NEUROLOGICAL PROGRESS
The Neurobiology, Diagnosis, and
Treatment of Narcolepsy
Thomas E. Scammell, MD
Narcolepsy is a common cause of chronic sleepiness distinguished by intrusions into wakefulness of physiological aspects
of rapid eye movement sleep such as cataplexy and hallucinations. Recent advances provide compelling evidence that
narcolepsy may be a neurodegenerative or autoimmune disorder resulting in a loss of hypothalamic neurons containing
the neuropeptide orexin (also known as hypocretin). Because orexin promotes wakefulness and inhibits rapid eye movement sleep, its absence may permit inappropriate transitions between wakefulness and sleep. These discoveries have
considerably improved our understanding of the neurobiology of sleep and should foster the development of rational
treatments for a variety of sleep disorders.
Ann Neurol 2003;53:154 –166
Narcolepsy was first described more than 100 years
ago, but until recently, the cause of this common sleep
disorder was largely unknown. Rare lesions of the posterior hypothalamus provided some hints, spurring von
Economo to predict that, “It is very probable though
not yet proved, that the narcolepsy of Gelineau, Westphal, and Redlich has its primary cause in a yet unknown disease of that region.”1 This review touches on
the compelling, recent evidence that narcolepsy is a disorder of neurons in the posterior hypothalamus that
produce the neuropeptide orexin.
Clinical Manifestations of Narcolepsy
Narcolepsy is characterized by chronic sleepiness and a
marked disorganization of sleep/wake behavior. It usually begins with excessive daytime sleepiness and unintentional naps in the teens and early twenties, although
symptoms can begin in young childhood or after the
age of 40 years.2,3 All narcoleptic subjects have chronic
sleepiness, but the intensity varies across the day and
between individuals. This sleepiness is most troublesome during periods of inactivity and is often improved temporarily by a brief nap. As a consequence of
sleepiness, patients may report inattention, poor memory, blurry vision, diplopia, and automatic behaviors
such as driving without awareness.
Researchers have debated whether this sleepiness is
caused by increased sleep drive or an impaired arousal
From the Department of Neurology, Beth Israel Deaconess Medical
Center, Boston, MA.
Received May 14, 2002, and in revised form Aug 5 and Oct 7.
Accepted for publication Oct 8, 2002.
154
© 2003 Wiley-Liss, Inc.
system. The latter appears more likely because narcoleptic subjects have normal amounts of sleep over 24
hours,4,5 but disrupted nighttime sleep is common in
narcolepsy and may partially contribute to this chronic
sleepiness. Narcoleptic patients with the greatest sleep
disturbance have more severe daytime sleepiness,6 but
even those with good nighttime sleep still have substantial daytime sleepiness. Thus, the quality of nighttime sleep is probably just a minor contributor to the
chronic sleepiness of most patients.6,7
Narcoleptic subjects often have abnormal manifestations of rapid eye movement (REM) sleep that intrude
into wakefulness, including cataplexy, hypnagogic hallucinations, and sleep paralysis. Hypnagogic hallucinations are dream-like, often frightening hallucinations
that typically occur with drowsiness or the onset of
sleep. These hallucinations are usually visual, with reports of seeing people or animals, but tactile, auditory,
or even vestibular hallucinations such as a sense of sudden falling are not uncommon. Sleep paralysis is profound weakness that occurs at the onset of sleep or on
awakening. This is probably an intrusion of REM sleep
paralysis into wakefulness, and can be associated with a
sensation of fear or suffocation. Hypnagogic hallucinations and sleep paralysis are not specific to narcolepsy
and can be seen with other conditions of increased
sleep pressure such as chronic sleep deprivation or ob-
Address correspondence to Dr Scammell, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Institutes of
Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115.
E-mail: [email protected]
structive sleep apnea, and occasionally in normal individuals.8,9
Cataplexy is sudden muscle weakness brought on by
strong emotions, particularly joking, laughter, or anger.2,10,11 Most likely, this also is an intrusion of REM
sleep atonia into wakefulness, but in contrast with
sleep paralysis, cataplexy occurs almost exclusively in
narcolepsy (see below). Sixty percent of narcoleptic
subjects develop cataplexy, usually around the onset of
sleepiness or within 3 to 5 years.2,3 Severe episodes
produce bilateral, generalized weakness sufficient to
cause a fall, although usually without injury. Other episodes may be partial, affecting only the face, voice, or
a limb. Consciousness is never impaired unless the patient subsequently falls asleep or begins having hypnagogic hallucinations. Episodes of cataplexy may begin
with clonic inhibitory movements leading to a fall, followed by a period of atonia and areflexia usually lasting
less than 2 minutes12 (a video of cataplexy is available at http://www-med.stanford.edu/school/Psychiatry/
narcolepsy/). Many normal individuals report slight
muscle weakness with intense emotion, and during
laughter the H-reflex is markedly reduced in controls
and in narcoleptic subjects.13,14 Cataplexy may result
from excessive activation of these same descending motor inhibitory pathways that are active during strong
emotions or REM sleep.15
Laboratory Findings
The history alone is often very suggestive of narcolepsy,
but a complete evaluation includes an overnight polysomnogram followed by a Multiple Sleep Latency Test
(MSLT).16 The polysomnogram helps evaluate sleep
quality and excludes other causes of sleepiness such as
obstructive sleep apnea, periodic limb movements of
sleep, or REM behavior disorder that are common in
narcolepsy and may warrant specific treatment.6,17,18
This overnight study is followed the next day by a
MSLT in which a patient is given four or five opportunities to nap every 2 hours.19 Normal subjects fall
asleep in approximately 10 to 15 minutes, but narcoleptic subjects often fall asleep in less than 5 minutes,
providing objective evidence of their sleep propensity.20,21 The naps of narcoleptic subjects often include
REM sleep,22 and the occurrence of these sleep-onset
REM periods (SOREMs) in two or more naps is
highly suggestive of narcolepsy. However, SOREMs
can be seen with other disorders that increase REM
sleep pressure such as sleep deprivation, sleep apnea,
or withdrawal from REM sleep–suppressing medications.23
Differential Diagnosis
In the absence of other neurological deficits, the combination of chronic sleepiness with cataplexy or more
than two SOREMs is almost always caused by narco-
lepsy. Sleepiness, cataplexy, and SOREMs can occur in
uncommon diseases such as Prader–Willi syndrome,
Niemann–Pick disease type C, and Norrie disease,24 –26
but all these individuals have mental retardation and
other obvious neurological deficits. In patients without
cataplexy, diagnosing narcolepsy can be difficult, and
one should consider other causes of sleepiness such as
sleep apnea, periodic limb movements of sleep, insufficient sleep, or the effects of sedating medications.21
Narcolepsy without cataplexy may overlap with idiopathic hypersomnia, a heterogeneous disorder of
chronic sleepiness.27 By definition, patients with idiopathic hypersomnia lack cataplexy and have less than
two SOREMs on the MSLT. Some of these individuals
have deep, excessively long periods of sleep, difficulty
waking from sleep, and long unrefreshing naps, but
many have symptoms similar to narcolepsy.8,27
Secondary Narcolepsy
On infrequent occasions, narcolepsy occurs as a consequence of a focal central nervous system lesion. These
lesions almost always involve the posterior hypothalamus, and tumors are the most common cause.28 –31
Strokes or arteriovenous malformations of the hypothalamus are rare but can cause narcolepsy.30,32,33 Hypothalamic sarcoidosis has caused narcolepsy in at least
two cases, although neither had cataplexy.29,30 Postencephalitic sleepiness resembling narcolepsy was common in the 1920s,34 –37 but we know of no similar
epidemic since then. A recent report described patients
with paraneoplastic anti–Ma antibodies who have hypothalamic inflammation, sleepiness, and cataplexy,
but polysomnograms were not reported.38 Melberg and
colleagues have described a Swedish family with autosomal dominant cerebellar ataxia, deafness, and narcolepsy.39 Affected members gradually develop chronic
sleepiness and cataplexy in young adulthood along with
enlargement of the third ventricle suggestive of hypothalamic atrophy.
Strokes or tumors of the brainstem can produce isolated cataplexy but rarely produce the full narcolepsy
syndrome.29,40 – 42 Most likely, these lesions affect descending pathways from the hypothalamus that regulate motor tone but not arousal.
The association of narcolepsy with head injury and
multiple sclerosis is more controversial. Most people
with hypersomnolence after closed head injury do not
have narcolepsy,43 but some patients with narcolepsy
report that their symptoms began after a head injury.
On several occasions, narcolepsy has occurred with
multiple sclerosis,30,44 – 47 but it is usually unclear
whether the narcolepsy was caused by a focal plaque.
Although these associations are rare, it remains possible
Scammell: The Neurobiology of Narcolepsy
155
that central nervous system inflammation or injury
could increase the risk of developing narcolepsy.
Epidemiology and Genetics of Idiopathic
Narcolepsy
Narcolepsy occurs in approximately 1 in 2,000 individuals, and most cases are sporadic.3,48 Genetic factors
play an important role because first-degree relatives
have a 40-fold increased risk of developing narcolepsy.49,50 Nevertheless, genetics are only a partial influence because even among monozygotic twins in
which one has narcolepsy, the second twin is affected
only approximately 25% of the time.50
The most robust of these genetic factors are specific
human leukocyte antigens (HLAs). Early studies using
low-resolution serological techniques found that narcolepsy is associated with two HLA class II antigens,
DR2 and DQ1. This association varies with ethnicity;
DR2 is found in 100% of Japanese, 90 to 95% of
whites, and 60% of African American narcoleptic subjects with cataplexy.49,51,52 High-resolution mapping
of these regions demonstrated the existence of numerous alleles, and DQB1*0602, a DQ1 subtype allele, is
strongly linked with narcolepsy. DQB1*0602 is found
in 88 to 98% of narcoleptic subjects with unambiguous cataplexy, whereas it is found in only 12% of white
American and 38% of African American controls.53,54
Testing for DQB1*0602 can be helpful, especially in
patients with questionable cataplexy, but this allele is
hardly predictive of narcolepsy because greater than
99% of DQB1*0602-positive individuals do not have
narcolepsy.
DQB1*0602 may influence the severity of narcolepsy. In part, this may be a direct effect on the expression of REM sleep because, even among normal
adults, DQB1*0602-positive subjects enter REM sleep
more quickly.55 DQB1*0602 also may affect the severity of narcolepsy because DQB1*0602-positive narcoleptic subjects have longer episodes of cataplexy, more
nocturnal sleep disruption, and more daytime sleepiness.2 Whether this more severe phenotype is caused
by more extensive neuropathology or altered regulation
of REM sleep remains unknown.
As in some other HLA-linked diseases, tumor necrosis factor-␣ (TNF-␣) has been implicated in narcolepsy. Polymorphisms in the TNF-␣ and TNF receptor
2 genes are associated with narcolepsy in Japan,56 –58
with especially high susceptibility when these alleles are
present in both genes.58 Plasma TNF-␣ levels are normal in narcolepsy,59 but these polymorphisms may still
affect TNF-␣ signaling, thus contributing to an inflammatory or degenerative process. Because TNF-␣
promotes sleep in laboratory animals,60 altered TNF
signaling also might directly influence the activity of
sleep/wake regulatory pathways in the brain.
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Neurobiological Control of Sleep and
Wakefulness
Substantial new evidence indicates that the neuropeptide orexin plays a critical role in the neurobiology of
narcolepsy. To understand this role, it is helpful to review some of the other pathways involved in the control of wakefulness, REM sleep, and non-REM sleep
(for detailed reviews, see Saper and colleagues61 and
Jones62). Normal wakefulness requires the coordinated
activity of several ascending arousal systems located in
the rostral brainstem and posterior hypothalamus (Fig
1). Magoun and colleagues demonstrated that brainstem transections below the midpons preserved wakefulness whereas those between the midbrain and pons
produced coma.63 These and other studies helped
identify a diverse collection of projections within the
brainstem tegmentum that innervate the thalamus and
hypothalamus. Some of these fibers originate in the
dorsal pons in cholinergic neurons of the laterodorsal
and pedunculopontine tegmental nuclei (LDT/PPT).
These neurons project to several thalamic nuclei including the reticular nucleus, a critical regulator of
thalamocortical transmission. During wakefulness, this
cholinergic input switches thalamic neurons from an
inherent oscillatory pattern seen during non-REM
sleep to a more active, “transmission mode,” facilitating
Fig 1. Major nuclei involved in the control of sleep and
wakefulness. Cell groups that promote wakefulness are found
between the pons and posterior hypothalamus. Cholinergic
(ACh) neurons in the laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT) innervate the thalamus, promoting
the flow of information to and from the cortex. Aminergic
neurons in the locus coeruleus (LC), raphe nuclei (Raphe),
and tuberomamillary nucleus (TMN) project diffusely throughout the forebrain increasing neuronal activity. These arousal
regions are inhibited by sleep-promoting neurons of the ventrolateral preoptic area (VLPO). NE ⫽ norepinephrine; 5HT ⫽
serotonin; HIST ⫽ histamine.
the flow of information to and from the cortex.64,65
During deep non-REM sleep, these cholinergic neurons are much less active, thus decreasing thalamic and
cortical activity. Attention and full cortical activation
depend on a separate population of cholinergic neurons
in the basal forebrain, but it is unclear whether these
cells are required for the production of wakefulness itself.66
Wake-promoting aminergic neurons in the rostral
brainstem also project through the pontine and midbrain tegmentum. These include noradrenergic neurons of the locus coeruleus (LC) and serotonergic neurons of the dorsal raphe (DR) nuclei. Histaminergic
neurons of the tuberomamillary nucleus (TMN) in the
ventral posterior hypothalamus also contribute to this
pathway. All three of these aminergic nuclei diffusely
innervate and activate much of the forebrain, firing
most rapidly during wakefulness, slower in non-REM
sleep, and then becoming silent in REM sleep.67– 69
Dopaminergic signaling also may promote wakefulness because dopamine antagonists can produce
sleep,70 and amphetamines primarily increase wakefulness by increasing the extracellular concentrations of
dopamine.71,72 The source of this dopaminergic signaling is unclear because the mean firing rates of neurons
in the substantia nigra and ventral tegmental area do
not vary with behavioral state.73,74 However, lesions of
dopaminergic cells in the ventral midbrain can reduce
wakefulness,75–77 and one population of dopaminergic
neurons in the ventral periaqueductal gray is active
during wakefulness,77 perhaps serving as a critical site
for dopaminergic effects on wakefulness.
These cholinergic and aminergic regions interact to
produce REM sleep.78 A distinct population of cholinergic neurons in the LDT/PPT activates the thalamus
during REM sleep, producing cortical desynchrony.
These REM-active cells also generate profound atonia
through a polysynaptic, descending pathway that uses
glycine to hyperpolarize ␣ motor neurons. Noradrenergic and serotonergic afferents from the LC and DR
inhibit the REM sleep–producing neurons during
wakefulness and non-REM sleep,79,80 but during REM
sleep, the LC and DR become inactive, thus disinhibiting the REM-generating neurons. This aminergic inhibition of REM sleep is commonly encountered in the
sleep laboratory; patients taking selective serotonin reuptake inhibitors usually have a marked decrease in
REM sleep.
Non-REM sleep is produced by neurons in the preoptic area and brainstem. The dorsal vagal complex,
raphe nuclei, and ventral midbrain contain some nonREM–generating cells,81,82 but the ventrolateral preoptic area (VLPO) is the best characterized sleepproducing region. VLPO neurons are active during
non-REM sleep83,84 and are necessary for sleep because
lesions of the VLPO produce marked insomnia.85
These GABA-containing neurons innervate and probably inhibit neurons in the TMN, LC, and DR.86 In
turn, VLPO neurons are inhibited by amines,87 thus
creating a reciprocally inhibitory circuit in which wakeand sleep-promoting regions inhibit one another.61
This type of mutually inhibitory circuit should demonstrate bistability, being most stable during full wakefulness or sleep. However, these elements alone could
produce a system with low thresholds to transition between behavioral states. This may be the fundamental
problem in narcolepsy in which irresistible sleep, intrusions of REM-like phenomena, and nocturnal awakenings result from abnormally low thresholds to transition between wakefulness, REM, and non-REM sleep.
The importance of these thresholds is evident during
periods of prolonged wakefulness when an individual
must remain awake despite a gradually increasing sleep
drive. An additional stabilizing influence is needed to
help maintain wakefulness and other states.
Neurobiology of Orexin/Hypocretin
Just a few years ago, two research groups simultaneously discovered a new neuropeptide that may provide this stabilizing influence (for review, see Willie
and colleagues88). One group named this peptide
orexin for its presumed role in appetite whereas another group named it hypocretin for its possible resemblance to secretin.89,90 This peptide exists in two
forms, orexin-A and orexin-B, which are derived from
the same precursor by proteolytic processing and are
colocalized in the same neurons. Orexin-containing
neurons are found only in the posterior and lateral hypothalamus,89 –91 but they project widely throughout
the central nervous system, innervating the aminergic
and cholinergic regions that promote wakefulness92,93
(Fig 2). These targets contain high levels of the two
orexin receptors, ox1 and ox2 (also known as
hypocretin-1 and -2 receptors).94 The ox1 and ox2 receptors are coupled to G proteins, and ligand binding
generally has excitatory effects.
Recent animal studies provide considerable evidence
that orexin promotes wakefulness and inhibits REM
sleep. The orexin neurons are active during wakefulness
as indicated by the expression of Fos,95 and extracellular concentrations of orexin are higher during periods
of wakefulness.96 Electrophysiological recordings from
the orexin neuron region identified many wake-active
neurons, with particularly high firing rates when an animal is physically active.97 In vitro, orexin excites LC
and other aminergic neurons.98 –102 In vivo, injections
of orexin into the lateral ventricles or near specific
arousal regions such as the LC increase wakefulness
and markedly suppress REM sleep.98,103 Currently, it
is only partially known which regions are necessary for
the wake-promoting effects of orexin, but the histaminergic neurons of the TMN may play an essential role.
Scammell: The Neurobiology of Narcolepsy
157
Fig 2. (A) Orexin-containing neurons of the posterior and
lateral hypothalamus heavily innervate and excite aminergic
regions that promote wakefulness such as the tuberomamillary
nucleus (TMN), raphe, and locus coeruleus (LC). These aminergic regions also inhibit rapid eye movement (REM)–producing neurons of the LDT/PPT. Decreases in orexin and amine
signaling allow the occurrence of REM sleep, with thalamic
activation and dreaming, and paralysis through intense inhibition of ␣ motor neurons. (B) Innervation of the human locus
coeruleus by orexin-containing fibers. Numerous black, orexinimmunoreactive boutons innervate a proximal dendrite of a
brown, tyrosine hydroxylase–immunoreactive locus coeruleus
neuron. Scale bar ⫽ 50␮m.
In normal mice, infusion of orexin near the TMN increases wakefulness, but orexin does not increase wakefulness in mice lacking the histamine H1 receptor.104
In addition, narcoleptic dogs have low cortical concentrations of histamine,105 and a histamine antagonist
partially blocks the wake-promoting effects of orexin.100
Suppression of REM sleep by orexin also may occur
through activation of these aminergic areas that then
inhibit the REM-producing neurons of the LDT/PPT.
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Impaired Orexin Signaling Causes Narcolepsy
Four years ago, two laboratories simultaneously discovered that the orexin system plays a critical role in narcolepsy. After a extensive linkage analysis of dogs with
autosomal recessive narcolepsy, Lin and colleagues
found exon-skipping mutations in the ox2 receptor
gene that probably result in a nonfunctional receptor.106 Meanwhile, Yanagisawa’s group found that
orexin knockout mice or mice lacking the orexin receptors have a phenotype strongly resembling human
narcolepsy, with brief periods of wakefulness, frequent
transitions into REM sleep, and behavior resembling
cataplexy.93,107,108 Mice lacking the ox2 receptor have
a more severe phenotype than those lacking the ox1
receptor, providing additional evidence that the ox2 receptor may play a more prominent role in the control
of sleep/wake behavior.
These studies demonstrated that congenitally impaired orexin signaling can produce symptoms of narcolepsy, but human narcolepsy is usually an acquired
disease. To create a mouse model similar to human
narcolepsy, Hara and colleagues produced mice in
which the orexin promoter drives the expression of
ataxin-3, a truncated Machado–Joseph disease gene
product that induces apoptosis in neurons.109 These
orexin/ataxin-3 mice have a normal number of orexin
neurons at birth, but as they approach adulthood, the
orexin neurons degenerate. This acquired loss of orexin
neurons roughly parallels the typical timing of human
narcolepsy, and, just as in humans, these mice cannot
remain awake for long periods, rapidly enter REM
sleep, and have behavioral arrests resembling cataplexy.
Mignot, Nishino, and colleagues rapidly confirmed
that most narcoleptic subjects with cataplexy have impaired orexin signaling.110 Approximately 90% of narcoleptic subjects with cataplexy have no detectable
orexin-A in their cerebrospinal fluid (CSF) even within
a few months of symptom onset.110 –115 In contrast,
nearly all narcoleptic subjects without cataplexy have
normal CSF concentrations of orexin.113,115 Undetectably low levels of orexin are not seen in other neurological diseases, except for some uncommon cases
of severe Guillain–Barre´ syndrome or myxedema
coma.111,115 Orexin levels may be low though not absent in some cases of secondary narcolepsy probably
because of partial lesions of the orexin neurons and
their projections to arousal regions.31,32,115,116 In some
cases of familial narcolepsy, orexin levels are normal in
younger patients but low in older patients, suggesting a
gradual failure to produce orexin.115
Neuropathology of Narcolepsy
Two landmark studies have shown that this marked
decrease in CSF orexin most likely results from a loss
of the orexin-producing neurons. Using in situ hybridization, Peyron and colleagues found no detectable
prepro-orexin mRNA in the hypothalamus of narcoleptic subjects with cataplexy.117 Thannickal and colleagues found a 90% reduction in the number of
orexin immunoreactive neurons.118 This elimination of
orexin-producing neurons is highly selective because
both studies showed no reduction in the number of
adjacent neurons containing melanin-concentrating
hormone. These two studies included a total of five
brains from narcoleptic subjects with cataplexy and one
without, and the case without cataplexy had the greatest number of remaining orexin neurons. Further studies may determine whether narcoleptic subjects with
cataplexy simply have a greater loss of orexin neurons
than those without cataplexy.
The process that causes this loss of orexin is unknown. In general, narcoleptic subjects lack mutations
in the genes coding for orexin or its receptors,117,119,120
although one individual with severe symptoms in infancy was found to have a mutation in the preproorexin gene that probably produces inappropriate trafficking of the peptide and possible degeneration of the
orexin neurons.117 Alternatively, impaired transcription
of the prepro-orexin gene or anti-orexin antibodies
could produce a loss of orexin without a loss of the
orexin neurons.
Many researchers have proposed that a selective loss
of the orexin neurons could be caused by an autoimmune or neurodegenerative process, but, thus far, there
is little evidence to support these ideas. Despite the association of narcolepsy with specific HLA and TNF
alleles, no changes in immune function have been
identified.59,117,121 Neuroimaging studies of idiopathic
narcolepsy generally have found no abnormalities.122–125
The CSF of narcoleptic subjects lacks increased protein
or oligoclonal bands, and their serum lacks autoantibodies including any against orexin126 –128 (E. Mignot,
personal communication). Microglia and TNF-␣
mRNA are not increased in the hypothalami of narcoleptic subjects examined decades after the onset of
symptoms,117 suggesting that there is no ongoing inflammation. However, the number of astrocytes may
be moderately increased in the orexin neuron region118,129 (but see Peyron and colleagues117). If supported by additional studies, this gliosis would be
consistent with a neurodegenerative or inflammatory
process.
Timing and Coordination of Sleep/Wake
Behavior with Other Hypothalamic Functions
Unstable sleep/wake behavior is the hallmark of narcolepsy, but narcoleptic subjects also have poor circadian
timing of sleep and wakefulness.5,130 In normal individuals, wakefulness is strongly promoted through
much of the day, and REM sleep occurs mainly between 2 and 8 AM.131 Narcoleptic subjects have difficulty maintaining wakefulness, and their naps often in-
clude bouts of REM sleep, regardless of the time of
day.130,132 Most likely, this is not caused by a simple
disinhibition of sleep because narcoleptic subjects have
normal amounts of sleep over 24 hours.4,5,130 In addition, this marked attenuation of the normal sleep/wake
rhythm is not caused by an underlying defect in the
generation of circadian rhythms because the rhythms of
body temperature, cortisol, and melatonin are essentially normal.133–135
The orexin neurons may play a central role in this
timing of sleep and wakefulness. The suprachiasmatic
nucleus is the main generator of circadian rhythms.136
This nucleus sends timing information to many areas,
but lesions dorsal and posterior to the suprachiasmatic
nucleus can disrupt the timing of sleep/wake behavior
without affecting other rhythms.137,138 This timing information then may be relayed to the orexin neuron
region. Lesions of this area also upset the timing of
sleep,139 and orexin knockout mice show a similar lack
of rhythmicity, especially in the timing of REM
sleep.93 By promoting wakefulness and inhibiting
REM sleep during the day, orexin may fundamentally
influence the circadian timing of sleep/wake behavior.
The orexin neurons may do more than just regulate
sleep and wakefulness. Orexin also increases feeding,
sympathetic tone, and motor activity.109,140 –142 The
importance of these effects becomes apparent in narcoleptic humans and mice. Around the time that their
orexin neurons are lost, orexin/ataxin-3 mice become
obese despite eating less than normal mice.109 Narcoleptic subjects with cataplexy are approximately 10 to
15% overweight,2,143–145 even though they may eat
less than average.146 Thus, this mild obesity may be
caused by a decrease in metabolic rate. Considered together, these findings suggest that the orexin neurons
may help ensure that one is alert, hungry, and metabolically active at the correct time of day.
Current Approaches to Treating Narcolepsy
Narcolepsy is a chronic disorder, requiring long-term
treatment. Symptoms sometimes worsen during the
first few years, but then generally remain stable, although cataplexy may partially improve with age.147
For most patients with narcolepsy, chronic sleepiness is
the most disabling symptom. Two 15-minute daytime
naps can temporarily reduce sleepiness, especially in patients with more severe sleepiness.148,149 However,
naps are rarely adequate as the sole therapy, and most
patients require treatment with a wake-promoting
drug. None of these drugs completely eliminates sleepiness, but these medications usually reduce sleepiness
enough for substantial improvements in performance
and quality of life.
Scammell: The Neurobiology of Narcolepsy
159
Pharmacological Treatment of Chronic Sleepiness
Traditionally, daytime sleepiness has been treated with
amphetamine-like drugs including methylphenidate,
dextroamphetamine, or methamphetamine, with the
latter two possibly being the most potent150 (Table 1).
Although it is moderately effective, pemoline produces
hepatic failure on rare occasions and should be used
only when other drugs have failed. The wakepromoting activity of these drugs is proportionate to
their ability to inhibit the reuptake of amines by the
dopamine transporter.71,72,151 By blocking this transporter, these drugs increase the release and inhibit the
reuptake of dopamine, norepinephrine, and serotonin,
resulting in higher synaptic concentrations. This increased aminergic signaling may promote wakefulness
through direct effects on the cortex or via activation of
subcortical pathways. Side effects include nervousness,
headaches, insomnia, loss of appetite, and palpitations,
and all have potential for abuse.150 After a morning
dose, many patients may experience some sleepiness in
the afternoon or evening, and a combination of
sustained-release methylphenidate or dextroamphetamine in the morning with additional short acting
drugs in the afternoon is often effective.
Modafinil is a new, wake-promoting drug that effectively treats sleepiness with a minimum of side effects.
Modafinil reduces subjective sleepiness and clearly improves the ability of narcoleptic subjects to stay awake,
although their latency to sleep is still shorter than normal.152,153 Unlike high doses of amphetamines,
modafinil does not reduce cataplexy, and an additional
anticataplexy medication may be needed. Modafinil has
a remarkably low incidence of side effects. Headache
can occur in 13%, and nervousness, nausea, or dry
mouth occurs in less than 10%,154,155 with fewer side
effects if treatment is begun with a low dose.153 In
contrast with amphetamines, typical doses of modafinil
do not produce hypertension, arrhythmias, restlessness,
anorexia, or disruption of nighttime sleep.153 Tolerance or difficulties during withdrawal are very rare,153
and modafinil appears to have little potential for addiction.156,157 Some patients find that modafinil is not
as effective as amphetamines, but the low incidence of
side effects and low potential for abuse have made it a
very popular treatment.
The mechanism through which modafinil promotes
wakefulness is only partially understood. Early work
suggested that modafinil might act through ␣-adrenergic
receptors, but modafinil does not bind to ␣ receptors,
or other receptors or reuptake site for noradrenaline,
GABA, benzodiazepines, or adenosine.158 Modafinil can
reduce the extracellular concentrations of GABA,159,160
and this decrease in GABA may disinhibit specific wakepromoting systems such as the tuberomamillary neurons.
Compelling, recent evidence suggests that modafinil may
increase dopaminergic signaling. All brain regions activated by modafinil receive dopaminergic innervation,161
and modafinil binds weakly to the dopamine reuptake
transporter.158 In mice lacking the dopamine transporter, modafinil fails to increase wakefulness.72
Whether this dopaminergic mechanism is the entire explanation awaits further characterization of new derivatives of modafinil that do not bind to the dopamine
transporter.162
Table 1. Drugs Commonly Used in the Treatment of Narcolepsy
Drug
Dosage
Excessive daytime sleepiness
Methylphenidate
10–30mg bid, or 20mg SR qam with
10–20mg qpm
Dextroamphetamine
5–30mg bid, or 10mg SR qam with
10–20mg qpm
Methamphetamine
5–20mg bid
Modafinil
100–400mg qam, or 200mg bid
Cataplexya
Venlafaxine
75–150mg bid, or 75–150 mg XR qam
Fluoxetine
20–80mg qam
Clomipramine
10–150mg qam or qhs
Protriptyline
5–60mg qam or qhs
␥-Hydroxybutyrate
1.5–4.5gm qhs and 2–3 hours later
Disrupted nighttime sleepb
Zolpidem
␥-Hydroxybutyrate
5–10mg qhs
1.5–4.5gm qhs and 2–4 hours later
a
Side Effects and Comments
Irritability, headaches, insomnia
Same, reduced appetite
Same
Few side effects, headache, nervousness
Few side effects, nausea
Same, dry mouth
Dry mouth, sweating
Same, anxiety, disturbed nighttime sleep
Morning sedation, nausea, dizziness, urinary
incontinence
Few side effects, daytime sleepiness, dizziness
Sedation, nausea, dizziness, urinary incontinence
Anti-cataplexy medications are also useful for problematic sleep paralysis or hypnagogic hallucinations.
Some sleep disruption in narcolepsy may be caused by additional sleep disorders that require specific treatment (for example, obstructive sleep
apnea or periodic limb movements of sleep).
bid ⫽ twice a day; qam ⫽ every morning; qpm ⫽ every evening; qhs ⫽ every bedtime.
b
160
Annals of Neurology
Vol 53
No 2
February 2003
Pharmacological Treatment of Cataplexy
Most patients with narcolepsy do not require treatment
of their cataplexy because it is mild or infrequent, but
in some patients, cataplexy occurs several times each
day, producing embarrassment or even injury. Nearly
all anticataplexy medications are potent inhibitors of
REM sleep, a phenomenon consistent with the hypothesis that cataplexy is the inappropriate occurrence of
REM sleep paralysis. Noradrenaline and serotonin inhibit REM-producing neurons in the dorsal pons, and
cataplexy is substantially reduced by drugs that increase
aminergic transmission, especially those that increase
noradrenergic signaling by blocking the norepinephrine
transporter.71,163,164 The norepinephrine/serotonin reuptake inhibitor venlafaxine has become the first
choice of many clinicians because it is very effective
and well tolerated. By blocking the reuptake of amines,
tricyclics are highly effective, but their use often is limited by their anticholinergic side effects. Abrupt withdrawal from these drugs can markedly worsen cataplexy, producing status cataplecticus.
␥-Hydroxybutyrate (GHB, sodium oxybate) can improve cataplexy and daytime sleepiness. GHB is a recently approved, sedating drug with a short half-life
that is given at bedtime with another dose part way
through the night. GHB occurs naturally in the brain
as a metabolite of GABA and binds strongly to GHBspecific receptors with weak binding to GABA-B receptors, although how it influences sleep and the symptoms of narcolepsy is unknown.165–167 In uncontrolled
studies, patients report clear reductions in the frequency and severity of cataplexy, and many feel more
alert during the day.168 Some hypothesize that these
improvements may be because of better nighttime sleep
because GHB increases sleep continuity, non-REM
sleep, and possibly REM sleep.169 In a small, early
study, GHB at bedtime reduced subjective daytime
sleepiness and the number of hypnagogic hallucinations and daytime naps.170 In a recent, larger study,
136 patients took 3 to 9gm GHB, with half of the
dose at bedtime and the remainder 2.5 to 4 hours
later.171 After 1 month of treatment the highest dose
substantially reduced the frequency of cataplexy attacks
and produced a moderate reduction in subjective sleepiness but lower doses were less effective. This high dose
also produced nausea and dizziness in one third of the
subjects, and 14% had urinary incontinence. Food and
Drug Administration approval of GHB was difficult
because of concerns about its safety and potential for
abuse. GHB and related drugs can produce vomiting,
incontinence, coma, respiratory depression, and
death,172 and withdrawal can cause anxiety, insomnia,
and delirium.172,173 GHB has achieved notoriety as a
date-rape drug that is water soluble and tasteless, producing sedation, disinhibition, and amnesia. Although
the clinical trials suggest clear benefits of GHB, the
potential for harmful side effects and abuse warrants
cautious use.
Future Directions
These recent advances in narcolepsy research have
spurred a new look at the nosology of narcolepsy. As
emphasized by Matsuki, Honda,175 and others174 narcolepsy with cataplexy may be a somewhat different
disease from narcolepsy without cataplexy or the related syndrome of idiopathic hypersomnia (Table 2).
Table 2. Features of Narcolepsy Syndromes
Feature
Nighttime sleep
Stage 1 (%)
Awakenings (n)
Sleep efficiency (%)
Daytime sleepiness
Daily nap (%)
Accidents due to sleepiness (%)
Hypnagogic hallucinations (%)
Sleep paralysis (%)
MSLT
Average sleep latency (min)
Sleep-onset REM periods (n)
DQB1*0602 (%)
CSF orexin
Neuropathology
Body mass index
Narcolepsy with Cataplexy
Narcolepsy without Cataplexy
Idiopathic Hypersomnia
24
13.5
81
16
8.5
91
ND
20
93
85
48
70–86
50–70
45
20
15–60
25–60
10
ND
40
40–50
2.7
3–3.7
90–100
Undetectable in 90%
Markedly reduced number
of orexin neurons
3–5
2–3.3
40–60
4.3
0.2
52
Normal
Unknown
Increased 5–15%
Normal
Possibly a partial loss of
orexin neurons or injury to
critical orexin pathways
Normal
Normal
6,8,112,113,115,176,177
Data are from articles cited in the text.
ND ⫽ not determined; MSLT ⫽ Multiple Sleep Latency Test; REM ⫽ rapid eye movement; CSF ⫽ cerebrospinal fluid.
Scammell: The Neurobiology of Narcolepsy
161
In contrast with these latter groups, nearly all narcoleptic subjects with cataplexy have very low CSF orexin
concentrations and HLA DQB1*0602112,113,115,176
Narcoleptic subjects with cataplexy also are sleepier,
have more SOREMs on the MSLT, and generally have
worse nighttime sleep.6,177
Do narcoleptic subjects without cataplexy simply
have milder or more focal neuropathology? Narcoleptic
subjects without cataplexy may have sufficient orexin
production to maintain normal CSF levels and stave
off cataplexy, but the loss may still be great enough to
produce sleepiness. Alternatively, patients with narcolepsy and normal CSF orexin concentrations may have
sleepiness from a loss of orexin projections to essential
wake-promoting regions, but other projections could
be intact, resulting in normal CSF levels.178
Perhaps narcolepsy is a disease similar to diabetes,
with a severe phenotype due to ligand deficiency and a
less severe phenotype without cataplexy when the ligand is present but somehow less effective. When
treated with orexin, narcoleptic subjects with cataplexy
might have a complete improvement in symptoms, but
narcoleptic subjects without cataplexy might have a
blunted or absent response because of abnormalities in
the orexin receptors or their signaling pathways.
With the discovery that orexin deficiency causes narcolepsy with cataplexy researchers are now seeking to
identify the cause. Might the orexin neurons be present
but failing to produce orexin? Is there a focal hypothalamic encephalitis at the onset of narcolepsy? Do
orexin neurons express a particular antigen that makes
them susceptible to an autoimmune attack? If narcoleptic subjects can be identified just as symptoms are
developing, would immune suppression alter the course
of disease? These and other questions will undoubtedly
be the focus of research in the years to come.
This work was supported by grants from the NIH (MH62589,
MH01507).
We thank C. Saper, J. Matheson, J. Mullington, and B. Murray for
thoughtful comments on this manuscript, and M. Papadopoulou for
excellent technical assistance.
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