Neil Freedman, M.D., F.C.C.P.
Narcolepsy is the most common neurologic cause of excessive daytime sleepiness. It is as common as multiple sclerosis, affecting approximately 0.05% of the population in the United States.
Narcolepsy is commonly associated with a tetrad of symptoms including excessive daytime sleepiness (EDS), sleep attacks known as cataplexy, extremely vivid dreams (hypnagogic hallucinations) and an inability to move upon awakening (sleep paralysis).
Although the symptoms typically begin during the second decade of life (70-80%), they may occur at any age. For the non-sleep physician, the daytime sleepiness is to such an extreme that most patients feel like you and I would after staying up most or all of the night. Cataplexy attacks, which are typically triggered by emotion, actually represent the inappropriate intrusion of dream (REM) sleep into wakefulness. It should be stressed that the classic tetrad of symptoms are not always present in all patients with narcolepsy, with only 14% to 42% of patients reporting all four symptoms. Patients also typically report poorer quality of life, with disease related symptoms affecting their personal, social, and professional lives.
Although the underlying mechanisms responsible for narcolepsy still remain unclear, several possible explanations have been put forth. Currently, no structural abnormalities of the brain have been consistently identified in patients with narcolepsy. Genetics likely play a role, with the most likely scenario being that of multiple genes influenced by environmental factors. A strong association has been demonstrated between two genetic locations on human chromosome 6: HLA DQB1*0602 and DQA1*0102 are found in 85% to 95% of narcoleptics as compared to 12% to 38% of the general U.S. population, with the HLA DQB1*0602 type being more closely associated with symptoms of cataplexy. Unfortunately, although these genes are more common in narcoleptics, they are not specific enough to diagnose the disease. Genetic testing is therefore not recommended for diagnostic purposes.
Some have proposed that narcolepsy may be an autoimmune disease; with an individual’s own antibodies attacking parts of the brain that control wakefulness or sleepiness. A recent study from the Mayo Clinic looked at several antibodies that were known to target the nervous system in other diseases, in a group of patients with narcolepsy. They found no significant links between these antibodies and a cause for narcolepsy. Although these finding do not rule out an autoimmune etiology, the results of this study, as well as others, currently do not support narcolepsy as an autoimmune phenomenon.
The most exciting developments in narcolepsy research have focused on hypocretins. Hypocretins, also known as orexins, are proteins released from the hypothalamus in the brain that regulate how much we eat, our blood pressure and the release of other hormones. They are also thought to play a critical role in the regulation of dream or rapid eye movement (REM) sleep. Hypocretins are found in the cerebrospinal fluid (CSF), the fluid that surrounds the brain and spinal cord, as well as in the blood.
Several studies in humans have demonstrated that quantities of hypocretin A are reduced or absent in the spinal fluid of patients with narcolepsy. Very low or absent hypocretin A levels were more closely associated with narcoleptic patients who had cataplexy as part of their symptoms and in patients who have the HLA DQB1*0602 gene. Narcolepsy patients without cataplexy demonstrated only mildly reduced or normal hypocretin A levels in their spinal fluid. These data suggest that hypocretins (orexins) may be the major neurotransmitters responsible for narcolepsy.
The current role of testing for reduced hypocretin A levels in the diagnosis of narcolepsy is unclear. It is not recommended at this time that hypocretin A levels be assessed on a routine basis. If the sleep specialist feels that the measurement of hypocretin A levels are to be used as an aid in the diagnosis of narcolepsy, specimens should be obtained from the cerebrospinal fluid by means of a lumbar puncture (spinal tap). Blood samples have been shown to be inaccurate. Since measurement of hypocretin A levels is not a routine test, specimens should then be sent to labs that have extensive experience with its determination.