(Doi 10.1038 - s41582-019-0226-9) PDF

ReviewS
Narcolepsy — clinical spectrum,

aetiopathophysiology, diagnosis
and treatment
Claudio L. A. Bassetti 1*, Antoine Adamantidis1, Denis Burdakov 2,3,4, Fang Han5,
Steffen Gay6, Ulf Kallweit1,7, Ramin Khatami1,8, Frits Koning 9, Brigitte R. Kornum10,
Gert Jan Lammers11,12, Roland S. Liblau13, Pierre H. Luppi14,15, Geert Mayer16,
Thomas Pollmächer17, Takeshi Sakurai18, Federica Sallusto19,20, Thomas E. Scammell21,
Mehdi Tafti 22,23 and Yves Dauvilliers24,25,26
Abstract | Narcolepsy is a rare brain disorder that reflects a selective loss or dysfunction of orexin
(also known as hypocretin) neurons of the lateral hypothalamus. Narcolepsy type 1 (NT1) is
characterized by excessive daytime sleepiness and cataplexy, accompanied by sleep–wake
symptoms, such as hallucinations, sleep paralysis and disturbed sleep. Diagnosis is based on these
clinical features and supported by biomarkers: evidence of rapid eye movement sleep periods
soon after sleep onset; cerebrospinal fluid orexin deficiency ; and positivity for HL A-DQB1*06:02.
Symptomatic treatment with stimulant and anticataplectic drugs is usually efficacious. This
Review focuses on our current understanding of how genetic, environmental and immune-related
factors contribute to a prominent (but not isolated) orexin signalling deficiency in patients with
NT1. Data supporting the view of NT1 as a hypothalamic disorder affecting not only sleep–
wake but also motor, psychiatric, emotional, cognitive, metabolic and autonomic functions are
presented, along with uncertainties concerning the ‘narcoleptic borderland’, including narcolepsy
type 2 (NT2). The limitations of current diagnostic criteria for narcolepsy are discussed, and a
possible new classification system incorporating the borderland conditions is presented. Finally,
advances and obstacles in the symptomatic and causal treatment of narcolepsy are reviewed.
Although narcolepsy had previously been described in narcolepsy type 2 (NT2) — remains poorly understood.
the literature1, three publications by Westphal, Gélinau Although the existence of mild and incomplete pres
and Fischer in the late 19th century (1877–1880)2–4 were entations of narcolepsy (the ‘narcoleptic borderland’) is
the first to clearly identify the two main manifestations generally accepted, their inclusion within the diagnosis
of narcolepsy: an irresistible or imperative excessive was (and still remains) controversial12,13.
daytime sleepiness (EDS) and brief episodes of loss In the past 20 years, considerable advances have been
of muscle tone or control triggered by emotions and made in our understanding of the clinical manifesta
accompanied by a preserved state of consciousness (var tions, aetiology, pathophysiology, diagnosis and man
iously termed astasia, catalepsy and cataplexy)5. Later agement of narcolepsy. Several biomarkers of narcolepsy
researchers confirmed these observations6,7, but nar have also been established, including polysomnography
colepsy was generally considered to be a rare (by 1924, findings of sleep-onset rapid eye movement (REM) sleep
only 35 patients had been reported) and nonspecific periods (SOREMPs)14, positivity for HLA-DQB1*06:02
manifestation of other diseases8. By 1960, however, the (refs15,16) and orexin deficiency in cerebrospinal fluid
main clinical features of narcolepsy had been precisely (CSF)17. These biomarkers have improved diagnostic
described in large case series that definitively established certainty and opened new avenues of research18. The
the specificity of the disease8–11. purpose of this Review is to provide an update on these
Classic or typical narcolepsy, now termed narcolepsy advances, discuss the unsolved challenges and present
*e-mail: claudio.bassetti@
insel.ch type 1 (NT1), is characterized by the presence of cata perspectives for the future.
https://doi.org/10.1038/ plexy and orexin deficiency. By contrast, narcolepsy with The material included in this Review summarizes
s41582-019-0226-9 out either cataplexy or orexin deficiency — now termed the results of an expert meeting (Think Tank) organized
Nature Reviews | Neurology

Reviews
Key points the narcoleptic borderland (particularly NT2, discussed

below), the exact incidence of narcolepsy remains
• Narcolepsy is a rare and often disabling hypothalamic disorder that presents with unknown. The highest prevalence of narcolepsy occurs
sleep–wake dysregulation (excessive daytime sleepiness (EDS), cataplexy, in Japanese populations (1,600 per million individu
hallucinations, sleep paralysis and disturbed sleep) and motor, cognitive, psychiatric, als), although this estimate comes from studies with
metabolic and autonomic disturbances.
uncertain methodology. The lowest prevalence occurs
• Narcolepsy arises from the interaction of genetic and environmental factors, which lead in Jewish and Arabic populations (2–40 per million indi
to an immune-mediated selective loss or dysfunction of orexin neurons in the lateral
viduals)19,23,24. In some series, narcolepsy affected more
hypothalamus.
male than female individuals24. Genetic and environ
• Patients with narcolepsy type 1 have cataplexy and little or no orexin in cerebrospinal
mental factors probably contribute to these differences.
fluid; narcolepsy type 2 is a diagnosis of exclusion requiring ancillary tests ruling out
other causes of EDS.
Data indicating increased mortality in patients with
narcolepsy remain controversial25,26.
• Several drugs (including modafinil, sodium oxybate, pitolisant, solriamfetol and
methylphenidate) improve narcoleptic symptoms in most patients.
Narcolepsy usually starts in adolescence, and a small
second peak of onset occurs at around age 35 years27.
• More research is needed to understand the clinical spectrum of narcolepsy, the exact
mechanisms leading to orexin neuronal loss and the value of new treatments,
In 10–15% of patients, narcolepsy starts before the age of
including orexin agonists and immunomodulation. 10 years28. However, narcolepsy in children was only rarely
systematically studied before the current century29–31.
• Awareness of narcolepsy, assessments of treatment efficacy, treatment of children
or during pregnancy and management of comorbidities are still suboptimal in Narcolepsy can have an acute course, in which symp
narcolepsy and require improvement. toms develop within a few days or weeks after a trigger
ing event, such as vaccination, stress or head trauma, a
chronic course, in which the onset of symptoms is diffi
by the European Sleep Foundation with the support of cult to determine, or a progressive course, in which the
the Grawe Foundation and held during 2–4 July 2015 onset of different symptoms is separated by years or even
in Ticino, Switzerland. The Think Tank comprised decades32. These differing presentations probably reflect
6 workshops on various aspects of narcolepsy (plus open different pathophysiological mechanisms32. In a series
ing and closing sessions) attended by 19 invited experts of 1,099 patients with narcolepsy, cataplexy most often
from all over the world. developed at the same time as EDS in 49% of the cohort
and developed after EDS in another 43%33. Cataplexy
Epidemiology preceded EDS in only 8% of the patients. The interval
The prevalence of narcolepsy in Europe and North between onset of EDS and onset of cataplexy is usually
America is estimated to be ~200–500 per million <2–3 years but can exceed 40–50 years33–36. Narcolepsy
individuals19–22. Because of uncertainties concerning without cataplexy can be transient, and patients can
Author addresses
1
Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
2
The Francis Crick Institute, London, UK.
3
Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK.
4
Department of Health Sciences and Technology, Swiss Federal Institute of Technology/ETH Zürich, Zurich, Switzerland.
5
Department of Pulmonary Medicine, Beijing University People’s Hospital, Beijing, China.
6
Department of Rheumatology, University Hospital, Zurich, Switzerland.
7
University of Witten/Herdecke, Institute of Immunology, Clinical Sleep and Neuroimmunology, Witten, Germany.
8
Centre of Sleep Medicine and Sleep Research, Klinik Barmelweid AG, Barmelweid, Switzerland.
9
Department of Immunohaematology, and Blood Transfusion, Leiden University Medical Centre, Leiden, Netherlands.
10
Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark.
11
Neurology Department, Leiden University Medical Centre, Leiden, Netherlands.
12
Sleep Wake Centre, Stichting Epilepsie Instellingen Nederland, Heemstede, Netherlands.
13
INSERM U1043 — Centre National de la Recherche Scientifique UMR 5282, Centre de Physiopathologie Toulouse-Purpan,
Université Toulouse III, Toulouse, France.
14
Centre de Recherche en Neurosciences de Lyon (CRNL), INSERM, Lyon, France.
15
Université Claude Bernard Lyon 1, Lyon, France.
16
Hephata-Klinik, Schwalmstadt, Philipps-Universität Marburg, Department of Neurology, Marburg, Germany.
17
Zentrum für psychische Gesundheit, Klinikum Ingolstadt, Ingolstadt, Germany.
18
Faculty of Medicine, University of Tsukuba, Ibaraki, Tsukuba, Japan.
19
Center of Medical Immunology, Institute for Research in Biomedicine, Bellinzona, Faculty of Biomedical Sciences,
Università della Svizzera Italiana, Lugano, Switzerland.
20
Institute of Microbiology, Eidgenössische Technische Hochschule, Zurich, Switzerland.
21
Department of Neurology, Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Harvard Medical School,
Boston, MA, USA.
22
Department of Physiology, University of Lausanne, Lausanne, Switzerland.
23
Center for Investigation and Research in Sleep, Vaud University Hospital, Lausanne, Switzerland.
24
Sleep-Wake Disorders Center, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of
Montpellier, Montpellier, France.
25
National Reference Network for Narcolepsy, Montpellier, France.
26
Institut National de la Santé et de la Recherche Médicale (INSERM) U1061, Montpellier, France.
www.nature.com/nrneurol
Reviews
enter remission37,38, whereas narcolepsy with cataplexy lost. No other adjacent neurons of the lateral hypo
typically does not remit (remission of this presentation thalamus were affected (such as those producing
has been reported only once, in a patient who received melanin-concentrating hormone (MCH)). The brain
immunotherapy soon after disease onset39). In addition, tissues showed increased gliosis but no inflammatory
narcoleptic symptoms often improve over time; the or neurodegenerative changes62,64.
severity of EDS and cataplexy typically decreases with In animal models, partial loss of orexin neurons leads
age, possibly as a result of coping mechanisms. to narcolepsy without cataplexy and with normal CSF
orexin levels62,65. In two patients with NT2, one had a
Aetiology normal number of orexin neurons and one had a 33%
By the 1920s, the possibility of an infectious and decrease in orexin neurons62. Of note, this decrease
post-traumatic origin of narcolepsy had already been occurred mainly in the posterior hypothalamus.
proposed8,40,41. In the early 1980s, evidence that narco Interestingly, two independent teams have reported an
lepsy was associated with the HLA system suggested increased number of histamine neurons (>50% higher
involvement of the immune system in its pathogene than in healthy individuals) in the tuberomammillary
sis15,16,42. The demonstration of low CSF levels of orexin A nucleus in patients with NT1 and in mouse models of
(and shortly thereafter of the selective loss of orexin narcolepsy63,66. This observation possibly reflects a com
neurons in the lateral hypothalamus) in patients with pensatory response to the loss of orexinergic excitatory
narcolepsy raised the possibility that these cells were the drive. However, this interpretation is controversial and
target of such a process17,43–45. limitations in the methods used to detect histamine
Orexin A and orexin B are small neuropeptides that neurons represent an alternative explanation63,66.
excite target neurons through orexin receptors type 1
and type 2, respectively46,47. Loss of this crucial system Genetic and epigenetic factors
disrupts the functioning of multiple frontal, limbic, In twin studies67–70, only ~25% of monozygotic twin pairs
diencephalic and brainstem networks and results in the are concordant for narcolepsy29. Familial narcolepsy rep
symptoms of narcolepsy48–50. This dysfunction has been resents 1–2% of cases. Less than 2% of individuals with
conceptualized as a state of instability or loss of bound narcolepsy have more than 1 affected family member,
ary control that manifests as an inability to remain in and multiplex families (those with more than 2 members
sleep or wake states for the normal length of time and who have cataplexy) are rare69–72.
by the inappropriate occurrence of sleep phenomena Narcolepsy is closely associated with the HLA class II
during wakefulness, and vice versa51. Therefore, bouts region, which encodes molecules that present antigenic
of both wakefulness and sleep are short in patients with peptides to CD4+ T cells15. Systematic studies demon
narcolepsy, REM sleep atonia occurs during wakefulness strated that HLA-DQB1*06:02 is expressed in 86–98%
(cataplexy), and dreaming can occur at sleep–wake and of patients who have NT1 and in ~40–50% of patients
wake–sleep transitions (hypnagogic or hypnopompic with NT2 (refs73,74). However, HLA-DQB1*06:02 is also
hallucinations). However, the existence of patients with expressed in 5–38% of the general population73,74, and
narcolepsy with and without cataplexy who have normal only 1 in 1,000 carriers of this allele will develop narco
CSF levels of orexin, and of patients with low or absent lepsy71,74. In addition, HLA-DQB1*06:02 positivity in
orexin levels in CSF secondary to hypothalamic dam the general population is associated with shorter REM
age who do not have narcolepsy or cataplexy symptoms, sleep latencies, suggesting the possibility that this sleep
raises the possibility that a deficiency in orexin produc EEG finding might represent a (first) biomarker of an
tion is not (always) necessary nor (always) sufficient to increased risk of developing narcolepsy75. The low fre
cause narcolepsy in humans52–57. quency of this allele in Jewish and Saudi populations
Today, narcolepsy is considered to arise from mul might explain the rarity of narcolepsy in these groups23,24.
tiple hits: the co-occurrence of genetic predisposition, Other HLA class II alleles are also associated with
environmental factors and triggering events eventually narcolepsy, albeit to a lesser extent73,74,76,77.
leads to the selective, immune-mediated destruction, Weak associations with narcolepsy have also been
dysfunction or silencing of orexin-producing neurons. reported for HLA class I genes (A, B and C), which encode
One study, published by some of the authors of this molecules that present antigenic peptides to CD8+
Review in 2018, reported the presence of autoreactive T cells. This observation suggests that patients with
CD8+ and CD4+ T cells in NT1 and NT2 (ref.58). Three narcolepsy might have an increased genetic susceptibi
subsequent reports, published in the past few months, lity to infections and that this disease involves cytotoxic
provide further support to the hypothesis of a pivotal immune mechanisms76,78. These studies also identified
role of specific T cells in the neuronal damage seen protective alleles in both HLA class I and class II genes,
in human narcolepsy59–61. The following discussion is which might play a part in the delay (or even absence)
devoted, unless otherwise specified, to NT1. of evolution of NT2 to NT1 seen in some patients74,76,79.
Genome-wide association studies found that polymor
Pathological findings phisms in TRAC (encoding the T cell receptor α-constant
Three autopsy series of patients with NT1 revealed a selec domain) were also associated with susceptibility to
tive loss of ~90% (range 75–95%) of the 50,000–70,000 narcolepsy, which further supports the hypothesis
orexin neurons in the lateral hypothalamus43,62,63. It is that narcolepsy is an immune-mediated disease77,80.
possible that some neurons are undetectable (owing Other studies have identified associations between
to silencing of orexin expression) but not irreversibly narcolepsy and polymorphisms in other immune-related

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genes, including P2RY11 (encoding P2Y purinoceptor 11, triggered by molecular mimicry of a particular piece of
a modulator of the autoimmune response to infection), the influenza haemagglutinin protein60. Narcolepsy has
CTSH (encoding pro-cathepsin H) and TNFSF4 (encod also been reported to occur following other vaccinations,
ing tumour necrosis factor (TNF) ligand superfamily although these relationships could be coincidental or not
member 4)74,81–83. Gene sequencing studies in patients with causal100,101. Finally, narcolepsy has occasionally been
rare familial narcolepsy with cataplexy have not shown reported to occur after traumatic brain injury8,102,103.
any consistent associations, although mutations have
been found in HCRT (encoding orexin), MOG (encod Immunological mechanisms
ing myelin oligodendrocyte glycoprotein) and P2RY11 A few types of autoantibodies have been identified in
genes, which modulate the immune response43,69,70. sera from patients with narcolepsy104,105. These antibodies
An epigenome-wide association study published in were, however, also detected in sera from patients with
2018 found that the genes containing the top-ranked dif other sleep disorders and sera from healthy controls.
ferentially methylated DNA sites in patients with narco In addition, passive transfer experiments involving
lepsy were associated with pathways of hormone secretion these autoantibodies did not reproduce narcolepsy in
and monocarboxylic acid metabolism. The top-ranked animal models. However, indirect evidence of an auto
narcolepsy-associated differentially methylated DNA immune pathogenesis of narcolepsy is provided by
sites were particularly abundant in non-CpG island the observation that narcolepsy occasionally occurs in
regions, and >95% of these sites were hypomethylated association with paraneoplastic syndromes and other
in patients with narcolepsy84. autoimmune diseases, such as multiple sclerosis, coeliac
disease and systemic lupus erythematosus5,106–111. In
Environmental factors addition, a few patients with narcolepsy respond to
The low concordance for narcolepsy with cataplexy in immunomodulatory treatment39,112–114.
monozygotic twins points to a contribution of environ The environmental and genetic factors discussed
mental factors67,68,85–87. Season of birth was associated in the preceding sections represent circumstantial evi
with the risk of narcolepsy in some but not all studies, dence that an autoimmune process contributes to narco
which suggested that exposure to viruses, bacteria or lepsy. Additional ancillary findings in humans offer
toxins early in life might alter the development of the further support for this hypothesis. Although evidence
immune system and thereby predispose individuals to of disease-specific antibodies is lacking, inflammatory
narcolepsy88–91. Subsequent exposure to these or other findings in CSF (namely, pleocytosis and oligoclonal
environmental factors (such as infections) might reac bands) can occasionally be observed115–119. Increased
tivate or trigger an immune response that leads to the levels of specific cytokines (TNF and IFNγ) and CD4+
destruction of orexin neurons. T cells, and activation of CD4+ and CD8+ T cells, have
A temporal association between influenza or enceph also been reported in sera (and to some extent also in
alitis epidemic infections and the onset of narcolepsy CSF)120–123. In 2018, some authors of this Review reported
was first noted in the 1920s8,40,41,92. In 2009, the find having identified autoreactive CD4+ and CD8+ T cells
ing of elevated titres of anti-streptococcal antibodies in patients with NT1 and NT2 that specifically target
in patients with recent-onset narcolepsy suggested an antigens expressed by orexin neurons58. In accordance
association with other upper airway infections, particu with this observation, two subsequent papers similarly
larly β-haemolytic streptococcal infections93. The most reported the presence of autoreactive CD8+ and CD4+
important association with infection involves the influ T cells in patients with NT1 (refs59–61).
enza A virus subtype H1N1. Following the 2009–2010
vaccination campaign against pandemic H1N1 influ Clinical features
enza, a statistically significant sixfold to ninefold increase Narcolepsy presents with a variable combination of
in the risk of narcolepsy was reported in Finland and sleep–wake symptoms and motor, psychiatric, emotional,
other northern European countries where the Pandemrix cognitive, metabolic and autonomic disturbances that
vaccine had been used94,95. Differences in vaccine content reflect the hypothalamic origin of the disorder (Box 1).
might explain why this association was not observed The following discussion of the clinical symptoms of
with any other influenza vaccines96,97. In the absence of narcolepsy refers to NT1 unless otherwise specified.
vaccination, a peak in the incidence of H1N1 infection
was seen in China in late 2009, which was followed dur Excessive daytime sleepiness
ing the winter of 2009–2010 by a threefold increase in EDS is usually the leading (and most disabling) symptom
the incidence of narcolepsy compared with both previ in most patients with narcolepsy and typically presents
ous and subsequent years98. However, this peak in narco as an inability to stay awake but is also reported as a
lepsy incidence was not observed in Taiwan despite its subjective feeling of sleepiness accompanied by dif
exposure to the same epidemic99. A trend towards earlier ficulties in sustaining attention (Fig. 1). EDS is often
onset of narcolepsy in childhood might also be related already present in the morning hours and is typically
to the influenza H1N1 pandemic of 2010–2011. These irresistible, with rapid transitions into sleep (so-called
observations suggest that influenza H1N1 infection sleep attacks). Involuntary napping was reported by
itself, as well as some influenza vaccines, might trig 80% of 1,079 patients in a large European study124.
ger the development of narcolepsy. An immunological These episodes predominantly occur in monotonous
study published in 2019 suggests the possibility that an situations but can also occur when patients are active.
autoimmune process targeting orexin neurons might be Naps are typically but not invariably short (15–20 min),
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Box 1 | Narcolepsy symptoms and associated features can also be observed, particularly in children7,130,131. Deep
tendon reflexes are typically transiently abolished but
The relative frequencies of these features are presented in the text. can persist in partial or mild episodes13,132. Babinski sign
leading symptoms (dorsiflexion of the big toe in response to stimulation
• Excessive daytime sleepiness (which can also manifest with sleep attacks, involuntary of the sole of the foot, rather than the plantar flexion
napping, automatic behaviours, difficulty sustaining attention and memory disturbances) normally seen in adults) can transiently appear, and
• Cataplexy (often partial, rarely complete with falls) Parkinson disease-related tremor might persist8,133. A few
patients experience complete inability to move (termed
Associated sleep–wake symptoms
cataplectic immobility5). Falls are reported by one-third
• Fatigue
of patients, but injuries are rare129.
• Sleep paralysis Partial attacks can evolve over seconds to complete
• Hallucinations (visual, auditory and tactile) attacks, which have a duration ≤2 min; a duration >5 min
• Frequent dreams, nightmares, lucid dreams and enacted dreams is unusual and often related to withdrawal of anti
• Disrupted night-time sleep cataplectic medications129,134. Unilateral dominance
• Restless legs syndrome is atypical135, and attacks involving single muscles are
• Parasomnias (including sleepwalking, REM sleep behaviour disorder and nocturnal exceptional10,13. Hyperkinesias, in the form of phasic
eating disorder) (twitching of facial muscles), tonic (tongue protrusion,
grimacing or neck extension) and repetitive motor
other associated manifestations
activities, can be superimposed on muscle atonia and
• Overweight
lead to the misdiagnosis of epilepsy or a movement dis
• Autonomic disturbances order8,130. These positive motor phenomena might be
• Depression, anxiety and functional disorders (such as pseudocataplexy) more common in children and at disease onset8,34,136–140.
• Attention-deficit hyperactivity disorder The frequency of attacks varies from dozens per day to
• Headache, olfactory dysfunction and digestive disturbances a few per year141.
• Decreased quality of life, car accidents and injuries Mirth with laughter is the most typical trigger; ≤50%
Ancillary findings of patients experience cataplexy while being tickled34,129.
Sudden or unexpected triumphant emotions (and, less
• Short sleep latencies and disturbed vigilance
commonly, aggressive emotions) favour cataplexy and
• Sleep-onset rapid eye movement (REM) episodes
explain its appearance during sports, hunting, playing
• Decreased or undetectable levels of orexin A in cerebrospinal fluid games (Fig. 2) and sexual intercourse (when it is termed
• HLA-DQB1*06:02 positivity orgasmolepsia)129,142. Negative emotions such as anger,
• Polysomnographic findings of sleep-disordered breathing, REM sleep behaviour fear, embarrassment, pain and sorrow rarely trigger
disorder, periodic limb movements, frequent arousals, stage shifts and loss of REM cataplexy34,129,143. Consciousness, ocular motility and
sleep atonia breathing are usually preserved during cataplexy attacks,
although some patients report blurring of vision and a
refreshing and associated with oneiric experiences34,125. feeling of suffocation. Autonomic symptoms such as
Patients can develop so-called automatic behaviours blood pressure and pulse changes, sweating, penile erec
— abnormal waking activities such as putting salt in tion and involuntary urination are possible8,144. Episodes
coffee, writing over the border of a piece of paper or of cataplexy can be associated with EDS, hallucinations,
driving to the wrong destination11,126 — for which they sleep paralysis, dreaming and REM sleep behaviour,
can be amnesiac, meaning that they are experienced as particularly when the duration of the attack is long141.
blackouts. Resisting sleep might predispose individuals
with narcolepsy to such behaviours, but they can also Sleep paralysis and hallucinations
manifest with nonspecific symptoms such as headache, These symptoms are reported, often in combination,
visual or sensory disturbances and hypoacusis. by 50–60% of patients with narcolepsy33,34. They can
Fatigue must be distinguished from EDS. Up to 60% occur at sleep onset (hypnagogic), during the night,
of patients with narcolepsy report fatigue, which is more on awakening (hypnopompic) and in association with
resistant to therapy than EDS127,128. In addition, fatigue can daytime naps. Sleep paralysis describes the inability to
increase the burden of EDS because it impairs daytime speak or move any voluntary muscle and usually occurs
activity, which is a major measure to combat EDS. during transitions between sleeping and waking. Attacks
of sleep paralysis can be accompanied by respiratory
Cataplexy distress and (predominantly visual) hallucinations,
Cataplexy is the only specific symptom of narcolepsy. although in up to 85% of hallucinations, senses other
This term refers to brief episodes of bilateral loss of mus than sight (gustatory, olfactory or vestibular–motor hal
cle tone triggered by sudden emotions in the presence of lucinations) are also involved145. The hallucinations can
a normal state of consciousness34,129. Partial attacks are be superimposed on the patient’s actual environment
very short (2–10 s) unless the trigger remains present. (that is, the room where they are).
Loss of muscle tone manifests as face drooping, eyelid The feeling of the presence of another person
closure, sagging of the jaw, dysarthria, passive tongue and assault scenarios are occasionally reported.
protrusion and bilateral loss of motor control of the Hallucinations can be frightening and cause fear of
extremities. Atonia of the facial muscles (termed facies sleep. Typically, patients realize immediately afterwards
cataplectica) with mouth opening and tongue protrusion that the experiences are not, or cannot be, real, but the

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Orexin loss
Acetylcholine
Histamine
Dopamine
Serotonin
Noradrenaline
Inconsistent release
of neurotransmitters that
promote wakefulness
Excessive sleepiness
and lapses into sleep
c
MT
Wake
Sleep stages
REM
S1
S2
S3
S4
09:25 09:30 09:35 09:40

Time
Fig. 1 | excessive daytime sleepiness in a patient with narcolepsy. a | A sleep episode or involuntary nap during quiet
reading. Naps can occur in the morning hours and are typically short and refreshing. Sleep episodes are less sudden than
cataplexy attacks and are not accompanied by muscle twitches. b | The specific loss of orexin-producing neurons in patients
with narcolepsy accompanied by cataplexy leads to inconsistent firing of the brainstem neurons responsible for arousal.
This change results in excessive daytime sleepiness and a predisposition to lapses into sleep. c | A neurophysiological
recording made during a multiple sleep latency test (MSLT) documents the transition from wakefulness into sleep.
A shortened sleep latency period is evident, and a so-called sleep-onset rapid eye movement (REM) period (SOREMP)
occurs within 15 min. In patients with narcolepsy accompanied by cataplexy , SOREMPs occur in ~50% of sleep episodes
(detected by MSLT or night-time polysomnography).
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hallucinations associated with narcolepsy can be severe other health problems25,172,184–186. Patients also have an
enough to prompt a misdiagnosis of schizophrenia85–87. increased incidence of psychiatric comorbidities, poor
Occasionally people with narcolepsy act according to school performance, occupational problems, reduced
previously experienced dreams without their neces self-esteem and interpersonal problems170,173,187–189.
sarily being typical hypnagogic hallucinations; these
experiences are called dream delusions146. Cognitive disturbances
Attention-deficit hyperactivity disorder (ADHD),
Sleep disturbances and parasomnias decreased cognitive performance, altered executive func
Although they often doze, patients with narcolepsy tioning, difficulty in sustaining attention and difficulties
usually do not spend a greater proportion of their time with decision making are all found in patients with narco
asleep than do people in the general population because lepsy190,191. These cognitive changes are considered to be
narcolepsy is often associated with sleep fragmentation mainly a consequence of EDS192–194. However, an adverse
(recurring wake periods during sleep)147. Moreover, effect of orexin loss on the turnover of (toxic) intra
sleep-onset insomnia is rare in patients with narco cerebral proteins and neurodegenerative changes has
lepsy147. Occasionally, however, patients with narcolepsy also been postulated195,196.
(particularly at disease onset and in childhood) present
with long and undisturbed sleep times, sleep inertia Metabolic disturbances
or sleep drunkeness148,149. The degree of nocturnal In the early 1920s, overweight was first recognized to
sleep disruption is only weakly correlated with EDS150,151. be common in patients with narcolepsy and cataplexy8,9.
Motor control dysfunction in sleep, which might be BMI is 10–20% higher in individuals with narcolepsy
present from childhood, can present as periodic limb than in the general population28,197–199. Patients with narco
movements (in 25–50% of patients), REM sleep behavi lepsy have a reduced rate of lipolysis and remain insulin-
our disorder (RBD) in 25–70% of patients, sleepwalking sensitive despite an increased prevalence of diabetes
and nocturnal eating8,28,152,153. Periodic limb movements mellitus, which is probably explained by their increased
can occur in non-REM and REM sleep as well as in BMI200. Reduced metabolic rate, decreased motor acti
wakefulness and correlate with the severity of EDS and vity and abnormal eating behaviours were observed
orexin deficiency154–156. Restless legs (or limbs) syn in some studies28,199,201–204. These changes are thought
drome might also be more frequent in patients with to arise from an underlying hypothalamo-pituitary
narcolepsy157. RBD in these individuals is character dysfunction, which could also explain the increased
ized by elementary rather than complex movements, frequency of precocious puberty 28,199,201–204 among
and its severity correlates with that of cataplexy and individuals with narcolepsy.
orexin deficiency155,158,159. Sleep-disordered breathing
is also frequent and can be severe, which can delay Autonomic disturbances
diagnosis154,160,161. Dreams are often reported as vivid Fainting spells, erectile dysfunction, night sweats, gas
and can have archaic or bizarre content and delusional tric or digestive disturbances, hypotension, dry mouth,
elements146. Nightmares and lucid dreaming are more palpitations, disturbed skin temperature profiles and
common in patients with narcolepsy than in the general abnormal pupillary function have all been described
population162,163. in association with narcolepsy but not systematically
studied205. Finally, patients with narcolepsy also have
Psychiatric and emotional disturbances increased rates of olfactory dysfunction, headache and
Until the 1950s, a psychiatric origin for narcolepsy was chronic lower back pain. The origin and relevance of
favoured, in the context of psychoanalytic theories of these features to the diagnosis of narcolepsy remain
dreams164–167. Indeed, several observations link narco unclear at this point174,206–208.
lepsy with psychiatric disease. First, stressful life events
can trigger the onset of narcolepsy168. Second, psychiatric Clinical features in children
disturbances are more frequent than in the general popu The first symptoms of narcolepsy in children are often
lation; for example, 20–30% of patients with narcolepsy weight gain and EDS. Sleepiness in children can lead
have depression and anxiety169–175. Third, narcolepsy-like to longer sleep times than in adults because nocturnal
symptoms have been reported in patients with schizo sleep can be normal in children even in the presence
phrenia and other psychiatric diseases48,176,177. Functional of severe EDS and cataplexy. Children fighting against
disorders associated with pseudocataplectic attacks can EDS might also appear restless and hyperactive. Cata
also be observed in patients with cataplexy, which com plexy episodes occurring soon after symptom onset are
plicates treatment choices for these individuals178,179. In characterized by a mixture of negative (facial atonia
addition, observations in humans and animal models with ptosis, mouth opening and tongue protrusion)
support the hypothesis that narcolepsy involves a prim and positive (perioral movements, dyskinetic–dystonic
ary dysfunction of reward and emotional processing movements and stereotypies) motor phenomena that
networks180–182. fluctuate with emotions137. These motor phenomena
The high frequency of psychiatric disturbances (termed facies cataplectica) tend to improve over time
(particularly in children) might reflect the psychosocial and can even disappear28. Occasionally, children pres
burden of narcolepsy, which is comparable to that of epi ent from symptom onset with hallucinations, sleep
lepsy28,183. Narcolepsy is associated with decreased quality paralysis, disrupted sleep and even RBD. Other manifes
of life and an increased risk of car accidents, injuries and tations of childhood narcolepsy with cataplexy include

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b
Sudden
positive
emotions
Orexin
Medial prefrontal
cortex
Reduced activity
in ventrolateral
Central amygdala periaqueductal
grey area
Increased activity
in sublaterodorsal
tegmental nucleus
Increased inhibition
of motor neurons
Cataplexy
c Cataplexy attack
EOG 1
EOG 2
Chin-EMG
C3-A2
C4-A1
O1-A2
O2-A1
Tibial EMG r
Tibial EMG l
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◀ Fig. 2 | Cataplexy in patients with narcolepsy. a | A cataplexy attack showing rapidly decrease to <110 pg/ml, the diagnosis of NT2 must be
progressive bilateral loss of muscle tone and control of facial, neck and upper extremity changed to NT1.
muscles during laughter triggered by tickling. Consciousness is preserved, and muscle Compared with patients with NT1, individuals with
twitching or face grimacing can occur. b | Sudden, positive emotions activate neurons
NT2 have less-severe EDS and a lower frequency of REM
in the medial prefrontal cortex that excite orexin neurons in the lateral hypothalamus
sleep-related symptoms, such as sleep paralysis, halluci
and the central amygdala. The absence of orexin leads to reduced activity of GABAergic
neurons in the periaqueductal grey area that inhibit rapid eye movement (REM) sleep nations and RBD211. Nonetheless, NT2 remains a con
and increases the activity of glutamatergic neurons in the sublaterodorsal tegmental troversial entity. This uncertainty persists partly because
nucleus involved in REM atonia. The imbalance in this pathway results in the activation NT2 is a diagnosis of exclusion, meaning that other rea
of descending pathways that inhibit spinal motor neurons and eventually to cataplexy. sons for the patient’s symptoms (such as chronic sleep
Pathways shown in blue are excitatory ; those in red are inhibitory. Open circles indicate loss or deprivation, sleep apnoea, circadian rhythm dis
neuron-cell bodies. Dotted lines indicate reduced activity. c | An electromyography orders and medication and/or substance abuse) must
(EMG) recording during a cataplexy episode (shaded area) documents a loss of muscle be excluded by ancillary tests. However, the existence
tone in multiple channels with superimposed bursts of increased muscle phasic activity of NT2 is supported by several observations. First, cata
(which present clinically as motor phenomena such as muscle twitching and face
plexy generally does develop in patients with initially
grimacing). EOG, electro-oculography channel; l, left; r, right.
isolated EDS — usually after some weeks, although the
interval can last several decades. Second, some degree of
cognitive, behavioural and psychiatric disturbances, orexin loss is evident in the brains of patients who have
including depression, hyperactivity, aggression and narcolepsy without cataplexy62. Third, animal models of
psychosis28,187,209. Some children with narcolepsy and cata partial orexin loss exhibit EDS but not cataplexy212.
plexy undergo precocious puberty, which is associated
with obesity201. Drawbacks of current criteria
The current international classification criteria have been
Diagnosis criticized because they overemphasize the value of ancil
Patients with narcolepsy are often undiagnosed or mis lary findings that are either nonspecific (SOREMPs) or
diagnosed. The mean interval between symptom onset not sufficiently validated (although orexin deficiency is
and diagnosis was found in a large-scale European study a well validated biomarker of narcolepsy, current tools
to be as long as 14 years33. Diagnosis of narcolepsy is for measuring CSF orexin levels exhibit some methodo
often particularly difficult and delayed in children, in logical issues213–215 and might also detect inauthentic
part because of their sometimes unusual presentations orexin metabolites216). In addition, they do not provide
of EDS and cataplexy. In addition, no normative data validated (operational) definitions for the diagnosis
exist for multiple sleep latency test (MSLT) findings in of cataplexy and do not take into account the existence of
children, and experience with CSF orexin measurements different phenotypes and aetiologies of narcolepsy. HLA-
in children aged <6 years is scarce. DQB1*06:02 positivity, SOREMPs and low CSF orexin
levels can also be observed in patients with partial or
Narcolepsy type 1 atypical or even without any clinical features of narco
The current international classification of sleep disor lepsy56,217,218. The authors of this Review suggest that the
ders defines NT1 as the presence of EDS for >3 months current criteria for narcolepsy require revision (and are
in association with either CSF orexin levels <110 pg/ml preparing a paper presenting their views). The future
(measured, however, using a method that has not been classification of narcolepsy should take into account its
validated internationally) or cataplexy and a mean sleep different clinical and aetiological phenotypes (Tables 1, 2).
latency <8 min on the MSLT and at least two SOREMPs
during the MSLT and/or night-time polysomnography. Narcolepsy phenotypes. From a clinical standpoint, sev
NT1 is the most common and best understood form eral possible phenotypes of narcolepsy can be identified:
of narcolepsy. narcolepsy with typical (unequivocal) cataplexy and
A positive diagnosis of NT1 can be made on clinical with all biological markers (namely, HLA-DQB1*06:02
grounds (Box 1). EDS is often the presenting symptom; positivity, sleep-onset REM episodes and low or absent
however, only cataplexy is pathognomonic for narco CSF levels of orexin A); narcolepsy with typical cata
lepsy. Thus, correct identification of cataplexy is cru plexy but without any biological markers; narcolepsy
cial. Cataplexy is, however, rarely observed and must be without cataplexy but with some biological markers;
diagnosed by history: no validated tools exist, although a and the presence of some biomarkers in the absence of
standardized trigger test might be useful210. Few papers narcolepsy symptoms36,62.
support the utility of videographic and neurophysiological Narcolepsy with typical cataplexy and with all typi
documentation of cataplexy130,136. cal biological markers can initially present as narcolepsy
without cataplexy and with normal CSF levels of orexin A.
Narcolepsy type 2 Narcolepsy with typical cataplexy but without any bio
In the current international classification of sleep dis logical markers is often familial or secondary narco
orders, NT2 is defined as the presence of EDS for lepsy. Finally, narcolepsy without cataplexy but with
>3 months in the absence of cataplexy, but with a mean some biological markers can evolve (within months but
sleep latency on the MSLT <8 min and ≤2 SOREMPs on also after years) into NT1. Familial and secondary forms
the MSLT and/or nocturnal polysomnography, as well of narcolepsy seem to be particularly likely to present
as CSF orexin levels >110 pg/ml (or not measured). as absence of HLA-DQB1*06:02 positivity and normal
If cataplexy develops over time or CSF orexin levels orexin levels, although the exact frequency of this

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Table 1 | Clinical phenotypes of narcolepsy in patients with brain and psychiatric diseases233,234.
On the other hand, severe EDS and sleep attacks can
Clinical phenotypes Proportion be misdiagnosed as epilepsy, syncope or transient loss
of cases (%)
of consciousness, blackouts or ADHD190,235 (Box 2).
Narcolepsy with typical cataplexy and with all typical biological 50–80 Cataplexy must be differentiated from mild episodes
markers (HL A DQB1*06:02, sleep onset rapid eye movement sleep
episodes, low or absent cerebrospinal fluid levels of orexin A) of loss of muscle tone, which can occur in 5–10% of
healthy individuals, particularly when laughing. These
Narcolepsy with typical cataplexy but without all typical biological 5–10 cataplexy-like episodes (colloquially termed being ‘weak
markers (often familial or secondary narcolepsy)
with laughter’) are usually not visible and involve mainly
Narcolepsy without cataplexy but with some typical biological markers 18–34 the lower limbs, whereas genuine cataplexy is visi
ble and involves the face (partial attacks) or the entire
phenotype is unknown. Lack of HLA-DQB1*06:02 body (generalized cataplexy)34,129,210,236–238. Videographic
positivity and orexin deficiency are rarely observed recordings can be helpful to correctly distinguish cata
in patients with narcolepsy and cataplexy but are not plexy from cataplexy-like episodes130 (Box 2). Cataplectic
infrequent in patients with atypical symptoms or rare attacks, often with atypical characteristics (long duration,
forms of the disease or without cataplexy33,219. asymmetric presentation, an unusual trigger or without
The existence of narcolepsy without cataplexy associated EDS), can occur in patients with hereditary
and without SOREMPs (so-called non-REM narco neuropaediatric syndromes (such as Prader–Willi syn
lepsy) is controversial220,221. Accordingly, current diag drome, Niemann–Pick disease type C and Norrie dis
nostic criteria do not recognize this disease entity ease), in individuals with brain lesions, most commonly
as a form of narcolepsy and do not differentiate it in the hypothalamus or brainstem, and in patients with
from idiopathic hypersomnia (except for one subtype psychiatric diseases48,52,225,240. Of note, patients with narco
of idiopathic hypersomnia that is associated with lepsy can present with both typical and psychogenic cata
prolonged sleep time and ‘sleep drunkenness’)220,222. plectic attacks (pseudocataplexy)48,178. Pseudocataplexy
is characterized by atypical triggers, a long or variable
Narcolepsy aetiologies. From an aetiological standpoint, duration of attacks, lack of facial involvement and the
four forms of narcolepsy can be differentiated: sporadic persistence of deep tendon reflexes during generalized
idiopathic narcolepsy, familial narcolepsy, sporadic secon attacks (these reflexes are absent in genuine general
dary narcolepsy (attributable to brain damage and ized cataplexy)48,130,178. Cataplexy-like episodes have also
other diseases)52 and hereditary secondary narcolepsy been described in the context of gelastic seizures and
(‘narcolepsy-plus’ syndromes)223,224 (Table 2). hyperkalaemic periodic paralysis241. In a few patients,
Sporadic secondary narcolepsy is most commonly typical cataplexy can remain isolated (that is, in the
caused by focal lesions in the hypothalamus (for exam absence of EDS) for decades35,242. Typical (‘true’) cataplexy
ple, in neurosarcoidosis or neuromyelitis optica) and can be misdiagnosed as syncope, transient loss of con
brainstem110,224,226–231. In hereditary narcolepsy syn sciousness, blackouts, epilepsy, exaggerated startle or falls
dromes, narcolepsy is associated with neurological defi of unknown origin and even as a transient ischaemic
cits or disturbances such as deafness, cerebellar ataxia attack or stroke235,243–245 (Box 2).
and polyneurop athy 223,224. An association between A high frequency of sleep paralysis and hallucinations
narcolepsy and multifocal brain diseases (such as trau (>3 per month) and their occurrence at sleep onset are
matic brain injury or multiple sclerosis) has also been suggestive of narcolepsy, but these symptoms also occur
reported5,8,102,106 in healthy individuals and in patients with other sleep,
neurological and psychiatric disorders34,239,246–249 (Box 2).
Differential diagnosis
The presence of EDS within a few hours after awaken Diagnostic tests
ing, involuntary napping during active situations and the Sleep questionnaires, video polysomnography, MSLTs
characteristics of these naps (short-lasting, refreshing and and orexin measurements are recommended by US
with dream content) are features suggestive of narco guidelines to confirm the diagnosis of narcolepsy as
lepsy220. Severe EDS and ‘sleep attacks’ can however occur defined by current international criteria18. However,
in sleep disorders other than narcolepsy, such as idiopathic some of these tests have limited sensitivity and specific
hypersomnia, chronic sleep deprivation or insufficiency ity. Genetic testing for HLA-DQB1*06:02 positivity adds
and sleep-disordered breathing, and in individuals doing little to the reliability of the diagnosis of NT1; however,
shift work34,232. Narcolepsy-like EDS can also be observed its absence makes the diagnosis of NT1 highly improb
able. In patients with unclear clinical findings, therefore,
Table 2 | Aetiological forms of narcolepsy genetic testing is helpful.
Aetiological forms Proportion Questionnaires. Patients with narcolepsy usually score
of cases (%)
~18 (range 14–20 out of a possible 24) points on the
Sporadic narcolepsy >90 nonspecific Epworth sleepiness scale33,34,250. The Swiss
Familial narcolepsy <5 Narcolepsy Scale was found to have the best sensitivity
Secondary (symptomatic) narcolepsy <5 and specificity (both ~90%) for the diagnosis of narco
lepsy with cataplexy in three separate populations and was
Hereditary ‘narcolepsy plus’ syndromes <1
also superior to the Ullanlinna Narcolepsy Scale20,34,250,251.
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Box 2 | Differential diagnosis of narcoleptic symptoms and specific diagnostic test for NT1, although the radio
immunoassay currently used to measure orexin A levels
excessive daytime sleepiness gives only relative values, cannot quantify small changes
• Other sleep disorders: idiopathic hypersomnia, sleep deprivation and and additionally might detect inauthentic orexin metab
sleep-disordered breathing olites216,261. In patients without cataplexy, CSF orexin
• Neurological and psychiatric diseases: Parkinson disease, atypical depression, levels are usually normal (so-called NT2). However,
epilepsy and attention disorders some of these patients (10–25% in large series; range
• Use of sedative or hypnotic agents, drugs or alcohol 0–40%) present with CSF levels of orexin A <110 pg/ml
• Syncope or transient loss of consciousness and blackouts can sometimes be and are therefore diagnosed as having NT1 (refs36,213,261).
misdiagnosed as ‘sleep attacks’ (and vice versa) Normal CSF levels of orexin are often found in patients
Cataplexy with familial and secondary narcolepsy and in
• Mild cataplexy (in the legs and often face but not visible) occurs with laughter in HLA-DQB1*06:02-negative patients36,213.
healthy individuals (feeling ‘weak with laughter’)
• Cataplexy-like episodes and/or atypical cataplectic attacks can occur in the context of Neuroimaging. A variety of neuroimaging studies have
hereditary paediatric syndromes (including Niemann–Pick disease type C, Prader–Willi been performed in patients with narcolepsy in the past
syndrome and Norrie disease), lesions in the hypothalamus or brainstem and psychiatric 20 years. Older structural imaging modalities showed
diseases (pseudocataplexy), gelastic seizures, and hyperkalaemic periodic paralysis normal findings; however, reports published in the past
• Syncope or transient loss of consciousness, ‘drop attacks’, blackouts, startle and 3–4 years, which used more-advanced techniques, sug
seizures can sometimes be misdiagnosed as cataplexy (and vice versa) gest that the frequency of brain abnormalities (such as
Sleep paralysis and hallucinations
demyelinating and vascular changes) might have been
underestimated106,262,263. The number of quantitative
• In healthy individuals
morphological, spectroscopic and metabolic imaging
• In patients with other sleep, neurological and psychiatric diseases
studies is limited, and their results often could not be
replicated49,264–268. Functional MRI studies have provided
Multiple sleep latency test. Typical findings of short sleep new insights into the neuronal networks underlying
latency and SOREMPs (Fig. 1) have a sensitivity and speci human cataplexy by showing altered patterns of activity
ficity of only ~70–80% for NT1 and (as per the definition) with laughter in the hypothalamus and cortico-limbic
of 100% for NT2. Of note, patients with NT2 had longer and brainstem reward pathways269. The documented
non-REM and REM sleep latency durations on the MSLT abnormalities in reward and emotional processing
than did patients with NT1211,219. However, MSLT findings observed in patients with narcolepsy might explain the
are influenced by age, shift work, sleep deprivation and high frequency of psychiatric disturbances in affected
medication217,218,252,253. The MSLT reveals ≥2 SOREMPs in individuals180,181,270,271.
4–13% of healthy individuals in the general population,
and ≤3–6% of this population fulfils the MSLT criteria Pathophysiology
for the diagnosis of narcolepsy217,218,254,255. The sequence In the 1920s, observations in patients with encephalitis
of sleep stages might differentiate the different aetiol lethargica led to the suggestion that narcolepsy origi
ogies of EDS better than sleep latency duration256,257. nates from the diencephalon and of its role in sleep
In patients with NT1, typical MSLT findings are also generation and the control of muscle tone8,40,92. The
present at follow-up examinations, whereas in individ discovery of SOREMPs in 1960, together with other
uals without cataplexy, the MSLT findings frequently neurophysiological and biochemical observations in
improve or SOREMPs disappear over time37,218. humans and dog models of narcolepsy, led to the pro
posal that narcolepsy results from an imbalance of
Video polysomnography. SOREMPs can be identified aminergic and cholinergic brainstem pathways14,272,273,
during nocturnal video polysomnography in ~50% as discussed in this section.
of patients with NT1 (refs258,259), and this test seems
to be more specific but less sensitive than the MSLT Neurochemistry
for the diagnosis of narcolepsy. Other findings on Orexin. Orexin-producing neurons regulate sleep–wake
video polysomnography in patients with narcolepsy behaviour and influence other brain functions, including
include awakenings and/or arousals after sleep onset, reward and metabolic circuits, through their effects on
an increased amount of stage 1 sleep, frequent shifts to numerous targets, including neurons producing hista
N1 sleep or waking from deeper stages of sleep, insuf mine and other monoamine neurotransmitters274–277.
ficient non-REM sleep density, increased frequency of Orexin-producing neurons are most active during wake
sleep-disordered breathing, minor motor events dur fulness, especially during periods of high muscle tone
ing REM sleep, RBD and periodic limb movements in and in motivated and exploratory behaviours, and they
sleep147,154,155,158,260. In toddlers and preschool children, help to sustain long periods of wakefulness and regulate
continuous 24 h polysomnographic recordings are pre REM sleep278.
ferred to conventional nocturnal polysomnography and Narcolepsy was first linked to reduced orexin sig
MSLT for the detection of EDS and SOREMPs. nalling when researchers observed narcolepsy pheno
types in mice lacking orexin neuropeptides and in dogs
Orexin levels. CSF levels of orexin A are either greatly with mutations in HCRTR2 (which encodes orexin recep
decreased (<110 pg/ml) or undetectable in 95% of tor type 2)279,280. Soon afterwards, researchers demon
patients with NT1 (refs56,213). This is the most sensitive strated low orexin levels and loss of orexin-producing

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neurons in ~90% of patients who had NT1 or narcolepsy Low CSF levels of orexin A predict an increased severity
with cataplexy17. of EDS in people with narcolepsy36,211.
The specific mechanisms through which loss of
orexin signalling results in EDS and cataplexy are still Cataplexy and rapid eye movement sleep symptoms.
being established, but signalling through monoamine During REM sleep, motor neurons are hyperpolarized
neurons seems to be important: in mice, restoration of by inhibitory interneurons (which produce GABA and
orexin signalling in the noradrenergic neurons of the glycine) in the spinal cord and by descending projections
locus coeruleus improves EDS, and restoration of orexin from the medial medulla (Fig. 2). These atonia-promoting
receptor expression in the serotoninergic neurons of the neurons are activated by glutamatergic neurons of the
dorsal raphe improves cataplexy281. Also in mice, intra sublaterodorsal nucleus295. During wakefulness and
cerebroventricular and intrathecal injections of orexin non-REM sleep, these sublaterodorsal nucleus neurons
and orexin agonists inhibit cataplexy282,283. are normally inhibited by neurons of the ventrolateral
The severity of sleepiness and cataplexy seem to be periaqueductal grey area and the adjacent lateral pon
correlated with the extent of orexin neuron loss and with tine tegmentum as well as by serotoninergic neurons
the decrease in CSF levels of orexin62,65. Loss of orexin of the dorsal raphe296. During normal REM sleep, these
neurons to below 50% of normal levels is found in neurons fall silent, permitting widespread muscle para
patients with NT2 and corresponding rodent models62,284. lysis296. Cataplexy can, therefore, be viewed as an altered
Symptoms in patients with NT2 might arise from orexin startle response accompanied by an inappropriate acti
loss but also other compensatory mechanisms. Of note, vation (that is, during wakefulness) of the pathways
low levels of orexin in CSF in these patients predicted the that normally produce muscle paralysis during REM
subsequent development of cataplexy36. sleep. However, these two phenomena, cataplexy and
REM atonia, are neither clinically nor physiologically
Histamine. Histaminergic neurons of the posterior (nor indeed pharmacologically) identical272,297–299. Sleep
hypothalamus are another major target of the orexin paralysis and hallucinations probably also arise from
system. Histaminergic neuron firing and histamine a dysregulation of REM sleep300,301. Accordingly, these
release are maximal during wakefulness, and wakeful symptoms in patients with narcolepsy are often referred
ness is diminished by the destruction of histaminergic to (together with cataplexy and RBD) as REM sleep
neurons and by inhibition of histamine synthesis, release manifestations.
or action285. In humans, CSF levels of histamine and its We are beginning to understand how strong, posi
main metabolite can be low in patients with narco tive emotions trigger cataplexy. Functional MRI stud
lepsy286–289, but this finding is controversial because it ies suggest that people with narcolepsy have altered
remains unclear whether these changes represent com patterns of activity with laughter in the hypothalamus
pensation for the loss of orexin neurons or are related and the cortico-limbic and brainstem reward path
to the underlying autoimmune or inflammatory pro ways180,269,270. The amygdala also contains neurons that
cess. Finally, pitolisant, a selective histamine H3 recep are active during cataplexy; in mice lacking orexins,
tor inverse agonist, improves wakefulness and reduces selective activation of GABAergic neurons in the central
cataplexy in mice and people with narcolepsy290. nucleus of the amygdala increases the severity of cata
plexy, whereas their selective inactivation reduces it302–304.
Other neurotransmitters. Orexin neurons also produce These amygdala neurons heavily innervate the ventro
glutamate, neuronal activity-regulated pentraxin and the lateral periaqueductal grey area, lateral pontine teg
endogenous opiate dynorphin45,57. Their role in narco mentum and dorsal raphe, and this inhibitory signal
lepsy remains unclear. A few studies have also suggested is likely to inhibit atonia-suppressing brain regions,
a link between narcolepsy and lipocalin-type pro enabling transitions into cataplexy. In line with this
staglandin D synthase (also known as prostaglandin H2 suggestion, lesions in the central and basolateral nuclei
D-isomerase), an enzyme involved in sleep–wake of the amygdala reduce cataplexy in a mouse model of
regulation in rodents, primates and humans291–293. narcolepsy305. Studies in patients with narcolepsy also
suggest that they have alterations not only in patterns
Neurophysiology of activation of the amygdala during cataplexy but also
Excessive daytime sleepiness. Orexin neurons heav in emotional processing, including of positive, aversive
ily innervate and excite all brain regions that promote and negative emotions181,269,306–308. In healthy individu
arousal, including noradrenergic neurons of the locus als, orexins excite the ventrolateral periaqueductal grey
coeruleus, dopaminergic neurons of the ventral tegmen area and the adjacent lateral pontine tegmentum and
tal area, histaminergic neurons of the tuberomammillary dorsal raphe, counterbalancing these inhibitory signals
nucleus and cholinergic neurons of the basal forebrain294 from the amygdala, but in individuals with narcolepsy,
(Fig. 1). In contrast to classic short-acting neurotrans the signals from the amygdala are unopposed, resulting
mitters, orexins persistently excite their target neurons; in cataplexy.
intraventricular injection of orexin A or administration Further upstream, the medial prefrontal cortex is a
of an orexin agonist increases wakefulness for several major input to the amygdala, and it is active in association
hours in mice282. However, the loss of orexin-producing with positive emotions and cataplexy in humans269. In
neurons in patients with narcolepsy probably means that mice lacking orexins, this region shows highly synchro
these wakefulness-promoting neurons fire less consist nous firing during cataplexy; inhibition of the medial pre
ently, resulting in EDS and rapid transitions into sleep. frontal cortex in these mice reduced cataplexy309,310.
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In EEG studies, the presence of hypersynchronous theta Symptomatic pharmacological approaches

oscillations during cataplexy episodes in rodents and Pharmacological treatments for narcolepsy (Table 3)
humans might reflect changes in prefrontal control of add to but do not replace non-pharmacological ther
reward-driven motor impulse, planning and conflict apies. In many patients, optimal control is possible
monitoring310. only with a combination of pharmacological and
non-pharmacological approaches.
Treatment Coffee, ephedrine and benzedrine in the 1930s and
Patients with narcolepsy require counselling (for example, methylphenidate in the 1950s were the earliest treat
for school-related and work-related issues), psycho ments for narcolepsy8,314. The anticataplectic effects of
social guidance and regular medical follow-up. Non- imipramine, clomipramine and other antidepressants
pharmacological approaches should always be discussed. were initially reported in Japan315. In humans, drugs that
Age, profession, specific life situations (such as preg increase noradrenergic and serotoninergic tone, such as
nancy) and comorbidities (including depression, obe the selective noradrenaline reuptake inhibitor venlafaxine
sity, cardiovascular disorders, restless legs syndrome, and the selective serotonin reuptake inhibitor fluoxetine,
periodic limb movements, RBD and sleep-disordered are effective in reducing the severity of cataplexy281,316,317.
breathing) all influence the choice of treatment but The efficacy of sodium oxybate (the sodium salt of
have been insufficiently studied. Sleep propensity can be γ-hydroxybutyric acid) as a treatment for both EDS and
assessed using the same questionnaires and sleep–wake cataplexy has been confirmed in double-blind randomized
tools (such as the Epworth sleepiness scale and mainte controlled trials318–321. Pitolisant (an inverse agonist of
nance of wakefulness test, respectively) that are used histamine) is also effective in the treatment of both EDS
to assess treatment response in clinical trials. New tools and cataplexy322,323. Codeine and opiates, which increased
that assess the quality of wakefulness and patients’ overall the number of orexin-producing cells detected in human
quality of life are increasingly also being used311,312. and mouse brains and reversed cataplexy in a rodent
model of narcolepsy, might have a symptomatic effect324–326.
Non-pharmacological approaches Additional drugs are currently in the pipeline, including
Non-pharmacological treatment strategies include small-molecule oral orexin agonists (which, unlike orexin
self-care, behavioural therapy (including scheduled itself, can pass through the blood–brain barrier)281,317.
napping and regular night sleep), self-help groups and
psychotherapy. Regular physical activity, adequate use of Excessive daytime sleepiness. Modafinil is a racemic
caffeine and a balanced diet that avoids large amounts compound, the active R-enantiomer of which, armo
of carbohydrates are also recommended313. dafinil, has a longer half-life. Both agents promote
Table 3 | Symptomatic narcolepsy treatment

Drug Daily dosage Indication Approval status
Modafinil 100–400 mg First-line treatment for EDS Approved by FDA and EMA for NT1
and NT2
Armodafinil 100–250 mg First-line treatment for EDS Approved by FDA for NT1 and NT2;
not available in Europe
Pitolisant 4.5–36.0 mg First-line treatment for EDS • Approved by EMA for NT1 and NT2
and cataplexy • Under review by FDAa
Sodium oxybate 4.5–9.0 g First-line treatment • Approved by FDA for NT1 and NT2
for cataplexy , disturbed • Approved by EMA for NT1
night-time sleep and EDS
Solriamfetol 75–150 mg First-line treatment for EDS • Approved by FDA for NT1 and NT2
• Under review by EMA
Antidepressants • Venlafaxine 37.5–300.0 mg First-line and second-line Clomipramine is approved in Germany
• Fluoxetine 20–60 mg treatment for cataplexy for the treatment of cataplexy
• Clomipramine 10–50 mg and third-line treatment
• Citalopram 10–75 mg for EDS
Methylphenidate 10–60 mg Second-line treatment Approved by FDA and EMA for NT1 and
for EDS NT2 (EMA approved immediate-release
formulation only for NT1)
Amphetamines • Amphetamine mixed Second-line treatment • Amphetamine mixed saltsb are
saltsb 10–60 mg for EDS approved by the FDA for NT1
• Dexamphetamine and NT2
10–60 mg • In Europe, dexamphetamine is
approved in Germany and Switzerland
These recommendations apply only to adults. The presence of comorbidities (and other medications) might also alter the choice
of pharmacological approach. EDS, excessive daytime sleepiness; EMA , European Medicines Agency ; NT1, narcolepsy type 1
(with cataplexy or a proven cerebrospinal fluid orexin deficiency); NT2, narcolepsy type 2 (without cataplexy). aDesignated as
a breakthrough therapy for cataplexy and fast-tracked as a treatment for EDS and cataplexy in patients with narcolepsy.
b
A mixture of four salts of the two enantiomers of amphetamine with dexamphetamine.

Reviews
Lateral hypothalamus
OT
MB
a Genetic factors b Environmental factors c Triggering events d Clinical symptoms

Cataplexy
Viral EDS
infection
Infection
Vaccination
Bacterial
infection
Orexin neurons
Viral or bacterial antigen
MHC class I Damaged
CD8+ T cell neuron
MHC class II
CD4+ T cell
B cell
Lymph node
Hypothalamus
Dendritic cell
Blood–brain barrier
Induction phase Effector phase
dopaminergic signal transmission. Modafinil is approved approved sodium oxybate for the treatment of narco
by the European Medicines Agency (EMA), and both lepsy with cataplexy317,322. Sodium oxybate might be the
modafinil and armodafinil are approved by the FDA as preferred option for patients with cataplexy, disturbed
a first-line treatment for EDS. These agents are effective nocturnal sleep and EDS, although its maximal effect is
within days317,327,328. Sodium oxybate is given at night and reached only after ~3 months329. Solriamfetol is a selec
has a complex mode of action that includes the stimu tive dopamine and noradrenaline reuptake inhibitor for
lation of GABA-B receptors. Pitolisant is approved by which favourable results have been reported in phase IIb
the EMA as a first-line treatment for EDS. The EMA has and phase III trials; in 2019, this agent was approved
Reviews
◀ Fig. 3 | The multiple-hit model of narcolepsy involves genetic, environmental and for the treatment for narcolepsy with EDS and cataplexy
triggering factors. a | Genetic factors (especially HL A-DQB1*06:02 positivity) are a strong in children. No other drugs are approved by either the
predisposition to narcolepsy. The first clinical marker of such a predisposition is a short EMA or FDA for use in children.
latency period before onset of rapid eye movement (REM) sleep. b | Environmental exposures
to bacterial and viral infections in early life might alter immune system development and
Special considerations. Although combined treatments
predispose individuals to narcolepsy later in life. It is possible, but still unproven, that these
changes might directly or indirectly cause the loss of some orexin neurons (as suggested are commonly used to treat EDS and cataplexy in
in this figure). Alternatively , these genetic and environmental factors might only increase adults, little formal evidence supports such an approach.
the vulnerability of these neurons. c | Triggering events, such as vaccinations and infections Concurrent administration of modafinil and sodium
by viruses such as influenza type A (H1N1) and bacteria such as Streptococcus spp., induce oxalate or pitolisant might have additive effects on EDS317.
or reactivate the immune response, leading to the destruction of orexin neurons (induction The effects of stimulants on cognitive disturbances have
phase). d | The clinical symptoms of narcolepsy progress over days to weeks and even been poorly studied. Sodium oxybate can improve obe
years, as an increasing number of orexin neurons is destroyed or silenced, causing an sity but might induce or worsen depression; the opposite
imbalance in brainstem sleep and wake pathways (effector phase) that leads to full-blown effects are observed with antidepressants.
narcolepsy with cataplexy. e | The exact sequence of events leading to the selective During pregnancy, delivery and breastfeeding (which
destruction of orexin neurons in the hypothalamus is still unknown, but inflammatory
probably do not differ much in women with narcolepsy
cytokines and activated immune cells (dendritic cells, antigen-specific CD4+ T cells and
cytotoxic CD8+ T cells), which eventually cross the blood–brain barrier, are thought to be from those in the general population), all drugs for EDS
involved. Antibodies can cross a disrupted blood–brain barrier and might also contribute and cataplexy should be discontinued, if possible337.
to neuronal destruction. EDS, excessive daytime sleepiness; MB, mammillary body; In some specific individuals with severe symptoms, low-
OT, optic tract. dose clomipramine and/or modafinil might exception
ally be prescribed; in data on hundreds of pregnancies,
these drugs seem to be safe337,338.
by the FDA for the treatment of EDS in patients with
narcolepsy330,331. Immunotherapy
A second-line approved drug for EDS is methyl Immunomodulatory treatments (including intravenous
phenidate. Amphetamine mixed salts (mixtures of four immunoglobulins, humanized monoclonal antibodies,
salts of the two enantiomers of amphetamine) and dexam high-dose corticosteroid therapy and plasmapheresis)
phetamine are third-line choices that are approved only have been investigated in small studies, with some suc
in some countries317,332. Mazindol (which is currently cess39,112,113,339,340. Natalizumab and alemtuzumab have
withdrawn from the market), selegiline, and to a lesser also shown some beneficial effects on EDS or cataplexy
extent venlafaxine, have been used off-label in patients in single patients106,341.
with EDS.
Conclusions and future perspectives
Cataplexy. Sodium oxybate is approved by the EMA and The clinical observations and research triggered by the
FDA as a first-line treatment for cataplexy317,328. The maxi discovery of the orexin system in the late 1990s have
mal effect of this agent is reached after ~3–6 months329. greatly increased our knowledge of the clinical features
Low-dose clomipramine and low-dose imipramine, as and neurobiology of narcolepsy. However, a few impor
well as venlafaxine, fluoxetine and other selective sero tant issues remain unclear. Six major areas of uncer
tonin reuptake inhibitors can improve cataplexy within tainty need to be addressed in the near future, discussed
days but are not approved (in most countries) for this below.
indication317,333. Pitolisant is also effective against cata Narcolepsy is a rare disease. However, its exact
plexy (class I evidence) and has been approved by the incidence and prevalence remain unknown owing to
EMA323. A network meta-analysis of 14 randomized the inadequacy of current diagnostic criteria. The fre
controlled trials in patients with narcolepsy found quency of narcolepsy and narcoleptic borderland con
that modafinil 200–400 mg daily in patients with EDS, ditions (including NT2) could be higher than currently
sodium oxybate 9 g daily in patients with EDS and suggested218.
cataplexy and pitolisant 40 mg daily in patients with In the clinic, narcolepsy should be considered as a
EDS and cataplexy were all considerably more effective global hypothalamic disorder rather than simply as
than placebo334. a sleep disorder. In addition to sleepiness and sleep dis
orders, patients with narcolepsy manifest various other
Other symptoms. Sodium oxybate is the only substance motor, cognitive, psychiatric, emotional, metabolic and
with a proven long-term benefit on nocturnal sleep335. autonomic disturbances. Although these disturbances
Sodium oxybate, clomipramine and venlafaxine can are still insufficiently characterized and poorly under
improve hallucinations. Sodium oxybate might worsen stood, they probably reflect an underlying hypothalamic
sleep-disordered breathing. Antidepressants can dysfunction in orexin signalling and connected neuronal
worsen both RBD and restless legs syndrome317. networks. Prospective and long-term clinical observa
tions are needed to increase our knowledge of the dif
Treatment of narcolepsy in children. Stimulants, modaf ferent forms of narcolepsy in terms of both their natural
inil, sodium oxybate and antidepressants improve nar history and evolution (that is, acute versus chronic or
coleptic symptoms in children. The clinical efficacy of progressive) and their severity (which ranges from
sodium oxybate for the treatment of EDS and cataplexy mild narcolepsy without cataplexy to severe narcolepsy
was reported in 2018 in a large study conducted in chil with cataplexy). These differences are suggestive of a
dren336. Sodium oxybate has been approved by the FDA multiple-hit aetiopathogenesis of narcolepsy (Fig. 3).

Reviews
Narcolepsy arises from the contribution of well- More-precise quantitative methods than the existing
identified genetic polymorphisms, still poorly character radioimmunoassay are needed to assess orexin defi
ized environmental exposures and possibly epigenetic ciency in CSF and possibly also in serum and might
factors. The extent (and nature) of these aetiological lead to an improvement in the early and accurate diag
contributions probably differs between idiopathic, nosis of mild forms of narcolepsy, including narcolepsy
familial and secondary variants of the disease. Systematic without cataplexy but with (presumably) normal CSF
assessments, including neuroimaging studies and orexin levels261,346. Systems biology approaches, such
measurements of inflammatory markers (such as cyto as genomic, transcriptomic, epigenomic, proteomic
kines and CD8+ and CD4+ lymphocytes), and com and microbiomic analyses, are needed to identify new
orbidities of narcolepsy might shed light on potential biomarkers of narcolepsy and borderland conditions.
disease-triggering or disease-modifying factors. Machine-learning approaches might also improve on the
Emerging evidence, gained in humans and rodent mod accuracy of current diagnostic methods219,345,347. Blood
els of the disease, supports the recruitment of immuno tests for immune markers might also have a diagnostic
logical mechanisms in the destruction or silencing of role in the future58. Finally, knowledge and awareness of
orexin neurons94,342,343. If confirmed, this information narcolepsy could be improved among physicians and in
will have profound consequences because it would the general population348.
enable the early diagnosis of incomplete phenotypes, the The symptomatic treatment of narcolepsy has
selection of appropriate treatment (symptomatic versus advanced considerably owing to the introduction of
immunomodulatory) and perhaps even the prevention effective drugs approved by the EMA and FDA. However,
of narcolepsy in predisposed individuals. compliance with treatment is not always sufficient.
Orexin deficiency is central to the pathophysiology Also, the measurements of treatment efficacy currently
of narcolepsy, although the exact underlying mecha used in clinical trials correlate poorly with narcolepsy-
nisms are still incompletely understood303. In addition, relevant outcome measures. New disease severity scales,
human as well as animal data suggest that other neuro vigilance tests, disease-specific measures of quality of
transmitters (such as histamine66) are dysregulated life and patient-reported outcomes are needed349–351.
in narcolepsy. The extent of such dysregulation, and Further clinical trials are also needed to investigate phar
whether it is a primary or secondary (that is, down macological treatments for narcolepsy in children and
stream or compensatory) effect of the disease, remains in other groups requiring special consideration (such
unclear but could be of interest for the development of as pregnant women and patients who have narcolepsy
new diagnostic and treatment strategies. without cataplexy and in the perioperative period). Non-
The current diagnostic criteria for narcolepsy are pharmacological approaches, including the role of nap
imprecise, particularly those for the identification of cata ping and diet, should also be studied in clinical trials336.
plexy and the exclusion of narcolepsy mimics. They are Treatment of comorbidities is often neglected but can be
also cumbersome to apply and do not adequately reflect very important in some patients.
the existence of different clinical phenotypes and aetiol Orexin-producing cell replacement, gene and stem cell
ogies of narcolepsy. These criteria should be revised using treatments and the use of orexin agonists are still exper
a scale for diagnostic probability of narcolepsy (possible, imental282. Conversely, immunomodulatory treatments
probable certain or certain diagnosis). The diagnosis of (which address the causative mechanisms of narco
cataplexy remains difficult: cataplexy-eliciting tests and lepsy) have been effective in single individuals and in
videographic analyses, which are well established in ani small series of patients and could be considered in the
mal models, have only rarely been systematically used future — if the autoimmune hypothesis of narcolepsy
in humans130,210,344. Simpler methods than the MLST are is confirmed — particularly in individuals in the early
also needed to increase the diagnostic sensitivity and stages of NT1 and in those with progressive narcolepsy
specificity of assessing neurophysiological sleep–wake or NT2 (refs317,342).
changes, including sequencing of sleep stages, in patients
with narcolepsy and narcolepsy-like phenotypes259,345. Published online xx xx xxxx
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Acknowledgements Competing interests declares that he is a member of the advisory board of Avadel,
The authors thank the Klaus-Grawe Foundation and the C.L.A.B. declares that he is a member of the advisory boards Harmony Biosciences, Idorsia, Jazz and Takeda. The other
European Sleep Foundation (formerly the Alpine Sleep of Idorsia, Jazz, Takeda and UCB. R.K. and M.T. declare that authors declare no competing interests.
Summer School) for enabling the Think Tank, which formed they are members of the advisory board of UCB. G.J.L. and
the basis of this article. They also thank A. Blank of Inselspital G.M. declare that they are members of the advisory boards
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All authors contributed to researching data for the article and grant from GSK. UK declares that he is a member of the advi- Reviewer information
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