5 - SLEEP DISORDERS
Narcolepsy and Other Hypersomnias
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.
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
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
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.
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
- 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
- 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.