<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Insomnia and explain in detail? [/INST] Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, irritability, and a depressed mood. It may result in an increased risk of motor vehicle collisions, as well as problems focusing and learning. Insomnia can be short term, lasting for days or weeks, or long term, lasting more than a month. The concept of the word insomnia has two possibilities: insomnia disorder and insomnia symptoms, and many abstracts of randomized controlled trials and systematic reviews often underreport on which of these two possibilities the word insomnia refers to.Insomnia can occur independently or as a result of another problem. Conditions that can result in insomnia include psychological stress, chronic pain, heart failure, hyperthyroidism, heartburn, restless leg syndrome, menopause, certain medications, and drugs such as caffeine, nicotine, and alcohol. Other risk factors include working night shifts and sleep apnea. Diagnosis is based on sleep habits and an examination to look for underlying causes. A sleep study may be done to look for underlying sleep disorders. Screening may be done with two questions: "do you experience difficulty sleeping?" and "do you have difficulty falling or staying asleep?"Although their efficacy as first line treatments is not unequivocally established, sleep hygiene and lifestyle changes are typically the first treatment for insomnia. Sleep hygiene includes a consistent bedtime, a quiet and dark room, exposure to sunlight during the day and regular exercise. Cognitive behavioral therapy may be added to this. While sleeping pills may help, they are sometimes associated with injuries, dementia, and addiction. These medications are not recommended for more than four or five weeks. The effectiveness and safety of alternative medicine is unclear.Between 10% and 30% of adults have insomnia at any given point in time and up to half of people have insomnia in a given year. About 6% of people have insomnia that is not due to another problem and lasts for more than a month. People over the age of 65 are affected more often than younger people. Females are more often affected than males. Descriptions of insomnia occur at least as far back as ancient Greece.

Signs and symptoms
Symptoms of insomnia:
Difficulty falling asleep, including difficulty finding a comfortable sleeping position
Waking during the night, being unable to return to sleep and waking up early
Not able to focus on daily tasks, difficulty in remembering
Daytime sleepiness, irritability, depression or anxiety
Feeling tired or having low energy during the day
Trouble concentrating
Being irritable, acting aggressive or impulsiveSleep onset insomnia is difficulty falling asleep at the beginning of the night, often a symptom of anxiety disorders. Delayed sleep phase disorder can be misdiagnosed as insomnia, as sleep onset is delayed to much later than normal while awakening spills over into daylight hours.It is common for patients who have difficulty falling asleep to also have nocturnal awakenings with difficulty returning to sleep. Two-thirds of these patients wake up in the middle of the night, with more than half having trouble falling back to sleep after a middle-of-the-night awakening.Early morning awakening is an awakening occurring earlier (more than 30 minutes) than desired with an inability to go back to sleep, and before total sleep time reaches 6.5 hours. Early morning awakening is often a characteristic of depression. Anxiety symptoms may well lead to insomnia. Some of these symptoms include tension, compulsive worrying about the future, feeling overstimulated, and overanalyzing past events.

Poor sleep quality
Poor sleep quality can occur as a result of, for example, restless legs, sleep apnea or major depression. Poor sleep quality is defined as the individual not reaching stage 3 or delta sleep which has restorative properties.Major depression leads to alterations in the function of the hypothalamic–pituitary–adrenal axis, causing excessive release of cortisol which can lead to poor sleep quality.
Nocturnal polyuria, excessive nighttime urination, can  also result in a poor quality of sleep.

Subjectivity
Some cases of insomnia are not really insomnia in the traditional sense, because people experiencing sleep state misperception often sleep for a normal amount of time.  The problem is that, despite sleeping for multiple hours each night and typically not experiencing significant daytime sleepiness or other symptoms of sleep loss, they do not feel like they have slept very much, if at all.  Because their perception of their sleep is incomplete, they incorrectly believe it takes them an abnormally long time to fall asleep, and they underestimate how long they remain asleep.

Causes
Symptoms of insomnia can be caused by or be associated with:

Sleep breathing disorders, such as sleep apnea or upper airway resistance syndrome
Use of psychoactive drugs (such as stimulants), including certain medications, herbs, caffeine, nicotine, cocaine, amphetamines, methylphenidate, aripiprazole, MDMA, modafinil, or excessive alcohol intake
Use of or withdrawal from alcohol and other sedatives, such as anti-anxiety and sleep drugs like benzodiazepines
Use of or withdrawal from pain-relievers such as opioids
Heart disease
Restless legs syndrome, which can cause sleep onset insomnia due to the discomforting sensations felt and the need to move the legs or other body parts to relieve these sensations
Periodic limb movement disorder (PLMD), which occurs during sleep and can cause arousals of which the sleeper is unaware
Pain: an injury or condition that causes pain can preclude an individual from finding a comfortable position in which to fall asleep, and can also cause awakening.
Hormone shifts such as those that precede menstruation and those during menopause
Life events such as fear, stress, anxiety, emotional or mental tension, work problems, financial stress, birth of a child, and bereavement
Gastrointestinal issues such as heartburn or constipation
Mental, neurobehavioral, or neurodevelopmental disorders such as bipolar disorder, clinical depression, generalized anxiety disorder, post traumatic stress disorder, schizophrenia, obsessive compulsive disorder, autism, dementia,: 326  ADHD, Asperger syndrome, and FASD
Disturbances of the circadian rhythm, such as shift work and jet lag, can cause an inability to sleep at some times of the day and excessive sleepiness at other times of the day. Chronic circadian rhythm disorders are characterized by similar symptoms.
Certain neurological disorders such as brain lesions, or a history of traumatic brain injury
Medical conditions such as hyperthyroidism
Abuse of over-the-counter or prescription sleep aids (sedative or depressant drugs) can produce rebound insomnia
Poor sleep hygiene, e.g., noise or over-consumption of caffeine
A rare genetic condition can cause a prion-based, permanent and eventually fatal form of insomnia called fatal familial insomnia
Physical exercise: exercise-induced insomnia is common in athletes in the form of prolonged sleep onset latency
Increased exposure to the blue light from artificial sources, such as phones or computers
Chronic pain
Lower back pain
AsthmaSleep studies using polysomnography have suggested that people who have sleep disruption have elevated nighttime levels of circulating cortisol and adrenocorticotropic hormone. They also have an elevated metabolic rate, which does not occur in people who do not have insomnia but whose sleep is intentionally disrupted during a sleep study. Studies of brain metabolism using positron emission tomography (PET) scans indicate that people with insomnia have higher metabolic rates by night and by day. The question remains whether these changes are the causes or consequences of long-term insomnia.

Genetics
Heritability estimates of insomnia vary between 38% in males to 59% in females. A genome-wide association study (GWAS) identified 3 genomic loci and 7 genes that influence the risk of insomnia, and showed that insomnia is highly polygenic. In particular, a strong positive association was observed for the MEIS1 gene in both males and females. This study showed that the genetic architecture of insomnia strongly overlaps with psychiatric disorders and metabolic traits.
It has been hypothesised that the epigenetics might also influence insomnia through a controlling process of both sleep regulation and brain-stress response having an impact as well on the brain plasticity.

Substance-induced
Alcohol-induced
Alcohol is often used as a form of self-treatment of insomnia to induce sleep. However, alcohol use to induce sleep can be a cause of insomnia. Long-term use of alcohol is associated with a decrease in NREM stage 3 and 4 sleep as well as suppression of REM sleep and REM sleep fragmentation. Frequent moving between sleep stages occurs, with awakenings due to headaches, the need to urinate, dehydration, and excessive sweating. Glutamine rebound also plays a role as when someone is drinking; alcohol inhibits glutamine, one of the bodys natural stimulants. When the person stops drinking, the body tries to make up for lost time by producing more glutamine than it needs.
The increase in glutamine levels stimulates the brain while the drinker is trying to sleep, keeping him/her from reaching the deepest levels of sleep. Stopping chronic alcohol use can also lead to severe insomnia with vivid dreams. During withdrawal REM sleep is typically exaggerated as part of a rebound effect.

Benzodiazepine-induced
Like alcohol, benzodiazepines, such as alprazolam, clonazepam, lorazepam, and diazepam, are commonly used to treat insomnia in the short-term (both prescribed and self-medicated), but worsen sleep in the long-term. While benzodiazepines can put people to sleep (i.e., inhibit NREM stage 1 and 2 sleep), while asleep, the drugs disrupt sleep architecture: decreasing sleep time, delaying time to REM sleep, and decreasing deep slow-wave sleep (the most restorative part of sleep for both energy and mood).

Opioid-induced
Opioid medications such as hydrocodone, oxycodone, and morphine are used for insomnia that is associated with pain due to their analgesic properties and hypnotic effects. Opioids can fragment sleep and decrease REM and stage 2 sleep. By producing analgesia and sedation, opioids may be appropriate in carefully selected patients with pain-associated insomnia. However, dependence on opioids can lead to long-term sleep disturbances.

Risk factors
Insomnia affects people of all age groups but people in the following groups have a higher chance of acquiring insomnia:
Individuals older than 60
History of mental health disorder including depression, etc.
Emotional stress
Working late night shifts
Traveling through different time zones
Having chronic diseases such as diabetes, kidney disease, lung disease, Alzheimers, or heart disease
Alcohol or drug use disorders
Gastrointestinal reflux disease
Heavy smoking
Work stress

Mechanism
Two main models exists as to the mechanism of insomnia, cognitive and physiological. The cognitive model suggests rumination and hyperarousal contribute to preventing a person from falling asleep and might lead to an episode of insomnia.
The physiological model is based upon three major findings in people with insomnia; firstly, increased urinary cortisol and catecholamines have been found suggesting increased activity of the HPA axis and arousal; second, increased global cerebral glucose utilization during wakefulness and NREM sleep in people with insomnia; and lastly, increased full body metabolism and heart rate in those with insomnia. All these findings taken together suggest a dysregulation of the arousal system, cognitive system, and HPA axis all contributing to insomnia. However, it is unknown if the hyperarousal is a result of, or cause of insomnia. Altered levels of the inhibitory neurotransmitter GABA have been found, but the results have been inconsistent, and the implications of altered levels of such a ubiquitous neurotransmitter are unknown. Studies on whether insomnia is driven by circadian control over sleep or a wake dependent process have shown inconsistent results, but some literature suggests a dysregulation of the circadian rhythm based on core temperature. Increased beta activity and decreased delta wave activity has been observed on electroencephalograms; however, the implication of this is unknown.Around half of post-menopausal women experience sleep disturbances, and generally sleep disturbance is about twice as common in women as men; this appears to be due in part, but not completely, to changes in hormone levels, especially in and post-menopause.Changes in sex hormones in both men and women as they age may account in part for increased prevalence of sleep disorders in older people.

Diagnosis
In medicine, insomnia is widely measured using the Athens insomnia scale. It is measured using eight different parameters related to sleep, finally represented as an overall scale which assesses an individuals sleep pattern.
A qualified sleep specialist should be consulted for the diagnosis of any sleep disorder so the appropriate measures can be taken. Past medical history and a physical examination need to be done to eliminate other conditions that could be the cause of insomnia. After all other conditions are ruled out a comprehensive sleep history should be taken. The sleep history should include sleep habits, medications (prescription and non-prescription), alcohol consumption, nicotine and caffeine intake, co-morbid illnesses, and sleep environment. A sleep diary can be used to keep track of the individuals sleep patterns. The diary should include time to bed, total sleep time, time to sleep onset, number of awakenings, use of medications, time of awakening, and subjective feelings in the morning. The sleep diary can be replaced or validated by the use of out-patient actigraphy for a week or more, using a non-invasive device that measures movement.Workers who complain of insomnia should not routinely have polysomnography to screen for sleep disorders. This test may be indicated for patients with symptoms in addition to insomnia, including sleep apnea, obesity, a thick neck diameter, or high-risk fullness of the flesh in the oropharynx. Usually, the test is not needed to make a diagnosis, and insomnia especially for working people can often be treated by changing a job schedule to make time for sufficient sleep and by improving sleep hygiene.Some patients may need to do an overnight sleep study to determine if insomnia is present. Such a study will commonly involve assessment tools including a polysomnogram and the multiple sleep latency test. Specialists in sleep medicine are qualified to diagnose disorders within the, according to the ICSD, 81 major sleep disorder diagnostic categories. Patients with some disorders, including delayed sleep phase disorder, are often mis-diagnosed with primary insomnia; when a person has trouble getting to sleep and awakening at desired times, but has a normal sleep pattern once asleep, a circadian rhythm disorder is a likely cause.
In many cases, insomnia is co-morbid with another disease, side-effects from medications, or a psychological problem. Approximately half of all diagnosed insomnia is related to psychiatric disorders. For those who have depression, "insomnia should be regarded as a co-morbid condition, rather than as a secondary one;" insomnia typically predates psychiatric symptoms. "In fact, it is possible that insomnia represents a significant risk for the development of a subsequent psychiatric disorder." Insomnia occurs in between 60% and 80% of people with depression. This may partly be due to treatment used for depression.Determination of causation is not necessary for a diagnosis.

DSM-5 criteria
The DSM-5 criteria for insomnia include the following:Predominant complaint of dissatisfaction with sleep quantity or quality, associated with one (or more) of the following symptoms:

Difficulty initiating sleep. (In children, this may manifest as difficulty initiating sleep without caregiver intervention.)
Difficulty maintaining sleep, characterized by frequent awakenings or problems returning to sleep after awakenings. (In children, this may manifest as difficulty returning to sleep without caregiver intervention.)
Early-morning awakening with inability to return to sleep.In addition:

The sleep disturbance causes clinically significant distress or impairment in social, occupational, educational, academic, behavioral, or other important areas of functioning.
The sleep difficulty occurs at least 3 nights per week.
The sleep difficulty is present for at least 3 months.
The sleep difficulty occurs despite adequate opportunity for sleep.
The insomnia is not better explained by and does not occur exclusively during the course of another sleep-wake disorder (e.g., narcolepsy, a breathing-related sleep disorder, a circadian rhythm sleep-wake disorder, a parasomnia).
The insomnia is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication).
Coexisting mental disorders and medical conditions do not adequately explain the predominant complaint of insomnia.

Types
Insomnia can be classified as transient, acute, or chronic.

Transient insomnia lasts for less than a week. It can be caused by another disorder, by changes in the sleep environment, by the timing of sleep, severe depression, or by stress. Its consequences – sleepiness and impaired psychomotor performance – are similar to those of sleep deprivation.
Acute insomnia is the inability to consistently sleep well for a period of less than a month. Insomnia is present when there is difficulty initiating or maintaining sleep or when the sleep that is obtained is non-refreshing or of poor quality. These problems occur despite adequate opportunity and circumstances for sleep and they must result in problems with daytime function. Acute insomnia is also known as short term insomnia or stress related insomnia.
Chronic insomnia lasts for longer than a month. It can be caused by another disorder, or it can be a primary disorder. Common causes of chronic insomnia include persistent stress, trauma, work schedules, poor sleep habits, medications, and other mental health disorders. People with high levels of stress hormones or shifts in the levels of cytokines are more likely than others to have chronic insomnia. Its effects can vary according to its causes. They might include muscular weariness, hallucinations, and/or mental fatigue.

Prevention
Prevention and treatment of insomnia may require a combination of cognitive behavioral therapy, medications, and lifestyle changes.Among lifestyle practices, going to sleep and waking up at the same time each day can create a steady pattern which may help to prevent insomnia. Avoidance of vigorous exercise and caffeinated drinks a few hours before going to sleep is recommended, while exercise earlier in the day may be beneficial. Other practices to improve sleep hygiene may include:
Avoiding or limiting naps
Treating pain at bedtime
Avoiding large meals, beverages, alcohol, and nicotine before bedtime
Finding soothing ways to relax into sleep, including use of white noise
Making the bedroom suitable for sleep by keeping it dark, cool, and free of devices, such as clocks, cell phones, or televisions
Maintain regular exercise
Try relaxing activities before sleeping

Management
It is recommended to rule out medical and psychological causes before deciding on the treatment for insomnia. Cognitive behavioral therapy is generally the first line treatment once this has been done. It has been found to be effective for chronic insomnia. The beneficial effects, in contrast to those produced by medications, may last well beyond the stopping of therapy.Medications have been used mainly to reduce symptoms in insomnia of short duration; their role in the management of chronic insomnia remains unclear. Several different types of medications may be used. Many doctors do not recommend relying on prescription sleeping pills for long-term use. It is also important to identify and treat other medical conditions that may be contributing to insomnia, such as depression, breathing problems, and chronic pain. As of 2022, many people with insomnia were reported as not receiving overall sufficient sleep or treatment for insomnia.

Non-medication based
Non-medication based strategies have comparable efficacy to hypnotic medication for insomnia and they may have longer lasting effects. Hypnotic medication is only recommended for short-term use because dependence with rebound withdrawal effects upon discontinuation or tolerance can develop.Non medication based strategies provide long lasting improvements to insomnia and are recommended as a first line and long-term strategy of management. Behavioral sleep medicine (BSM) tries to address insomnia with non-pharmacological treatments. The BSM strategies used to address chronic insomnia include attention to sleep hygiene, stimulus control, behavioral interventions, sleep-restriction therapy, paradoxical intention, patient education, and relaxation therapy. Some examples are keeping a journal, restricting the time spent awake in bed, practicing relaxation techniques, and maintaining a regular sleep schedule and a wake-up time. Behavioral therapy can assist a patient in developing new sleep behaviors to improve sleep quality and consolidation. Behavioral therapy may include, learning healthy sleep habits to promote sleep relaxation, undergoing light therapy to help with worry-reduction strategies and regulating the circadian clock.Music may improve insomnia in adults (see music and sleep). EEG biofeedback has demonstrated effectiveness in the treatment of insomnia with improvements in duration as well as quality of sleep. Self-help therapy (defined as a psychological therapy that can be worked through on ones own) may improve sleep quality for adults with insomnia to a small or moderate degree.Stimulus control therapy is a treatment for patients who have conditioned themselves to associate the bed, or sleep in general, with a negative response. As stimulus control therapy involves taking steps to control the sleep environment, it is sometimes referred interchangeably with the concept of sleep hygiene. Examples of such environmental modifications include using the bed for sleep and sex only, not for activities such as reading or watching television; waking up at the same time every morning, including on weekends; going to bed only when sleepy and when there is a high likelihood that sleep will occur; leaving the bed and beginning an activity in another location if sleep does not occur in a reasonably brief period of time after getting into bed (commonly ~20 min); reducing the subjective effort and energy expended trying to fall asleep; avoiding exposure to bright light during nighttime hours, and eliminating daytime naps.A component of stimulus control therapy is sleep restriction, a technique that aims to match the time spent in bed with actual time spent asleep. This technique involves maintaining a strict sleep-wake schedule, sleeping only at certain times of the day and for specific amounts of time to induce mild sleep deprivation. Complete treatment usually lasts up to 3 weeks and involves making oneself sleep for only a minimum amount of time that they are actually capable of on average, and then, if capable (i.e. when sleep efficiency improves), slowly increasing this amount (~15 min) by going to bed earlier as the body attempts to reset its internal sleep clock. Bright light therapy may be effective for insomnia.Paradoxical intention is a cognitive reframing technique where the insomniac, instead of attempting to fall asleep at night, makes every effort to stay awake (i.e. essentially stops trying to fall asleep). One theory that may explain the effectiveness of this method is that by not voluntarily making oneself go to sleep, it relieves the performance anxiety that arises from the need or requirement to fall asleep, which is meant to be a passive act. This technique has been shown to reduce sleep effort and performance anxiety and also lower subjective assessment of sleep-onset latency and overestimation of the sleep deficit (a quality found in many insomniacs).

Sleep hygiene
Sleep hygiene is a common term for all of the behaviors which relate to the promotion of good sleep. They include habits which provide a good foundation for sleep and help to prevent insomnia. However, sleep hygiene alone may not be adequate to address chronic insomnia. Sleep hygiene recommendations are typically included as one component of cognitive behavioral therapy for insomnia (CBT-I). Recommendations include reducing caffeine, nicotine, and alcohol consumption, maximizing the regularity and efficiency of sleep episodes, minimizing medication usage and daytime napping, the promotion of regular exercise, and the facilitation of a positive sleep environment. The creation of a positive sleep environment may also be helpful in reducing the symptoms of insomnia.

Cognitive behavioral therapy
There is some evidence that cognitive behavioral therapy for insomnia (CBT-I) is superior in the long-term to benzodiazepines and the nonbenzodiazepines in the treatment and management of insomnia. In this therapy, patients are taught improved sleep habits and relieved of counter-productive assumptions about sleep. Common misconceptions and expectations that can be modified include

Unrealistic sleep expectations
Misconceptions about insomnia causes
Amplifying the consequences of insomnia
Performance anxiety after trying for so long to have a good nights sleep by controlling the sleep processNumerous studies have reported positive outcomes of combining cognitive behavioral therapy for insomnia treatment with treatments such as stimulus control and the relaxation therapies. Hypnotic medications are equally effective in the short-term treatment of insomnia, but their effects wear off over time due to tolerance. The effects of CBT-I have sustained and lasting effects on treating insomnia long after therapy has been discontinued. The addition of hypnotic medications with CBT-I adds no benefit in insomnia. The long lasting benefits of a course of CBT-I shows superiority over pharmacological hypnotic drugs. Even in the short term when compared to short-term hypnotic medication such as zolpidem, CBT-I still shows significant superiority. Thus CBT-I is recommended as a first line treatment for insomnia.Common forms of CBT-I treatments include stimulus control therapy, sleep restriction, sleep hygiene, improved sleeping environments, relaxation training, paradoxical intention, and biofeedback. CBT is the well-accepted form of therapy for insomnia since it has no known adverse effects, whereas taking medications to alleviate insomnia symptoms have been shown to have adverse side effects. Nevertheless, the downside of CBT is that it may take a lot of time and motivation.Metacognition is a recent trend in approach to behaviour therapy of insomnia.

Internet interventions
Despite the therapeutic effectiveness and proven success of CBT, treatment availability is significantly limited by a lack of trained clinicians, poor geographical distribution of knowledgeable professionals, and expense. One way to potentially overcome these barriers is to use the Internet to deliver treatment, making this effective intervention more accessible and less costly. The Internet has already become a critical source of health-care and medical information. Although the vast majority of health websites provide general information, there is growing research literature on the development and evaluation of Internet interventions.These online programs are typically behaviorally-based treatments that have been operationalized and transformed for delivery via the Internet. They are usually highly structured; automated or human supported; based on effective face-to-face treatment; personalized to the user; interactive; enhanced by graphics, animations, audio, and possibly video; and tailored to provide follow-up and feedback.There is good evidence for the use of computer based CBT for insomnia.

Medications
Many people with insomnia use sleeping tablets and other sedatives. In some places medications are prescribed in over 95% of cases. They, however, are a second line treatment. In 2019, the US Food and Drug Administration stated it is going to require warnings for eszopiclone, zaleplon, and zolpidem, due to concerns about serious injuries resulting from abnormal sleep behaviors, including sleepwalking or driving a vehicle while asleep.The percentage of adults using a prescription sleep aid increases with age. During 2005–2010, about 4% of U.S. adults aged 20 and over reported that they took prescription sleep aids in the past 30 days. Rates of use were lowest among the youngest age group (those aged 20–39) at about 2%, increased to 6% among those aged 50–59, and reached 7% among those aged 80 and over. More adult women (5%) reported using prescription sleep aids than adult men (3%). Non-Hispanic white adults reported higher use of sleep aids (5%) than non-Hispanic black (3%) and Mexican-American (2%) adults. No difference was shown between non-Hispanic black adults and Mexican-American adults in use of prescription sleep aids.

Antihistamines
As an alternative to taking prescription drugs, some evidence shows that an average person seeking short-term help may find relief by taking over-the-counter antihistamines such as diphenhydramine or doxylamine. Diphenhydramine and doxylamine are widely used in nonprescription sleep aids. They are the most effective over-the-counter sedatives currently available, at least in much of Europe, Canada, Australia, and the United States, and are more sedating than some prescription hypnotics. Antihistamine effectiveness for sleep may decrease over time, and anticholinergic side-effects (such as dry mouth) may also be a drawback with these particular drugs. While addiction does not seem to be an issue with this class of drugs, they can induce dependence and rebound effects upon abrupt cessation of use. However, people whose insomnia is caused by restless legs syndrome may have worsened symptoms with antihistamines.

Antidepressants
While insomnia is a common symptom of depression, antidepressants are effective for treating sleep problems whether or not they are associated with depression. While all antidepressants help regulate sleep, some antidepressants, such as amitriptyline, doxepin, mirtazapine, trazodone, and trimipramine, can have an immediate sedative effect, and are prescribed to treat insomnia. Amitriptyline, doxepin, and trimipramine all have antihistaminergic, anticholinergic, antiadrenergic, and antiserotonergic properties, which contribute to both their therapeutic effects and side effect profiles, while mirtazapines actions are primarily antihistaminergic and antiserotonergic and trazodones effects are primarily antiadrenergic and antiserotonergic. Mirtazapine is known to decrease sleep latency (i.e., the time it takes to fall asleep), promoting sleep efficiency and increasing the total amount of sleeping time in people with both depression and insomnia.Agomelatine, a melatonergic antidepressant with claimed sleep-improving qualities that does not cause daytime drowsiness, is approved for the treatment of depression though not sleep conditions in the European Union and Australia. After trials in the United States, its development for use there was discontinued in October 2011 by Novartis, who had bought the rights to market it there from the European pharmaceutical company Servier.A 2018 Cochrane review found the safety of taking antidepressants for insomnia to be uncertain with no evidence supporting long term use.

Melatonin agonists
Melatonin receptor agonists such as melatonin and ramelteon are used in the treatment of insomnia. The evidence for melatonin in treating insomnia is generally poor. There is low-quality evidence that it may speed the onset of sleep by 6 minutes. Ramelteon does not appear to speed the onset of sleep or the amount of sleep a person gets.Usage of melatonin as a treatment for insomnia in adults has increased from 0.4% between 1999 and 2000 to nearly 2.1% between 2017 and 2018. Most melatonin agonists have not been tested for longitudinal side effects. Prolonged-release melatonin may improve quality of sleep in older people with minimal side effects.Studies have also shown that children who are on the autism spectrum or have learning disabilities, attention-deficit hyperactivity disorder (ADHD) or related neurological diseases can benefit from the use of melatonin. This is because they often have trouble sleeping due to their disorders. For example, children with ADHD tend to have trouble falling asleep because of their hyperactivity and, as a result, tend to be tired during most of the day. Another cause of insomnia in children with ADHD is the use of stimulants used to treat their disorder. Children who have ADHD then, as well as the other disorders mentioned, may be given melatonin before bedtime in order to help them sleep.

Benzodiazepines
The most commonly used class of hypnotics for insomnia are the benzodiazepines.: 363  Benzodiazepines are not significantly better for insomnia than antidepressants. Chronic users of hypnotic medications for insomnia do not have better sleep than chronic insomniacs not taking medications. In fact, chronic users of hypnotic medications have more regular nighttime awakenings than insomniacs not taking hypnotic medications. Many have concluded that these drugs cause an unjustifiable risk to the individual and to public health and lack evidence of long-term effectiveness. It is preferred that hypnotics be prescribed for only a few days at the lowest effective dose and avoided altogether wherever possible, especially in the elderly. Between 1993 and 2010, the prescribing of benzodiazepines to individuals with sleep disorders has decreased from 24% to 11% in the US, coinciding with the first release of nonbenzodiazepines.The benzodiazepine and nonbenzodiazepine hypnotic medications also have a number of side-effects such as day time fatigue, motor vehicle crashes and other accidents, cognitive impairments, and falls and fractures. Elderly people are more sensitive to these side-effects. Some benzodiazepines have demonstrated effectiveness in sleep maintenance in the short term but in the longer term benzodiazepines can lead to tolerance, physical dependence, benzodiazepine withdrawal syndrome upon discontinuation, and long-term worsening of sleep, especially after consistent usage over long periods of time. Benzodiazepines, while inducing unconsciousness, actually worsen sleep as – like alcohol – they promote light sleep while decreasing time spent in deep sleep. A further problem is, with regular use of short-acting sleep aids for insomnia, daytime rebound anxiety can emerge. Although there is little evidence for benefit of benzodiazepines in insomnia compared to other treatments and evidence of major harm, prescriptions have continued to increase. This is likely due to their addictive nature, both due to misuse and because – through their rapid action, tolerance and withdrawal they can "trick" insomniacs into thinking they are helping with sleep. There is a general awareness that long-term use of benzodiazepines for insomnia in most people is inappropriate and that a gradual withdrawal is usually beneficial due to the adverse effects associated with the long-term use of benzodiazepines and is recommended whenever possible.Benzodiazepines all bind unselectively to the GABAA receptor. Some theorize that certain benzodiazepines (hypnotic benzodiazepines) have significantly higher activity at the α1 subunit of the GABAA receptor compared to other benzodiazepines (for example, triazolam and temazepam have significantly higher activity at the α1 subunit compared to alprazolam and diazepam, making them superior sedative-hypnotics – alprazolam and diazepam, in turn, have higher activity at the α2 subunit compared to triazolam and temazepam, making them superior anxiolytic agents). Modulation of the α1 subunit is associated with sedation, motor impairment, respiratory depression, amnesia, ataxia, and reinforcing behavior (drug-seeking behavior). Modulation of the α2 subunit is associated with anxiolytic activity and disinhibition. For this reason, certain benzodiazepines may be better suited to treat insomnia than others.

Z-Drugs
Nonbenzodiazepine or Z-drug sedative–hypnotic drugs, such as zolpidem, zaleplon, zopiclone, and eszopiclone, are a class of hypnotic medications that are similar to benzodiazepines in their mechanism of action, and indicated for mild to moderate insomnia. Their effectiveness at improving time to sleeping is slight, and they have similar—though potentially less severe—side effect profiles compared to benzodiazepines. Prescribing of nonbenzodiazepines has seen a general increase since their initial release on the US market in 1992, from 2.3% in 1993 among individuals with sleep disorders to 13.7% in 2010.

Orexin antagonists
Orexin receptor antagonists are a more recently introduced class of sleep medications and include suvorexant, lemborexant, and daridorexant, all of which are FDA-approved for treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.

Antipsychotics
Certain atypical antipsychotics, particularly quetiapine, olanzapine, and risperidone, are used in the treatment of insomnia. However, while common, use of antipsychotics for this indication is not recommended as the evidence does not demonstrate a benefit, and the risk of adverse effects are significant. A major 2022 systematic review and network meta-analysis of medications for insomnia in adults found that quetiapine did not demonstrate any short-term benefits for insomnia. Some of the more serious adverse effects may also occur at the low doses used, such as dyslipidemia and neutropenia. Concerns regarding side effects are greater in the elderly.

Other sedatives
Gabapentinoids like gabapentin and pregabalin have sleep-promoting effects but are not commonly used for treatment of insomnia.Barbiturates, while once used, are no longer recommended for insomnia due to the risk of addiction and other side effects.

Comparative effectiveness
A major systematic review and network meta-analysis of medications for the treatment of insomnia was published in 2022. It found a wide range of effect sizes (standardized mean difference (SMD)) in terms of efficacy for insomnia. The assessed medications included benzodiazepines (SMDs 0.58 to 0.83), Z-drugs (SMDs 0.03 to 0.63), sedative antidepressants and antihistamines (SMDs 0.30 to 0.55), quetiapine (SMD 0.07), orexin receptor antagonists (SMDs 0.23 to 0.44), and melatonin receptor agonists (SMDs 0.00 to 0.13). The certainty of evidence varied and ranged from high to very low depending on the medication. The meta-analysis concluded that the orexin antagonist lemborexant and the Z-drug eszopiclone had the best profiles overall in terms of efficacy, tolerability, and acceptability.

Alternative medicine
Herbal products, such as valerian, kava, chamomile, and lavender, have been used to treat insomnia. However, there is no quality evidence that they are effective and safe. The same is true for cannabis and cannabinoids. It is likewise unclear if acupuncture is useful in the treatment of insomnia.

Prognosis
A survey of 1.1 million residents in the United States found that those that reported sleeping about 7 hours per night had the lowest rates of mortality, whereas those that slept for fewer than 6 hours or more than 8 hours had higher mortality rates. Getting 8.5 or more hours of sleep per night was associated with a 15% higher mortality rate. Severe insomnia – sleeping less than 3.5 hours in women and 4.5 hours in men – is associated with a 15% increase in mortality.With this technique, it is difficult to distinguish lack of sleep caused by a disorder which is also a cause of premature death, versus a disorder which causes a lack of sleep, and the lack of sleep causing premature death. Most of the increase in mortality from severe insomnia was discounted after controlling for associated disorders. After controlling for sleep duration and insomnia, use of sleeping pills was also found to be associated with an increased mortality rate.The lowest mortality was seen in individuals who slept between six and a half and seven and a half hours per night </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Radiologically isolated syndrome and explain in detail? [/INST] Radiologically isolated syndrome (RIS) is a clinical situation in which a person has white matter lesions suggestive of multiple sclerosis (MS), as shown on an MRI scan that was done for reasons unrelated to MS symptoms. The nerve lesions in these people show dissemination in space with an otherwise normal neurological examination and without historical accounts of typical MS symptoms.MRI findings that are consistent with multiple sclerosis have been observed in healthy people who underwent MRI scanning, and 50% go on to develop symptomatic MS, sometimes with a primary progressive course.  This condition was first characterized in 2009.

Diagnosis
The criteria for an RIS diagnosis are as follows:
The presence of incidental MRI findings in the CNS white matter:
Ovoid and well-circumscribed homogeneous foci, with or without involvement of the corpus callosum
T2 hyperintensities larger than 3 mm in diameter, which fulfill at least 3 of the 4 Barkhof MRI criteria for DIS
The CNS abnormalities are not consistent with a vascular condition
No historical accounts of clinical symptoms consistent with neurological dysfunction.
MRI anomalies do not account for apparent impairment in social, occupational, or generalized areas of functioning.
MRI anomalies are not due to substance abuse, such as recreational drug use, toxic exposure, or a prior known medical condition.
Exclusion of a differential diagnosis of leukoaraiosis, or extensive white matter pathology excluding the corpus callosum.
MRI anomalies of the CNS are not accounted for by another disease.

Discovery
RIS is discovered when an MRI scan is performed for other reasons.  The most common symptom that led to the incidental discovery of RIS is headache.  Other common reasons are trauma, psychiatric disorders, and endocrinological disorders.

Management
Currently, routine clinical follow-up and MRI neuroimaging surveillance is the standard by which patients are observed. While treatment of MS disease modifying therapies have been given to some individuals with RIS, the majority opt for active surveillance and the appearance of clinical symptoms before commencing treatment, as treatment is considered controversial.

Prognosis
In a 5 year study, clinical events, which refers to the first symptoms of exacerbations, clinical attacks, flare ups, or severe symptoms, indicative of MS, appeared in 34% of individuals. Of those who developed symptoms, 9.6% fulfilled criteria for primary progressive multiple sclerosis (PPMS).

Epidemiology
Due to the incidental nature of RIS, exact figures on prevalence is unknown, though it has been suggested that RIS is the most common type of asymptomatic MS. The prevalence may be higher in relatives of patients with MS </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Pseudoxanthoma elasticum and explain in detail? [/INST] Pseudoxanthoma elasticum (PXE) is a genetic disease that causes mineralization of elastic fibers in some tissues. The most common problems arise in the skin and eyes, and later in blood vessels in the form of premature atherosclerosis. PXE is caused by autosomal recessive mutations in the ABCC6 gene on the short arm of chromosome 16 (16p13.1).

Signs and symptoms
Usually, pseudoxanthoma elasticum affects the skin first, often in childhood or early adolescence. Small, yellowish papular lesions form and cutaneous laxity mainly affect the neck, axillae (armpits), groin, and flexural creases (the inside parts of the elbows and knees). Skin may become lax and redundant. Many individuals have "oblique mental creases" (horizontal grooves of the chin)PXE first affects the retina through a dimpling of the Bruch membrane (a thin membrane separating the blood vessel-rich layer from the pigmented layer of the retina), that is only visible during ophthalmologic examinations.  This is called peau dorange (a French term meaning "skin of the orange"). Eventually the mineralization of the elastic fibers in the Bruch membrane create cracks called angioid streaks that radiate out from the optic nerve. Angioid streaks themselves do not cause distortion of vision, even if they cross into the foveal area. This symptom is present in almost all PXE patients and is usually noticed a few years after the onset of cutaneous lesions. These cracks may allow small blood vessels that were originally held back by Bruchs membrane to penetrate the retina. These blood vessels sometimes leak, and these retinal hemorrhages may lead to the loss of central vision. Vision loss is a major issue in many PXE patients.PXE may affect the gastrointestinal and cardiovascular systems. Gastrointestinal bleeding is a rare symptom and usually involved bleeding from the stomach. In the circulatory system, intermittent claudication, a condition in which cramping pain in the leg is induced by exercise, is a prominent feature. At later stages, coronary artery disease may develop, leading to angina and myocardial infarction (heart attack). Cerebral ischemia in PXE is caused by small vessel occlusive disease.
Other rare neurological complications may include intracranial aneurysms, subarachnoid and intracerebral hemorrhages.

Genetics
80% of clinical cases of pseudoxanthoma elasticum have detectable mutations in the ABCC6 gene. Mutations in almost all parts of the gene have been described, of all types (missense, nonsense, splice alteration, insertion, small deletion or large deletion). Although there have been reports of autosomal dominant inheritance, the inheritance is typically autosomal recessive (both parents need to be carriers, and there is a 25% chance that a child will inherit both abnormal copies of the gene and therefore develop the condition).Strong genetic linkage was found with mutations in the ABCC6 gene, which codes for the ABCC6 protein, which is a membrane transporter from the large ATP-binding cassette transporter family. The protein is expressed in most organs, but mainly in the liver and kidney. ABCC6 mediates ATP release in the liver. This is the main source of circulating pyrophosphate (PPi), and individuals affected by PXE have strongly reduced plasma PPi levels, explaining their mineralization disorder. One study suggested that mutations causing total absence of an ABCC6 protein caused a more severe disease, but this could not be confirmed in a subsequent case series. Given the variations in age of onset and severity it is likely that other unknown risk factors (genetic, environmental, and lifestyle) may be involved.Premature atherosclerosis is also associated with mutations in the ABCC6 gene, even in those without PXE. A syndrome almost indistinguishable from hereditary PXE has been described in patients with hemoglobinopathies (sickle-cell disease and thalassemia) through a poorly understood mechanism. In addition, there appears to be another PXE-like syndrome with a similar phenotype but as a result of problems with another gene, gamma-glutamyl carboxylase. Mutations in ABCC6 can also cause generalized arterial calcification of infancy. In some cases of PXE, mutations in ABCC6 cannot be found, and other genes such as ENPP1 may be implicated

Pathophysiology
In PXE, there is mineralization (accumulation of calcium and other minerals) and fragmentation of the elastin-containing fibers in connective tissue, but primarily in the midlaminar layer of the dermis, Bruchs membrane and the midsized arteries. Recent studies have confirmed that PXE is a metabolic disease, and that its features arise because metabolites of vitamin K cannot reach peripheral tissues. Low levels of PPi cause mineralization in peripheral tissues.

Diagnosis
The diagnostic criteria for PXE are the typical skin biopsy appearance and the presence of angioid streaks in the retina. Criteria were established by consensus of clinicians and researchers at the 2010 biennial research meeting of the PXE Research Consortium. and confirmed at the 2014 meeting These consensus criteria state that definitive PXE is characterized by two pathogenic mutations in the ABCC6 or ocular findings – angioid streaks > 1 DD or peau d’orange in an individual <20 years of age together with skin findings:

Characteristic pseudoxanthomatous papules and plaques on the neck or flexural creases.
Diagnostic histopathological changes in lesional skin: Calcified elastic fibers in the mid and lower dermis, confirmed by positive calcium stain

Differential diagnosis
Treatment
There is no confirmed treatment that directly interferes with the disease process.Cosmetic surgery to remove excessive skin has been used to improve aesthetic appearance in PXE patients but because of the non-life-threatening nature of these symptoms, should be used with caution.One of the most critical symptom of PXE is choroidal neovascularization which can lead to deterioration of central vision. Photodynamic therapy has been used as a treatment, but this has been replaced with endothelial growth factor (VEGF) inhibitors (such as bevacizumab, ranibizumab, and aflibercept) with efficacy similar to their use in treatment of age-related macular degeneration.To limit cardiovascular symptoms, reduction of cardiovascular risk factors through lifestyle changes is recommended. Generally clinicians recommend avoidance of non-steroidal anti-inflammatory drugs (NSAIDS) that increase bleeding risk, such as aspirin, and ibuprofen to prevent eye and gastrointestinal bleeding.Formerly, dietary restriction of calcium was tried with no benefit, and in fact accelerated mineralization in mice. There are a number of potential treatments that are currently being tested or have just undergone testing including magnesium, etidronate, PPi, and tissue-nonspecific alkaline phosphatase inhibitors.Given that ABCC6 heterozygous mutations result in few symptoms of PXE, this disease is a candidate for gene therapy.  Some initial proof-of-principle experiments have been done in mice that have relieved some of symptoms of PXE, but as with all gene therapy treatments, there are many hurdles that must be over come including insuring that the treatment will be long-lasting and reducing the risk of insertional mutagenesis and severe immune reactions.

Epidemiology
The reported prevalence of pseudoxanthoma elasticum is about 1:25,000. Females are twice as likely to be affected as males </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Ring chromosome 14 syndrome and explain in detail? [/INST] Ring chromosome 14 syndrome is a very rare human chromosome abnormality. It occurs when one or both of the telomeres that mark the ends of chromosome 14 are lost allowing the now uncapped ends to fuse together forming a ring chromosome. It causes a number of serious health issues.

Symptoms and signs
The most common symptoms are intellectual disability and recurrent seizures developing in infancy or early childhood. Typically the seizures are resistant to treatment with anti-epileptic drugs. Other symptoms may include:
Microcephaly
Lymphedema
Facial abnormalities
Immune deficiencies
Abnormalities of retina
Slow growth
Short stature

Cause
The syndrome is caused by the loss of genetic material near the end of the long arm (q) of chromosome 14 . The break that causes the telomere(s) to be lost occurs near the end of the chromosome, and is called a constitutional ring. These rings arise spontaneously ( it is rarely inherited).The genetic abnormality occurs randomly in sperm or egg cells or it may occur in early embryonic growth, if it occurs during embryonic growth the ring chromosome may be present in only some of a persons cells.

Diagnosis
Diagnosis is achieved by examining the structure of the chromosomes through karyotyping; while once born, one can do the following to ascertain a diagnosis of the condition:
MRI
EEG

Management
In terms of the management of ring chromosome 14 syndrome, anticonvulsive medication for seizures, as well as, proper therapy to help prevent respiratory infections in the affected individual are management measures that can be taken.

Epidemiology
Ring chromosome 14 syndrome is extremely rare, the true rate of occurrence is unknown (as it is less than 1 per 1,000,000), but there are at least 50 documented cases in the literature.

See also
Ring chromosome 18 syndrome
Ring chromosome 20 syndrome

References
Further reading
Disorders, National Organization for Rare (2003-01-01) </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Spinocerebellar ataxia and explain in detail? [/INST] Spinocerebellar ataxia (SCA) is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a neurological condition in its own right. An estimated 150,000 people in the United States have a diagnosis of spinocerebellar ataxia at any given time. SCA is hereditary, progressive, degenerative, and often fatal. There is no known effective treatment or cure. SCA can affect anyone of any age. The disease is caused by either a recessive or dominant gene. In many cases people are not aware that they carry a relevant gene until they have children who begin to show signs of having the disorder.

Signs and symptoms
Spinocerebellar ataxia (SCA) is one of a group of genetic disorders characterized by slowly progressive incoordination of gait and is often associated with poor coordination of hands, speech, and eye movements. A review of different clinical features among SCA subtypes was recently published describing the frequency of non-cerebellar features, like parkinsonism, chorea, pyramidalism, cognitive impairment, peripheral neuropathy, seizures, among others. As with other forms of ataxia, SCA frequently results in atrophy of the cerebellum, loss of fine coordination of muscle movements leading to unsteady and clumsy motion, and other symptoms.
The symptoms of an ataxia vary with the specific type and with the individual patient. In many cases a person with ataxia retains full mental capacity but progressively loses physical control.

Cause
The hereditary ataxias are categorized by mode of inheritance and causative gene or chromosomal locus. The hereditary ataxias can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.
Many types of autosomal dominant cerebellar ataxias for which specific genetic information is available are now known. Synonyms for autosomal-dominant cerebellar ataxias (ADCA) used prior to the current understanding of the molecular genetics were Maries ataxia, inherited olivopontocerebellar atrophy, cerebello-olivary atrophy, or the more generic term "spinocerebellar degeneration." (Spinocerebellar degeneration is a rare inherited neurological disorder of the central nervous system characterized by the slow degeneration of certain areas of the brain. There are three forms of spinocerebellar degeneration: Types 1, 2, 3. Symptoms begin during adulthood.)
There are five typical autosomal-recessive disorders in which ataxia is a prominent feature: Friedreich ataxia, ataxia-telangiectasia, ataxia with vitamin E deficiency, ataxia with oculomotor apraxia (AOA), spastic ataxia. Disorder subdivisions: Friedreichs ataxia, Spinocerebellar ataxia, Ataxia telangiectasia, Vasomotor ataxia, Vestibulocerebellar, Ataxiadynamia, Ataxiophemia, and Olivopontocerebellar atrophy.
There have been reported cases where a polyglutamine expansion may lengthen when passed down, which often can result in an earlier age-of-onset and a more severe disease phenotype for individuals who inherit the disease allele.  This falls under the category of genetic anticipation. Several types of SCA are characterized by repeat expansion of the trinucleotide sequence CAG in DNA that encodes a polyglutamine repeat tract in protein.  The expansion of CAG repeats over successive generations appears to be due to slipped strand mispairing during DNA replication or DNA repair.

Diagnosis
Classification
A few SCAs remain unspecified and can not be precisely diagnosed, but in the last decade genetic testing has allowed precise identification of dozens of different SCAs  and more tests are being added each year. In 2008, a genetic ataxia blood test developed to test for 12 types of SCA, Friedreichs ataxia, and several others.  However, since not every SCA has been genetically identified some SCAs are still diagnosed  by neurological examination, which  may include a physical exam, family history, MRI scanning of the brain and spine, and spinal tap.Many SCAs below fall under the category of polyglutamine diseases, which are caused when a disease-associated protein (i.e., ataxin-1, ataxin-3, etc.) contains a large number of repeats of glutamine residues, termed a polyQ sequence or a "CAG trinucleotide repeat" disease for either the one-letter designation or codon for glutamine respectively. The threshold for symptoms in most forms of SCA is around 35, though for SCA3 it extends beyond 50. Most polyglutamine diseases are dominant due to the interactions of resulting polyQ tail.The first ataxia gene was identified in 1993 and called "Spinocerebellar ataxia type 1" (SCA1); later genes were called SCA2, SCA3, etc. Usually, the "type" number of "SCA" refers to the order in which the gene was found. At this time, there are at least 29 different gene mutations that have been found.The following is a list of some of the many types of Spinocerebellar ataxia.

Others include SCA18, SCA20, SCA21, SCA23, SCA26, SCA28, and SCA29.
Four X-linked types have been described ( 302500,  302600,  301790,  301840), but only the first of these has so far been tied to a gene (SCAX1).

Treatment
Medication
There is no cure for spinocerebellar ataxia, which is currently considered to be a progressive and irreversible disease, although not all types cause equally severe disability.In general, treatments are directed towards alleviating symptoms, not the disease itself. Many patients with hereditary or idiopathic forms of ataxia have other symptoms in addition to ataxia. Medications or other therapies might be appropriate for some of these symptoms, which could include tremor, stiffness, depression, spasticity, and sleep disorders, among others. Both onset of initial symptoms and duration of disease are variable. If the disease is caused by a polyglutamine trinucleotide repeat CAG expansion, a longer expansion may lead to an earlier onset and a more radical progression of clinical symptoms. Typically, a person with this disease will eventually be unable to perform daily tasks (ADLs). However, rehabilitation therapists can help patients to maximize their ability of self-care and delay deterioration to certain extent. Researchers are exploring multiple avenues for a cure including RNAi and the use of Stem Cells and several other avenues.On January 18, 2017, BioBlast Pharma announced completion of Phase 2a clinical trials of their medication, Trehalose, in the treatment of SCA3.  BioBlast has received FDA Fast Track status and Orphan Drug status for their treatment.  The information provided by BioBlast in their research indicates that they hope this treatment may prove efficacious in other SCA treatments that have similar pathology related to PolyA and PolyQ diseases.In addition, Dr. Beverly Davidson has been working on a methodology using RNAi technology to find a potential cure for over 2 decades.  Her research began in the mid-1990s and progressed to work with mouse models about a decade later and most recently has moved to a study with non-human primates.  The results from her most recent research "are supportive of clinical application of this gene therapy".Finally, another gene transfer technology discovered in 2011 has also been shown by Boudreau et al. to hold great promise and offers yet another avenue to a potential future cure.

N-Acetyl-Leucine
N-Acetyl-Leucine is an orally administered, modified amino acid that is being developed as a novel treatment for multiple rare and common neurological disorders by IntraBio Inc (Oxford, United Kingdom).N-Acetyl-Leucine has been granted multiple orphan drug designations from the U.S. Food & Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of various genetic diseases, including Spinocerebellar Ataxias. N-Acetyl-Leucine has also been granted Orphan Drug Designations in the US and EU for the related inherited cerebellar ataxia Ataxia-Telangiectasia U.S. Food & Drug Administration (FDA) and the European Medicines Agency (EMA).Published case series studies have demonstrated the effects of acute treatment with N-Acetyl-Leucine for the treatment of inherited cerebellar ataxias, including Spinocerebellar Ataxias. These studies further demonstrated that the treatment is well tolerated, with a good safety profile.
A multinational clinical trial investigating N-Acetyl-L-Leucine for the treatment of a related inherited cerebellar ataxia, Ataxia-Telangiectasia, began in 2019.IntraBio is also conducting parallel clinical trials with N-Acetyl-L-Leucine for the treatment of Niemann-Pick disease type C and GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease). Future opportunities to develop N-Acetyl-Leucine include Lewy Body Dementia, Amyotrophic lateral sclerosis, Restless Leg Syndrome, Multiple Sclerosis, and Migraine.

Rehabilitation
Physical therapists can assist patients in maintaining their level of independence through therapeutic exercise programmes.  One recent research report demonstrated a gain of 2 SARA points (Scale for the Assessment and Rating of Ataxia) from physical therapy. In general, physical therapy emphasises postural balance and gait training for ataxia patients. General conditioning such as range-of-motion exercises and muscle strengthening would also be included in therapeutic exercise programmes.  Research showed that spinocerebellar ataxia 2 (SCA2) patients with a mild stage of the disease gained significant improvement in static balance and neurological indices after six months of a physical therapy exercise training program. Occupational therapists may assist patients with incoordination or ataxia issues through the use of adaptive devices. Such devices may include a cane, crutches, walker, or wheelchair for those with impaired gait. Other devices are available to assist with writing, feeding, and self care if hand and arm coordination are impaired. A randomised clinical trial revealed that an intensive rehabilitation program with physical and occupational therapies for patients with degenerative cerebellar diseases can significantly improve functional gains in ataxia, gait, and activities of daily living </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Peri-implant mucositis and explain in detail? [/INST] Peri-implant mucositis is defined as an inflammatory lesion of the peri-implant mucosa in the absence of continuing marginal bone loss.The American Academy of Periodontology defines peri‐implant mucositis as a disease in which inflammation of the soft tissues surrounding a dental implant is present without additional bone loss after the initial bone remodeling that may occur during healing following the surgical placement of the implant.Peri-implant mucositis is largely accepted as the precursor of peri-implantitis and corresponds to gingivitis around natural teeth.Important criteria to defining peri-implant mucositis are, the inflammation of mucosa surrounding an endosseous implant and the absence of continuing marginal peri-implant bone loss.

Aetiology
A shift in bacterial biofilm composition, from uninterrupted plaque maturation, and the immune system disintegration causes peri-implant mucosa inflammation to occur.
In peri-implant mucositis, there is an increase in proportion of bacteria from the orange complex: F. nucleatum, P. intermedia and Eubacterium species. A decrease in proportion of Streptococci and Actinomoyces species is also observed.Accumulation of bacteria around osseointegrated dental implants has been proven to be a cause of peri-implant mucositis by demonstrating this under experimental conditions and the development of an inflammatory response due to this has also been shown experimentally. When the surfaces of the implant in the mouth are colonised by pathogenic bacteria, plaque-induced inflammation can go on to cause destruction of the tissues around the implant. The presence of an inflammatory cell infiltrate in the connective tissue lateral to the junctional epithelium has been discovered in this condition, contributing to its development. The bacterial biofilm disrupts the host-microbe homeostasis, creating a dysbiosis which results in an inflammatory lesion. The inflammatory cell infiltrate has been found to increase in size as the peri-implant mucositis develops.Where peri-implant mucositis has been brought about by the accumulation of bacteria and their formation of a biofilm, it has been shown to be eventually reversible once the biofilm has been brought under control by regular cleaning by both patient and dental professional. This has been shown as studies display a clear reduction in redness, swelling and bleeding on probing in lesions of the peri-implant soft tissue after bacterial load has been minimised. This was shown in an experiment where bacteria were encouraged to accumulate for a period of time in which no oral hygiene was undertaken, allowing all of the patients to develop peri-implant mucositis. When oral hygiene was regularly commenced once again, all of the periodontal tissues eventually became healthy once more. However, the best management of peri-implant mucositis is not reversing it but preventing this from occurring in the first instance.The presence of excess luting cement has been demonstrated to contribute to causing peri-implant mucositis. One study gleaned results that suggested that in both patients with and without a history of periodontal problems, implants with extracoronal residual cement developed statistically significantly more cases of peri-implant mucositis as well as other periodontal problems. In this study 85% of implants in patients with previous periodontal conditions went on to develop peri-implant mucositis, which then progressed to peri-implantitis. In the group with no previous history of periodontal issues, 65% of implants still developed peri-implant mucositis, but significantly fewer of these implants then developed peri-implantitis. In contrast, the group with no extracoronal residual cement only had 30% of implants develop peri-implant mucositis. Therefore, cement remnants may be more likely to cause patients to develop peri-implant mucositis.Other causal factors of peri-implant mucositis include radiation and smoking, in addition to accretion of oral bacteria at the site. Other factors that are thought to contribute to the condition include lack of keratinised mucosa and diabetes mellitus, particularly poorly-controlled diabetes which will mean the patient will have a high level of blood glucose over longer periods. Understanding and controlling peri-implant mucositis is essential as it often leads to peri-implantitis.

Signs and Symptoms
Clinical signs and symptoms of peri-implant mucositis involves the localised surrounding gingival tissues (gum tissue) of a dental implant. These include:-
Bleeding on probing with no supporting bone loss.
Localised swelling
Redness/erythema.
Increased shininess of soft tissue surface.
Soreness

Risk Factors
Risk Factors of PIM are categorised into General and Local Risk Factors
General Risk Factors

Smoking
Radiation Therapy
Poorly controlled Diabetes Mellitus (HbA1c >10.1)Local Risk Factors

Oral Hygiene
Poor compliance / access to regular supportive implant therapy
Design of Implant-supported prostheses affecting accessibility for plaque removal
Sub-mucosal restorations
Dimension of Keratinized Peri-implant mucosa
Excess CementPossible Risk Factors:
Some other possible risk factors may include the location the implant is placed, type of implant placed and the age of the subject, as it was found that these factors had significant influences on bleeding on probing (BOP).Although it is uncertain whether increased abutment roughness will cause an increase in plaque accumulation and hence increase the risk of peri-implant mucositis, a 12-month comparative analysis in humans found that “a further reduction of the surface roughness, below a certain "threshold R(a)" (0.2 microns), has no major impact on the supra‐ and subgingival microbial composition.”Implants and abutments made of zirconium dioxide (ZrO2) were claimed to be more bio-compatible compared to those made of titanium but clinical studies show that there were slightly higher BOP scores or no significant difference in BOP scores around ZrO2 compared to titanium abutments.

Diagnosis
In order to diagnose peri-implant mucositis, it is essential to investigate probing parameters and complete a radiographic assessment. Correct diagnosis of peri-implant diseases is essential to allow appropriate management of the condition present. Failure to identify a peri-implant disease can lead to a complete loss of osseointegration and eventual loss of the implant.Though there are clear structural differences between dental implants and natural teeth, peri-implant health shares many common features with periodontal health around natural teeth. This is especially true with respect to their surrounding tissues and biological attachment.The diagnosis of peri-implant mucositis should be based on clinical signs of inflammatory disease, and radiographic assessment should be carried out to exclude bone level changes as this is an indication that peri-implant disease has already progressed to peri-implantitis stage.
Clinical presentations to diagnose peri-implant mucositis include:--        Red, swollen and soft peri-implant tissues
-        Bleeding on probing (BoP) and/or suppuration on probing
-        Increased probing depths compared to baseline measurements
-        Absence of bone loss beyond crestal bone level changes as a result of initial remodelling following implant placement
It has been suggested that the soft tissue cuff surrounding implants are less resistant to probing than the gingiva at adjacent teeth sites. This potentially leads to mechanically induced BoP on dental implants that are clinically healthy, as a result of trauma-induced BoP rather than a sign of biofilm-induced inflammation which represent the presence of peri-implant disease. Increased levels of bleeding on probing was present at 67% of sites where there is peri-implant mucositis as it is indicative of the presence of active disease and inflammation of the peri-implant mucosa. A light probing force of 0.25N should be used to probe the gingival margins so as not to damage the soft periodontal tissues. Bleeding on probing can be used in order to predict future loss of support from surrounding tissues. Microbiological testing was shown to improve the prognostic features compared to recording bleeding on probing alone as this was better for recognising the disease advancement around implants.
Increased probing depths over time is linked to loss of attachment and a reduction in the supporting alveolar bone levels. When bone becomes involved, the disease has progressed to peri-implantitis and this site is no longer diagnosed with peri-implant mucositis. The presence of bleeding on probing, the probing depths measured to the base of any pocketing and suppuration should all be assessed regularly in order to correctly diagnose peri-implant mucositis. Mucosal recession, a draining sinus or fistula and swelling or hyperplasia of the gingivae surrounding the implant can all signify the presence of peri-implant disease and should all prompt further investigations to ascertain whether this is the case.Radiographs are required to distinguish between peri-implant mucositis and peri-implantitis as the supporting alveolar bone levels must be evaluated in order to decide on a diagnosis. Dental Panoramic Tomography or a variety of intra-oral radiographs can be used to monitor marginal bone levels and evaluate interproximal bone loss in particular, but most agree peri-apical radiographs show bone loss more comprehensively. Current radiographs can be compared to previous radiographs and the distance from a fixed point, such as the implant shoulder, used to measure the bone loss in mm over time. If an implant is mobile, this is indicative of a deficiency in osseointegration and at this point the implant should be removed. Therefore, this is not a valuable factor for early diagnosis of peri-implant mucositis.
Alveolar bone loss following implant placement after first year in function should not exceed 2mm as generally between 0.5 – 2 mm of crestal bone height is lost during remodelling/healing process. As such changes ≥ 2mm during or after the first year should be considered as pathologic. Ie Peri-implant disease-induced.
There are currently no biochemical diagnostic tests clinically available, as no sensitive diagnostic test has yet been found that can detect reversible changes before this is clinically visible and detectable. There are many salivary biomarkers and biomarkers in the crevicular fluid surrounding implants that are present in much higher levels when there is peri-implant mucositis or peri-implant disease but all these present after or at the same time as clinical signs and symptoms. Therefore, there is currently no benefit to assessing the peri-implant fluid or analysing the saliva. Research continues in this field, though there is also no biochemical diagnostic test clinically available to detect the progression of gingivitis or periodontitis as of yet.

Prevention and Maintenance
The best management of peri-implant mucositis is preventing it from occurring through maintenance of the implants. This involves regular cleaning from both the patient and a dental professional and antibacterial mouthwashes may help reduce plaque and bleeding around dental implants.

Self-care
Various mechanical ways of removing bacteria from around implants are available to be used by patients in their own homes, including but not limited to nylon-coated interdental brushes, soft-bristled toothbrushes and hard plastic cleaning instruments. These are all designed to prevent damage of the implant abutment, which would roughen the surface and lead to the accumulation of more bacteria on the surface which would contribute to the formation of more biofilms in the area.
However, it was found that there were no statistically significant differences between some types of self administered antimicrobials, as they were all equally successful at maintaining the health of the soft tissues. One study was done comparing hyaluronic acid gel and chlorhexidine gel and another compared amine fluoride/stannous fluoride mouthwash to chlorhexidine mouthwash, but neither study showed either antimicrobial to be more effective at preventing peri-implant mucositis.It was found that there was no statistically significant difference between the effectiveness of using a powered/sonic toothbrush and using a manual toothbrush, although participants reported that they preferred the sonic toothbrush as they felt that it was better at keeping the areas around the implants clean.

Dental Professional
In terms of professionally administered treatment done by a dentist, there was no evidence to suggest that phosphoric acid etching gel is any more clinically advantageous than scaling or mechanical debridement and polishing or that enclosing chlorhexidine in the inner part of an implant is in any way superior to a physiological solution.It was also shown that a topical antibiotic inserted submucosally is no more successful at preventing peri-implant mucositis than a chlorhexidine gel.Debridement with manual curettes, followed by air polishing with glycine powder, and a prophylaxis brush, showed significant differences in BOP and peri-implant pocket depths. The use of manual curettes, sonic-driven scaler, and prophylaxis brush were found to be effective in maintaining the tissues around an implant, preventing inflammation. Applying chlorhexidine varnish in addition to debridement on implant surfaces had no significant additional benefit.

Treatment
When prevention of peri-implant mucositis fails, there are several options available to treat it.
A similar study was conducted to assess if there was a difference between using sonic/powered toothbrushes and using manual toothbrushes in the treatment of peri-implant mucositis and it was found that there is no statistically significant difference between the two in terms of intervention either.Irrigants were also tested as part of a set of interventions administered by dental professionals but it was found that there was no statistically significant difference between chlorhexidine and physiologic solutions when used as irrigants at second state surgery to maintain health of soft tissues.Reduced mean plaque scores and reduced marginal bleeding scores were achieved more effectively from chlorhexidine irrigation than from the use of chlorhexidine mouthwash. Listerine mouthwash was found to be statistically significantly better than a placebo at attaining reduced mean plaque scores and reduced marginal bleeding scores. When Listerine mouthwash was used twice daily for 30 seconds in addition to routine oral hygiene, it was shown that a reduction of 54% in mean plaque and 34% in marginal bleeding compared to a placebo. Chlorhexidine irrigations reduced mean plaque by 20% and marginal bleeding by 35% in comparison to a chlorhexidine mouthwash. Chlorhexidine is the most effective antiplaque agent used in the mouth to date. Reducing the mean plaque scores and the marginal bleeding scores contributes to both the prevention and the treatment of peri-implant mucositis. Initially, the use of mouthwashes was only proposed for patients with physical disabilities which would result in decreased manual dexterity and hence make active cleaning difficult. However, it is now thought that this will lead to less peri-implant mucositis being caused in all implant patients. Despite this, there have been concerns about the link between mouthwashes containing alcohol and the incidence of oral cancer.Some studies looked solely at interventions which contribute to the reversal of peri-implant mucositis. One such study found no statistically significant difference between triclosan dentrifice in comparison to sodium fluoride dentrifice at recovering soft tissue health </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Mucous membrane pemphigoid and explain in detail? [/INST] Mucous membrane pemphigoid is a rare chronic autoimmune subepithelial blistering disease characterized by erosive lesions of the mucous membranes and skin. It is one of the pemphigoid diseases that can result in scarring.

Signs and symptoms
The autoimmune reaction most commonly affects the oral mucosa in the mouth, causing lesions in the gums (gingiva), known as desquamative gingivitis. More severe cases can also affect areas of mucous membrane elsewhere in the body, such as the sinuses, genitals, anus, and cornea.  When the cornea of the eye is affected, repeated scarring may result in blindness.
Brunsting–Perry cicatricial pemphigoid is a rare variant of mucous membrane pemphigoid involving the scalp and the neck without mucosal involvement. It is proposed by some authors that this be called a variant of epidermolysis bullosa acquisita.Nikolskys sign (gentle lateral pressure) on unaffected mucosa or skin raises a bulla. If no lesions are present on examination it may be useful way of demonstrating reduced epithelial adhesion. In contrast, in Pemphigus, the epithelium tends to disintegrate rather than form a bulla.
Nikolskys sign is present in pemphigus and mucous membrane pemphigoid, but not in bullous pemphigoid.

Pathophysiology
In mucous membrane pemphigoid, the autoimmune reaction occurs in the skin, specifically at the level of the basement membrane, which connects the lower skin layer (dermis) to the upper skin layer (epidermis) and keeps it attached to the body.
When the condition is active, the basement membrane is dissolved by the antibodies produced, and areas of skin lift away at the base, causing hard blisters which scar if they burst. In other words, this is a desquamating/blistering disease in which the epithelium "unzips" from the underlying connective tissue, allowing fluid to gather that subsequently manifest as bullae, or blisters.

Diagnosis
Diagnostic techniques:

antibodies (IgG) precipitate complement (C3) in the lamina lucida of the basement membrane.
Circulating auto-antibodies to BP-1 antigen (located in hemidesmosome).  50% have BP-2.
Positive Nikolsky sign.
IgG, C3 deposition at BM creating smooth line in immunofluorescent analysis.

Management
The management depends upon the severity of the condition </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Optic disc drusen and explain in detail? [/INST] Optic disc drusen (ODD)  are globules of mucoproteins and mucopolysaccharides that progressively calcify in the optic disc. They are thought to be the remnants of the axonal transport system of degenerated retinal ganglion cells.
ODD have also been referred to as congenitally elevated or anomalous discs, pseudopapilledema, pseudoneuritis, buried disc drusen, and disc hyaline bodies.

Anatomy
The optic nerve is a cable connection that transmits images from the retina to the brain. It consists of over one million retinal ganglion cell axons. The optic nerve head, or optic disc is the anterior end of the nerve that is in the eye and hence is visible with an ophthalmoscope. It is located nasally and slightly inferior to the macula of the eye. There is a blind spot at the optic disc because there are no rods or cones beneath it to detect light. The central retinal artery and vein can be seen in the middle of the disc as it exits the scleral canal with the optic nerve to supply the retina. The vessels send branches out in all directions to supply the retina.

Pathophysiology
In children, optic disc drusen are usually buried and undetectable by fundoscopy except for a mild or moderate elevation of the optic disc. With age, the overlying axons become atrophied and the drusen become exposed and more visible. They may become apparent with an ophthalmoscope and some visual field loss at the end of adolescence. ODD can compress and eventually compromise the vasculature and retinal nerve fibers. Rarely, choroidal neovascularization may develop as the juxtapapillary nerve fibers are disrupted, with subsequent subretinal hemorrhage and retinal scarring. Even more rarely, vitreous hemorrhage may develop.

Diagnosis
Differential diagnosis
In most patients, optic disc drusen are an incidental finding. It is important to differentiate them from other conditions that present with optic disc elevation, especially papilledema, which could imply raised intracranial pressure or tumors. True papilledema may present with exudates or cotton-wool spots, unlike ODD. The optic disc margins are characteristically irregular in ODD but not blurred as there is no swelling of the retinal nerve fibers. Spontaneous venous pulsations are present in about 80 percent of patients with ODD, but absent in cases of true disc edema. Other causes of disc elevation clinicians must exclude may be: hyaloid traction, epipapillary glial tissue, myelinated nerve fibres, scleral infiltration, vitreopapillary traction and high hyperopia. Disorders associated with disc elevation include:  Alagille syndrome, Down syndrome, Kenny-Caffey syndrome, Leber Hereditary Optic Neuropathy and linear nevus sebaceous syndrome.

Management
Patients with optic disc drusen should be monitored periodically via ophthalmoscopy, Snellen acuity, contrast sensitivity, color vision, intraocular pressure and   threshold visual fields.  For those with visual field defects optical coherence tomography has been recommended for follow up of nerve fiber layer thickness. Associated conditions such as angioid streaks and retinitis pigmentosa should be screened for. Both the severity of optic disc drusen and the degree of intraocular pressure elevation have been associated with visual field loss. There is no widely accepted treatment for ODD, although some clinicians will prescribe eye drops designed to decrease the intra-ocular pressure and theoretically relieve mechanical stress on fibers of the optic disc. Rarely choroidal neovascular membranes may develop adjacent to the optic disc threatening bleeding and retinal scarring. Laser treatment or photodynamic therapy or other evolving therapies may prevent this complication.

Prognosis
Optic nerve damage is progressive and insidious.  Some of patients will develop some peripheral field defects. These can include nasal step defects, enlarged blind spots, arcuate scotomas, sectoral field loss and altitudinal defects. Clinical symptoms correlate to visibility of the drusen. Central vision loss is a rare complication of bleeding  from peripapillar choroidal neovascular membranes. Anterior ischemic optic neuropathy (AION) is a potential complication.

Epidemiology
Optic disc drusen are found clinically in about 1% of the population but this increases to 3.4% in individuals with a family history of ODD. About two thirds to three quarters of clinical cases are bilateral. A necropsy study of 737 cases showed a 2.4% incidence with 2 out of 15 (13%) bilateral, perhaps indicating the insidious nature of many cases </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Osteopathia striata and explain in detail? [/INST]  </s>