use (with the exception of non-nano zinc oxide which provides uniform protection between 290–400 nm and some protection up to 700 nm).  Sun protective clothing can also be very helpful, although clothing with UPF values are only rated based on their UV protection (up to 400 nm) and not on their protection from the visible spectrum.  Some sun protective clothing manufacturers use zinc oxide in their fabrics, such as Coolibars ZnO Suntect line, which will offer protection from visible light.Some patients gradually build a protective layer of melanin by regularly exposing themselves for short times to ultraviolet radiation.Window films which block UV and visible light up to 450 nm can provide relief from symptoms if applied to the patients automobile and home windows.  An example of such would be Madico Amber 81 which can protect through the 500 nm range.
Blue blocking screen protectors can help provide relief from symptoms caused by televisions, phones, tablets and computer screens.
EPP is considered one of the least severe of the porphyrias. Unless there is liver failure, it is not a life-threatening disease.

Approved therapies
Afamelanotide, developed by Australian-based Clinuvel Pharmaceuticals, was approved in Europe in December 2014 and in the United States in October 2019 for treatment or prevention of phototoxicity in adults with EPP.

Off-label therapies
Several drugs are used off label by patients with EPP:

Ursodeoxycholic acid is a bile acid that is administered to promote biliary secretion of protoporphyrin. Results of its use in EPP are controversial. However, it is known to alter the composition of bile, to protect hepatocytes from the cytotoxic effect of hydrophobic bile acids, and to stimulate biliary secretion by several distinct mechanisms.
Hematin appears to reduce excess protoporphyrin production in the bone marrow </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Cerebrospinal fluid leak and can you explain it in depth? [/INST] A cerebrospinal fluid leak (CSF leak or CSFL) is a medical condition where the cerebrospinal fluid (CSF) surrounding the brain or spinal cord leaks out of one or more holes or tears in the dura mater. A cerebrospinal fluid leak can be either cranial or spinal, and these are two different disorders. A spinal CSF leak can be caused by one or more meningeal diverticula or CSF-venous fistulas not associated with an epidural leak.A CSF leak is either caused by trauma including that arising from medical interventions or spontaneously sometimes in those with predisposing conditions (known as a spontaneous cerebrospinal fluid leak or sCSF leak). Traumatic causes include a lumbar puncture noted by a post-dural-puncture headache, or a fall or other accident. Spontaneous CSF leaks are associated with heritable connective tissue disorders including Marfan syndrome and Ehlers–Danlos syndromes.A loss of CSF greater than its rate of production leads to a decreased volume inside the skull known as intracranial hypotension.
Any CSF leak is most often characterized by orthostatic headaches, which worsen when standing, and improve when lying down. Other symptoms can include neck pain or stiffness, nausea, vomiting, dizziness, fatigue, and a metallic taste in the mouth. A CT myelography scan can identify the site of a cerebrospinal fluid leakage. Once identified, the leak can often be repaired by an epidural blood patch, an injection of the patients own blood at the site of the leak, a fibrin glue injection, or surgery.
The set of symptoms associated with a sCSF leak is referred to as a spontaneous cerebrospinal fluid leak syndrome (SCSFLS). A sCSF leak is uncommon but not rare, affecting at least one in 20,000 people and many more who go undiagnosed every year. On average, the condition develops at age 42, and women are twice as likely to be affected. Some people with a sCSF leak have a chronic leak of cerebrospinal fluid despite repeated patching attempts, leading to long-term disability due to pain and being unable to be upright, and surgery is often needed. SCSFLS was first described by German neurologist Georg Schaltenbrand in 1938 and by American neurologist Henry Woltman of the Mayo Clinic in the 1950s.

Classification
Spontaneous cerebrospinal fluid leaks are classified into two main types: cranial leaks, and spinal leaks. The vast majority of leaks are spinal. Cranial leaks occur in the head, and in some of these cases, CSF can leak from the nose, or from the ear. Spinal leaks occur when one or more holes form in the dura along the spinal cord. Both cranial and spinal spontaneous CSF leaks cause neurological symptoms as well as spontaneous intracranial hypotension, diminished volume, and pressure of the cranium. While this symptom can be referred to as intracranial hypotension, the intracranial pressure may be normal, with the underlying issue instead being low CSF volume. For this reason, a SCSFL is referred to as CSF hypovolemia as opposed to CSF hypotension.Spontaneous intracranial hypotension, a subtype of CSF leak, refers to lower than normal than CSF volume due to an initially unknown or insidious cause. This differentiates it from CSF leaks of known causes such as cranial or spinal trauma, surgery or lumbar puncture or spinal anesthesia (most common cause of CSF leak). The International Classification of Headache Disorders (ICHD) Third Edition diagnostic criteria for spontaneous intracranial hypotension includes any headache attributed to low CSF pressure (low CSF opening pressure) or CSF leakage (evidence of CSF leakage on imaging). Further, the headache must have a temporal relation to the low CSF pressure or leakage and the headache cannot be better explained by another ICHD diagnosis. The final criteria is that in the rare cases of spontaneous intracranial hypotension with no headache present, the neurologic symptoms that are present must be attributable to low CSF or explained by the diagnosis of spontaneous intracranial hypotension.

Signs and symptoms
The most common symptom of a CSF leak is a fast-onset, extremely painful orthostatic headache or thunderclap headache. This headache is usually made worse by standing and typically becomes prominent throughout the day, with the pain becoming less severe when lying down. Orthostatic headaches can become chronic and disabling to the point of incapacitation. Some patients with a SCSFL will develop headaches that begin in the afternoon. This is known as second-half-of-the-day headache. This may be an initial presentation of a spontaneous CSF leak or appear after treatment such as an epidural patch, and likely indicates a slow CSF leak. While high CSF pressure can make lying down unbearable, low CSF pressure due to a leak can be relieved by lying flat on the back.About 50% of people with a CSFL experience neck pain or stiffness, nausea, and vomiting.Other symptoms of a CSF leak include photophobia, dizziness and vertigo, gait disturbances, tinnitus, facial numbness or weakness, visual disturbances, brain fog or difficulties with concentration, neuralgia, fatigue, fluid dripping from the nose or ears,Aural symptoms are also present in many cases of intracranial hypotension due to CSF leak; including muffled hearing, pulsatile tinnitus, hearing loss. Less common symptoms include double vision (due to cranial nerve 6 palsy) or tremor.Movement disorders are uncommon in spontaneous CSF leaks but occasionally can be one of the major components of the clinical presentation.Some cases of chronic intracranial hypotension due to CSF leak may present as personality changes, altered behaviors and impairment of executive functions, similar to behavioral-variant frontotemporal dementia as the frontal and temporal lobes are affected by downward sagging due to reduced intra-cranial pressures.An untreated CSF leak can result in coma or death as late stage findings as the brainstem herniates through the skull base or foramen magnum .

Causes
A spontaneous CSF leak is termed so as it has previously been thought to be idiopathic, meaning the cause is unknown. The evidence of the last decade suggests however, that these leaks result from either a discogenic pathology, such as microspur, osteophyte or intra-dural disc herniation that pierces the dura like a knife, connective tissue disorder (which can often lead to discogenic pathology), or spinal drainage problems.A cerebrospinal fluid leak can be a rare complication of an anterior cervical discectomy and fusion (ACDF). One study suggested a CSF leak to follow from 0.5% of operations. Another study suggests a CSF leak to follow from 1% of operations. In most of these cases repair is successful.

Discogenic causes
The most common cause of an intractable "sCSF" leak is discogenic, either from an intra-dural disc herniation, osteophyte or microspur on the disc or vertebral body. "Recent radiological and microsurgical investigations revealed that a calcified, degenerative bony microspur is often the culprit lesion in cases of intractable CSF leaks. Arising from the level of the intervertebrate disk space, these microspurs pierce the ventral dura and produce a slit-like defect a few millimeters in length. These microspurs and the associated CSF leak have to be localized exactly, and then they are amenable to surgical treatment."

Connective tissue theory
Various scientists and physicians have suggested that SCSFLs may be the result of an underlying connective tissue disorder affecting the spinal dura. It may also run in families and be associated with aortic aneurysms and joint hypermobility.Up to two thirds of those affected demonstrate some type of generalized connective tissue disorder. Marfan syndrome, Ehlers–Danlos syndrome, and autosomal dominant polycystic kidney disease are the three most common connective tissue disorders associated with SCSFLs. Roughly 20% of patients with a SCSFL exhibit features of Marfan syndrome, including tall stature, hollowed chest (pectus excavatum), joint hypermobility and arched palate. However, no other Marfan syndrome presentations are shown.

Spinal drainage theory
Some studies have proposed that issues with the spinal venous drainage system may cause a CSF leak. According to this theory, dural holes and intracranial hypotension are symptoms caused by low venous pressure in the epidural space. When inferior limb muscles pump blood towards the heart and pressure in the inferior vena cava vein becomes negative, the network of epidural veins is overdrained, causing CSF to be aspirated into the epidural space. True leaks can form at weak points in the spinal meninges. Therefore, the observed CSF hypotension is a result of CSF hypovolemia and reduced epidural venous pressure.

Other causes
Cranial CSF leaks result from intracranial hypertension in a vast majority of cases. The increased pressure causes a rupture of the cranial dura mater, leading to CSF leak and intracranial hypotension. Patients with a nude nerve root, where the root sleeve is absent, are at increased risk for developing recurrent CSF leaks. Lumbar disc herniation has been reported to cause CSF leaks in at least one case. Degenerative spinal disc diseases cause a disc to pierce the dura mater, leading to a CSF leak.CSF leaks can result from a lumbar puncture procedure.

Complications
Several complications can occur as a result of SCSFLS including decreased cranial pressure, brain herniation, infection, blood pressure problems, transient paralysis, and coma. The primary and most serious complication of SCSFLS is spontaneous intracranial hypotension, where pressure in the brain is severely decreased. This complication leads to the hallmark symptom of severe orthostatic headaches.People with cranial CSF leaks, the rarer form, have a 10% risk of developing meningitis per year. If cranial leaks last more than seven days, the chances of developing meningitis are significantly higher. Spinal CSF leaks cannot result in meningitis due to the sterile conditions of the leak site. When a CSF leak occurs at the temporal bone, surgery becomes necessary in order to prevent infection and repair the leak. Orthostatic hypotension is another complication that occurs due to autonomic dysfunction when blood pressure drops significantly. The autonomic dysfunction is caused by compression of the brainstem, which controls breathing and circulation.Low CSF volume can cause the cerebellar tonsil position to descend, which can be mistaken for Chiari malformation; however when the CSF leak is repaired the tonsil position often returns to normal (as seen in upright MRI) in this "pseudo-Chiari" condition.
A further, albeit rare, complication of CSF leak is transient quadriplegia due to a sudden and significant loss of CSF. This loss results in hindbrain herniation and causes major compression of the upper cervical spinal cord. The quadriplegia dissipates once the patient lies supine. An extremely rare complication of SCSFLS is third nerve palsy, where the ability to move ones eyes becomes difficult and interrupted due to compression of the third cranial nerve.There are documented cases of reversible frontotemporal dementia and coma. Coma due to a CSF leak has been successfully treated by using blood patches and/or fibrin glue and placing the person in the Trendelenburg position. Empty sella syndrome, a bony structure that surround the pituitary gland, occurs in CSF leak patients.

Pathophysiology
Cerebrospinal fluid is produced by the choroid plexus in the ventricles of the brain and contained by the dura and arachnoid layers of the meninges. The brain floats in CSF, which also transports nutrients to the brain and spinal cord. As holes form in the spinal dura mater, CSF leaks out into the surrounding space. The CSF is then absorbed into the spinal epidural venous plexus or soft tissues around the spine. Due to the sterile conditions of the soft tissues around the spine, there is no risk of meningitis.Lack of CSF pressure and volume can allow the brain to sag and descend through the foramen magnum (large opening) of the occipital bone, at the base of the skull. The lower portion of the brain is believed to stretch or impact one or more cranial nerve complexes, thereby causing a variety of sensory symptoms. Nerves that can be affected and their related symptoms are detailed in the table at right.

Diagnosis
Diagnosis of CSF leakage can be done by various imaging techniques, chemical tests of bodily fluid discharged from a head orifice, or clinical examination. The use of CT, MRI, and assays are the most common types of CSF leak instrumental tests. Many CSF leaks do not show up on imaging and chemical assays, thus such diagnostic tools are not definitive to rule out CSF leaks. A clinician may often depend upon patient history and exam to diagnose, for example: discharge of excessive amount of clear fluid from the nose upon bending over, the increase in headache following a Valsalva maneuver or the reduction of headache when the patient takes a prone position are positive indicators.
A clinical exam is often used as a means to diagnose CSF leaks. Improved patient response to conservative treatment may further define a positive diagnosis. The lack of clinician awareness of the signs -symptoms and ailments- of a CSF leak is the greatest challenge to proper diagnosis and treatment, in particular: the loss of the orthostatic characteristic of headache and that every chronic CSF leaker will have a unique symptom set that as a whole contributes to the underlying condition, and diagnosis of, a CSF leak.
The primary place of first complaint to a physician is a hospital emergency room. Up to 94% of those with SCSFLS are initially misdiagnosed. Incorrect diagnoses include migraines, meningitis, Chiari malformation, and psychiatric disorders. The average time from onset of symptoms until definitive diagnosis is 13 months. A 2007 study found a 0% success rate for proper diagnosis in the emergency department.

CT
Diagnosis of a cerebrospinal fluid leak is performed through a combination of measurement of the CSF pressure and a computed tomography myelogram (CTM) scan of the spinal column for fluid leaks. The opening fluid pressure in the spinal canal is obtained by performing a lumbar puncture, also known as a spinal tap. Once the pressure is measured, a radiocontrast agent is injected into the spinal fluid. The contrast then diffuses out through the dura sac before leaking through dural holes. This allows for a CTM with fluoroscopy to locate and image any sites of dura rupture via contrast seen outside the dura sac in the imagery.

MRI
There is disagreement over whether MRI should be the diagnostic tool of choice. Magnetic resonance imaging is less effective than CT at directly imaging sites of CSF leak. MRI studies may show pachymeningeal enhancement (when the dura mater looks thick and inflamed), sagging of the brain, pituitary enlargement, subdural hygromas, engorgement of cerebral venous sinuses, and other abnormalities. For 20% of patients, MRIs present as completely normal. MRIs performed with the patient seated upright (vs. laying supine) are not better for diagnosing CSF leaks, but are more than twice as effective at diagnosing cerebellar tonsillar ectopia, also known as Chiari malformation. Cerebellar tonsillar ectopia shares many of the same symptoms as CSF leak, but originates either congenitally or from trauma, including whiplash strain to the dura.An alternate method of locating the site of a CSF leak is to use heavily T2-weighted MR myelography. This has been effective in identifying the sites of a CSF leak without the need for a CT scan, lumbar puncture, and contrast and at locating fluid collections such as CSF pooling. Another highly successful method of locating a CSF leak is intrathecal contrast and MR Myelography.Contrast-enhanced brain MRI with sagittal reformats can assess for the following:
Subdural fluid collections
Enhancement of the meninges
Engorgement of venous structures
Pituitary swelling
Sagging of the brainFor suspected spinal CSF leaks, spine imaging can be used to guide treatment.

Assay
Fluid dripping from the nose (CSF rhinorrhoea) or ears (CSF otorrhea) should be collected and tested for the protein Beta-2 transferrin which would be highly accurate in identifying CS fluid and diagnosing a cranial CSF leak.

CSF analysis
Patients with CSF leaks have been noted to have very low or even negative opening pressures during lumbar puncture. However, patients with confirmed CSF leaks may also demonstrate completely normal opening pressures. In 18–46% of cases, the CSF pressure is measured within the normal range. Analysis of spinal fluid may demonstrate  lymphocytic pleocytosis and elevated protein content or xanthochromia. This is hypothesized to be due to increased permeability of dilated meningeal blood vessels and a decrease of CSF flow in the lumbar subarachnoid space.

Myelography
A myelogram can be used to more precisely identify the location of a CSF leak by injecting a dye to further enhance the imaging.  However, CSF leaks are frequently not visible on imaging.For patients with recalcitrant spontaneous intracranial hypotension and no leak found on conventional spinal imaging, digital subtraction myelography, CT myelography and dynamic myelography (a modified conventional myelography technique) should be considered to rule out a CSF-venous fistula. In addition, presence of a hyperdense paraspinal vein should be investigated in imaging as it is highly suggestive of a CSF venous fistula.

Treatment
Symptomatic treatment usually involves analgesics for both cranial and spinal CSF leaks. Initial measures can include rest, caffeine intake (via coffee or intravenous infusion), and hydration. Corticosteroids may provide transient relief for some patients. An abdominal binder, which increases intracranial pressure by compressing the abdomen, can temporarily relieve symptoms for some people. Sometimes a CSF leak will heal on its own. Otherwise, symptoms may last months or even years.

Epidural blood patch
The treatment of choice for this condition is the surgical application of epidural blood patches, which has a higher success rate than conservative treatments of bed rest and hydration. Through the injection of a persons own blood into the area of the hole in the dura, an epidural blood patch uses bloods clotting factors to clot the sites of holes. The volume of autologous blood and number of patch attempts for patients is highly variable. One-quarter to one-third of SCSFLS patients do not have relief of symptoms from epidural blood patching. Finding the location of a cerebrospinal fluid leak is not required prior to using an epidural blood patch as initial lumbar epidural blood patches often provide relief of symptoms and resolve the leak without further intervention.

Fibrin glue sealant
If blood patches alone do not succeed in closing the dural tears, placement of percutaneous fibrin glue can be used in place of blood patching, raising the effectiveness of forming a clot and arresting CSF leakage.

Surgical drain technique
In extreme cases of intractable CSF leak, a surgical lumbar drain has been used. This procedure is believed to decrease spinal CSF volume while increasing intracranial CSF pressure and volume. This procedure restores normal intracranial CSF volume and pressure while promoting the healing of dural tears by lowering the pressure and volume in the dura. This procedure has led to positive results leading to relief of symptoms for up to one year.

Neurosurgical repair
Surgery to treat a CSF-venous fistula in CSF leak patients is highly effective. Neurosurgery is available to directly repair leaking meningeal diverticula. The areas of dura leak can be tied together in a process called ligation and then a metal clip can be placed in order to hold the ligation closed. Alternatively, a small compress called a pledget can be placed over the dura leak and then sealed with gel foam and fibrin glue. Primary suturing is rarely able to repair a CSF leak, and in some patients exploration of the dura may be required to properly locate all sites of CSF leak.

Adjunct measures
The use of antibiotics to prevent meningitis in those with a CSF leak due to a skull fracture is of unclear benefit.

Prognosis
Long-term outcomes for people with SCSFLS remain poorly studied. Symptoms may resolve in as little as two weeks, or persist for months. Less commonly, patients may have unremitting symptoms for many years. People with chronic SCSFLS may be disabled and unable to work. Recurrent CSF leak at an alternate site after recent repair is common.

Epidemiology
A 1994 community-based study indicated that two out of every 100,000 people with SCSFLS, while a 2004 emergency room-based study indicated five per 100,000. SCSFLS generally affects the young and middle aged; the average age for onset is 42.3 years, but onset can range from ages 22 to 61. In an 11-year study, women were found to be twice as likely to be affected as men.Studies have shown that SCSFLS runs in families. It is suspected that genetic similarity in families includes weakness in the dura mater which leads to SCSFLS. Large scale population-based studies have not yet been conducted. While a majority of SCSFLS cases continue to be undiagnosed or misdiagnosed, an actual increase in occurrence is unlikely.

History
Spontaneous CSF leaks have been described by notable physicians and reported in medical journals dating back to the early 1900s. German neurologist Georg Schaltenbrand reported in 1938 and 1953 what he termed "aliquorrhea", a condition marked by very low, unobtainable, or even negative CSF pressures </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Acute motor axonal neuropathy and can you explain it in depth? [/INST] Acute motor axonal neuropathy (AMAN) is a variant of Guillain–Barré syndrome. It is characterized by acute paralysis and loss of reflexes without sensory loss. Pathologically, there is motor axonal degeneration with antibody-mediated attacks of motor nerves and nodes of Ranvier.

Signs and symptoms
Causes
A link to Campylobacter jejuni was suspected when a young girl was admitted to Second Teaching Hospital. She had become ill after feeding the family chickens. She developed acute paralysis and respiratory failure. Investigators discovered that several of the chickens in the home displayed similar symptoms and C. jejuni was found in their droppings. Several of the paralysis patients were found to have antibodies to C. jejuni and anti-GD1a antibodies, suggesting a link between the pathogen and the disease. In 2015, Zika virus was linked to AMAN.

Diagnosis
The syndrome typically presents as a progressive flaccid symmetric paralysis with areflexia, often causing respiratory failure.  Electromyographic studies and nerve conduction studies show normal motor conduction velocity and latency with decreased amplitude of compound muscle action potentials. Pathologically, it is a noninflammatory axonopathy without demyelination. Antibodies attack the coating of the motor neurons without causing inflammation or loss of myelin </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Ataque de nervios and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Umbilical cord compression and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Keratoderma and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Laryngospasm and can you explain it in depth? [/INST] Laryngospasm is an uncontrolled or involuntary muscular contraction (spasm) of the vocal folds. The condition typically lasts less than 60 seconds, but in some cases can last 20–30 minutes and causes a partial blocking of breathing in, while breathing out remains easier. It may be triggered when the vocal cords or the area of the trachea below the vocal folds detects the entry of water, mucus, blood, or other substance.  It is characterized by stridor or retractions. Some people have frequent laryngospasms, whether awake or asleep. In an ear, nose, and throat practice, it is typically seen in people who have silent reflux disease. It is also a well known, infrequent, but serious perioperative complication.It is likely that more than 10% of drownings involve laryngospasm, but the evidence suggests that it is not usually effective at preventing water from entering the trachea.

Signs and symptoms
The main symptom is choking and difficulty or inability to breathe or speak, a feeling of suffocation, which may be followed by hypoxia-induced loss of consciousness. As the airway reopens, breathing may cause a high-pitched sound called stridor. The episode seldom lasts over a couple of minutes before breathing is back to normal.

Causes
Various stimuli including asthma, allergies, exercise, stress, and irritants such as smoke, dust, fumes, liquids, and food can trigger laryngospasm. It is common in drowning, both as a direct response to inhalation of water, and as a complication during rescue and resuscitation due to aspiration of vomit.In some individuals laryngospasm can occur spontaneously or as a result of reflux or impaired swallowing. Gastroesophageal reflux disease (GERD) is a common cause of spontaneous laryngospasm.  Treating GERD can lessen the frequency of spasms.  The onset of spasms may be caused by a viral infection.It is also a complication associated with anesthesia.  The spasm can happen often without any provocation, but tends to occur after tracheal extubation. In children, the condition can be particularly deadly, leading to cardiac arrest within 30–45 seconds, and is a possible cause of death associated with the induction of general anesthesia in the pediatric population </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Posterior cerebral artery syndrome and can you explain it in depth? [/INST]  </s>