SECTION 5 - SLEEP DISORDERS

Narcolepsy and Other Hypersomnias

Background

Narcolepsy is a disabling neurological disorder characterized by sleepiness and symptoms of abnormal REM sleep such as sleep paralysis, hypnagogic hallucination, cataplexy and, frequently, disturbed nocturnal sleep. Narcolepsy is most commonly diagnosed using nocturnal polysomnography and the Multiple Sleep Latency Test (MSLT). In this test, sleep latencies and the occurrence of REM sleep are evaluated during 4 to 5 naps, scheduled every 2 hours during the daytime. Narcoleptic patients typically display a short mean sleep latency indicative of daytime sleepiness and more than 2 REM episodes in the MSLT.

Narcolepsy-cataplexy affects 1 in 2,000 people and is the 4th most common condition treated in sleep disorder clinics. The exact prevalence of essential hypersomnia and of narcolepsy without cataplexy, two related disorders characterized by sleepiness and abnormal MSLT results, is unknown. These two disabling disorders are at least of similar frequency as narcolepsy with cataplexy, but few research data are available0.

In humans, narcolepsy-cataplexy is genetically complex, Human Leukocyte Antigen (HLA) associated, and environmentally influenced. Fine mapping studies in the HLA class II region indicate a primary role for HLA-DQ. Multiplex families are rare but relative risk in first-degree relatives is 20-40 fold higher than in the general population for narcolepsy-cataplexy. HLA susceptibility genes play a minor role in overall genetic susceptibility. Human narcolepsy is currently treated symptomatically with dopaminergic amphetamine-like stimulants, gammahydroxybutyrate and monoaminergic antidepressant therapy. Behavioral and social interventions are also helpful.

The study of narcolepsy is facilitated by the existence of two animal models, canine and murine narcolepsy. A 10-year positional cloning study identified canarc-1 as the hypocretin (orexin) receptor-2 gene (Hcrtr2). This was followed by the discovery that preprohypocretin knockout mice also have narcolepsy and by the discovery that human narcolepsy is associated with decreased hypocretin transmission. Hypocretin-1 and 2 (orexin-1 and 2) are excitatory neuropeptides encoded by a single gene selectively expressed in a small subset of lateral hypothalamic neurons. Hypocretin neurons project widely in the central nervous system and have especially dense monoaminergic cell group projections. Two hypocretin receptors (Hcrtr1 and Hcrtr2) with differential neuroanatomical distribution are currently known.

In humans, narcolepsy cases are not associated with hypocretin ligand or receptor mutations but, rather, with undetectable cerebral spinal fluid (CSF) hypocretin-1 levels. Only a single hypocretin gene mutation in an unusual patient with a very early onset (6 month of age) disorder and severe symptomatology has been reported to date. In sporadic cases, neuropathological studies indicate a dramatic loss of both hypocretin-1 and hypocretin-2 in the brain and a disappearance of hypocretin-containing cells in the hypothalamus. Together with the observation that hypocretin-1 is potently wake-promoting in vivo, these results demonstrate that narcolepsy-cataplexy is due to a hypocretin deficiency. HLA association in humans suggests the possibility of an autoimmune disorder directed against hypocretin-containing cells in the lateral hypothalamus.

The cause(s) of narcolepsy without cataplexy and of other hypersomnias of central origin (e.g., idiopathic hypersomnia) are currently unknown.

Progress In The Last 5 Years

- Our understanding of narcolepsy-cataplexy has been revolutionized in the last 5 years. The discovery in 1999 that hypocretin gene alterations produce narcolepsy in canines and mice rapidly led to the finding that human narcolepsy is associated with decreased hypocretin transmission.

- Novel pharmaceutical treatments have been developed including modafinil, a wake promoting compound, and Gammahydroxybutyric acid, a sedative used for treating disturbed nocturnal sleep and cataplexy. These are useful therapeutic treatments but only symptomatically treat the condition.

Research Recommendations

- Conduct basic research on hypocretins in animal models. Even though recent findings have stimulated some basic research studies on hypocretins, the exact role of this system in the regulation of normal sleep and other behaviors is still unknown.

- Study the epidemiology and pathophysiology of narcolepsy without cataplexy, essential hypersomnia, and periodic hypersomnia. Our understanding of narcolepsy has been largely limited to cases with cataplexy, and little information is available on these other conditions. With the increased availability of wake-promoting medications such as modafinil, there is an urgent need to evaluate the prevalence, treatment strategies and etiologies of these related conditions.

- The field is also ready for direct clinical applications. Measuring CSF hypocretin-1 has been shown to be a reliable diagnostic procedure for narcolepsy-cataplexy in limited case series. Efforts should be made to further validate and distribute this new diagnostic procedure. Additionally, efforts should be made to design alternate diagnostic procedures based on the knowledge that narcolepsy is caused by hypocretin abnormalities. These may involve (but are not limited to) measuring hypocretin levels in blood or imaging studies of the hypothalamus.

- Study the effectiveness of replacing hypocretins or hypocretin-producing cells. Since animal models are available to test this hypothesis and design new treatments, studies should be conducted in both in animals and humans. Hypocretin peptide supplementation, the development of hypocretin receptor agonists, cell transplantation, and gene therapy are all possible treatments.

- Studies are needed to identify the causes of destruction of hypocretin containing cells in human narcolepsy. Studies are needed to define the immune connection in narcolepsy and/or to discover why narcolepsy is HLA-associated. In this regard, the study of cases of recent onset (most likely still at the stage of active destruction) may be critical.

- Studies are needed to find other narcolepsy genes and to identify rare cases of narcolepsy without known hypocretin abnormalities in order to better understand these pathologies.

- Studies of new medications such as modafinil and Gammahydroxybutyric acid are needed to determine their mode of action. Efforts to study the mode of action of current narcolepsy treatments could lead to improving current treatments. Additionally, there is a need for studies on the effect of drugs used in other areas of neurology and psychiatry as novel indications in narcolepsy (e.g. stimulants for daytime sleepiness, antidepressants for cataplexy, sedative agents for disturbed nocturnal sleep).

- Since narcolepsy typically starts in childhood or early adolescence, management of these patients is particularly challenging and clinical protocols need to be developed. Studying narcolepsy as closely as possible to the onset, generally during childhood, may also provide unique clues to the cause of the disorder.

- Commonly used therapies in narcolepsy include napping and other behavioral treatments, but data establishing efficacy are sparse. More research in this area is needed.

- Studies in twins indicate that not only genetic background but also environmental factors are involved in the pathophysiology of narcolepsy. Studies are needed to characterize these factors and determine the potential effectiveness of prevention strategies.