<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 Hereditary spastic paraplegia and can you explain it in depth? [/INST] Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive gait disorder. The disease presents with progressive stiffness (spasticity)  and contraction in the lower limbs. HSP is also known as hereditary spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell disease, or Strumpell-Lorrain disease.  The symptoms are a result of dysfunction of  long axons in the spinal cord. The affected cells are the primary motor neurons; therefore, the disease is an upper motor neuron disease. HSP is not a form of cerebral palsy even though it physically may appear and behave much the same as spastic diplegia. The origin of HSP  is different from cerebral palsy. Despite this, some of the same anti-spasticity medications used in spastic cerebral palsy are sometimes used to  treat HSP symptoms.
HSP is caused by defects in  transport of  proteins, structural proteins, cell-maintaining proteins, lipids, and other substances through the cell. Long nerve fibers (axons) are affected because  long distances make nerve cells particularly sensitive to defects in these mentioned mechanisms.The disease was first described in 1880 by the German neurologist Adolph Strümpell. It was described more extensively in 1888 by Maurice Lorrain, a French physician.  Due to their contribution in describing the disease, it is still called Strümpell-Lorrain disease in French-speaking countries. The term hereditary spastic paraplegia was coined by Anita Harding in 1983.

Signs and symptoms
Symptoms depend on the type of HSP inherited. The main feature of the disease is progressive spasticity in the lower limbs due to pyramidal tract dysfunction. This also results in brisk reflexes, extensor plantar reflexes, muscle weakness, and variable bladder disturbances. Furthermore, among the core symptoms of HSP are also included abnormal gait and difficulty in walking, decreased vibratory sense at the ankles, and paresthesia.
Individuals with HSP can experience extreme fatigue associated with central nervous system and neuromuscular disorders, which can be disabling. Initial symptoms are typically difficulty with balance, stubbing the toe or stumbling. Symptoms of HSP may begin at any age, from infancy to older than 60 years. If symptoms begin during the teenage years or later, then spastic gait disturbance usually progresses over many years. Canes, walkers, and wheelchairs may eventually be required, although some people never require assistance devices. Disability has been described as progressing more rapidly in adult onset forms.More specifically, patients with the autosomal dominant pure form of HSP reveal normal facial and extraocular movement. Although jaw jerk may be brisk in older subjects, there is no speech disturbance or difficulty of swallowing. Upper extremity muscle tone and strength are normal. In the lower extremities, muscle tone is increased at the hamstrings, quadriceps and ankles. Weakness is most notable at the iliopsoas, tibialis anterior, and to a lesser extent, hamstring muscles.
In the complex form of the disorder, additional symptoms are present. These include: peripheral neuropathy, amyotrophy, ataxia, intellectual disability, ichthyosis, epilepsy, optic neuropathy, dementia, deafness, or problems with speech, swallowing or breathing.Anita Harding classified the HSP in a pure and complicated form. Pure HSP presents with spasticity in the lower limbs, associated with neurogenic bladder disturbance as well as lack of vibration sensitivity (pallhypesthesia). On the other hand, HSP is classified as complex when lower limb spasticity is combined with any additional neurological symptom.This classification is subjective and patients with complex HSPs are sometimes diagnosed as having cerebellar ataxia with spasticity, intellectual disability (with spasticity), or  leukodystrophy. Some of the genes listed below have been described in other diseases than HSP before. Therefore, some key genes overlap with other disease groups.

Age of onset
In the past, HSP has been classified as early onset beginning in early childhood or later onset in adulthood. The age of onsets has two points of maximum at age 2 and around age 40. New findings propose that an earlier onset leads to a longer disease duration without loss of ambulation or the need for the use of a wheelchair. This was also described earlier, that later onset forms evolve more rapidly.

Cause
HSP is a group of genetic disorders. It follows general inheritance rules and can be inherited in an autosomal dominant, autosomal recessive or X-linked recessive manner. The mode of inheritance involved has a direct impact on the chances of inheriting the disorder. Over 70 genotypes had been described, and over 50 genetic loci have been linked to this condition. Ten genes have been identified with autosomal dominant inheritance. One of these, SPG4, accounts for ~50% of all genetically solved cases, or approximately 25% of all HSP cases. Twelve genes are known to be inherited in an autosomal recessive fashion. Collectively this latter group account for ~1/3 cases.Most altered genes have known function, but for some the function havent been identified yet. All of them are listed in the gene list below, including their mode of inheritance.  Some examples are spastin (SPG4) and paraplegin (SPG7) are both AAA ATPases.

Genotypes
The genes are designated SPG (Spastic gait gene). The gene locations are in the format: chromosome - arm (short or p: long or q) - band number. These designations are for the human genes only. The locations may (and probably will) vary in other organisms.
Despite the number of genes known to be involved in this condition ~40% of cases have yet to have their cause identified. In the table below SPG? is used to indicate a gene that has been associated with HSP but has not yet received an official HSP gene designation.

Pathophysiology
The major feature of HSP is a length-dependent axonal degeneration. These include the crossed and uncrossed corticospinal tracts to the legs and fasciculus gracilis. The spinocerebellar tract is involved to a lesser extent. Neuronal cell bodies of degenerating axons are preserved and there is no evidence of primary demyelination. Loss of anterior horn cells of the spinal cord are observed in some cases. Dorsal root ganglia, posterior roots and peripheral nerves are not directly affected.HSP affects several pathways in motor neurons. Many genes were identified and linked to HSP. It remains a challenge to accurately define the key players in each of the affected pathways, mainly because many genes have multiple functions and are involved in more than one pathway.

Axon pathfinding
Pathfinding is important for axon growth to the right destination (e.g. another nerve cell or a muscle). Significant for this mechanism is the L1CAM gene, a cell surface glycoprotein of the immunoglobulin superfamily. Mutations leading to a loss-of-function in L1CAM are also found in other X-linked syndromes. All of these disorders display corticospinal tract impairment (a hallmark feature of HSP). L1CAM participates in a set of interactions, binding other L1CAM molecules as well as extracellular cell adhesion molecules, integrins, and proteoglycans or intracellular proteins like ankyrins.The pathfinding defect occurs via the association of L1CAM with neuropilin-1. Neuropilin-1 interacts with Plexin-A proteins to form the Semaphorin-3A receptor complex. Semaphorin-a3A is then released in the ventral spinal cord to steer corticospinal neurons away from the midline spinal cord / medullary junction. If L1CAM does not work correctly due to a mutation, the cortiocospinal neurons are not directed to the correct position and the impairment occurs.

Lipid metabolism
Axons in the central and peripheral nervous system are coated with an insulation, the myelin layer, to increase the speed of action potential propagation. Abnormal myelination in the CNS is detected in some forms of hsp HSP. Several genes were linked to myelin malformation, namely PLP1, GFC2 and FA2H. The mutations alter myelin composition, thickness and integrity.Endoplasmic reticulum (ER) is the main organelle for lipid synthesis. Mutations in genes encoding proteins that have a role in shaping ER morphology and lipid metabolism were linked to HSP. Mutations in ATL1, BSCL2 and ERLIN2 alter ER structure, specifically the tubular network and the formation of three-way junctions in ER tubules. Many mutated genes are linked to abnormal lipid metabolism. The most prevalent effect is on arachidonic acid (CYP2U1) and cholesterol (CYP7B1) metabolism, phospholipase activity (DDHD1 and DDHD2), ganglioside formation (B4GALNT-1) and the balance between carbohydrate and fat metabolism (SLV33A1).

Endosomal trafficking
Neurons take in substances from their surrounding by endocytosis. Endocytic vesicles fuse to endosomes in order to release their content. There are three main compartments that have endosome trafficking: Golgi to/from endosomes; plasma membrane to/from early endosomes (via recycling endosomes) and late endosomes to lysosomes. Dysfunction of endosomal trafficking can have severe consequences in motor neurons with long axons, as reported in HSP. Mutations in AP4B1 and KIAA0415 are linked to disturbance in vesicle formation and membrane trafficking including selective uptake of proteins into vesicles. Both genes encode proteins that interact with several other proteins and disrupt the secretory and endocytic pathways.

Mitochondrial function
Mitochondrial dysfunctions have been connected with developmental and degenerative neurological disorders. Only a few HSP genes encode mitochondrial proteins. Two mitochondrial resident proteins are mutated in HSP: paraplegin and chaperonin 60. Paraplegin is a m-AAA metalloprotease of the inner mitochondrial membrane. It functions in ribosomal assembly and protein quality control. The impaired chaperonin 60 activity leads to impaired mitochondrial quality control. Two genes DDHD1 and CYP2U1 have shown alteration of mitochondrial architecture in patient fibroblasts. These genes encode enzymes involved in fatty-acid metabolism.

Diagnosis
Initial diagnosis of HSPs relies upon family history, the presence or absence of additional signs and the exclusion of other nongenetic causes of spasticity, the latter being particular important in sporadic cases.Cerebral and spinal MRI is an important procedure performed in order to rule out other frequent neurological conditions, such as multiple sclerosis, but also to detect associated abnormalities such as cerebellar or corpus callosum atrophy as well as white matter abnormalities. Differential diagnosis of HSP should also exclude spastic diplegia which presents with nearly identical day-to-day effects and even is treatable with similar medicines such as baclofen and orthopedic surgery; at times, these two conditions may look and feel so similar that the only perceived difference may be HSPs hereditary nature versus the explicitly non-hereditary nature of spastic diplegia (however, unlike spastic diplegia and other forms of spastic cerebral palsy, HSP cannot be reliably treated with selective dorsal rhizotomy).Ultimate confirmation of HSP diagnosis can only be provided by carrying out genetic tests targeted towards known genetic mutations.

Classification
Hereditary spastic paraplegias can be classified based on the symptoms; mode of inheritance; the patients age at onset; the affected genes; and biochemical pathways involved.

Treatment
No specific treatment is known that would prevent, slow, or reverse HSP. Available therapies mainly consist of symptomatic medical management and promoting physical and emotional well-being. Therapeutics offered to HSP patients include:

Baclofen – a voluntary muscle relaxant to relax muscles and reduce tone. This can be administered orally or intrathecally </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 Barbiturate overdose and can you explain it in depth? [/INST] Barbiturate overdose is poisoning due to excessive doses of barbiturates. Symptoms typically include difficulty thinking, poor coordination, decreased level of consciousness, and a decreased effort to breathe (respiratory depression). Complications of overdose can include noncardiogenic pulmonary edema. If death occurs this is typically due to a lack of breathing.Barbiturate overdose may occur by accident or purposefully in an attempt to cause death. The toxic effects are additive to those of alcohol and benzodiazepines. The lethal dose varies with a persons tolerance and how the drug is taken. The effects of barbiturates occur via the GABA neurotransmitter. Exposure may be verified by testing the urine or blood.Treatment involves supporting a persons breathing and blood pressure. While there is no antidote, activated charcoal may be useful. Multiple doses of charcoal may be required. Hemodialysis may occasionally be considered. Urine alkalinisation has not been found to be useful. While once a common cause of overdose, barbiturates are now a rare cause.

Mechanism
Barbiturates increase the time that the chloride pore of the GABAA receptor is opened, thereby increasing the efficacy of GABA. In contrast, benzodiazepines increase the frequency with which the chloride pore is opened, thereby increasing GABAs potency.

Treatment
Treatment involves supporting a persons breathing and blood pressure. While there is no antidote, activated charcoal may be useful. Multiple doses of charcoal may be required. Hemodialysis may occasionally be considered. Urine alkalinisation has not been found to be useful.If a person is drowsy but awake and can swallow and breathe without difficulty, the treatment can be as simple as monitoring the person closely. If the person is not breathing, it may involve mechanical ventilation until the drug has worn off. Psychiatric consult is generally recommended.

Notable cases
People who are known to have died by suicide from barbiturate overdose include, Gillian Bennett, Charles Boyer, Ruan Lingyu, Victor Folke Nelson, Dalida, Jeannine "The Singing Nun" Deckers, Felix Hausdorff, Abbie Hoffman, Phyllis Hyman, Marilyn Monroe, C </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 Conversion disorder and can you explain it in depth? [/INST] Conversion disorder (CD), or functional neurologic symptom disorder, is a diagnostic category used in some psychiatric classification systems. It is sometimes applied to patients who present with neurological symptoms, such as numbness, blindness, paralysis, or fits, which are not consistent with a well-established organic cause, which cause significant distress, and can be traced back to a psychological trigger. It is thought that these symptoms arise in response to stressful situations affecting a patients mental health or an ongoing mental health condition such as depression. Conversion disorder was retained in DSM-5, but given the subtitle functional neurological symptom disorder. The new criteria cover the same range of symptoms, but remove the requirements for a psychological stressor to be present and for feigning to be disproved. ICD-10 classifies conversion disorder as a dissociative disorder while DSM-IV classifies it as a somatoform disorder.

Signs and symptoms
Conversion disorder begins with some stressor, trauma, or psychological distress. Usually the physical symptoms of the syndrome affect the senses or movement. Common symptoms include blindness, partial or total paralysis, inability to speak, deafness, numbness, difficulty swallowing, incontinence, balance problems, seizures, tremors, and difficulty walking. The symptom of feeling unable to breathe, but where the lips are not turning blue, can indicate conversion disorder or sleep paralysis. Sleep paralysis and narcolepsy can be ruled out with sleep tests. These symptoms are attributed to conversion disorder when a medical explanation for the conditions cannot be found. Symptoms of conversion disorder usually occur suddenly. Conversion disorder is typically seen in people aged 10 to 35, and affects between 0.011% and 0.5% of the general population.Conversion disorder can present with motor or sensory symptoms including any of the following:
Motor symptoms or deficits:

Impaired coordination or balance
Weakness/paralysis of a limb or the entire body (hysterical paralysis or motor conversion disorders)
Impairment or loss of speech (hysterical aphonia)
Difficulty swallowing (dysphagia) or a sensation of a lump in the throat
Urinary retention
Psychogenic non-epileptic seizures or convulsions
Persistent dystonia
Tremor, myoclonus or other movement disorders
Gait problems (astasia-abasia)
Loss of consciousness (fainting)Sensory symptoms or deficits:

Impaired vision (hysterical blindness), double vision
Impaired hearing (deafness)
Loss or disturbance of touch or pain sensationConversion symptoms typically do not conform to known anatomical pathways and physiological mechanisms. It has sometimes been stated that the presenting symptoms tend to reflect the patients own understanding of anatomy and that the less medical knowledge a person has, the more implausible are the presenting symptoms. However, no systematic studies have yet been performed to substantiate this statement.

Diagnosis
Definition
Conversion disorder is now contained under the umbrella term functional neurological symptom disorder. In cases of conversion disorder, there is a psychological stressor.
The diagnostic criteria for functional neurological symptom disorder, as set out in DSM-5, are:

Specify type of symptom or deficit as:

With weakness or paralysis
With abnormal movement (e.g. tremor, dystonic movement, myoclonus, gait disorder)
With swallowing symptoms
With speech symptoms (e.g. dysphonia, slurred speech)
With attacks or seizures
With amnesia or memory loss
With special sensory loss symptoms (e.g. visual blindness, olfactory loss, or hearing disturbance)
With mixed symptoms.Specify if:

Acute episode: symptoms present for less than six months
Persistent: symptoms present for six months or more.Specify if:

Psychological stressor (conversion disorder)
No psychological stressor (functional neurological symptom disorder)

Exclusion of neurological disease
Conversion disorder presents with symptoms that typically resemble a neurological disorder such as stroke, multiple sclerosis, epilepsy, hypokalemic periodic paralysis or narcolepsy. The neurologist must carefully exclude neurological disease, through examination and appropriate investigations. However, it is not uncommon for patients with neurological disease to also have conversion disorder.In excluding neurological disease, the neurologist has traditionally relied partly on the presence of positive signs of conversion disorder, i.e. certain aspects of the presentation that were thought to be rare in neurological disease but common in conversion. The validity of many of these signs has been questioned, however, by a study showing they also occur in neurological disease. One such symptom, for example, is la belle indifférence, described in DSM-IV as "a relative lack of concern about the nature or implications of the symptoms". In a later study, no evidence was found that patients with functional symptoms are any more likely to exhibit this than patients with a confirmed organic disease. In DSM-V, la belle indifférence was removed as a diagnostic criterion.
Another feature thought to be important was that symptoms tended to be more severe on the non-dominant (usually left) side of the body. There have been a number of theories about this, such as the relative involvement of cerebral hemispheres in emotional processing, or more simply, that it was "easier" to live with a functional deficit on the non-dominant side. However, a literature review of 121 studies established that this was not true, with publication bias the most likely explanation for this commonly held view. Although agitation is often assumed to be a positive sign of conversion disorder, release of epinephrine is a well-demonstrated cause of paralysis from hypokalemic periodic paralysis.Misdiagnosis does sometimes occur. In a highly influential study from the 1960s, Eliot Slater demonstrated that misdiagnoses had occurred in one third of his 112 patients with conversion disorder. Later authors have argued that the paper was flawed, however, and a meta-analysis has shown that misdiagnosis rates since that paper was published are around four percent, the same as for other neurological diseases.

Deliberate feigning
Conversion disorder, by its nature, is more prone to deliberate feigning. One neuroimaging study suggested that feigning may be distinguished from conversion by the pattern of frontal lobe activation.

Psychological mechanism
The psychological mechanism of conversion can be the most difficult aspect of a conversion diagnosis. Even if there is a clear antecedent trauma or other possible psychological trigger, it is still not clear exactly how this gives rise to the symptoms observed. Patients with medically unexplained neurological symptoms may not have any psychological stressor, hence the use of the term "functional neurological symptom disorder" in DSM-5 as opposed to "conversion disorder", and DSM-5s removal of the need for a psychological trigger.

Treatment
There are a number of different treatments available to treat and manage conversion syndrome. Treatments for conversion syndrome include hypnosis, psychotherapy, physical therapy, stress management, and transcranial magnetic stimulation. Treatment plans will consider duration and presentation of symptoms and may include one or multiple of the above treatments. This may include the following:
Occupational therapy to maintain autonomy in activities of daily living;
Physiotherapy where appropriate.
Treatment of comorbid depression or anxiety if present.
Educating patients on the causes of their symptoms might help them learn to manage both the psychiatric and physical aspects of their condition. Psychological counseling is often warranted given the known relationship between conversion disorder and emotional trauma. This approach ideally takes place alongside other types of treatment.There is little evidence-based treatment of conversion disorder. Other treatments such as cognitive behavioral therapy, hypnosis, EMDR, and psychodynamic psychotherapy, EEG brain biofeedback need further trials. Psychoanalytic treatment may possibly be helpful. However, most studies assessing the efficacy of these treatments are of poor quality and larger, better controlled studies are urgently needed. Cognitive Behavioural Therapy is the most common treatment, however boasts a mere 13% improvement rate.

Prognosis
Empirical studies have found that the prognosis for conversion disorder varies widely, with some cases resolving in weeks, and others enduring for years or decades. There is also evidence that there is no cure for conversion disorder, and that although patients may go into remission they can relapse at any point. Furthermore, many patients can get rid of their symptoms with time, treatments and reassurance.

Epidemiology
Frequency
Information on the frequency of conversion disorder in the West is limited, in part due to the complexities of the diagnostic process. In neurology clinics, the reported prevalence of unexplained symptoms among new patients is very high (between 30 and 60%). However, diagnosis of conversion typically requires an additional psychiatric evaluation, and since few patients will see a psychiatrist it is unclear what proportion of the unexplained symptoms are actually due to conversion. Large scale psychiatric registers in the US and Iceland found incidence rates of 22 and 11 newly diagnosed cases per 100,000 person-years, respectively. Some estimates claim that in the general population, between 0.011% and 0.5% of the population have conversion disorder.

Culture
Although it is often thought that the frequency of conversion may be higher outside of the West, perhaps in relation to cultural and medical attitudes, evidence of this is limited. A community survey of urban Turkey found a prevalence of 5.6%. Many authors have found occurrence of conversion to be more frequent in rural, lower socio-economic groups, where technological investigation of patients is limited and people may know less about medical and psychological concepts.

Gender
Historically, the concept of hysteria was originally understood to be a condition exclusively affecting women, though the concept was eventually extended to men. In recent surveys of conversion disorder (formerly classified as "hysterical neurosis, conversion type"), females predominate, with between two and six female patients for every male but some research suggests this gender disparity may be confounded by higher rates of violence against women.

Age
Conversion disorder may present at any age but is rare in children younger than ten or in the elderly. Studies suggest a peak onset in the mid-to-late 30s.

History
The first evidence of functional neurological symptom disorder dates back to 1900 BC, when the symptoms were blamed on the uterus moving within the female body. The treatment varied "depending on the position of the uterus, which must be forced to return to its natural position. If the uterus had moved upwards, this could be done by placing malodorous and acrid substances near the womans mouth and nostrils, while scented ones were placed near her vagina; on the contrary, if the uterus had lowered, the document recommends placing the acrid substances near her vagina and the perfumed ones near her mouth and nostrils."In Greek mythology, hysteria, the original name for functional neurological symptom disorder, was thought to be caused by a lack of orgasms, uterine melancholy and not procreating. Plato, Aristotle and Hippocrates believed a lack of sex upsets the uterus. The Greeks believed it could be prevented and cured with wine and orgies. Hippocrates argued that a lack of regular sexual intercourse led to the uterus producing toxic fumes and caused it to move in the body, and that this meant all women should be married and enjoy a satisfactory sexual life.From the 13th century, women with hysteria were exorcised, as it was believed that they were possessed by the devil. It was believed that if doctors could not find the cause of a disease or illness, it must be caused by the devil.At the beginning of the 16th century, women were sexually stimulated by midwives in order to relieve their symptoms. Gerolamo Cardano and Giambattista della Porta believed polluted water and fumes caused the symptoms of hysteria. Towards the end of the century, however, the role of the uterus was no longer thought central to the disorder, with Thomas Willis discovering that the brain and central nervous system were the cause of the symptoms. Thomas Sydenham argued that the symptoms of hysteria may have an organic cause. He also proved the uterus is not the cause of symptom.In 1692, in the US town of Salem, Massachusetts, there was an outbreak of hysteria. This led to the Salem witch trials, where the women accused of being witches had symptoms such as sudden movements, staring eyes and uncontrollable jumping.During the 18th century, there was a move from the idea of hysteria being caused by the uterus to it being caused by the brain. This led to an understanding that it could affect both sexes. Jean-Martin Charcot argued that hysteria was caused by "a hereditary degeneration of the nervous system, namely a neurological disorder".In the 19th century, hysteria moved from being considered a neurological disorder to being considered a psychological disorder, when Pierre Janet argued that "dissociation appears autonomously for neurotic reasons, and in such a way as to adversely disturb the individuals everyday life". However, as early as 1874, doctors including W. B. Carpenter and J. A. Omerod began to speak out against the hysteria phenomenon as there was no evidence to prove its existence.Sigmund Freud referred to the condition as both hysteria and conversion disorder throughout his career. He believed those with the condition could not live in a mature relationship, and that those with the condition were unwell in order to achieve a "secondary gain", in that they are able to manipulate their situation to fit their needs or desires. He also found that both men and women could have the disorder.Freuds model suggested the emotional charge deriving from painful experiences would be consciously repressed as a way of managing the pain, but that the emotional charge would be somehow "converted" into neurological symptoms. Freud later argued that the repressed experiences were of a sexual nature. As Peter Halligan comments, conversion has "the doubtful distinction among psychiatric diagnoses of still invoking Freudian mechanisms".Pierre Janet, the other great theoretician of hysteria, argued that symptoms arose through the power of suggestion, acting on a personality vulnerable to dissociation. In this hypothetical process, the subjects experience of their leg, for example, is split off from the rest of their consciousness, resulting in paralysis or numbness in that leg.
Later authors have attempted to combine elements of these various models, but none of them has a firm empirical basis. In 1908, Steyerthal predicted that: "Within a few years the concept of hysteria will belong to history ... there is no such disease and there never has been. What Charcot called hysteria is a tissue woven of a thousand threads, a cohort of the most varied diseases, with nothing in common but the so-called stigmata, which in fact may accompany any disease." However, the term "hysteria" was still being used well into the 20th century.
Some support for the Freudian model comes from findings of high rates of childhood sexual abuse in conversion patients. Support for the dissociation model comes from studies showing heightened suggestibility in conversion patients. However, critics argue that it can be challenging to find organic pathologies for all symptoms, and so the practice of diagnosing patients with such symptoms as having hysteria led to the disorder being meaningless, vague and a sham diagnosis, as it does not refer to any definable disease. Furthermore, throughout its history, many patients have been misdiagnosed with hysteria or conversion disorder when they had organic disorders such as tumours or epilepsy or vascular diseases. This has led to patient deaths, a lack of appropriate care and suffering for the patients. Eliot Slater, after studying the condition in the 1950s, stated: "The diagnosis of hysteria is all too often a way of avoiding a confrontation with our own ignorance. This is especially dangerous when there is an underlying organic pathology, not yet recognised. In this penumbra we find patients who know themselves to be ill but, coming up against the blank faces of doctors who refuse to believe in the reality of their illness, proceed by way of emotional lability, overstatement and demands for attention ... Here is an area where catastrophic errors can be made. In fact it is often possible to recognise the presence though not the nature of the unrecognisable, to know that a man must be ill or in pain when all the tests are negative. But it is only possible to those who come to their task in a spirit of humility. In the main the diagnosis of hysteria applies to a disorder of the doctor–patient relationship. It is evidence of non-communication, of a mutual misunderstanding ... We are, often, unwilling to tell the full truth or to admit to ignorance ... Evasions, even untruths, on the doctors side are among the most powerful and frequently used methods he has for bringing about an efflorescence of hysteria".Much recent work has been done to identify the underlying causes of conversion and related disorders and to better understand why conversion disorder and hysteria appear more commonly in women. Current theoreticians tend to believe there is no single cause for these disorders </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 Kabuki syndrome and can you explain it in depth? [/INST] Kabuki syndrome (also previously known as Kabuki-makeup syndrome (KMS) or Niikawa–Kuroki syndrome) is a congenital disorder of genetic origin. It affects multiple parts of the body, with varying symptoms and severity, although the most common is the characteristic facial appearance.It is quite rare, affecting roughly one in 32,000 births. It was first identified and described in 1981 by two Japanese groups, led by scientists Norio Niikawa and Yoshikazu Kuroki. It is named Kabuki syndrome because of the facial resemblance of affected individuals to stage makeup used in kabuki, a Japanese traditional theatrical form.

Signs and symptoms
Specific symptoms for Kabuki syndrome vary, with large differences between affected individuals. Most people with Kabuki syndrome have distinctive facial features that include arched eyebrows, long eyelashes, elongated eyelids with lower lids that turn out, prominent ears, a flat tip of the nose and a downward slant to the mouth.Overlapping phenotypic features for patients between KDM6A and KDM6B variations include prominent ears, abnormal dentition, congenital heart disease, feeding difficulties, cryptorchidism, joint hypermobility, developmental delay, hypotonia, and behavioral difficulties.
Other common symptoms are skeletal abnormalities, short stature, heart defects, feeding difficulties and a failure to thrive, vision and hearing difficulties, weak muscle tone (hypotonia), small head size (microcephaly), and frequent infections.Mild to moderate intellectual disability and mild to severe developmental delay are often associated with Kabuki syndrome. Infants and young children often experience difficulties relating to hypotonia, feeding issues/failure to thrive, infections, surgical repair of heart and palate defects and developmental delays.Young children with Kabuki syndrome benefit from early intervention services. School age children tend to have fewer medical issues requiring hospitalization, though frequent infections, hearing loss and feeding issues occur. In addition, intellectual impairment, difficulty with visuospatial tasks and maintaining attention usually require an IEP (individualized education plan) if the child attends public school. Older children and adults report difficulties with anxiety. Endocrine abnormalities and immune system abnormalities such as ITP (idiopathic thrombocytopenia) and CVID (common variable immune deficiency) are medical issues that tend to present in older children, adolescents and adults.

Causes
Type 1 Kabuki syndrome is caused by germline heterozygous loss of function variants in KMT2D (formerly known as the MLL2), located on human chromosome 12. It is estimated that between 55 and 80% of cases of Kabuki syndrome are of Type 1.  Type 1 Kabuki syndrome demonstrates an autosomal dominant pattern of inheritance.
Type 2 Kabuki syndrome is caused by germline hemizygous (in males) or heterozygous (in females) chromosome deletions or loss of function point variants involving KDM6A, located on the X chromosome. Approximately 5% of cases of Kabuki syndrome are of Type 2. Type 2 Kabuki syndrome demonstrates an X-linked dominant pattern of inheritance.Most cases of Kabuki syndrome occur de novo, that is, the parents are unaffected and the gene was mutated early in embryological development. However, several cases of inherited mutations causing Type 1 or Type 2 Kabuki syndrome are now known.About 30% of cases have no identifiable causative mutation. These may represent individuals with types of mutations that are challenging to detect via current routine investigations or patients who have disorders that share some features with Kabuki syndrome.

Pathophysiology
The KMT2D and KDM6A genes belong to a family of genes called chromatin-modifying enzymes. Specifically, these genes code for a histone methyltransferase (KMT2D) and a histone demethylase (KDM6A), and play a part in the regulation of gene expression. Under normal circumstances, these enzymes transfer methyl groups on and off histones to regulate genes via epigenetic pathways. When the genes that encode these enzymes are mutated, epigenetic activation of certain developmental genes is impaired and developmental abnormalities occur, leading to the characteristics of Kabuki syndrome patients. The specific developmental genes that are affected by the impaired epigenetic mechanisms in Kabuki syndrome are not yet fully known.There are hundreds of different mutations that have been identified in Kabuki syndrome patients. Most of these mutations are in the KMT2D gene and involve a change in amino acid sequence that creates a shortened and nonfunctional chromatin-modifying enzyme.

Diagnosis
A consensus on clinical diagnostic criteria for Kabuki syndrome (KS) was defined in December 2018 by an international group of experts. The authors propose that a definitive diagnosis can be made in an individual of any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in KMT2D or KDM6A; and (2) typical dysmorphic features (defined below) at some point of life. Typical dysmorphic features include long palpebral fissures with eversion of the lateral third of the lower eyelid and two or more of the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent or cupped ears; and (4) persistent fingertip pads. Further criteria for a probable and possible diagnosis, including a table of suggestive clinical features, were included in the publication.The original description of Kabuki syndrome by Niikawa et al. defined five cardinal manifestations, although some of these “cardinal manifestations” may or may not be present in a patient with Kabuki syndrome.

Typical facial features: Elongated palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows with the lateral third displaying sparseness or notching; short columella with depressed nasal tip; large, prominent, or cupped ears
Skeletal anomalies: Spinal column abnormalities, including sagittal cleft vertebrae, butterfly vertebrae, narrow intervertebral disc space, and/or scoliosis, Brachydactyly V Brachymesophalangy Clinodactyly of fifth digits
Dermatoglyphic abnormalities: persistence of fetal fingertip pads
Mild to moderate intellectual disability
Postnatal growth deficiencyKabuki syndrome is diagnosed clinically (through identifying symptoms, physical exams, and lab results), most commonly by a geneticist. Alternatively, it may be discovered using genetic testing (whole exome or whole genome sequencing).Diagnosis can be difficult given the large spectrum of disease. The fact that some patients do not carry one of the two known mutations or can carry multiple mutations complicates the diagnosis further.

Screening
Due to its rarity, Kabuki syndrome is not screened for in routine prenatal testing including blood tests, chorionic villus sampling (CVS), or amniocentesis. Although not routine for the general population, if Kabuki syndrome is a specific concern (i.e. expectant mother who has been diagnosed with Kabuki syndrome or sibling with KS), it is possible to test for one of the specific mutations. This prenatal testing does require a CVS or amniocentesis. However Kabuki syndrome is usually not inherited and therefore most cases do not have a positive family history. Kabuki syndrome can have positive screening tests, such as cystic hygroma seen on nuchal translucency ultrasound screening, although these findings are non-specific and have a wide differential diagnosis.

Management
Newly diagnosed patients with Kabuki syndrome will often undergo tests that are aimed at detecting common abnormalities associated with the syndrome. They include an echocardiogram (ultrasound of the heart) for detection of structural heart defects, kidney ultrasound for detection of structural renal abnormalities, immunoglobulin levels, pneumococcal titers and a hearing screening test. Further evaluation and testing by specialists may be indicated in addition to cardiology, nephrology, allergy/immunology, audiology-mentioned above. This may include orthopedics (such as hip dysplasia), pulmonary (sleep study to rule out obstructive sleep apnea due to hypotonia), ophthalmology evaluation (vision screen), ENT evaluation (hearing evaluation), Neurology evaluation (i.e. if seizures present), Hematology evaluation (if bleeding disorder), GI evaluation (if gi abnormalities), or others as needed.
There is no specific treatment for Kabuki syndrome. Treatment plans are customized to address the symptoms the individual is experiencing. For example, someone experiencing seizures will be treated with the standard anti-epilepsy therapies. Additionally, patients with Kabuki syndrome are routinely evaluated and monitored to address problems that may develop, such as vision or hearing problems, or cognitive difficulties. If congenital heart disease is present, prophylactic antibiotics may be recommended before any procedures such as dental work that might cause infection.

Prognosis
Life expectancy is not shortened in most cases of Kabuki syndrome. Some patients have coexisting conditions which may shorten life expectancy, such as hypoplastic left heart syndrome or kidney dysfunction. It is important that patients with cardiac, renal, or immunologic issues are identified and well-managed.

Epidemiology
Kabuki syndrome occurs about once in every 32,000 births. The disease appears to affect all population groups equally, with no differences based on sex, race, or environment.

Research
Research on Kabuki syndrome is extremely limited due to its low incidence. Despite this, several groups around the world are studying Kabuki syndrome. In the United States, these include the Epigenetics and Chromatin Clinic at Johns Hopkins University (led by Dr. Hans Bjornsson), The Roya Kabuki Program at Boston Childrens Hospital, Dr. Mark Hannibal at the University of Michigan, groups at University of Colorado, University of Utah, University of South Florida and others. In the UK, Prof Siddharth Bankas group at the University of Manchester and Manchester University Hospitals has a research program for Kabuki syndrome </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 Bethlem myopathy and can you explain it in depth? [/INST] Bethlem myopathy is an autosomal dominant myopathy, classified as a congenital form of muscular dystrophy, that is caused by a mutation in one of the three genes coding for type VI collagen. These include COL6A1, COL6A2, and COL6A3.  Gowers sign, tiptoe-walking and contractures of the joints (especially the fingers) are typical signs and symptoms of the disease. Bethlem myopathy could be diagnosed based on clinical examinations and laboratory tests may be recommended. Currently there is no cure for the disease and symptomatic treatment is used to relieve symptoms and improve quality of life. Bethlem myopathy affects about 1 in 200,000 people.

Signs and symptoms
The onset of this disease can begin even before birth but is more commonly in childhood or later into adult life. The progression is slow, with symptoms of weakness and walking difficulties sometimes not presenting until middle age. Early symptoms include Gowers sign ("climbing" up the thighs with the hands when rising from the floor) and tiptoe-walking caused by the beginning of contractures.Contractures of the fingers are a typical symptom of Bethlem myopathy but not of the related Ullrichs myopathy (which does include contractures of arms and legs, as does Bethlem myopathy). Serum creatine kinase is elevated in Bethlem myopathy, as there is ongoing muscle cell death. Patients with Bethlem myopathy may expect a normal life span and continued mobility into adulthood.

Diagnosis
The disease could be diagnosed based on a clinical examination, which identifies signs and symptoms generally associated with the people who have the condition. Additional laboratory tests may be recommended. Creatine kinase (CK) blood test results will generally be normal or only slightly elevated </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 Minimally conscious state and can you explain it in depth? [/INST] A minimally conscious state (MCS) is a disorder of consciousness distinct from persistent vegetative state and locked-in syndrome. Unlike persistent vegetative state, patients with MCS have partial preservation of conscious awareness. MCS is a relatively new category of disorders of consciousness. The natural history and longer term outcome of MCS have not yet been thoroughly studied. The prevalence of MCS was estimated to be 112,000 to 280,000 adult and pediatric cases.

Pathophysiology
Neuroimaging
Because minimally conscious state is a relatively new criterion for diagnosis, there are very few functional imaging studies of patients with this condition. Preliminary data has shown that overall cerebral metabolism is less than in those with conscious awareness (20–40% of normal) and is slightly higher but comparable to those in vegetative states. Activation in the medial parietal cortex and adjacent posterior cingulate cortex are brain regions that seem to differ between patients in MCS and those from vegetative states. These areas are most active during periods of conscious waking and are least active when in altered states of consciousness, such as general anesthesia, propofol, hypnotic state, dementia, and Wernicke–Korsakoff syndrome. Auditory stimulation induced more widespread activation in the primary and pre-frontal associative areas of MCS patients than vegetative state patients. There were also more cortiocortical functional connectivity between the auditory cortex and a large network of temporal and prefrontal cortices in MCS than vegetative states. These findings encourage treatments based on neuromodulatory and cognitive revalidation therapeutic strategies for patients with MCS.
One study used diffusion tensor imaging (DTI) in two case studies. They found that there were widespread cerebral atrophy in both patients. The lateral ventricles were increased in size, and the corpus callosum and the periventricular white matter were diminished. The DTI maps showed that there was significant reduction of volume in the medial corpus callosum and other parts of the brain compared to normal subjects. They also found markedly lower diffusion values in white matter and increased cerebral spinal fluid compartments. Cortical injuries at this level provides a particular favorable environment for sprouting of new axons to occur in the intact areas of the cortex, which may explain some of the greater recovery rates in minimally conscious state patients. The axonal regrowth has been correlated with functional motor recovery. The regrowth and rerouting of the axons may explain some of the changes to brain structure. These findings support the efforts to prospectively and longitudinally characterize neuroplasticity in both brain structure and function following severe injuries. Utilizing DTI and other neuroimaging techniques may further shed light on the debates on long-distance cortical rewiring and may lead to better rehabilitation strategies.Some areas of the brain that are correlated with the subjective experience of pain were activated in MCS patients when noxious stimulation was present. Positron emission tomography (PET) scans found increased blood flow to the secondary sensory cortex, posterior parietal cortex, premotor cortex, and the superior temporal cortex. The pattern of activation, however, was with less spatial extent. Some parts of the brain were less activated than normal patients during noxious stimulus processing. These were the posterior cingulate, medial prefrontal cortex, and the occipital cortex. Even though functional brain imaging can objectively measure changes in brain function during noxious stimulation, the role of different areas of the brain in pain processing is only partially understood. Furthermore, there is still the problem of the subjective experience. MCS patients by definition cannot consistently and reliably communicate their experiences. Even if they were able to answer the question "are you in pain?", there would not be a reliable response. Further clinical trials are needed to access the appropriateness of the use of analgesia in patients with MCS.

Residual language function
A functional magnetic resonance imaging (fMRI) study found that minimally conscious state patients showed activation in auditory networks when they heard narratives that had personally meaningful content that were read forwards by a familiar voice. These activations were not seen when the narratives were read backwards.Another study compared patients in vegetative state and minimally conscious state in their ability to recognize language. They found that some patients in minimally conscious state demonstrated some evidence of preserved speech processing. There was more activation in response to sentences compared to white noise.

Diagnostic
Medical definition
Minimally conscious state (MCS) is defined as a condition of severely altered consciousness in which minimal but definite behavioral evidence of self or environmental awareness is demonstrated.

Diagnosis
Although MCS patients are able to demonstrate cognitively mediated behaviors, they occur inconsistently. They are, however, reproducible or can be sustained long enough to be differentiated from reflexive behavior. Because of this inconsistency, extended assessment may be required to determine if a simple response (e.g. a finger movement or a blink) occurred because of a specific environmental event (e.g. a command to move the finger or to blink) or was merely a coincidental behavior. Distinguishing between VS and MCS is often difficult because the diagnosis is dependent on observation of behavior that show self or environmental awareness and because those behavioral responses are markedly reduced. One of the more common diagnostic errors involving disorders of consciousness is mistaking MCS for VS which may lead to serious repercussions related to clinical management.Giacino et al. have suggested demonstration of the following behaviors in order to make the diagnosis of MCS.

Following simple commands.
Gestural or verbal yes/no responses (regardless of accuracy).
Intelligible verbalization.
Purposeful behavior such as those that are contingent due to appropriate environmental stimuli and are not reflexive. Some examples of purposeful behavior include:
appropriate smiling or crying in response to the linguistic or visual content of emotional but not to neutral topics or stimuli.
vocalizations or gestures that occur in direct response to the linguistic content of questions.
reaching for objects that demonstrates a clear relationship between object location and direction of reach.
touching or holding objects in a manner that accommodates the size and shape of the object.
pursuit eye movement or sustained fixation that occurs in direct response to moving or salient stimuli.

Treatment
There is currently no definitive evidence that support altering the course of the recovery of minimally conscious state. There are currently multiple clinical trials underway investigating potential treatments.
In one case study, stimulation of thalamus using deep brain stimulation (DBS) led to some behavioral improvements. The patient was a 38-year-old male who had remained in minimally conscious state following a severe traumatic brain injury. He had been unresponsive to consistent command following or communication ability and had remained non-verbal over two years in inpatient rehabilitation. fMRI scans showed preservation of a large-scale, bi-hemispheric cerebral language network, which indicates that possibility for further recovery may exist. Positron emission tomography showed that the patients global cerebral metabolism levels were markedly reduced. He had DBS electrodes implanted bilaterally within his central thalamus. More specifically, the DBS electrodes targeted the anterior intralaminar nuclei of thalamus and adjacent paralaminar regions of thalamic association nuclei. Both electrodes were positioned within the central lateral nucleus, the paralaminar regions of the median dorsalis, and the posterior-medial aspect of the centromedian/parafasicularis nucleus complex. This allowed maximum coverage of the thalamic bodies. A DBS stimulation was conducted such that the patient was exposed to various patterns of stimulation to help identify optimal behavioral responses. Approximately 140 days after the stimulation began, qualitative changes in behavior emerged. There were longer periods of eye opening and increased responses to command stimuli as well as higher scores on the JFK coma recovery scale (CRS). Functional object use and intelligible verbalization was also observed. The observed improvements in arousal level, motor control, and consistency of behavior could be a result of direct activation of frontal cortical and basal ganglia systems that were innervated by neurons within the thalamic association nuclei. These neurons act as a key communication relay and form a pathway between the brainstem arousal systems and frontal lobe regions. This pathway is crucial for many executive functions such as working memory, effort regulation, selective attention, and focus.In another case study of a 50-year-old woman who had symptoms consistent with MCS, administration of zolpidem, a sedative hypnotic drug improved the patients condition significantly. Without treatment, the patient showed signs of mutism, athetoid movements of the extremities, and complete dependence for all personal care. 45 minutes after 5 to 10 mg of zolpidem was administered, the patient ceased the athetoid movements, regained speaking ability, and was able to self-feed. The effect lasted 3–4 hours from which she returned to the former state. The effects were repeated on a daily basis. PET scans showed that after zolpidem was administered, there was a marked increase in blood flow to areas of the brain adjacent to or distant from damaged tissues. In this case, these areas were the ipsilateral cerebral hemispheres and the cerebellum. These areas are thought to have been inhibited by the site of injury through a GABA-mediated mechanism and the inhibition was modified by zolpidem which is a GABA agonist. The fact that zolpidem is a sedative drug that induces sleep in normal people but causes arousal in a MCS patient is paradoxical. The mechanisms to why this effect occurs is not entirely clear.There is recent evidence that transcranial direct current stimulation (tDCS), a technique that supplies a small electric current in the brain with non-invasive electrodes, may improve the clinical state of patients with MCS. In one study with 10 patients with disorders of consciousness (7 in VS, 3 in MCS), tDCS was applied for 20 minutes every day for 10 days, and showed clinical improvement in all 3 patients who were in MCS, but not in those with VS. These results remained at 12-month follow-up. Two of the patients in MCS that had their brain insult less that 12 months recovered consciousness in the following months. One of these patients received a second round of tDCS treatment 4 months after his initial treatment, and showed further recovery and emerged into consciousness, with no change of clinical status between the two treatments.

Prognosis
One of the defining characteristics of minimally conscious state is the more continuous improvement and significantly more favorable outcomes post injury when compared with vegetative state. One study looked at 100 patients with severe brain injury. At the beginning of the study, all the patients were unable to follow commands consistently or communicate reliably. These patients were diagnosed with either MCS or vegetative state based on performance on the JFK Coma Recovery Scale and the diagnostic criteria for MCS as recommended by the Aspen Consensus Conference Work-group. Both patient groups were further separated into those that had traumatic brain injury and those that had non-traumatic brain injures (anoxia, tumor, hydrocephalus, infection). The patients were assessed multiple times over a period of 12 months post injury using the Disability Rating Scale (DRS) which ranges from a score of 30=dead to 0=no disabilities. The results show that the DRS scores for the MCS subgroups showed the most improvement and predicted the most favorable outcomes 12 months post injury. Amongst those diagnosed with MCS, DRS scores were significantly lower for those with non-traumatic brain injuries in comparison to the vegetative state patients with traumatic brain injury. DRS scores were also significantly lower for the MCS non-traumatic brain injury group compared to the MCS traumatic brain injury group. Pairwise comparisons showed that DRS scores were significantly higher for those that suffered from non-traumatic brain injuries than those with traumatic brain injuries. For the patients in vegetative states there were no significant differences between patients with non-traumatic brain injury and those with traumatic brain injuries. Out of the 100 patients studied, 3 patients fully recovered (had a DRS score of 0). These 3 patients were diagnosed with MCS and had suffered from traumatic brain injuries.In summary, those with minimally conscious state and non-traumatic brain injuries will not progress as well as those with traumatic brain injuries while those in vegetative states have an all around lower to minimal chance of recovery.
Because of the major differences in prognosis described in this study, this makes it crucial that MCS be diagnosed correctly. Incorrectly diagnosing MCS as vegetative state may lead to serious repercussions related to clinical management.

History
Prior to the mid-1990s, there was a lack of operational definitions available to clinicians and researchers to guide the differential diagnosis among disorders of consciousness. As a result, patients were lumped together into broad categories often based on the severity of the disability (e.g. moderate, severe, extremely severe). These diagnoses were performed without regard to salient differences in behavioral and pathological characteristics. In a three-year period spanning from 1994 to 1996, three position statements regarding the diagnostic criteria of disorder of consciousness were published. The "Medical Aspects of the Persistent Vegetative State" was published by
the American Academy of Neurology (AAN) in 1994. In 1995, "Recommendations for Use of Uniform Nomenclature Pertinent to Patients With Severe Alterations in Consciousness" was published by the American Congress of Rehabilitation Medicine (ACRM). In 1996 the "International Working Party on the Management of the Vegetative State: Summary Report" was published by a group of international delegates from neurology, rehabilitation, neurosurgery, and neuropsychology. However, because the diagnostic criteria were published independently from one another, the final recommendations differed greatly from one another. The Aspen Neurobehavioral Work-group was convened to explore the underlying causes of these disparities. In the end, the Aspen Work-group provided a consensus statement regarding definitions and diagnostic criteria disorder of consciousness which include the vegetative state (VS) and the minimally conscious state (MCS).

Ethical issues
One of the major ethical concerns involving patients with severe brain damage is their inability to communicate. By definition, patients who are unconscious or are minimally conscious are incapable of giving informed consent which is required for participation in clinical research. Typically, written approval is obtained from family members or legal representatives. The inability to receive informed consent has led to much research being refused grants, ethics committee approval, or research publication. This puts patients in these conditions at risk of being denied therapy that may be life-saving.

The right to die
The right to die in patients with severe cognitive impairment has developed over time because of their grave neurological state and the perceived futility of continued treatment. Such cases have been debated vigorously in the past, as in the case with Terri Schiavo who was diagnosed with persistent vegetative state </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 Retiform parapsoriasis 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 Perforating granuloma annulare 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 Erdheim–Chester disease and can you explain it in depth? [/INST] Erdheim–Chester disease (ECD)  is an extremely rare disease characterized by the abnormal multiplication of a specific type of white blood cells called histiocytes, or tissue macrophages (technically, this disease is termed a non-Langerhans-cell histiocytosis). It was declared a histiocytic neoplasm by the World Health Organization in 2016. Onset typically is in middle age. The disease involves an infiltration of lipid-laden macrophages, multinucleated giant cells, an inflammatory infiltrate of lymphocytes and histiocytes in the bone marrow, and a generalized sclerosis of the long bones.

Signs and symptoms
Long bone involvement is almost universal in ECD patients and is bilateral and symmetrical in nature. More than 50% of cases have some sort of extraskeletal involvement. This can include kidney, skin, brain and lung involvement, and less frequently retroorbital tissue, pituitary gland and heart involvement is observed.Bone pain is the most frequent of all symptoms associated with ECD and mainly affects the lower limbs, knees and ankles. The pain is often described as mild but permanent, and juxtaarticular in nature. Exophthalmos occurs in some patients and is usually bilateral, symmetric and painless, and in most cases it occurs several years before the final diagnosis. Recurrent pericardial effusion can be a manifestation, as can morphological changes in adrenal size and infiltration.A review of 59 case studies by Veyssier-Belot et al. in 1996 reported the following symptoms in order of frequency of occurrence:
Bone pain
Retroperitoneal fibrosis
Diabetes insipidus
Exophthalmos
Xanthomas
Neurological signs (including ataxia)
Dyspnea caused by interlobular septal and pleural thickening.
Kidney failure
Hypopituitarism
Liver failure

Diagnosis
Radiologic osteosclerosis and histology are the main diagnostic features. Diagnosis can often be difficult because of the rareness of ECD as well as the need to differentiate it from LCH. A diagnosis from neurological imaging may not be definitive. The presence of symmetrical cerebellar and pontine signal changes on T2-weighted images seem to be typical of ECD, however, multiple sclerosis and metabolic diseases must also be considered in the differential diagnosis. ECD is not a common cause of exophthalmos but can be diagnosed by biopsy.  However, like all biopsies, this may be inconclusive. Video-assisted thoracoscopic surgery may be used for diagnostic confirmation and also for therapeutic relief of recurrent pericardial fluid drainage.

Histology
Histologically, ECD differs from Langerhans cell histiocytosis (LCH) in a number of ways. Unlike LCH, ECD does not stain positive for S-100 proteins or Group 1 CD1a glycoproteins, and electron microscopy of cell cytoplasm does not disclose Birbeck granules.  Tissue samples show xanthomatous or xanthogranulomatous infiltration by lipid-laden or foamy histiocytes, and are usually surrounded by fibrosis. Bone biopsy is said to offer the greatest likelihood of reaching a diagnosis </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 Dentigerous cyst and can you explain it in depth? [/INST] Dentigerous cyst, also known as follicular cyst is an epithelial-lined developmental cyst formed by accumulation of fluid between the reduced enamel epithelium and crown of an unerupted tooth. It is formed when there is an alteration in the reduced enamel epithelium and encloses the crown of an unerupted tooth at the cemento-enamel junction. Fluid is accumulated between reduced enamel epithelium and the crown of an unerupted tooth. Dentigerous cyst is the second most common form of benign developmental odontogenic cysts.
Dentigerous cyst is the second most prevalent type of odontogenic cysts after radicular cyst. 70 percent of the cases occurs in the mandible. Dentigerous cyst is usually painless. Patient usually comes with a concern of delayed tooth eruption or facial swelling. Dentigerous cyst can go unnoticed and may be discovered coincidentally on a regular radiographic examination.

Pathogenesis
Odontogenesis happens by means of a complex interaction between oral epithelium and surrounding mesenchymal tissue. Abnormal tissue interaction during this process can result in ectopic tooth development. Ectopic tooth eruption may result due to pathological process, such as a tumor or cyst or developmental disturbance. The pathogenesis of dentigerous cyst is still controversial.
The accumulation of fluid either between the reduced enamel epithelium and enamel or in between the layers of enamel organ seems to be the key to the formation of dentigerous cysts.
A potentially erupting tooth on an impacted follicle can obstruct the venous outflow, inducing rapid transudation of serum across the capillary walls.
Main suggested that this may exert pressure, causing the accumulation of fluid. On the contrary, Toiler suggested that the breakdown of proliferating cells of the follicle after impeded eruption is likely to be the origin of the dentigerous cyst. The breakdown products may result in increased osmotic tension, resulting in cyst formation.
The exact histogenesis of dentigerous cysts remains unknown, but most authors favor a developmental origin from the tooth follicle. In 1928, Bloch-Jorgensen suggested that the overlying necrotic deciduous tooth is the origin of all dentigerous cysts. The resultant periapical inflammation might spread to involve the follicle of the unerupted permanent successor, an inflammatory exudate ensued with resultant dentigerous cyst formation. He reported 22 cases of follicular cysts and stated that in each case a deciduous tooth or the remnants thereof was found in direct contact with the cyst cavity and that the related deciduous tooth always was diseased.
Azaz and Shteyer similarly suggested that the persistent and prolonged periapical inflammation caused chronic irritation to the follicle of the successors. This may trigger and hasten the formation of a dentigerous cyst developing around the permanent teeth. They reported five cases of dentigerous cysts which involved the second mandibular premolar in four children aged 8 to 11 years old. These children were referred for extraction of carious, nonvital primary molars with swelling of the surrounding soft tissue. Occlusal radiographs showed buccal expansion of bone at the affected site. The primary teeth were not in direct contact with the underlying dentigerous cyst.
It has been suggested that dentigerous cysts may be either extrafollicular or intrafollicular in origin. There were three possible mechanisms exist. Firstly, surrounding the crowns of affected teeth, the intrafollicular developmental dentigerous cysts may be formed. These cysts may be secondarily inflamed and infected as a result of periapical inflammation spreading from non vital deciduous predecessors. Benn and Altini (1996) claimed that this possibility was unlikely as all the cases reported were not associated with tooth impaction.
Secondly, radicular cysts developed at the apices of non vital primary teeth. These radicular cysts may fuse with the follicles of the unerupted successors, causing the eruption of the successors into the cyst cavity. This may result in the formation of extrafollicular dentigerous cyst. Shear regarded this to be exceptionally rare because radicular cyst is uncommon in the primary dentition.
The third possibility is that periapical inflammation could be of any source but usually from a non vital deciduous tooth spreading to involve the follicles of unerupted permanent successors. The inflammatory exudate causes separation of reduced enamel epithelium from the enamel with resultant cyst formation.

Clinical Features
The dentigerous cyst commonly involves a single tooth and rarely affects multiple teeth. The most frequently involved tooth is the mandibular third molar followed by the maxillary canine, but they may be associated with supernumerary or ectopic tooth. Any permanent tooth can be involved. Regezi and Sciubba stated that the impacted teeth were most commonly seen in the third molar and maxillary canine teeth, and hence dentigerous cysts occur most frequently in these teeth. The involved teeth may be displaced into ectopic positions. In the maxilla, these teeth are often displaced into the maxillary sinus. Classic symptoms of sinus disease such as headache, facial pain, purulent nasal discharge or nasolacrimal obstruction may occur when maxillary sinus is involved.
According to a study, 45.7 percent of dentigerous cysts involved mandibular third molar. On the other hand, only 2.7 percent of dentigerous cysts involved the maxillary premolar. Mourshed stated that the incidence of dentigerous cyst has been reported as 1.44 in every 100 unerupted teeth, so dentigerous cysts involving the premolars are rare.
Dentigerous cysts most commonly occur in the 2nd and 3rd decades of life. Males have been reported to be more prevalent than females with a ratio of 1.8:1. These cysts can also be found in young children and adolescents. The age of presentation of these cysts range from 3 years to 57 years with a mean of 22.5 years.
These cysts are commonly single lesions. Bilateral and multiple dentigerous cysts are very rare although they have been reported. Bilateral or multiple dentigerous cysts have been reported in Maroteaux-Lamy syndrome, cleidocranial dysplasia and Gardners syndrome In the absence of these syndromes, the occurrence of multiple dentigerous cysts is rare. Sometimes multiple dentigerous cysts are suggested to be induced by prescribed drugs. The combined effect of cyclosporine and a calcium channel blocker is reported to cause bilateral dentigerous cyst
Dentigerous cyst is potentially capable of becoming an aggressive lesion. The possible sequelae of continuous enlargement of dentigerous cyst are expansion of the alveolar bone, displacement of teeth, severe root resorption of teeth, expansion of buccal and lingual cortex and pain.
Potential complications are development of cellulitis, deep neck infection, ameloblastoma, epidermoid carcinoma or mucoepidermoid carcinoma.

Investigations
Early detection and removal of the cysts is essential to reduce morbidity since dentigerous cyst can attain considerable size without any symptoms. Patient who presents with unerupted teeth should be thoroughly examined with radiographic examinations to check our for dentigerous cysts. Panoramic radiographs may be indicated for this purpose. CT imaging becomes necessary for extensive lesion.
Pathologic analysis of the lesion is important for the definitive diagnosis even though radiographs provide valuable information.

Histopathologic Features
The histopathologic features of dentigerous cyst are dependent on the nature of the cyst, whether it is inflamed or not inflamed.

Non-inflamed dentigerous cystThe specimen will present with loosely arranged fibrous connective tissue wall that contains considerable glycosaminoglycan ground substance. Small islands or cords of inactive-appearing odontogenic epithelial rests are usually scattered within the connective tissue and most commonly located near the epithelial lining. These rests may appear numerous in the fibrous connective tissue wall occasionally, which may be misinterpreted as ameloblastoma by some pathologists who are unfamiliar with oral lesions. The epithelial lining is composed of two to four layers of flattened non-keratinizing cells, with a flat epithelium and connective tissue interface.

Inflamed dentigerous cystOccurrence of inflamed dentigerous cyst is fairly common. Histologic examination reveals a more collagenized fibrous connective tissue wall, with a variable infiltration of chronic inflammatory cells. Cholesterol slits and their associated multinucleated giant cells may be present and are generally associated with the connective tissue wall. The cyst is lined mostly or entirely by non-keratinizing squamous epithelium which display varying amounts of hyperplasia with the development of anastomosing rete ridges and more definite squamous features. Dentigerous cysts presenting with these features may histologically be indistinguishable from radicular cysts. A keratinized surface is occasionally present, which must be differentiated from those observed in the odontogenic keratocyst(OKC). Focal areas of mucus cells or rarely, ciliated columnar cells may be found in the epithelial lining of dentigerous cysts. In addition, small nests of sebaceous cells infrequently may be present within the fibrous connective tissue wall. These mucous, ciliated and sebaceous elements are postulated to represent the multipotentiality of the odontogenic epithelial lining in a dentigerous cyst.
One or several areas of nodular thickening may be seen on the luminal surface in the gross examination of the fibrous wall of a dentigerous cyst. Careful examination of these areas microscopically is mandatory to rule out the presence of early neoplastic change.
As the dental follicle surrounding the crown of an unerupted tooth usually is lined by a thin layer of reduced enamel epithelium, this may render it difficult to distinguish a small dentigerous cyst from a normal or enlarged dental follicle based on microscopic features alone.

Imaging Features
As the epithelial lining is derived from the reduced enamel epithelium, on radiographic examination, a dentigerous cyst appears as a unilocular radiolucent area that is associated with just the crown of an unerupted tooth and is attached to the tooth at the cementoenamel junction. Dentigerous cysts may also involve odontomas, which by their nature also have “tooth crowns”. The radiolucency is generally well-defined and well-corticated. The radiolucency often have a sclerotic border indicating bony reaction, but a secondarily infected cyst may display ill-defined borders. However, a large dentigerous cyst may give the impression of a multilocular process due to the persistence of bone trabeculae within the radiolucency.
The cyst-to-crown relationship presents several radiographic variations which are explained as follows:
Central variantThis is the most common variant which the cyst surrounds the crown of the tooth and the crown projects into the cyst.

Lateral variantThis variant is usually associated with a mesioangular impacted mandibular third molar that is partially erupted. The cyst develops laterally along the root surface and partially surrounds the crown.

Circumferential variantThe cyst surrounds the crown and extends for some distance along the root surface so that a significant portion of the root appears to lie within the cyst, as if the tooth was erupting through the centre of the cyst.
The radiographic distinction between an enlarged dental follicle and a small dentigerous cyst can be difficult and fairly arbitrary. Generally, any pericoronal radiolucency that is greater than 3 to 4mm in diameter is considered suggestive of cyst formation.
Some dentigerous cysts may result in considerable displacement of the involved tooth. Infrequently, a third molar may be displaced to the lower border of the mandible or into the ascending ramus. On the other hand, maxillary anterior teeth may be displaced into the floor of the nasal cavity, while other maxillary teeth may be displaced through the maxillary sinus to the floor of the orbit. Furthermore, larger cysts can lead to resorption of adjacent unerupted teeth. Some dentigerous cysts may also grow to considerable size and produce bony expansion that is usually painless, unless secondarily infected. However, any particularly large dentigerous radiolucency should clinically be suspected of a more aggressive odontogenic lesion such as an odontogenic keratocyst or ameloblastoma. For this reason, biopsy is mandated for all significant pericoronal radiolucencies to confirm the diagnosis.
The role of CT (computerized tomography) imaging in the evaluation of cystic lesions has been well-documented. CT imaging aids to rule out solid and fibro-osseous lesions, displays bony detail, and provides precise information about the size, origin, content, and relationships of the lesions.On CT imaging, a mandibular dentigerous cyst appears as a well-circumscribed unilocular area of osteolysis that incorporates the crown of a tooth. Displacement of adjacent teeth may be seen and they may be partly eroded. Dentigerous cysts in the maxilla often extend into the antrum, displacing and remodeling the bony sinus wall. Large cysts which may project into the nasal cavity or infratemporal fossa and may elevate the floor of the orbit can be noted on CT imaging. In the mandible, buccal or lingual cortical expansion and thinning are noted.On MR imaging, the contents of the cyst display low to intermediate signal intensity on T1-weighted images and high signal intensity on T2-weighted images. The tooth itself is a zone of signal void. The lining of the cyst is thin with regular thickness and may show slight enhancement after contrast injection.

Treatment and Prognosis
The treatment of choice for dentigerous cyst is enucleation along with extraction of the impacted teeth. If eruption of the unerupted tooth is considered feasible, the tooth may be left in place after partial removal of the cyst wall. Orthodontic treatment may subsequently be required to assist eruption. Similarly, if displacement of the associated tooth by the cyst has occurred and extraction may prove to be difficult, orthodontic movement of the tooth to a more advantageous location for extraction may be accomplished. Marsupialization may also be used to treat large dentigerous cysts. This permits the decompression of the cyst, with a resulting decrease in the size of the bone defect. The cyst can then be excised at a later date, with a less extensive surgical procedure.
The prognosis for the dentigerous cyst is excellent, and recurrence is rare. This is related to the exhausted nature of the reduced enamel epithelium, which has differentiated and formed tooth crown enamel before developing into a cyst. Nevertheless, several potential complications must be considered. The possibility that the lining of a dentigerous cyst might undergo neoplastic transformation to an ameloblastoma has been well-documented. Mourshed showed that 33% of ameloblastomas arose from the epithelial lining of a dentigerous cyst. Although undeniably this can occur, the frequency of such neoplastic transformation is low. In addition, a squamous cell carcinoma may rarely arise in the lining of a dentigerous cyst. Transformation from normal epithelial cyst lining to SCC is due to chronic inflammation. It is likely that some intraosseous mucoepidermoid carcinomas develop from mucous cells in the lining of a dentigerous cyst. Malignancy in the cyst wall is usually unexpected at the time of presentation and the diagnosis is usually made following enucleation. Jagged or irregular margins with indentations and indistinct borders are considered to be suggestive of possible malignant change. Due to the potential for occurrence of an odontogenic keratocyst or the development of an ameloblastoma or, more rarely, mucoepidermoid carcinoma, all such lesions, when excised, should be submitted for histopathologic evaluation.

Differential Diagnosis
The differential diagnoses of dentigerous cysts are as follows:

Radicular cystIt is an odontogenic cyst that is a sequela of periapical granuloma in a carious tooth.
Odontogenic keratocyst(OKC)It is often multilocular and most commonly located in the body or the ramus of the mandible.Histologically, the epithelium is uniform in nature, usually four to eight cells in thickness </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 Granular cell tumor and can you explain it in depth? [/INST] Granular cell tumor is a tumor that can develop on any skin or mucosal surface, but occurs on the tongue 40% of the time.
It is also known as Abrikossoffs tumor, Granular cell myoblastoma, Granular cell nerve sheath tumor, and Granular cell schwannoma.)Granular cell tumors (GCTs) affect females more often than males.

Pathology
Granular cell tumors are derived from neural tissue, as can be demonstrated by immunohistochemistry and ultrastructural evidence using electron microscopy. These lesions characteristically consist of polygonal cells with bland nuclei, abundant cytoplasm and fine eosinophilic cytoplasmic granules. The tumor cells stain positively for S-100 as they are of Schwann cell origin. Both malignant and benign versions of the tumor exist, where malignant tumors are characterized histologically by features such as spindling, high nuclear to cytoplasmic ratios, pleomorphism, and necrosis. Multiple granular cell tumors may seen in the context of LEOPARD syndrome, due to a mutation in the PTPN11 gene.These tumors, on occasion, may appear similar to neoplasms of renal (relating to the kidneys) origin or other soft tissue neoplasms.

Treatment
The primary method for treatment is surgical, not medical.  Radiation and chemotherapy are not needed for benign lesions and are not effective for malignant lesions.
Benign granular cell tumors have a recurrence rate of 2% to 8% when resection margins are deemed clear of tumor infiltration.  When the resection margins of a benign granular cell tumor are positive for tumor infiltration the recurrence rate is increased to 20%.  Malignant lesions are aggressive and difficult to eradicate with surgery and have a recurrence rate of 32%.

Epidemiology
Granular cell tumors can affect all parts of the body; however, the head and neck areas are affected 45% to 65% of the time.  Of the head and neck cases 70% of lesions are located intraorally (tongue, oral mucosa, hard palate) </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 Butchers wart and can you explain it in depth? [/INST]  </s>