Narcolepsy

Narcolepsy is a long-term neurological disorder characterized by a decreased ability to regulate sleep-wake cycles. People with narcolepsy often experience periods of excessive daytime sleepiness and brief involuntary sleep episodes. Approximately 70% of affected individuals also experience episodes of sudden loss of muscle strength, known as cataplexy, which can be triggered by strong emotions. Less commonly, individuals may experience vivid hallucinations or an inability to move (sleep paralysis) while falling asleep or waking up. Although people with narcolepsy sleep for about the same number of hours per day as those without the disorder, the quality of their sleep is generally reduced.

Causes

The exact cause of narcolepsy remains unknown, with potentially several contributing factors. In up to 10% of cases, there is a family history of the disorder. Affected individuals often have low levels of the neuropeptide orexin, which could be due to an autoimmune disorder. Trauma, infections, toxins, or psychological stress might also play a role.

Genetics

There is a strong link between narcolepsy and certain genetic variants, particularly in the human leukocyte antigen (HLA) complex on chromosome 6. Specific variations in HLA genes are strongly correlated with the presence of narcolepsy, but they are not required for the condition to occur and can sometimes be found in individuals without narcolepsy. These genetic variations in the HLA complex are thought to increase the risk of an auto-immune response to orexin-releasing neurons in the lateral hypothalamus.

Signs and symptoms

Narcolepsy is characterized by two main symptoms: excessive daytime sleepiness (EDS) and abnormal REM sleep. EDS occurs even after adequate nighttime sleep, leading individuals to become drowsy or fall asleep at inappropriate times and places. Narcoleptics often experience vivid dreams, even during very brief naps.

Cataplexy

Cataplexy is an episodic loss of muscle function that can range from slight weakness, such as limpness at the neck or knees, to complete body collapse. Episodes may be triggered by sudden emotional reactions, such as laughter, anger, surprise, or fear. The person remains conscious throughout the episode. In some cases, cataplexy may resemble epileptic seizures.

Sleep paralysis and hypnagogic hallucinations

Sleep paralysis is the temporary inability to talk or move when waking or, less often, when falling asleep. It may last a few seconds to minutes and can be frightening but is not dangerous. Hypnagogic hallucinations are vivid, often frightening, dreamlike experiences that occur while dozing or falling asleep. Hypnopompic hallucinations refer to the same sensations experienced while awakening from sleep.

Diagnosis and treatment

Diagnosis of narcolepsy is typically based on symptoms and sleep studies after ruling out other potential causes, such as sleep apnea, major depressive disorder, anemia, heart failure, alcohol consumption, or insufficient sleep.

While there is no cure for narcolepsy, a combination of lifestyle changes and medications may help. Lifestyle changes include taking regular short naps and practicing good sleep hygiene. Medications used to treat narcolepsy include modafinil, sodium oxybate, and methylphenidate. Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) may improve cataplexy.

Prevalence

Estimates of the frequency of narcolepsy 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.

Signs and symptoms

There are two main characteristics of narcolepsy: excessive daytime sleepiness (EDS) and abnormal REM sleep. EDS occurs even after adequate night time sleep. A person with narcolepsy is likely to become drowsy or fall asleep, often at inappropriate times and places, or just be very tired throughout the day. Narcoleptics are not able to experience the amount of restorative deep sleep that healthy people experience – they are not "over-sleeping". In fact, narcoleptics live their entire lives in a constant state of extreme sleep deprivation.

• Excessive sleepiness can vary in severity, and it appears most commonly during monotonous situations that don't require much 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 few hours or less. Vivid dreams may be experienced on a regular basis, even during very brief naps. Drowsiness may persist for prolonged periods or remain constant. In addition, night-time sleep may be fragmented, with frequent awakenings. A second prominent symptom of narcolepsy is abnormal REM sleep. Narcoleptics are unique in that they enter into the REM phase of sleep in the beginnings 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 may include automatic behaviors and night-time wakefulness. These symptoms may not occur in all people with narcolepsy.
• Cataplexy is an episodic loss of muscle function, ranging from slight weakness such as limpness at the neck or knees, sagging facial muscles, weakness at the knees often referred to as "knee buckling", or inability to speak clearly, to a complete body collapse. Episodes may be triggered by sudden emotional reactions such as laughter, anger, surprise, or fear. The person remains conscious throughout the episode. In some cases, cataplexy may resemble epileptic seizures. Usually speech is slurred and vision is impaired (double vision, inability to focus), but hearing and awareness remain normal. Cataplexy also has a severe emotional impact on narcoleptics, as it can cause extreme anxiety, fear, and avoidance of people or situations that might elicit an attack. Cataplexy is generally considered to be unique to narcolepsy and is analogous to sleep paralysis in that the usually protective paralysis mechanism occurring during sleep is inappropriately activated. The opposite of this situation (failure to activate this protective paralysis) occurs in RBD.
• Sleep paralysis is the temporary inability to talk or move when waking (or less often, when falling asleep). It may last a few seconds to minutes. This is often frightening but is not dangerous.
• Hypnagogic hallucinations are vivid, often frightening, dreamlike experiences that occur while dozing or falling asleep. Hypnopompic hallucinations refer to the same sensations while awakening from sleep. These hallucinations may manifest in the form of visual or auditory sensations.
• Automatic behaviors occur when a person continues to function (talking, putting things away, etc.) during sleep episodes but awakens with no memory of performing such activities. It is estimated that up to 40 percent of people with narcolepsy experience automatic behavior during sleep episodes.

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 suffer from insomnia for extended periods of time. 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 EDS. People with narcolepsy may visibly fall asleep at unpredicted 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 prior to falling asleep.

Narcoleptics can gain excess weight; children can gain 20 to 40 lb (9 to 18 kg) when they first develop narcolepsy; in adults, the body-mass index is about 15% above average.

Causes

The exact cause of narcolepsy is unknown, and it may be caused by several distinct factors. The mechanism involves the loss of orexin-releasing neurons within the lateral hypothalamus.

• In up to 10% of cases, there is a family history of the disorder. Family history is more common in narcolepsy with cataplexy. There is a strong link with certain genetic variants. In addition to genetic factors, low levels of orexin peptides have been correlated with a past history of infection, diet, contact with toxins such as pesticides, and brain injuries due to head trauma, brain tumors, or strokes. Autoimmunity may also play a role.
• The primary genetic factor that has been strongly implicated in the development of narcolepsy involves an area of chromosome 6 known as the human leukocyte antigen (HLA) complex. Specific variations in HLA genes are strongly correlated with the presence of narcolepsy; however, these variations are not required for the condition to occur and sometimes occur in individuals without narcolepsy. These genetic variations in the HLA complex are thought to increase the risk of an auto-immune response to orexin-releasing neurons in the lateral hypothalamus.
• The allele HLA-DQB106:02 of the human gene HLA-DQB1 was reported in more than 90% of people with narcolepsy, and alleles of other HLA genes such as HLA-DQA101:02 have been linked. A 2009 study found a strong association with polymorphisms in the TRAC gene locus (dbSNP IDs rs1154155, rs12587781, and rs1263646). A 2013 review article reported additional but weaker links to the loci of the genes TNFSF4 (rs7553711), Cathepsin H (rs34593439), and P2RY11-DNMT1 (rs2305795). Another gene locus that has been associated with narcolepsy is EIF3G (rs3826784).
• A link between GlaxoSmithKline's H1N1 flu vaccine Pandemrix and narcolepsy has been found in both children and adults. Finland's National Institute of Health and Welfare recommended that Pandemrix vaccinations be suspended pending further investigation into narcolepsy. This vaccine was available only in Europe.

Pathophysiology

• Orexin, otherwise known as hypocretin, is a neuropeptide that acts within the brain to regulate appetite and wakefulness as well as a number of other cognitive and physiological processes. While there are billions of cells in the human brain, only 10,000–20,000 neurons secrete orexin peptides; all of these neurons project out of the lateral hypothalamus. Loss of these orexin-producing neurons causes narcolepsy, and most individuals with narcolepsy have a reduced number of these neurons in their brains.
• The neural control of normal sleep states and the relationship to narcolepsy are only partially understood. In humans, narcoleptic sleep is characterized by a tendency to go abruptly from a waking state to REM sleep with little or no intervening non-REM sleep. The changes in the motor and proprioceptive systems during REM sleep have been studied in both human and animal models. During normal REM sleep, spinal and brainstem alpha motor neuron hyperpolarization produces almost complete atonia of skeletal muscles via an inhibitory descending reticulospinal pathway. Acetylcholine may be one of the neurotransmitters involved in this pathway. In narcolepsy, the reflex inhibition of the motor system seen in cataplexy has features normally seen only in normal REM sleep.
• The exact mechanism by which the loss of orexin-producing neurons leads to narcolepsy is not fully understood. However, it is believed that without the orexin neuropeptide, the normal functioning of the sleep-wake cycle is disrupted. The loss of orexin also leads to the disruption of the normal functioning of other physiological processes, such as metabolism and immune system regulation.
• Research has shown that narcolepsy is often associated with an autoimmune response that attacks and destroys the orexin-producing neurons in the hypothalamus. The autoimmune response may be triggered by environmental factors, such as viral infections or exposure to certain toxins. Genetic factors also appear to play a role in the development of narcolepsy, as certain variations in the HLA complex have been strongly correlated with the condition.
• The loss of orexin-producing neurons also leads to the disruption of the normal functioning of other physiological processes, such as metabolism and immune system regulation. This may explain why individuals with narcolepsy are more likely to experience obesity and other metabolic disorders.

Summary

In summary, narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, abnormal REM sleep, and other symptoms such as cataplexy, sleep paralysis, and hypnagogic hallucinations. The exact cause of narcolepsy is unknown, but it is believed to be caused by a combination of genetic and environmental factors that lead to the destruction of orexin-producing neurons in the hypothalamus. Further research is needed to fully understand the pathophysiology of narcolepsy and develop more effective treatments for the condition.

External links

Classification	ICD-10: G47.4 ICD-9-CM: 347 OMIM: 161400 MeSH: D009290 DiseasesDB: 8801
External resources	MedlinePlus: 000802 eMedicine: neuro/522

• "Narcolepsy Information Page". National Institute of Neurological Disorders and Stroke.

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