Background

Narcolepsy is characterized by the classic tetrad of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. Note that this tetrad is seen only rarely in children. The term narcolepsy is derived from Greek, "seized by somnolence." Gelineau was the first to delineate the syndrome in 1880. Narcolepsy frequently is unrecognized, with a typical delay of 10 years between onset and diagnosis. Approximately 50% of adults with the disorder retrospectively report symptoms beginning in their teenage years. This disorder may lead to impairment of social and academic performance in otherwise intellectually normal children. The implications of the disease are often misunderstood by patients, parents, teachers, and health care professionals. Narcolepsy is treatable. However, a multimodal approach is required for the most favorable outcome.

Pathophysiology
Narcolepsy is thought to result from genetic predisposition, abnormal neurotransmitter functioning and sensitivity, and abnormal immune modulation. Current data implicate certain human leukocyte antigen (HLA) subtypes and abnormalities in monoamine synaptic transmission, particularly in the pontine reticular activating system. Understanding of the neurochemistry of narcolepsy stems primarily from research involving narcoleptic dogs (eg, special laboratory-bred Dobermans and Labradors). In these animal models, the disorder is transmitted in an autosomal recessive fashion with full penetrance and is characterized mainly by cataplexy.

Muscarinic cholinergic stimulation increases cataplexy in these animals, and cholinergic blockade eliminates the symptom. Nicotinic agents have no effect on cataplexy. The muscarinic receptor subtype M2 is up-regulated in the pontine reticular formation in narcoleptic canines, especially in the nucleus reticularis, pontis caudalis, nucleus reticularis gigantocellularis, reticularis pontis parvi, tegmenti pontis, and interpeduncularis. Other receptor subtypes such as the alpha1-noradrenergic receptor appear to mediate cataplexy. Prazosin, an alpha1-antagonist, worsens symptoms in human and canine subjects. The pons is not the only neuroanatomic site that is responsible for mediating cataplexy. Experiments in narcoleptic Dobermans with selective injections of a muscarinic agonist have demonstrated that the basal forebrain structures (ie, nucleus basalis, substantia innominata, diagonal band, medial septum) also induce status cataplecticus. The meso-cortico-limbic dopaminergic system also has been implicated. This connection with the limbic system in part explains the relationship of cataplexy to emotion.

Dysfunction and inappropriate regulation of rapid eye movement (REM) sleep are thought to cause narcolepsy.

Neuroanatomic control of REM sleep appears to be localized to the pontine reticular activating system. The brain contains REM-on cells, which fire selectively during REM sleep periods, and REM-off cells, for which the converse holds true. Most REM-on cells function through cholinergic transmission, whereas REM-off cells are noradrenergic or serotonergic. In narcolepsy, monoamine-dependent inhibition of REM-on cells may be defective. Symptoms can be viewed as REM sleep components intruding into wakeful states. For example, cataplexy and sleep paralysis represent an intrusion of REM sleep atonia, whereas hallucinations represent an intrusion of dreams.

Narcolepsy-cataplexy is associated strongly with HLA DR2: 85-98% of Caucasian patients are DR2 positive. In other ethnic groups (particularly black populations), the DR2 allele is a poor marker for narcolepsy, whereas another allele, DQB1*0602, is associated with the disorder. DQB1*0602 positivity is associated more strongly with narcolepsy-cataplexy than with narcolepsy without cataplexy. In a recent clinical trial, 76% of DQB1*0602-positive patients with narcolepsy had cataplexy, while only 41% of those who were DQB1*0602 negative had narcolepsy with cataplexy. Homozygosity for this allele confers a higher relative risk of developing narcolepsy. DQB1*0602 is found in 24% of normal healthy subjects. HLA DQA1*0602 also has proven to be associated with increased susceptibility for developing narcolepsy. The association of HLA subtypes with narcolepsy raises the question of whether narcolepsy is an autoimmune disease.

HLA expression appears to be diffuse in the white matter of narcoleptic canines. Cytokines also have been implicated in inducing sleep. Between 12% and 35% of the population carry this gene, but only 0.02-0.18% have the disease. First-degree relatives have a 10- to 40-fold higher risk than the general population. Of first-degree relatives, 4.7% have excessive sleepiness. Monozygotic twin studies have only shown a 25-31% concordance for the disorder. This suggests that both genetic and environmental factors may play a role in the etiology of narcolepsy.

Autosomal recessive canine narcolepsy has been linked to canarc-1. This gene is highly homologous to the human immunoglobulin switch gene, but it appears to be located on a different chromosome. A development in the pathogenesis of narcolepsy is identification of an abnormality in the hypocretin (orexin) receptor 2 gene (Hcrtr2) in the canine model.[1] Hypocretins are neuropeptides that have been localized to the tuberis of the hypothalamus and appear to have an excitatory effect on this structure. Orexin knockout mice also have been engineered, resulting in a mouse model of narcolepsy.[2] The hypocretin system plays an important role in the pathophysiology of human narcolepsy as well. Low or absent levels of cerebrospinal fluid (CSF) hypocretin were demonstrated in patients with sporadic narcolepsy. This is especially the case for HLA DQB1*0602-positive patients suffering from narcolepsy with cataplexy. Postmortem pathological examination of the brains of people with narcolepsy with cataplexy have demonstrated dramatically reduced hypocretin neurons. Recent pathological studies of brains of patients with narcolepsy without cataplexy have demonstrated partial loss of hypocretin neurons in the hypothalamus.[3, 4]

More recently, investigators identified low CSF histamine levels in patients with hypocretindeficient narcolepsy. The levels of CSF histamine were lower in patients with narcolepsy with low CSF hypocretin levels compared to those with normal CSF hypocretin levels and in patients with idiopathic hypersomnia. Interestingly, the investigators did not find low CSF histamine levels in patients with hypersomnia secondary to obstructive sleep apnea syndrome. The authors concluded that perhaps CSF histamine serves as a biomarker reflecting the degree of hypersomnia of central origin.[5, 6] The close HLA association of narcolepsy has led to the theory that narcolepsy is caused by an autoimmune destruction of hypocretin cells in susceptible individuals. An interplay of genetics and environmental factors results in selective destruction of hypocretin neurons. Once enough hypocretin neurons are lost, the symptoms of narcolepsy emerge. Currently, the susceptibility model and selective loss of hypocretin neurons remains the most attractive theory. This theory has led to a recent report of intravenous immunoglobulin (IVIG) therapy in patients with acute narcolepsy with cataplexy. IVIG not only improved the patient's symptoms of excessive daytime sleepiness, but it also normalized the patient's CSF hypocretin levels. While only a case report, the intriguing findings support the autoimmune susceptibility model and warrant further research.[7]

Epidemiology
Frequency
United States The incidence of narcolepsy is 0.02-0.18% (which is comparable to that of multiple sclerosis). Prevalence of narcolepsy has been studied in the following populations:

North American blacks, 0.02% Northern Californians, 0.05% Southern California Caucasians, 0.07% First-degree relatives, 1-2% risk (10-40 times greater than general population)

International Prevalence of narcolepsy has been studied in the following populations:

Israeli Jews and Arabs, 0.002% Czech Caucasians, 0.02% Finnish Caucasians, 0.026% United Kingdom Caucasians, 0.04% French Caucasians, 0.05% Fujisawa Japanese teenagers, 0.16% Japanese general population, 0.18%

Mortality/Morbidity

Adult patients often perceive narcoleptic symptoms as embarrassing, and social isolation may result. o They may encounter interpersonal stress in relationships, sexual dysfunction, and difficulty working due to the disease itself or its treatment. o They may experience job impairment from sleep attacks, memory problems, cataplexy, interpersonal problems, and personality changes. These symptoms may lead coworkers to perceive narcoleptics as lazy, inattentive, and lacking motivation. o Patients with narcolepsy sometimes are falsely suspected of illegal drug use. Patients should inform employers concerning their stimulant medications, because they may test positive for amphetamines on screening preemployment drug tests. o In one study, 24% of narcoleptic patients had to quit working and 18% were terminated from their jobs because of their disease. o Left untreated, narcolepsy may be psychosocially devastating. Morbidity in narcoleptic children includes poor school performance, social impairment, ridicule from peers, and dysfunction in other activities of normal childhood development.

Race
See Frequency.

Sex
The male-to-female ratio is 1.64:1.

Age

Narcolepsy has been reported in children as young as 2 years. The age-of-onset distribution is bimodal. The highest peak occurs at 15 years, while a less pronounced peak occurs at 36 years.