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Narcolepsy

Chronic neurological sleep disorder

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Solution phase NMR structure of orexin A based on the PDB coordinates 1R02. Created based on the 1R02 crystallographic coordinates and using PyMol.
Boghog2 , English Wikipedia · Public domain

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There are two recognized forms of narcolepsy: type 1 and type 2. Narcolepsy type 1 features EDS with either cataplexy or cerebrospinal fluid (CSF) orexin levels of less than 110 pg/ml, but most cases present with both. Cataplexy appears as transient episodes of aberrant muscle tone (typically loss of muscle tone) triggered by strong emotion. In pediatric-onset narcolepsy, cataplexy can present with transient hyperkinetic features. Cataplexy may be mistaken for syncope, tics, or seizures. Narcolepsy type 2 (NT2) does not feature cataplexy, and CSF orexin levels are normal. Sleep-related hallucinations, both hypnagogic (going to sleep) and hypnopompic (on awakening), can be auditory, visual, or tactile and may occur independently of or in combination with an inability to move (sleep paralysis).

Narcolepsy is a clinical syndrome of hypothalamic disorder, but the exact cause of narcolepsy is unknown, with potentially several causes. A leading consideration for the cause of narcolepsy type 1 is that it is an autoimmune disorder. Proposed pathophysiology as an autoimmune disease suggest antigen presentation by DQ0602 to specific CD4+ T cells resulting in CD8+ T-cell activation and consequent injury to orexin producing neurons. Relative risk for narcolepsy in a first-degree relative is considered to be at least 10 times higher than the general population, Having multiple relatives with a primary sleep disorder significantly increases the relative risk but absolute risk still remains low due to the rarity of the condition.

The autoimmune process is thought to be triggered in genetically susceptible individuals by an immune-provoking experience, such as an infection with H1N1 influenza. Secondary narcolepsy can occur as a consequence of another neurological disorder. Secondary narcolepsy can be seen in some individuals with traumatic brain injury, tumors, Prader–Willi syndrome or other diseases affecting the parts of the brain that regulate wakefulness or REM sleep. Diagnosis is typically based on the symptoms and sleep studies, after excluding alternative causes of EDS. EDS can also be caused by other sleep disorders such as insufficient sleep syndrome, sleep apnea, major depressive disorder, anemia, heart failure, and drinking alcohol.

While there is no cure, behavioral strategies, lifestyle changes, social support, and medications may help. Lifestyle and behavioral strategies can include identifying and avoiding or desensitizing emotional triggers for cataplexy, dietary strategies that may reduce sleep-inducing foods and drinks, scheduled or strategic naps, and maintaining a regular sleep-wake schedule. Social support, social networks, and social integration are resources that may lie in the communities related to living with narcolepsy. Medications used to treat narcolepsy primarily target EDS or cataplexy. These medications include alerting agents (e.g., modafinil, armodafinil, pitolisant, solriamfetol), oxybate medications (e.g., twice nightly sodium oxybate, twice nightly mixed oxybate salts, and once nightly extended-release sodium oxybate), and other stimulants (e.g., methylphenidate, amphetamine). There is also the use of antidepressants such as tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotonin–norepinephrine reuptake inhibitors (SNRIs) for the treatment of cataplexy.

Estimates of frequency range from 0.2 to 600 per 100,000 people in various countries. The condition often begins in childhood, with males and females being affected equally. Untreated narcolepsy increases the risk of motor vehicle collisions and falls. Narcolepsy generally occurs anytime between early childhood and 50 years of age, and most commonly between 15 and 36 years of age. However, it may also rarely appear at any time outside of this range.

Signs and symptoms

There are two main characteristics of narcolepsy: excessive daytime sleepiness and abnormal REM sleep. Excessive daytime sleepiness occurs even after adequate night time sleep. A person with narcolepsy is likely to become drowsy or fall asleep, often at inappropriate or undesired times and places, or just be very tired throughout the day. Narcoleptics may not be able to experience the amount of restorative deep sleep that healthy people experience due to abnormal REM regulation – they are not "oversleeping". Narcoleptics typically have higher REM sleep density than non-narcoleptics, but also experience more REM sleep without atonia. Many narcoleptics have sufficient REM sleep, but do not feel refreshed or alert throughout the day.

Excessive sleepiness can vary in severity and appears most commonly during monotonous situations that require little interaction. Daytime naps may occur with little warning and may be physically irresistible. These naps can occur several times a day. They are typically refreshing, but only for a brief period. Vivid dreams may be experienced regularly, even during short naps. Drowsiness may persist for prolonged periods or remain constant. Additionally, nighttime sleep may be fragmented, with frequent awakenings. A second prominent symptom of narcolepsy is abnormal REM sleep. Narcoleptics are unique in that instead of following the typical sleep cycle, they enter into the REM phase of sleep at the beginning of sleep, even when sleeping during the day. The classic symptoms of the disorder, often referred to as the "tetrad of narcolepsy", are cataplexy, sleep paralysis, hypnagogic hallucinations, and excessive daytime sleepiness. Other symptoms include automatic behaviors and night-time wakefulness. These symptoms may not occur in all people with narcolepsy.

  • A very brief (from a few seconds to a couple of minutes) and episodic loss of muscle tone (or limbs going "floppy") on both sides of the body (bilateral as opposed to stroke which is unilateral) which is not associated with the onset of sleep or waking. Cataplexy can range from transient weakness in the neck, knees or facial muscles to a complete loss of muscle tone leading to a fall. Typical cataplexy is triggered by sudden emotional reactions such as laughter, other positive emotions, anger or surprise. The person remains conscious throughout the episode. In some cases, cataplexy may resemble epileptic seizures. Cataplexy can have a significant impact on people with narcolepsy, as it can cause extreme anxiety, fear, and avoidance of people or situations that might elicit an attack. Cataplexy is considered to be unique to narcolepsy (pathognomonic).
  • Periods of wakefulness at night.
  • The temporary inability to talk or move when waking (or, less often, when falling asleep), known as sleep paralysis. It may last a few seconds to minutes. This is often frightening but it is not dangerous.
  • Vivid, often frightening, dreamlike experiences that occur while dozing or falling asleep, known as hypnagogic hallucinations. Hypnopompic hallucinations refer to the same sensations while awakening from sleep. These hallucinations may manifest in the form of visual or auditory sensations.

In most cases, the first symptom of narcolepsy to appear is excessive and overwhelming daytime sleepiness. The other symptoms may begin alone or in combination months or years after the onset of the daytime naps. There are wide variations in the development, severity, and order of appearance of cataplexy, sleep paralysis, and hypnagogic hallucinations in individuals. Only about 20 to 25 percent of people with narcolepsy experience all four symptoms. The excessive daytime sleepiness generally persists throughout life, but sleep paralysis and hypnagogic hallucinations may not.

Many people with narcolepsy also have insomnia for extended periods. The excessive daytime sleepiness and cataplexy often become severe enough to cause serious problems in a person's social, personal, and professional life. Normally, when an individual is awake, brain waves show a regular rhythm. When a person first falls asleep, the brain waves become slower and less regular, which is called non-rapid eye movement (NREM) sleep. After about an hour and a half of NREM sleep, the brain waves begin to show a more active pattern again, called REM sleep (rapid eye movement sleep), when most remembered dreaming occurs. Associated with the EEG-observed waves during REM sleep, muscle atonia is present, called REM atonia.

In narcolepsy, the order and length of NREM and REM sleep periods are disturbed, with REM sleep occurring at sleep onset instead of after a period of NREM sleep. Also, some aspects of REM sleep that normally occur only during sleep, like lack of muscular control, sleep paralysis, and vivid dreams, occur at other times in people with narcolepsy. For example, the lack of muscular control can occur during wakefulness in a cataplexy episode; it is said that there is an intrusion of REM atonia during wakefulness. Sleep paralysis and vivid dreams can occur while falling asleep or waking up. Simply put, the brain does not pass through the normal stages of dozing and deep sleep but goes directly into (and out of) rapid eye movement (REM) sleep.

As a consequence, nighttime sleep does not include as much deep sleep, so the brain tries to "catch up" during the day, hence excessive daytime sleepiness. People with narcolepsy may visibly fall asleep at unpredictable moments (such motions as head bobbing are common). People with narcolepsy fall quickly into what appears to be very deep sleep, and they wake up suddenly and can be disoriented when they do (dizziness is a common occurrence). They have very vivid dreams, which they often remember in great detail. People with narcolepsy may dream even when they only fall asleep for a few seconds. Along with vivid dreaming, people with narcolepsy are known to have audio or visual hallucinations before falling asleep or before waking up. Narcoleptics can gain excess weight; children can gain 20 to 40 pounds (9.1 to 18.1 kg) when they first develop narcolepsy; in adults, the body-mass index is about 15% above average.

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