<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 Delirium and can you explain it in depth? [/INST] Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances in attention, consciousness, and cognition. It may also involve other neurological deficits, such as psychomotor disturbances (e.g. hyperactive, hypoactive, or mixed), impaired sleep-wake cycle, emotional disturbances, and perceptual disturbances (e.g. hallucinations and delusions), although these features are not required for diagnosis.
Delirium is caused by an acute organic process, which is a physically identifiable structural, functional, or chemical problem in the brain that may arise from a disease process outside the brain that nonetheless affects the brain. It may result from an underlying disease process (e.g. infection, hypoxia), side effect of a medication, withdrawal from drugs, over-consumption of alcohol, usage of hallucinogenic deliriants, or from any number of factors affecting ones overall health (e.g. malnutrition, pain, etc.). In contrast, fluctuations in mental status/function due to changes in primarily psychiatric processes or diseases (e.g. schizophrenia, bipolar disorder) do not, by definition, meet the criteria for delirium.Delirium may be difficult to diagnose without the proper establishment of a persons usual mental function. Without careful assessment and history, delirium can easily be confused with a number of psychiatric disorders or chronic organic brain syndromes because of many overlapping signs and symptoms in common with dementia, depression, psychosis, etc. Delirium may manifest from a baseline of existing mental illness, baseline intellectual disability, or dementia, without being due to any of these problems.
Treatment of delirium requires identifying and managing the underlying causes, managing delirium symptoms, and reducing the risk of complications. In some cases, temporary or symptomatic treatments are used to comfort the person or to facilitate other care (e.g. preventing people from pulling out a breathing tube). Antipsychotics are not supported for the treatment or prevention of delirium among those who are in hospital; however they will be used in cases where a patient has a history of anxiety, hallucinations or if they are a danger to themselves or others. When delirium is caused by alcohol or sedative hypnotic withdrawal, benzodiazepines are typically used as a treatment. There is evidence that the risk of delirium in hospitalized people can be reduced by systematic good general care. In a DSM assessment, delirium was found to affect 14–24% of all hospitalized individuals, with an overall prevalence for the general population as 1–2%, increasing with age, reaching 14% of adults over age 85. Among older adults, delirium was found to occur in 15–53% of those post-surgery, 70–87% of those in the ICU, and in up to 60% of those in nursing homes or post-acute care settings. Among those requiring critical care, delirium is a risk for death within the next year.

Definition
In common usage, delirium is often used to refer to drowsiness, disorientation, and hallucination. In medical terminology, however, acute disturbance in consciousness/attention and a number of different cognitive symptoms are the core features of delirium.
Several medical definitions of delirium exist (including those in the DSM and ICD-10), but the core features remain the same. In 2013, the American Psychiatric Association released the fifth edition of the DSM (DSM-5) with the following criteria for diagnosis:
A. Disturbance in attention and awareness. This is a required symptom and involves easy distraction, inability to maintain attentional focus, and varying levels of alertness.
B. Onset is acute (from hours to days), representing a change from baseline mentation with fluctuations throughout the day
C. At least one additional cognitive disturbance (in memory, orientation, language, visuospatial ability, or perception)
D. The disturbances (criteria A and C) are not better explained by another neurocognitive disorder
E. There is evidence that the disturbances above are a "direct physiological consequence" of another medical condition, substance intoxication or withdrawal, toxin, or various combinations of causes

Signs and symptoms
Delirium exists as a stage of consciousness somewhere in the spectrum between normal awakeness/alertness and coma. While requiring an acute disturbance in consciousness/attention and cognition, delirium is a syndrome encompassing an array of neuropsychiatric symptoms.The range of clinical features include: poor attention/vigilance (100%), memory impairment (64–100%), clouding of consciousness (45–100%), disorientation (43–100%), acute onset (93%), disorganized thinking/thought disorder (59–95%), diffuse cognitive impairment (77%), language disorder (41–93%), sleep disturbance (25–96%), mood lability (43–63%), psychomotor changes (e.g. hyperactive, hypoactive, mixed) (38–55%), delusions (18–68%), and perceptual change/hallucinations (17–55%). These various features of delirium are further described below:

Inattention: As a required symptom to diagnose delirium, this is characterized by distractibility and an inability to shift and/or sustain attention.
Memory impairment: Memory impairment is linked to inattention, especially reduced formation of new long-term memory where higher degrees of attention is more necessary than for short-term memory. Since older memories are retained without need of concentration, previously formed long-term memories (i.e. those formed before the onset of delirium) are usually preserved in all but the most severe cases of delirium.
Disorientation: As another symptom of confusion, and usually a more severe one, this describes the loss of awareness of the surroundings, environment and context in which the person exists. One may be disoriented to time, place, or self.
Disorganized thinking: Disorganized thinking is usually noticed with speech that makes limited sense with apparent irrelevancies, and can involve poverty of speech, loose associations, perseveration, tangentiality, and other signs of a formal thought disorder.
Language disturbances: Anomic aphasia, paraphasia, impaired comprehension, agraphia, and word-finding difficulties all involve impairment of linguistic information processing.
Sleep changes: Sleep disturbances in delirium reflect disturbed circadian rhythm regulation, typically involving fragmented sleep or even sleep-wake cycle reversal (i.e. active at night, sleeping during the day) and often preceding the onset of a delirium episode
Psychotic symptoms: Symptoms of psychosis include suspiciousness, overvalued ideation and frank delusions. Delusions are typically poorly formed and less stereotyped than in schizophrenia or Alzheimers disease. They usually relate to persecutory themes of impending danger or threat in the immediate environment (e.g. being poisoned by nurses).
Mood lability: Distortions to perceived or communicated emotional states as well as fluctuating emotional states can manifest in a delirious person (e.g. rapid changes between terror, sadness and joking).
Motor activity changes: Delirium has been commonly classified into psychomotor subtypes of hypoactive, hyperactive, and mixed, though studies are inconsistent as to the prevalence of these subtypes. Hypoactive cases are prone to non-detection or misdiagnosis as depression. A range of studies suggest that motor subtypes differ regarding underlying pathophysiology, treatment needs, and prognosis for function and mortality though inconsistent subtype definitions and poorer detection of hypoactive subtypes impacts interpretation of these findings. Liptzin and Levkoff first described these subtypes in 1992 as following:
Hyperactive symptoms include hyper-vigilance, restlessness, fast or loud speech, irritability, combativeness, impatience, swearing, singing, laughing, uncooperativeness, euphoria, anger, wandering, easy startling, fast motor responses, distractibility, tangentiality, nightmares, and persistent thoughts (hyperactive sub-typing is defined with at least three of the above).
Hypoactive symptoms include unawareness, decreased alertness, sparse or slow speech, lethargy, slowed movements, staring, and apathy (hypoactive sub-typing is defined with at least four of the above).

Causes
Delirium arises through the interaction of a number of predisposing and precipitating factors.Individuals with multiple and/or significant predisposing factors are at high risk for an episode of delirium with a single and/or mild precipitating factor. Conversely, delirium may only result in low risk individuals if they experience a serious or multiple precipitating factors. It is important to note that the factors affecting those of an individual can change over time, thus an individuals risk of delirium is dynamic.

Predisposing factors
The most important predisposing factors are:
65 or more years of age
Male sex
Cognitive impairment/dementia
Physical comorbidity (biventricular failure, cancer, cerebrovascular disease)
Psychiatric comorbidity (e.g., depression)
Sensory impairment (vision, hearing)
Functional dependence (e.g., requiring assistance for self-care or mobility)
Dehydration/malnutrition
Drugs and drug-dependence
Alcohol dependence

Precipitating factors
Any acute factors that affect neurotransmitter, neuroendocrine, or neuroinflammatory pathways can precipitate an episode of delirium in a vulnerable brain. Clinical environments can also precipitate delirium. Some of the most common precipitating factors are listed below:
Prolonged sleep deprivation
Environmental, physical/psychological stress
Inadequately controlled pain
Admission to an intensive care unit
Immobilization, use of physical restraints
Urinary retention, use of bladder catheter,
Emotional stress
Severe constipation/fecal impaction
MedicationsSedatives (benzodiazepines, opioids), anticholinergics, dopaminergics, corticosteroids, polypharmacy
General anesthetic
Substance intoxication or withdrawal
Primary neurologic diseases
Severe drop in blood pressure, relative to the patients normal blood pressure (orthostatic hypotension) resulting in inadequate blood flow to the brain (cerebral hypoperfusion)
Stroke/Transient ischemic attack(TIA)
Intracranial bleeding
Meningitis, encephalitis
Concurrent illness
Infections – especially respiratory (e.g. pneumonia, COVID-19) and urinary tract infections
Iatrogenic complications
Hypoxia, hypercapnea, anemia
Poor nutritional status, dehydration, electrolyte imbalances, hypoglycemia
Shock, heart attacks, heart failure
Metabolic derangements (e.g. SIADH, Addisons disease, hyperthyroidism, )
Chronic/terminal illness (e.g. cancer)
Post-traumatic event (e.g. fall, fracture)
Mercury poisoning (e.g. Erethism)
Surgery
Cardiac, orthopedic, prolonged cardiopulmonary bypass, thoracic surgeries

Pathophysiology
The pathophysiology of delirium is still not well understood, despite extensive research.

Animal models
The lack of animal models that are relevant to delirium has left many key questions in delirium pathophysiology unanswered. Earliest rodent models of delirium used atropine (a muscarinic acetylcholine receptor blocker) to induce cognitive and electroencephalography (EEG) changes similar to delirium, and other anticholinergic drugs, such as biperiden and hyoscine, have produced similar effects. Along with clinical studies using various drugs with anticholinergic activity, these models have contributed to a "cholinergic deficiency hypothesis" of delirium.Profound systemic inflammation occurring during sepsis is also known to cause delirium (often termed sepsis-associated encephalopathy). Animal models used to study the interactions between prior degenerative disease and overlying systemic inflammation have shown that even mild systemic inflammation causes acute and transient deficits in working memory among diseased animals. Prior dementia or age-associated cognitive impairment is the primary predisposing factor for clinical delirium and "prior pathology" as defined by these new animal models may consist of synaptic loss, abnormal network connectivity, and "primed microglia" brain macrophages stimulated by prior neurodegenerative disease and aging to amplify subsequent inflammatory responses in the central nervous system (CNS).

Cerebrospinal fluid
Studies of cerebrospinal fluid (CSF) in delirium are difficult to perform. Apart from the general difficulty of recruiting participants who are often unable to give consent, the inherently invasive nature of CSF sampling makes such research particularly challenging. However, a few studies have exploited the opportunity to sample CSF from persons undergoing spinal anesthesia for elective or emergency surgery.A 2018 systematic review showed that, broadly, delirium may be associated with neurotransmitter imbalance (namely serotonin and dopamine signaling), reversible fall in somatostatin, and increased cortisol. The leading "neuroinflammatory hypothesis" (where neurodegenerative disease and aging leads the brain to respond to peripheral inflammation with an exaggerated CNS inflammatory response) has been described, but current evidence is still conflicting and fails to concretely support this hypothesis.

Neuroimaging
Neuroimaging provides an important avenue to explore the mechanisms that are responsible for delirium. Despite progress in the development of magnetic resonance imaging (MRI), the large variety in imaging-based findings has limited our understanding of the changes in the brain that may be linked to delirium. Some challenges associated with imaging people diagnosed with delirium include participant recruitment and inadequate consideration of important confounding factors such as history of dementia and/or depression, which are known to be associated with overlapping changes in the brain also observed on MRI.Evidence for changes in structural and functional markers include: changes in white-matter integrity (white matter lesions), decreases in brain volume (likely as a result of tissue atrophy), abnormal functional connectivity of brain regions responsible for normal processing of executive function, sensory processing, attention, emotional regulation, memory, and orientation, differences in autoregulation of the vascular vessels in the brain, reduction in cerebral blood flow and possible changes in brain metabolism (including cerebral tissue oxygenation and glucose hypometabolism). Altogether, these changes in MRI-based measurements invite further investigation of the mechanisms that may underlie delirium, as a potential avenue to improve clinical management of people with this condition.

Neurophysiology
Electroencephalography (EEG) allows for continuous capture of global brain function and brain connectivity, and is useful in understanding real-time physiologic changes during delirium. Since the 1950s, delirium has been known to be associated with slowing of resting-state EEG rhythms, with abnormally decreased background alpha power and increased theta and delta frequency activity.From such evidence, a 2018 systematic review proposed a conceptual model that delirium results when insults/stressors trigger a breakdown of brain network dynamics in individuals with low brain resilience (i.e. people who already have underlying problems of low neural connectivity and/or low neuroplasticity like those with Alzheimers disease).

Neuropathology
Only a handful of studies exist where there has been an attempt to correlate delirium with pathological findings at autopsy. One research study has been reported on 7 patients who died during ICU admission. Each case was admitted with a range of primary pathologies, but all had acute respiratory distress syndrome and/or septic shock contributing to the delirium, 6 showed evidence of low brain perfusion and diffuse vascular injury, and 5 showed hippocampal involvement. A case-control study showed that 9 delirium cases showed higher expression of HLA-DR and CD68 (markers of microglial activation), IL-6 (cytokines pro-inflammatory and anti-inflammatory activities) and GFAP (marker of astrocyte activity) than age-matched controls; this supports a neuroinflammatory cause to delirium, but the conclusions are limited by methodological issues.A 2017 retrospective study correlating autopsy data with MMSE scores from 987 brain donors found that delirium combined with a pathological process of dementia accelerated MMSE score decline more than either individual process.

Diagnosis
Using the DSM-5 criteria for delirium as framework, the early recognition of signs/symptoms and a careful history, along with any of multiple clinical instruments, can help in making a diagnosis of delirium. A diagnosis of delirium cannot be made without a previous assessment of the patients baseline level of cognitive function. In other words, a mentally-disabled or impaired person might appear to be delirious, but may actually just be operating at their baseline mental ability.

General setting
Multiple guidelines recommend that delirium should be diagnosed when it presents to healthcare services. Much evidence reveal, however, that delirium is greatly under-diagnosed. Higher rates of detection of delirium in general settings can be assisted by the use of validated delirium screening tools. Many such tools have been published. They differ in duration, complexity, need for training, etc.
Examples of tools in use in clinical practice are:

Richmond Agitation and Sedation Scale (RASS) – highly sensitive and specific for diagnosing delirium in older patients
Observational Scale of Level of Arousal (OSLA) – highly sensitive and specific for diagnosing delirium in older patients
Confusion Assessment Method (CAM)
Delirium Observation Screening Scale (DOS)
Nursing Delirium Screening Scale (Nu-DESC)
Recognizing Acute Delirium As part of your Routine (RADAR)
4AT (4 As Test)
Delirium Diagnostic Tool-Provisional (DDT-Pro), also for subsyndromal delirium

Intensive care unit
People who are in the ICU are at greater risk of delirium and ICU delirium may lead to prolonged ventilation, longer stays in the hospital, increased stress on family and caregivers, and an increased chance of death. In the ICU, international guidelines recommend that every patient gets checked for delirium every day (usually twice or more a day) using a validated clinical tool. The definition of delirium that healthcare professionals use at the bedside is whether or not a patient can pay attention and follow simple commands. The two most widely used are the Confusion Assessment Method for the ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC). Translations of these tools exist in over 20 languages and are used ICUs globally with instructional videos and implementation tips available.More emphasis is placed on regular screening over the choice of tool used. This, coupled with proper documentation and informed awareness by the healthcare team, can affect clinical outcomes. Without using one of these tools, 75% of ICU delirium can be missed by the healthcare team, leaving the patient without any likely interventions to help reduce the duration of delirium.

Differential diagnosis
There are conditions that might have similar clinical presentations to those seen in delirium. These include dementia, depression, psychosis, and other conditions that affect cognitive function.
Dementia: This group of disorders is acquired (non-congenital) with usually irreversible cognitive and psychosocial functional decline. Dementia usually results from an identifiable degenerative brain disease (e.g. Alzheimer disease or Huntingtons disease), requires chronic impairment (versus acute onset in delirium), and is typically not associated with changes in level of consciousness. Dementia is different from delirium in that dementia lasts long-term while delirium lasts short-term.
Depression: Similar symptoms exist between depression and delirium (especially the hypoactive subtype). Gathering a history from other caregivers can clarify baseline mentation.
Other mental illnesses: Some mental illnesses, such as a manic episode of bipolar disorder, depersonalization disorder, or some types of acute psychosis may cause a rapidly fluctuating impairment of cognitive function and ability to focus. These, however, are not technically causes of delirium per DSM-5 criteria D (i.e. fluctuating cognitive symptoms occurring as part of a primary mental disorder are results of the said mental disorder itself), while physical disorders (e.g. infections, hypoxia, etc.) can precipitate delirium as a mental side-effect/symptom.
Psychosis: Consciousness and cognition may not be impaired (however, there may be overlap, as some acute psychosis, especially with mania, is capable of producing delirium-like states).

Prevention
Using a tailored multi-faceted approach as outlined above can decrease rates of delirium by 27% among the elderly. At least 30–40% of all cases of delirium could be prevented, and high rates of delirium reflect negatively on the quality of care. Episodes of delirium can be prevented by identifying hospitalized people at risk of the condition. This includes individuals over age 65, with a cognitive impairment, with hip fracture, or with severe illness. Close observation for the early signs is recommended in such populations.
Delirium may be prevented and treated by using non-pharmacologic approaches focused on risk factors, such as constipation, dehydration, low oxygen levels, immobility, visual or hearing impairment, sleep deprivation, functional decline and removing or minimizing problematic medications. Ensuring a therapeutic environment (e.g. individualized care; clear communication; adequate reorientation and lighting during daytime; promoting uninterrupted sleep hygiene with minimal noise and light at night; minimizing bed relocation; having familiar objects like family pictures; providing earplugs; and providing adequate nutrition, pain control, and assistance toward early mobilization) can also yield benefit toward preventing delirium. Research into pharmacologic prevention and treatment is weak and insufficient to make proper recommendations.Melatonin and other pharmacological agents have been studied for prevention of postoperative delirium, but evidence is not clear. Avoidance or cautious use of benzodiazepines has been recommended for reducing the risk of delirium in critically ill individuals. It is unclear if the medication donepezil, a cholinesterase inhibitor, reduces delirium following surgery. There is also no clear evidence to suggest that citicoline, methylprednisolone, or antipsychotic medications prevent delirium.
A review of intravenous versus inhalational maintenance of anaesthesia for postoperative cognitive outcomes in elderly people undergoing non-cardiac surgery showed little or no difference in postoperative delirium according to the type of anaesthetic maintenance agents in five studies (321 participants). The authors of this review were uncertain whether maintenance of anaesthesia with propofol-based total intravenous anaesthesia (TIVA) or with inhalational agents can affect the incidence rate of postoperative delirium.
Interventions for preventing delirium in older people in institutional long-term care
The current evidence suggests that software-based interventions to identify medications that could contribute to delirium risk and recommend a pharmacists medication review probably reduces incidence of delirium in older adults in long-term care. The benefits of hydration reminders and education on risk factors and care homes solutions for reducing delirium is still uncertain.

Treatment
Delirium is a reversible impairment, however, people that are ill with delirium may need to be treated in order to prevent injury and poor outcomes.Treatment of delirium requires attention to multiple domains including: identify and treat the underlying medical disorder or cause(s), optimize physiology, optimize conditions for brain recovery, detect and manage distress and behavioral disturbances, maintaining mobility, provide rehabilitation through cognitive engagement and mobilization, communicate effectively with the patient and their carers, and provide adequate follow-up including consideration of possible dementia and post-traumatic stress. This involves optimizing oxygenation, hydration, nutrition, electrolytes/metabolites, comfort, mobilization, pain control, mental stress, therapeutic medication levels, and addressing any other possible predisposing and precipitating factors that might be disrupting brain function.

Multidomain interventions
These interventions are the first steps in managing acute delirium and there are many overlaps with delirium preventative strategies. In addition to treating immediate life-threatening causes of delirium (e.g. low O2, low blood pressure, low glucose, dehydration), interventions include optimizing the hospital environment by reducing ambient noise, providing proper lighting, offering pain relief, promoting healthy sleep-wake cycles, and minimizing room changes. Although multicomponent care and comprehensive geriatric care are more specialized for a person experiencing delirium, several studies have been unable to find evidence showing they reduce the duration of delirium.Family, friends, and other caregivers can offer frequent reassurance, tactile and verbal orientation, cognitive stimulation (e.g. regular visits, familiar objects, clocks, calendars, etc.), and means to stay engaged (e.g. making hearing aids and eyeglasses readily available). Sometimes verbal and non-verbal deescalation techniques may be required to offer reassurances and calm the person experiencing delirium. Restraints should rarely be used as an intervention for delirium. The use of restraints has been recognized as a risk factor for injury and aggravating symptoms, especially in older hospitalized people with delirium. The only cases where restraints should sparingly be used during delirium is in the protection of life-sustaining interventions, such as endotracheal tubes.Another approached called the "T-A-DA (tolerate, anticipate, dont agitate) method" can be an effective management technique for older people with delirium, where abnormal patient behaviors (including hallucinations and delusions) are tolerated and unchallenged, as long as caregiver and patient safety is not threatened. Implementation of this model may require a designated area in the hospital. All unnecessary attachments are removed to anticipate for greater mobility, and agitation is prevented by avoiding excessive reorientation/questioning.

Medications
Low-dose haloperidol when used short term (one week or less) is the most studied and standard drug for delirium. Evidence for efficacy of atypical antipsychotics (i.e. risperidone, olanzapine, ziprasidone, and quetiapine) is emerging, with the benefit for fewer side effects Use antipsychotic drugs with caution or not at all for people with conditions such as Parkinsons disease or dementia with Lewy bodies. Evidence for the effectiveness of medications (including antipsychotics and benzodiazepines) in treating delirium is weak.Benzodiazepines themselves can trigger or worsen delirium, and there is no reliable evidence for use in non-alcohol-related delirium. If the delirium involves alcohol withdrawal, benzodiazepine withdrawal, or contraindications to antipsychotics (e.g. in Parkinsons disease or neuroleptic malignant syndrome), then benzodiazepines are recommended. Similarly, people with dementia with Lewy bodies may have significant side effects to antipsychotics, and should either be treated with a none or small doses of benzodiazepines.The antidepressant trazodone is occasionally used in the treatment of delirium, but it carries a risk of over-sedation, and its use has not been well studied.For adults with delirium that are in the ICU, medications are used commonly to improve the symptoms. Dexmedetomidine may shorten the length of the delirium in adults who are critically ill and rivastigmine is not suggested. For adults with delirium who are near the end of their life (on palliative care) high quality evidence to support or refute the use of most medications to treat delirium is not available. Low quality evidence indicates that the antipsychotic medications risperidone or haloperidol may make the delirium slightly worse in people who are terminially ill, when compared to a placebo treatment. There is also moderate to low quality evidence to suggest that haloperidol and risperidone may be associated with a slight increase in side effects, specifically extrapyramidol symptoms, if the person near the end of their life has delirium that is mild to moderate in severity.

Prognosis
There is substantial evidence that delirium results in long-term poor outcomes in older persons admitted to hospital. This systematic review only included studies that looked for an independent effect of delirium (i.e., after accounting for other associations with poor outcomes, for example co-morbidity or illness severity).
In older persons admitted to hospital, individuals experiencing delirium are twice as likely to die than those who do not (meta-analysis of 12 studies). In the only prospective study conducted in the general population, older persons reporting delirium also showed higher mortality (60% increase). A large (N=82,770) two-centre study in unselected older emergency population found that delirium detected as part of normal care using the 4AT tool was strongly linked to 30-day mortality, hospital length of stay, and days at home in the year following the 4AT test date.Institutionalization was also twice as likely after an admission with delirium (meta-analysis of 7 studies). In a community-based population examining individuals after an episode of severe infection (though not specifically delirium), these persons acquired more functional limitations (i.e. required more assistance with their care needs) than those not experiencing infection. After an episode of delirium in the general population, functional dependence increased threefold.The association between delirium and dementia is complex. The systematic review estimated a 13-fold increase in dementia after delirium (meta-analysis of 2 studies). However, it is difficult to be certain that this is accurate because the population admitted to hospital includes persons with undiagnosed dementia (i.e. the dementia was present before the delirium, rather than caused by it). In prospective studies, people hospitalised from any cause appear to be at greater risk of dementia and faster trajectories of cognitive decline, but these studies did not specifically look at delirium. In the only population-based prospective study of delirium, older persons had an eight-fold increase in dementia and faster cognitive decline. The same association is also evident in persons already diagnosed with Alzheimers dementia.Recent long-term studies showed that many patients still meet criteria for delirium for a prolonged period after hospital discharge, with up to 21% of patients showing persistent delirium at 6 months post-discharge.

Dementia in ICU survivors
Dementia is supposed to be an entity that continues to decline, such as Alzheimers disease. Another way of looking at dementia, however, is not strictly based on the decline component, but on the degree of memory and executive function problems. It is now known, for example, that between 50% and 70% of ICU patients have tremendous problems with ongoing brain dysfunction similar to those experienced by Alzheimers or TBI (traumatic brain injury) patients, leaving many ICU survivors permanently disabled. This is a distressing personal and public health problem and is getting an increasing amount of scrutiny in ongoing investigations.The implications of such an "acquired dementia-like illness" can profoundly debilitate a persons livelihood level, often dismantling his/her life in practical ways like impairing ones ability to find a car in a parking lot, complete shopping lists, or perform job-related tasks done previously for years. The societal implications can be enormous when considering work-force issues related to the inability of wage-earners to work due to their own ICU stay or that of someone else they must care for.

Epidemiology
The highest rates of delirium (often 50% to 75% of people) is seen among those who are critically ill in the intensive care unit (ICU) As a result, this was referred to as "ICU psychosis" or "ICU syndrome", terms largely abandoned for the more widely accepted term ICU delirium </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 Metachondromatosis and can you explain it in depth? [/INST] Metachondromatosis is an autosomal dominant, incompletely penetrant genetic disease affecting the growth of bones, leading to exostoses primarily in the hands and feet as well as enchondromas of long bone metaphyses and iliac crests.  This syndrome affects mainly tubular bones, though it can also involve the vertebrae, small joints, and flat bones. The disease is thought to affect exon 4 of the PTPN11 gene. Metachondromatosis is believed to be caused by an 11 base pair deletion resulting in a frameshift and nonsense mutation. The disease was discovered and named in 1971 by Pierre Maroteaux, a French physician, when he observed two families with skeletal radiologic features with exostoses and Ollier disease.  The observation of one family with five affected people led to the identification of the disease as autosomal dominant.  There have been less than 40 cases of the disease reported to date.

Signs and Symptoms
Metachondromatosis is identified by the presence of both multiple enchondromas and osteochondromas in the patient, although other less characteristic symptoms are often associated with the disease.  The symptoms usually become apparent in the first 10 years of life and disappear later in life. The symptoms of Metachondromatosis are seen as follows:

Enchondromas
Enchondromas are benign tumors present on the inside of bones. In Metachondromatosis, enchondromas involves the iliac crests and metaphyses of long bones, often the proximal femur. Usually, these tumors are painless; however, when present in the hands or feet, or in multiple lesions, as typically seen, bone deformity can occur.

Osteochondromas
Osteochondromas are benign tumors located on the surface of bone near growth plates.  These tumors also often in the hands and feet, primarily affecting the digits of fingers and toes.  These tumors tend to subside after 10-20 years of life.  These tumors can become painful if they pressure sensitive tissue or nerves.  Metachondromatosis is differentiated from hereditary multiple osteochondromas by the location of the location of Osteochondromas tumors as well as the lack of bone-shortening.

Abnormality of epiphysis morphology
The epiphysis is the rounded end part of bone.  The structure of the epiphysis can be abnormal in metachondromatosis.

Abnormality of the metaphysis
The metaphysis is wide portion of a long bone, and also has abnormal structure in the disease.

Avascular necrosis
Avascular necrosis is the death of bone due to a decreased blood supply.

Bone pain
People with metachondromatosis often experience bone pain due to abnormal bone shapes.

Cranial nerve paralysis
Cranial nerve paralysis can affect the functions associated with the cranial nerve.

Genetics
Metachondromatosis is inherited in an autosomal dominant manner, needing only one copy of the defective gene to cause the disorder.  The cause of the disorder has been linked to an 11 base pair deletion in exon four of the PTPN11 gene  (12q24.13).  This deletion causes a frameshift, resulting in a nonsense mutation with a premature stop codon. This causes severe truncation and loss of function in the gene’s protein product, tyrosine phosphatase SHP-2. SHP-2 plays an important role in regulating expression of the Indian Hedgehog gene (IHH),  which is associated with differentiation in chondrocytes (specialized cells in cartilage tissue).  Individuals affected by metachondromatosis generally demonstrate high levels of IHH expression, which is believed to be responsible for the tumor growth. Given that the mutation causes a loss of protein function and displays a dominant inheritance pattern, it is hypothesized that individuals homozygous for the disorder would display greater symptoms than heterozygous individuals, though insufficient data is available to evaluate these claims due to the rarity of the disease.  Conversely, some heterozygous individuals have shown minimal effects, leading to the disorder’s designation as incompletely penetrant.  The cause of this is not fully understood, but may be due to other factors influencing IHH expression.

Diagnosis
Because of its rarity, metachondromatosis is often a difficult disease to recognize and diagnose. Diagnosis can be made based on clinical observations and radiographic findings as well as family history </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 Subcortical dementia and can you explain it in depth? [/INST]  </s>


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<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 Ovotestis 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 Supernumerary phantom limb 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 Graves disease and can you explain it in depth? [/INST] Graves disease (German: Morbus Basedow), also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss. Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves ophthalmopathy. About 25 to 30% of people with the condition develop eye problems.The exact cause of the disease is unclear; however, it is believed to involve a combination of genetic and environmental factors. A person is more likely to be affected if they have a family member with the disease. If one twin is affected, a 30% chance exists that the other twin will also have the disease. The onset of disease may be triggered by physical or emotional stress, infection or giving birth. Those with other autoimmune diseases such as type 1 diabetes and rheumatoid arthritis are more likely to be affected. Smoking increases the risk of disease and may worsen eye problems. The disorder results from an antibody, called thyroid-stimulating immunoglobulin (TSI), that has a similar effect to thyroid stimulating hormone (TSH). These TSI antibodies cause the thyroid gland to produce excess thyroid hormones. The diagnosis may be suspected based on symptoms and confirmed with blood tests and radioiodine uptake. Typically, blood tests show a raised T3 and T4, low TSH, increased radioiodine uptake in all areas of the thyroid and TSI antibodies.The three treatment options are radioiodine therapy, medications, and thyroid surgery. Radioiodine therapy involves taking iodine-131 by mouth, which is then concentrated in the thyroid and destroys it over weeks to months. The resulting hypothyroidism is treated with synthetic thyroid hormones. Medications such as beta blockers may control some of the symptoms, and antithyroid medications such as methimazole may temporarily help people while other treatments are having effect. Surgery to remove the thyroid is another option. Eye problems may require additional treatments.Graves disease will develop in about 0.5% of males and 3% of females. It occurs about 7.5 times more often in women than in men. Often, it starts between the ages of 40 and 60 but can begin at any age. It is the most common cause of hyperthyroidism in the United States (about 50 to 80% of cases). The condition is named after Irish surgeon Robert Graves, who described it in 1835. A number of prior descriptions also exist.

Signs and symptoms
The signs and symptoms of Graves disease virtually all result from the direct and indirect effects of hyperthyroidism, with main exceptions being Graves ophthalmopathy, goiter, and pretibial myxedema (which are caused by the autoimmune processes of the disease). Symptoms of the resultant hyperthyroidism are mainly insomnia, hand tremor, hyperactivity, hair loss, excessive sweating, oligomenorrhea, itching, heat intolerance, weight loss despite increased appetite, diarrhea, frequent defecation, palpitations, periodic partial muscle weakness or paralysis in those especially of Asian descent, and skin warmth and moistness. Further signs that may be seen on physical examination are most commonly a diffusely enlarged (usually symmetric), nontender thyroid, lid lag, excessive lacrimation due to Graves ophthalmopathy, arrhythmias of the heart, such as sinus tachycardia, atrial fibrillation, and premature ventricular contractions, and hypertension.

Cause
The exact cause is unclear; however, it is believed to involve a combination of genetic and environmental factors. While a theoretical mechanism occurs by which exposure to severe stressors and high levels of subsequent distress such as PTSD (Post traumatic stress disorder) could increase the risk of immune disease and cause an aggravation of the autoimmune response that leads to Graves disease, more robust clinical data are needed for a firm conclusion.

Genetics
A genetic predisposition for Graves disease is seen, with some people more prone to develop TSH receptor activating antibodies due to a genetic cause. Human leukocyte antigen DR (especially DR3) appears to play a role. To date, no clear genetic defect has been found to point to a single-gene cause.Genes believed to be involved include those for thyroglobulin, thyrotropin receptor, protein tyrosine phosphatase nonreceptor type 22 (PTPN22), and cytotoxic T-lymphocyte–associated antigen 4, among others.

Infectious trigger
Since Graves disease is an autoimmune disease which appears suddenly, often later in life, a viral or bacterial infection may trigger antibodies which cross-react with the human TSH receptor, a phenomenon known as antigenic mimicry.The bacterium Yersinia enterocolitica bears structural similarity with the human thyrotropin receptor and was hypothesized to contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals.
In the 1990s, it was suggested that Y. enterocolitica may be associated with Graves disease.
More recently, the role for Y. enterocolitica has been disputed.Epstein–Barr virus (EBV) is another potential trigger.

Mechanism
Thyroid-stimulating immunoglobulins recognize and bind to the thyrotropin receptor (TSH receptor) which stimulates the secretion of thyroxine (T4) and triiodothyronine (T3).  Thyroxine receptors in the pituitary gland are activated by the surplus hormone, suppressing additional release of TSH in a negative feedback loop.  The result is very high levels of circulating thyroid hormones and a low TSH level.

Pathophysiology
Graves disease is an autoimmune disorder, in which the body produces antibodies that are specific to a self-protein: the receptor for thyroid-stimulating hormone. (Antibodies to thyroglobulin and to the thyroid hormones T3 and T4 may also be produced.)
These antibodies cause hyperthyroidism because they bind to the TSHr and chronically stimulate it. The TSHr is expressed on the thyroid follicular cells of the thyroid gland (the cells that produce thyroid hormone), and the result of chronic stimulation is an abnormally high production of T3 and T4. This, in turn, causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland visible as goiter.
The infiltrative exophthalmos frequently encountered has been explained by postulating that the thyroid gland and the extraocular muscles share a common antigen which is recognized by the antibodies. Antibodies binding to the extraocular muscles would cause swelling behind the eyeball.
The "orange peel" skin has been explained by the infiltration of antibodies under the skin, causing an inflammatory reaction and subsequent fibrous plaques.
The three types of autoantibodies to the TSH receptor currently recognized are:

Thyroid stimulating immunoglobulins: these antibodies (mainly IgG) act as long-acting thyroid stimulants, activating the cells through a slower and more drawn out process compared to TSH, leading to an elevated production of thyroid hormone.
Thyroid growth immunoglobulins: these antibodies bind directly to the TSH receptor and have been implicated in the growth of thyroid follicles.
Thyrotrophin binding-inhibiting immunoglobulins: these antibodies inhibit the normal union of TSH with its receptor.
Some actually act as if TSH itself is binding to its receptor, thus inducing thyroid function.
Other types may not stimulate the thyroid gland, but prevent TSI and TSH from binding to and stimulating the receptor.Another effect of hyperthyroidism is bone loss from osteoporosis, caused by an increased excretion of calcium and phosphorus in the urine and stool. The effects can be minimized if the hyperthyroidism is treated early. Thyrotoxicosis can also augment calcium levels in the blood by as much as 25%. This can cause stomach upset, excessive urination, and impaired kidney function.

Diagnosis
Graves disease may present clinically with one or more of these characteristic signs:
Rapid heartbeat (80%)
Diffuse palpable goiter with audible bruit (70%)
Tremor (40%)
Exophthalmos (protuberance of one or both eyes), periorbital edema (25%)
Fatigue (70%), weight loss (60%) with increased appetite in young people and poor appetite in the elderly, and other symptoms of hyperthyroidism/thyrotoxicosis
Heat intolerance (55%)
Tremulousness (55%)
Palpitations (50%)Two signs are truly diagnostic of Graves disease (i.e., not seen in other hyperthyroid conditions): exophthalmos and nonpitting edema (pretibial myxedema). Goiter is an enlarged thyroid gland and is of the diffuse type (i.e., spread throughout the gland). Diffuse goiter may be seen with other causes of hyperthyroidism, although Graves disease is the most common cause of diffuse goiter. A large goiter will be visible to the naked eye, but a small one (mild enlargement of the gland) may be detectable only by physical examination. Occasionally, goiter is not clinically detectable, but may be seen only with computed tomography or ultrasound examination of the thyroid.
Another sign of Graves disease is hyperthyroidism; that is, overproduction of the thyroid hormones T3 and T4. Normal thyroid levels are also seen, and occasionally also hypothyroidism, which may assist in causing goiter (though it is not the cause of the Graves disease). Hyperthyroidism in Graves disease is confirmed, as with any other cause of hyperthyroidism, by measuring elevated blood levels of free (unbound) T3 and T4.Other useful laboratory measurements in Graves disease include thyroid-stimulating hormone (TSH, usually undetectable in Graves disease due to negative feedback from the elevated T3 and T4), and protein-bound iodine (elevated).  Serologically detected thyroid-stimulating antibodies, radioactive iodine (RAI) uptake, or thyroid ultrasound with Doppler all can independently confirm a diagnosis of Graves disease.
Biopsy to obtain histiological testing is not normally required, but may be obtained if thyroidectomy is performed.
The goiter in Graves disease is often not nodular, but thyroid nodules are also common. Differentiating common forms of hyperthyroidism such as Graves disease, single thyroid adenoma, and toxic multinodular goiter is important to determine proper treatment. The differentiation among these entities has advanced, as imaging and biochemical tests have improved. Measuring TSH-receptor antibodies with the h-TBII assay has been proven efficient and was the most practical approach found in one study.

Eye disease
Thyroid-associated ophthalmopathy (TAO), or thyroid eye disease (TED), is the most common extrathyroidal manifestation of Graves disease. It is a form of idiopathic lymphocytic orbital inflammation, and although its pathogenesis is not completely understood, autoimmune activation of orbital fibroblasts, which in TAO express the TSH receptor, is thought to play a central role.Hypertrophy of the extraocular muscles, adipogenesis, and deposition of nonsulfated glycosaminoglycans and hyaluronate, causes expansion of the orbital fat and muscle compartments, which within the confines of the bony orbit may lead to dysthyroid optic neuropathy, increased intraocular pressures, proptosis, venous congestion leading to chemosis and periorbital edema, and progressive remodeling of the orbital walls. Other distinctive features of TAO include lid retraction, restrictive myopathy, superior limbic keratoconjunctivitis, and exposure keratopathy.Severity of eye disease may be classified by the mnemonic: "NO SPECS":
Class 0: No signs or symptoms
Class 1: Only signs (limited to upper lid retraction and stare, with or without lid lag)
Class 2: Soft tissue involvement (oedema of conjunctivae and lids, conjunctival injection, etc.)
Class 3: Proptosis
Class 4: Extraocular muscle involvement (usually with diplopia)
Class 5: Corneal involvement (primarily due to lagophthalmos)
Class 6: Sight loss (due to optic nerve involvement)Typically the natural history of TAO follows Rundles curve, which describes a rapid worsening during an initial phase, up to a peak of maximum severity, and then improvement to a static plateau without, however, resolving back to a normal condition.

Management
Treatment of Graves disease includes antithyroid drugs that reduce the production of thyroid hormone, radioiodine (radioactive iodine I-131) and thyroidectomy (surgical excision of the gland). As operating on a hyperthyroid patient is dangerous, prior to thyroidectomy, preoperative treatment with antithyroid drugs is given to render the patient euthyroid. Each of these treatments has advantages and disadvantages, and no single treatment approach is considered the best for everyone.Treatment with antithyroid medications must be administered for six months to two years to be effective. Even then, upon cessation of the drugs, the hyperthyroid state may recur. The risk of recurrence is about 40–50%, and lifelong treatment with antithyroid drugs carries some side effects such as agranulocytosis and liver disease. Side effects of the antithyroid medications include a potentially fatal reduction in the level of white blood cells. Therapy with radioiodine is the most common treatment in the United States, while antithyroid drugs and/or thyroidectomy are used more often in Europe, Japan, and most of the rest of the world.
β-Blockers (such as propranolol) may be used to inhibit the sympathetic nervous system symptoms of tachycardia and nausea until antithyroid treatments start to take effect. Pure β-blockers do not inhibit lid retraction in the eyes, which is mediated by alpha adrenergic receptors.

Antithyroid drugs
The main antithyroid drugs are carbimazole (in the UK), methimazole (in the US), and propylthiouracil/PTU. These drugs block the binding of iodine and coupling of iodotyrosines. The most dangerous side effect is agranulocytosis (1/250, more in PTU). Others include granulocytopenia (dose-dependent, which improves on cessation of the drug) and aplastic anemia. Patients on these medications should see a doctor if they develop sore throat or fever. The most common side effects are rash and peripheral neuritis. These drugs also cross the placenta and are secreted in breast milk. Lugols iodine may be used to block hormone synthesis before surgery.A randomized control trial testing single-dose treatment for Graves found methimazole achieved euthyroid state more effectively after 12 weeks than did propylthyouracil (77.1% on methimazole 15 mg vs 19.4% in the propylthiouracil 150 mg groups).No difference in outcome was shown for adding thyroxine to antithyroid medication and continuing thyroxine versus placebo after antithyroid medication withdrawal. However, two markers were found that can help predict the risk of recurrence. These two markers are a positive TSHr antibody (TSHR-Ab) and smoking. A positive TSHR-Ab at the end of antithyroid drug treatment increases the risk of recurrence to 90% (sensitivity 39%, specificity 98%), and a negative TSHR-Ab at the end of antithyroid drug treatment is associated with a 78% chance of remaining in remission. Smoking was shown to have an impact independent to a positive TSHR-Ab.

Radioiodine
Radioiodine (radioactive iodine-131) was developed in the early 1940s at the Mallinckrodt General Clinical Research Center. This modality is suitable for most patients, although some prefer to use it mainly for older patients. Indications for radioiodine are failed medical therapy or surgery and where medical or surgical therapy are contraindicated. Hypothyroidism may be a complication of this therapy, but may be treated with thyroid hormones if it appears. The rationale for radioactive iodine is that it accumulates in the thyroid and irradiates the gland with its beta and gamma radiations, about 90% of the total radiation being emitted by the beta (electron) particles. The most common method of iodine-131 treatment is to administer a specified amount in microcuries per gram of thyroid gland based on palpation or radiodiagnostic imaging of the gland over 24 hours. Patients who receive the therapy must be monitored regularly with thyroid blood tests to ensure they are treated with thyroid hormone before they become symptomatically hypothyroid.Contraindications to RAI are pregnancy (absolute), ophthalmopathy (relative; it can aggravate thyroid eye disease), or solitary nodules.Disadvantages of this treatment are a high incidence of hypothyroidism (up to 80%) requiring eventual thyroid hormone supplementation in the form of a daily pill(s). The radioiodine treatment acts slowly (over months to years) to destroy the thyroid gland, and Graves disease–associated hyperthyroidism is not cured in all persons by radioiodine, but has a relapse rate that depends on the dose of radioiodine which is administered. In rare cases, radiation induced thyroiditis has been linked to this treatment.

Surgery
This modality is suitable for young and pregnant people. Indications for thyroidectomy can be separated into absolute indications or relative indications. These indications aid in deciding which people would benefit most from surgery. The absolute indications are a large goiter (especially when compressing the trachea), suspicious nodules or suspected cancer (to pathologically examine the thyroid), and people with ophthalmopathy and additionally if it is the persons preferred method of treatment or if refusing to undergo radioactive iodine treatment. Pregnancy is advised to be delayed for 6 months after radioactive iodine treatment.Both bilateral subtotal thyroidectomy and the Hartley-Dunhill procedure (hemithyroidectomy on one side and partial lobectomy on other side) are possible.
Advantages are immediate cure and potential removal of carcinoma. Its risks are injury of the recurrent laryngeal nerve, hypoparathyroidism (due to removal of the parathyroid glands), hematoma (which can be life-threatening if it compresses the trachea), relapse following medical treatment, infections (less common), and scarring. The increase in the risk of nerve injury can be due to the increased vascularity of the thyroid parenchyma and the development of links between the thyroid capsule and the surrounding tissues. Reportedly, a 1% incidence exists of permanent recurrent laryngeal nerve paralysis after complete thyroidectomy. Risks related to anesthesia are many, thus coordination with the anesthesiologist and patient optimization for surgery preoperatively are essential.  Removal of the gland enables complete biopsy to be performed to have definite evidence of cancer anywhere in the thyroid. (Needle biopsies are not so accurate at predicting a benign state of the thyroid).  No further treatment of the thyroid is required, unless cancer is detected.  Radioiodine uptake study may be done after surgery, to ensure  all remaining (potentially cancerous) thyroid cells (i.e., near the nerves to the vocal cords) are destroyed. Besides this, the only remaining treatment will be levothyroxine, or thyroid replacement pills to be taken for the rest of the patients life.
A 2013 review article concludes that surgery appears to be the most successful in the management of Graves disease, with total thyroidectomy being the preferred surgical option.

Eyes
Mild cases are treated with lubricant eye drops or nonsteroidal anti-inflammatory drops. Severe cases threatening vision (corneal exposure or optic nerve compression) are treated with steroids or orbital decompression. In all cases, cessation of smoking is essential. Double vision can be corrected with prism glasses and surgery (the latter only when the process has been stable for a while).
Difficulty closing eyes can be treated with lubricant gel at night, or with tape on the eyes to enable full, deep sleep.
Orbital decompression can be performed to enable bulging eyes to retreat back into the head.  Bone is removed from the skull behind the eyes, and space is made for the muscles and fatty tissue to fall back into the skull.
Eyelid surgery can be performed on upper and/or lower eyelids to reverse the effects of Graves disease on the eyelids. Eyelid muscles can become tight with Graves disease, making it impossible to close the eyes all the way.  Eyelid surgery involves an incision along the natural crease of the eyelid, and a scraping away of the muscle that holds the eyelid open. This makes the muscle weaker, which allows the eyelid to extend over the eyeball more effectively. Eyelid surgery helps reduce or eliminate dry eye symptoms.
For management of clinically active Graves disease, orbitopathy (clinical activity score >2) with at least mild to moderate severity, intravenous glucocorticoids are the treatment of choice, usually administered in the form of pulse intravenous methylprednisolone. Studies have consistently shown that pulse intravenous methylprednisolone is superior to oral glucocorticoids both in terms of efficacy and decreased side effects for managing Graves orbitopathy.

Prognosis
If left untreated, more serious complications could result, including birth defects in pregnancy, increased risk of a miscarriage, bone mineral loss and, in extreme cases, death. Graves disease is often accompanied by an increase in heart rate, which may lead to further heart complications, including loss of the normal heart rhythm (atrial fibrillation), which may lead to stroke. If the eyes are proptotic (bulging) enough that the lids do not close completely at night, dryness will occur – with the risk of a secondary corneal infection, which could lead to blindness. Pressure on the optic nerve behind the globe can lead to visual field defects and vision loss, as well. Prolonged untreated hyperthyroidism can lead to bone loss, which may resolve when treated.

Epidemiology
Graves disease occurs in about 0.5% of people. Graves disease data has shown that the lifetime risk for women is around 3% and 0.5% for men. It occurs about 7.5 times more often in women than in men and often starts between the ages of 40 and 60. It is the most common cause of hyperthyroidism in the United States (about 50 to 80% of cases).

History
Graves disease owes its name to the Irish doctor Robert James Graves, who described a case of goiter with exophthalmos in 1835. Medical eponyms are often styled nonpossessively; thus Graves disease and Graves disease are variant stylings of the same term.
The German Karl Adolph von Basedow independently reported the same constellation of symptoms in 1840. As a result, on the European Continent, the terms Basedow syndrome, Basedow disease, or Morbus Basedow are more common than Graves disease.Graves disease has also been called exophthalmic goiter.Less commonly, it has been known as Parry disease, Begbie disease, Flajan disease, Flajani–Basedow syndrome, and Marsh disease.  These names for the disease were derived from Caleb Hillier Parry, James Begbie, Giuseppe Flajani, and Henry Marsh. Early reports, not widely circulated, of cases of goiter with exophthalmos were published by the Italians Giuseppe Flajani and Antonio Giuseppe Testa, in 1802 and 1810, respectively. Prior to these, Caleb Hillier Parry, a notable provincial physician in England of the late 18th century (and a friend of Edward Miller-Gallus), described a case in 1786 </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 Waardenburg Syndrome Type 1 and can you explain it in depth? [/INST] Waardenburg Syndrome Type 1 is a congenital disorder that caused by a mutation in the PAX3 gene that results in abnormal development in the neural crest during early development. Type 1 results in early graying and white forelock and a notable distance between the eyes, noted as dystopia canthorum. Common symptoms of the disease also includes non-progressive hearing loss in majority of patients with Type 1. Patients can display complete or partial heterochromia and hypoplastic blue irides and congenital leukemia.

Presentation
Type 1 of the Waardenburg Syndrome’s notable feature is dystopia canthorum. Along with this feature, some patients eyelids are fused medially, resulting in medial sclerae. Inferior lachrymal is moved laterally, along with punctae opposite of the cornea. Other features include high and broad nasal root and also nasi hypoplasia. A squared jaw is reported in some patients. Others present with spina bifida due to the mutation in the neural crest during early development. Other features include the white forelock and graying that occurs in most patients prior to reaching age thirty. In extremely rare cases, the forelock may even be colored red rather than white. The coloring of the forelock may differ from patient to patient. It can appear at birth, or later in the life of those affected and size may vary. It is usually observed in the midline of the hair, but it can appear in other locations as well. Associated with the hair forelock, skin pigmentation can also appear in different parts of the body and limbs (suspected to be caused by the mutation in KIT). In parts of the body of some patients, congenital leukoderma is observed.Similar to other types of the syndrome, Type 1 displays heterochromia in some patients, sometimes complete or partial. If it happens to be partial, the differently colored iris is separated from the radial segment of the eye. Deficient iris stroma along with hypoplastic blue arises have also been found in some patients with Type 1. Another one of the symptoms is hearing loss, presenting in about 69% of cases. The types of hearing loss reported in patients differ over a great spectrum. Some of which could be bilateral or unilateral, sensorineural sometimes a combination of different ones in each ear. The most common loss types reported for Type 1 are profound and bilateral.  Waardenburg Type 1 is estimated to cause 3% of overall congenital deaf children.

Genetics
Type 1 Waardenburg Syndrome is a dominant autosomal disease, with extremely high penetrance of nearly 85%  Type 1, as well as type 3, are linked to a mutation in the PAX3 gene located in chromosome 2q35. This gene is responsible for encoding a transaction factor named Drosophila paired (noted as prd) resulting in essential proteins. These proteins are responsible for multiple functions in early human development such as stem cell pluripotency, as well as inhibition of differentiation when needed and cell-lineage specification, migration, and proliferation in the cells . These functions are essential in properly developing the central nervous system, somites, skeletal muscles, and neural crest-derived cells that are present throughout various cell types in the body. PAX3 controls the neural crest development through regulation of c-RET, TGF-b2, and WNT1 which are essential controllers of migration and differentiation.PAX3 in combination with other transcription factors such as MITF and TRP1 can control melanocyte development. This gene also plays a major role in muscle development as it regulated myoD and myf-5, essential transcription factors in muscle development.The structure of the gene and protein are well understood in research, PAX3 consists of 10 exons and results in major proteins that has 479 amino acids. It has also been found that a majority of the mutations that occur on the PAX3 gene is located on the 2-6 exons. Heterozygous mutation is the basis of the majority of Type 1 Waardenburg Syndrome mutations.

Diagnosis
Type 1 Waardenburg Syndrome is sometimes misdiagnosed as Type 2, therefore when measuring dystopia canthorum if present in a certain patient has been set in strict guidelines. There is a biometric index used as well formula to create a discriminant analysis. These measurements are based on three indices, based on the distances of the inner canthal, interpupillary, and outer canthal. This testing of the dystopia canthorum is referred to as the W index. Other features and dysfunctions are used for diagnoses such as hearing loss or pigmentation of the skin and the notable forelock that appears in the hair. A  diagnosis can also be provided through genetic testing and identification of the PAX3 mutation in the patient’s genes. Gene analysis can take on a variety of tests such as single-gene testing (focus on PAX3), a multigene panel (PAX3 along with other genes), and a more comprehensive genomic testing when available.A list of major criteria was created to assess patients for Type 1 Waardenburg Syndrome. The list includes similar features as listed above such as congenital sensorineural hearing loss, white forelock, and hair pigmentation, pigmentation abnormality of the iris, dystopia canthorum, and related family members who exhibit the disease.

Management
There is no direct treatment for the patients with Waardenburg Syndrome Type 1, however, there are multiple ways in which the symptoms are managed. There are some options for hearing loss aid depending on the type faced by the patient </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 Middle-of-the-night insomnia 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 Taijin kyofusho and can you explain it in depth? [/INST] Taijin kyofusho (Japanese: 対人恐怖症, TKS, for taijin kyofusho symptoms) is a Japanese culture-specific syndrome. The term taijin kyofusho translates into the disorder (sho) of fear (kyofu) of interpersonal relations (taijin). Those who have taijin kyofusho are likely to be extremely embarrassed about themselves or fearful of displeasing others when it comes to the functions of their bodies or their appearances. These bodily functions and appearances include their faces, odor, actions, or even looks. They do not want to embarrass other people with their presence. This culture-bound syndrome is a social phobia based on fear and anxiety.The symptoms of this disorder include avoiding social outings and activities, rapid heartbeat, shortness of breath, panic attacks, trembling, and feelings of dread and panic when around people. The causes of this disorder are mainly from emotional trauma or psychological defense mechanism. It is more common in men than women. Lifetime prevalence is estimated at 3–13%.

Subcategories
Taijin kyofusho is commonly described as a form of social anxiety (social phobia), with the person dreading and avoiding social contact, and as a subtype of shinkeishitsu (anxiety disorder). However, instead of a fear of embarrassing themselves or being harshly judged by others because of their social ineptness, sufferers of taijin kyofusho report a fear of offending or harming other people. The focus is thus on avoiding harm to others rather than to oneself.
In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) it is instead considered a sub-category of the "Other Specified Obsessive-Compulsive and Related Disorder" category [300.3 (F42)], where variants of taijin kyofusho are "Shubo-kyofu [...] that is similar to body dysmorphic disorder and is characterized by excessive fear of having a bodily deformity" and "Jikoshu-kyofu [...] characterized by fear of having an offensive body odor".One source even breaks taijin kyofusho into two different subtypes: neurotic and offensive. The first subtype can be broken into two parts that are classical type and avoidant type. The classical type being afraid of being judged negatively because of physical signs of anxiety and feeling shame due to anxiety. The physical signs that can cause fear of being judged include sweating and tremors. The second subtype deals with people thinking something about them is offensive. Some of their fears include body odor, gas, excessive or insufficient eye contact, blushing, etc.
In the official Japanese diagnostic system, taijin kyofusho is subdivided into the following categories:
Sekimen-kyofu (Japanese: 赤面恐怖), the phobia of blushing (ereuthophobia)
Shubo-kyofu (Japanese: 醜貌恐怖), the phobia of a deformed body, similar to body dysmorphic disorder
Jikoshisen-kyofu (Japanese: 自己視線恐怖), the phobia of eye contact
Jikoshu-kyofu (Japanese: 自己臭恐怖), the phobia of having foul body odor (also termed olfactory reference syndrome, osmophobia or bromidrosiphobia)Japan psychology also recognizes additional types of taijin kyofusho based on severity:

Transient: This type of taijin kyofusho is short-lived and moderately severe. It most commonly appears in teens, but may occur at any time.
Delusional: This is the most common type of taijin kyofusho and is the most similar to social phobia. It is chronic, often begins before the age of 30, and varies in severity from moderate to severe.
Phobic with schizophrenia: This is a more complicated disorder. In such cases, rather than a phobia, taijin kyofusho is a manifestation of schizophrenic symptoms.

Diagnosis
A person may be diagnosed with taijin kyofusho if they feel as if their attitudes, behavior, and physical characteristics are inadequate in social situations. As a result of these feelings, they also experience persistent suffering in the form of emotional distress through shame, embarrassment, anxiety, fear, and other tense feelings that occur when confronted with social circumstances. In addition, individuals also worry about being unable to maintain healthy relationships with others. When it comes to socializing, taijin kyofusho sufferers avoid painful social and interpersonal situations, while simultaneously being averse to doing so. Those likely to develop taijin kyofusho have more of a temperamental characteristic of being hypochondriacal. The balance between introversion and extroversion in hypochondriacal temperament is geared more towards introversion. The introversion causes sufferers to focus on themself and problems they have, and by fixating on their weaknesses they become more anxious and depressed.

Treatment
The standard Japanese treatment for taijin kyofusho is Morita therapy, developed by Shoma Morita in the 1910s as a treatment for the Japanese mental disorders taijin kyofusho and shinkeishitsu (nervousness). The original regimen involved patient isolation, enforced bed rest, diary writing, manual labor, and lectures on the importance of self-acceptance and positive endeavor. Since the 1930s, the treatment has been modified to include out-patient and group treatments. This modified version is known as neo-Morita therapy. Medications have also gained acceptance as a treatment option for taijin kyofusho. Other treatments include systematic desensitization, which includes slowly exposing one self to the fear, and learning relaxation skills, to extinguish fear and anxiety.
Milnacipran, a serotonin–norepinephrine reuptake inhibitor (SNRI), is currently used in the treatment of taijin kyofusho and has been shown to be efficacious for the related social anxiety disorder. The primary aspect of treating this disorder is getting patients to focus their attention on their body parts and sensations.

Prevalence
Typically, this disease is presaged by a childhood history of social inhibition and shyness. It is possible that it could result from a humiliating traumatic experience, or it could emerge from a lifelong onset of the illness that only comes to the surface after time.Clinical data indicates that more males have the condition than females, despite the fact that females scored higher on a social phobia scale than men, and report higher scores on proclivity towards feelings of embarrassment. This differs from Western society where the prevalence of females with social phobias is to some extent greater than that of males. The lifetime prevalence of the disorder falls anywhere between 3% and 13% with changes in severity occurring throughout ones lifetime. It is estimated that about 17% of individuals with taijin kyofusho have fears of releasing foul body odor.

See also
Anthropophobia
Avoidant personality disorder
Hikikomori
NEET
Obsessive–compulsive disorder

References
Further reading
Suzuki, K. (2003). "Is Taijin Kyofusho a Culture-Bound Syndrome?". American Journal of Psychiatry. 160 (7): 1358. doi:10.1176/appi.ajp.160.7.1358. PMID 12832264.
Maeda, F; Nathan, JH (1999). "Understanding taijin kyofusho through its treatment, Morita therapy". Journal of Psychosomatic Research. 46 (6): 525–30. doi:10.1016/S0022-3999(98)00113-5. PMID 10454167.
Matsunaga, Hisato; Kiriike, Nobuo; Matsui, Tokuzo; Iwasaki, Yoko; Stein, Dan J. (2001). "Taijin kyofusho: A form of social anxiety disorder that responds to serotonin reuptake inhibitors?". The International Journal of Neuropsychopharmacology. 4 (3): 231–7. doi:10.1017/S1461145701002474. PMID 11602029.
Nagata T.; Oshima J.; Wada A.; Yamada H.; Iketani T.; Kiriike N </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 Serpiginous choroiditis 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 Ecthyma 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 Chorea-acanthocytosis and can you explain it in depth? [/INST] Chorea-acanthocytosis (ChAc, also called choreoacanthocytosis) is a rare hereditary disease caused by a mutation in a gene that directs structural proteins in red blood cells. It belongs to a group of four diseases characterized under the name neuroacanthocytosis. When a patients blood is viewed under a microscope, some of the red blood cells appear thorny. These thorny cells are called acanthocytes.
Other effects of the disease may include epilepsy, behaviour changes, muscle degeneration, and neuronal degradation similar to Huntingtons disease </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 Trichophyton and can you explain it in depth? [/INST] Trichophyton is a genus of fungi, which includes the parasitic varieties that cause tinea, including athletes foot, ringworm, jock itch, and similar  infections of the nail, beard, skin and scalp. Trichophyton fungi are molds characterized by the development of both smooth-walled macro- and microconidia. Macroconidia are mostly borne laterally directly on the hyphae or on short pedicels, and are thin- or thick-walled, clavate to fusiform, and range from 4 to 8 by 8 to 50 μm in size. Macroconidia are few or absent in many species. Microconidia are spherical, pyriform to clavate or of irregular shape, and range from 2 to 3 by 2 to 4 μm in size.

Species and their habitat preference
According to current classification, the genus includes anthropophilic and zoophilic species. Anthropophilic fungi prefer to infect humans. Zoophilic fungi prefer to infect animals other than humans. Humans and animals are natural reservoirs for parasitic or dermatophytic fungi.

Other accepted species;

Mating and meiosis
Trichophyton mentagrophytes (Family Arthrodermataceae, Genus Trichophyton) is capable of both mating and meiosis.

Effect on humans
The anthropophilic varieties cause forms of dermatophytosis, that is, fungal infection of the skin.  They are keratinophilic: they feed on the keratin in nails, hair, and dead skin.
Trichophyton concentricum causes "Malabar itch", a skin infection consisting of an eruption of a number of concentric rings of overlapping scales forming papulosquamous patches.Trichophyton rubrum and Trichophyton interdigitale cause athletes foot (tinea pedis), toenail fungal infections (a.k.a. tinea unguium, a.k.a. onychomycosis), crotch itch (a.k.a. tinea cruris), and ringworm (a misnomer, as there is no worm involved; it is also known as tinea corporis). Trichophyton schoenleinii cause favus (tinea capitis),Trichophyton mentagrophytes var. mentagrophytes and Trichophyton verrucosum cause Kerion (violent reaction results from infection with an animal dermatophytes) </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 Dariers disease and can you explain it in depth? [/INST] Dariers disease (DAR) is an inherited skin disorder that presents with multiple greasy, crusting, thick brown bumps that merge into patches.It is an autosomal dominant disorder discovered by French dermatologist Ferdinand-Jean Darier. Dariers is characterized by dark crusty patches on the skin that are mildly greasy and that emit a strong odor. These patches, also known as keratotic papules, keratosis follicularis, or dyskeratosis follicularis, most often appear on the scalp, forehead, upper arms, chest, back, knees, elbows, and behind the ear.Mild forms of the disease are the most common, consisting solely of skin rashes that flare up under certain conditions such as high humidity, high stress, or tight-fitting clothes. Short stature, when combined with poorly-formed fingernails that contain vertical striations, is diagnostic even for mild forms of DAR. Symptoms will usually appear in late childhood or early adulthood  between the ages of 15 to 30 years and will vary over the course of ones life.

Signs and symptoms
Clinical symptoms  of the disease:Seborrhoeic areas
This is defined as areas where excess oil and sebum is released.
Overall greasy or scaly skin either in the central chest and back or in the folds of the skin.
Fragile or poorly formed fingernails
Nail disease leading to V-shaped nicks at the edge of the nail.
Rash that covers many areas of the body
The rash is often associated with a strong unpleasant odor
The rash can be aggravated by heat, humidity, and exposure to sunlight.
Mucosal manifestation
White cobblestone pattern of small papules
Overgrowth of gums
Usually affects the mouth, esophagus, rectum, vulva, vagina
Oral symptoms  can be diagnosed by a routine dental examination
Other symptoms and their overall prevalence in the affected population:In 80 to 90% of patients
Acrokeratosis verruciformisAcrokeratosis is characterized by several small wart-like and flat-topped bumps that line the skin on typically the hand and feet.
Hypermelanotic macule
Patches on the skin that contain excess pigment, they often appear as dark patches in the skin.
Pruritus
Itching
Subungual hyperkeratotic fragments
Thickened skin that is often discolored, under nails, on either hands or feet.
Palmar pits
Usually red in color, they are pits or depressions in the palms or soles of the hands and feet.
In 30 to 79% of patients
Abnormal hair morphology
Acne conglobata
Typically described as cystic acne

Genetics
Mutations in a single gene, ATP2A2, are responsible for the development of Dariers disease. ATP2A2 encodes the SERCA2 protein, which is a calcium pump localized to the membranes of the endoplasmic reticulum (ER) in nearly all cells and the sarcoplasmic reticulum (SR) in muscle cells. The ER is where protein processing and transport begins for proteins targeted for secretion.  The SR is a specialized form of ER found in muscle cells that sequesters calcium, the regulated efflux of which into the cytosol stimulates muscle fiber contraction. Calcium acts as a second messenger in many cellular signal transduction pathways.  SERCA2 is required for Ca2+ signaling in cells by removing nearly all Ca2+ ions from the cytoplasm and storing them in the ER/SR compartments.

A large number of mutant alleles of ATP2A2 have been identified in association with Dariers Disease. One study of 19 families and 6 sporadic cases found 24 specific, novel mutations associated with DAR symptoms. This study reported a loose, imperfect correlation between the severity of ATP2A2 mutations with the severity of the condition.  Significant variability in disease severity between members of the same family carrying the same mutation was also reported by this study, suggesting that genetic modifiers contribute to the phenotypic penetrance of certain mutations.The mutation is inherited in an autosomal dominant pattern. This means that only one allele needs to be mutated  in order to express the trait. This also means that someone who is born to one parent with DAR has a 50% chance of inheriting the mutant allele and having the disease. Loss-of-function mutations typically display recessive inheritance while the gain-of-function or hyperactive function of proteins is characteristic of dominant mutations.  The observation that only one mutated allele of the SERCA2 is sufficient to produce clinical symptoms suggests that proper “gene dosage” is necessary for maintaining Ca2+ homeostasis in cells. This means that two wild type copies of ATP2A2 are needed for proper cell function, which provides a logical basis for dominant phenotypes arising from loss-of-function alleles.  Most ATP2A2 mutations are haploinsufficiency mutations, which means that only having only one functional copy of the functional gene results in a reduced level of protein expression that is not sufficient for wild type function for making enough of the coded protein for the cell to function properly. However, there is significant variability in disease severity in how the mutations are expressed even within families that have the same mutation. It is currently unclear in the current research why a reduction in SERCA2 expression/activity causes clinical symptoms restricted to the epidermis.  One hypothesis that some researchers have given is that other cell types express additional “back-up” Ca2+ pumps that can compensate for the reduced function or expression of the SERCA2 protein, while skin cells rely exclusively on the SERCA2 gene for calcium sequestration, meaning only they are affected by its reduction in expression.As mentioned above, some cases of DAR result from somatic mutations to ATP2A2 in epidermal stem cells. These cases are referred to as instances of "linear" Dariers disease. Such individuals display phenotypic mosaicism, where the Dariers phenotype only affects the subset of epidermal tissue arising from the mutated progenitor cell.  Somatic mutations are not inherited by the offspring of such individuals.

Diagnosis
Diagnosis of Darier disease is often made by the appearance of the skin, family history, or genetic testing for the mutation in the ATP2A2 gene. However, many individuals affected by this disorder are never diagnosed, due to the mildness of symptoms in most cases. Mild cases present clinically are minor rashes (without odor) that can become exacerbated by heat, humidity, stress, and sunlight. The symptoms of the disease are thought to be caused by an abnormality in the desmosome-keratin filament complex leading to a breakdown in cell adhesion.

Dariers disease is an incommunicable disorder that is seen in males and females equally. Symptoms typically arise between the ages of 15 and 30.  One study of 100 British individuals diagnosed with Dariers disease reported that affected individuals display elevated frequencies of neuropsychiatric conditions. There were high lifetime rates for mood disorders (50%), including depression (30%), bipolar disorder (4%), suicidal thoughts (31%), and suicide attempts (13%), suggesting a possible common genetic link.  Several case studies have suggested affected populations display elevated frequencies of learning disorders, but this has yet to be confirmed.

Treatment
Treatment of Darier disease depends on the severity of the presented clinical symptoms. In most minor cases, the disorder can be managed using sunscreen, moisturizing lotions, avoidance of non-breathable clothing, and excessive perspiration. In more severe cases of Dariers disease, hospitalisation may be required to heal affected individuals who display frequent relapse and remit patterns. In less severe cases, signs and symptoms may clear up completely through hygienic interventions. Most patients with Dariers disease live normal, healthy lives. Rapid resolution of rash symptoms can be complicated due to the increased vulnerability of affected skin surfaces by secondary bacterial or viral infections. Epidermal Staphylococcus aureus, human papillomavirus (HPV) and herpes simplex virus (HSV) infections have been reported </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 Xanthopsia and can you explain it in depth? [/INST]  </s>