Cataplexy - Clinical aspects, pathophysiology and management strategy

Abstract

Cataplexy is the pathognomonic symptom of narcolepsy, and is the sudden uncontrollable onset of skeletal muscle paralysis or weakness during wakefulness. Cataplexy is incapacitating because it leaves the individual awake but temporarily either fully or partially paralyzed. Occurring spontaneously, cataplexy is typically triggered by strong positive emotions such as laughter and is often underdiagnosed owing to a variable disease course in terms of age of onset, presenting symptoms, triggers, frequency and intensity of attacks. This disorder occurs almost exclusively in patients with depletion of hypothalamic orexin neurons. One pathogenetic mechanism that has been hypothesized for cataplexy is the activation, during wakefulness, of brainstem circuitry that normally induces muscle tone suppression in rapid eye movement sleep. Muscle weakness during cataplexy is caused by decreased excitation of noradrenergic neurons and increased inhibition of skeletal motor neurons by γ-aminobutyric acid-releasing or glycinergic neurons. The amygdala and medial prefrontal cortex contain neural pathways through which positive emotions probably trigger cataplectic attacks. Despite major advances in understanding disease mechanisms in cataplexy, therapeutic management is largely symptomatic, with antidepressants and γ-hydroxybutyrate being the most effective treatments. This Review describes the clinical and pathophysiological aspects of cataplexy, and outlines optimal therapeutic management strategies.

Full text

NATURE REVIEWS
|
NEUROLOGY ADVANCE ONLINE PUBLICATION
|
1
Department of
Neurology, INSERM
U1061, University of
Montpellier,
Montpellier34295,
France (Y.D., R.L.).
Neurobiology Research
151A3, University
College Los Angeles,
Veterans Administration
Greater Los Angeles
Healthcare System,
16111 Plummer Street,
North Hills, CA 91343,
USA (J.M.S.). Centre for
Brain Sciences,
Department of Cell and
Systems Biology,
University of Toronto,
Toronto, ON M4X 1H7,
Canada (Z.A.T., J.H.P.).
Correspondence to: Y.D.
ydauvilliers@yahoo.fr
Cataplexy—clinical aspects, pathophysiology
and management strategy
Yves Dauvilliers, Jerry M. Siegel, Regis Lopez, Zoltan A. Torontali and John H. Peever
Abstract | Cataplexy is the pathognomonic symptom of narcolepsy, and is the sudden uncontrollable onset
of skeletal muscle paralysis or weakness during wakefulness. Cataplexy is incapacitating because it leaves
the individual awake but temporarily either fully or partially paralyzed. Occurring spontaneously, cataplexy is
typically triggered by strong positive emotions such as laughter and is often underdiagnosed owing to a variable
disease course in terms of age of onset, presenting symptoms, triggers, frequency and intensity of attacks. This
disorder occurs almost exclusively in patients with depletion of hypothalamic orexin neurons. One pathogenetic
mechanism that has been hypothesized for cataplexy is the activation, during wakefulness, of brainstem
circuitry that normally induces muscle tone suppression in rapid eye movement sleep. Muscle weakness during
cataplexy is caused by decreased excitation of noradrenergic neurons and increased inhibition of skeletal motor
neurons by γ‑aminobutyric acid‑releasing or glycinergic neurons. The amygdala and medial prefrontal cortex
contain neural pathways through which positive emotions probably trigger cataplectic attacks. Despite major
advances in understanding disease mechanisms in cataplexy, therapeutic management is largely symptomatic,
with antidepressants and γ‑hydroxybutyrate being the most effective treatments. This Review describes the
clinical and pathophysiological aspects of cataplexy, and outlines optimal therapeutic management strategies.
Dauvilliers, Y. etal. Nat. Rev. Neurol. advance online publication 3 June 2014; doi:10.1038/nrneurol.2014.97
Introduction
Cataplexy is defined as sudden involuntary muscle weak-
ness or paralysis during wakefulness, typically triggered
by strong emotions, and is the pathognomonic symptom
of narcolepsy with cataplexy—a sleep disorder that affects
0.06% of the adult population.1,2 In addition to cataplexy,
narcolepsy is characterized by sleep paralysis, sleep-onset
rapid eye movement (REM) periods, hypnagogic hallu-
cinations, and fragmented night-time sleep.3,4 Cataplexy
is virtually exclusive to patients with narcolepsy, and is
the optimal behavioural biomarker of this disease.2–4
Excessive daytime sleepiness (EDS) is usually the present-
ing symptom of narcolepsy, and cata plexy often develops
within 1year of birth and persists for life, although some
patients report a delay between EDS and the onset of cata-
plexy of more than 5years.5 The age of onset of narco-
lepsy ranges from early childhood (with 5% of patients in
the prepubertal stage) to the fifth decade, with a bimodal
distribution that peaks at 15years and 35years of age.5
Patients with narcolepsy have difficulty in executing daily
activities, socializing and maintaining personal relation-
ships mainly due to cataplexy and EDS, and are esti-
mated to experience a quality of life that is comparable or
inferiorto that of patients with epilepsy or sleep apnoea.6,7
Cataplexy has been identified in a range of species,
including humans, horses, dogs and mice.8,9 Genetic
studies of cataplexy in dogs and mice indicate that loss
of functional orexin or mutations in the genes encod-
ing orexin receptors underlie the pathophysiology.10–13
Humans with narcolepsy and cataplexy have a marked
decrease in orexin levels in cerebrospinal fluid (CSF),
together with a decreased number of orexin neurons
in postmortem brain tissue.2,14–16 The close associa-
tions of narcolepsy or cataplexy with HLA-DQB1*06:02,
polymorphisms in the T-cell receptor α and P2RY11
genes, and the pandemic anti-H1N1 vaccination,
suggest that the loss of orexin neurons might have an
autoimmuneorigin.17–23
This Review is timely because cataplexy is still an
under-recognized symptom of narcolepsy—a disease
that is currently underdiagnosed, especially in children.
In Europe, the delay between the onset of symptoms and
a correct diagnosis is about 10years, due to insufficient
awareness and understanding of the condition among
clinicians and individuals.24 Considering that the onset of
narcolepsy is mainly in the second decade of life, and the
condition can remain untreated for a further 10years,
many patients are affected during the most important
period in their education and/or career. To overcome
these consequences of narcolepsy and cataplexy, early
diagnosis and treatment are essential to best improve
patient quality of life.
Features of cataplexy
Cataplexy can be difficult to diagnose, as the symp-
toms vary not only between patients but also within
Competing interests
Y.D. declares that he has received speaker honoraria and
support for travel to meetings and has participated on the
advisory boards for the following companies: UCB Pharma, JAZZ
and Bioprojet. The other authors declare no competing interests.
REVIEWS
© 2014 Macmillan Publishers Limited. All rights reserved

2
|
ADVANCE ONLINE PUBLICATION www.nature.com/nrneurol
individuals. For example, different cataplexy phenotypes
exist in terms of age of onset, presenting symptoms (that
is, the muscles affected), triggers (for example, laughter
versus anger), frequency and severity, and the frequency
of attacks often decreases with time.4,25,26 Cataplectic
attacks range from partial muscle weakness to complete
paralysis, but are always bilateral, even if one side of the
body is more affected than the other. These attacks are
debilitating for patients because they leave the affected
individual awake but either fully or partially para lyzed.
Cataplexy affects all skeletal muscles apart from the dia-
phragm and extraocular muscles, but its greatest effect
is on facial and neck muscles. Typically, the result is
dysarthria, twitching of the facial muscles, jaw tremor,
head dropping or jaw dropping, dropping of objects,
and/or buckling of the knees (Supplementary Video 1
online). Extreme muscle weakness in the knees, arms and
shoulders is also common. 50% of patients with cataplexy
experience both partial muscle weakness and complete
paralysis, whereas 30% experience only partial paraly-
sis.25,27 Injury during cataplexy is uncommon because
most patients ‘feel’ the onset of muscle weakness and
are able to sit or lie down. In rare instances, however, a
cataplectic attack may result in fractures or bruises to the
patient, and might be dangerous in certain settings (for
example, during swimming).
During a cataplectic attack, patients remain con-
scious and are able to remember what happened to them
before, during and after the cataplectic episode.28 Some
patients with narcolepsy report hypnagogic hallucina-
tions during attacks, and some patients enter into REM
sleep, but this is rare.29 Skeletal muscle tone is reduced or
absent during a cataplectic episode. A study of the neuro-
physiology of cataplexy indicates waxing and waning of
postural muscle tone during cataplexy attacks that pro-
gresses along muscle groups rostro-caudally. Most epi-
sodes are accompanied by reduced heart rate and EEG
desynchronization (Figure1).29,30
The duration of an attack varies from several seconds
to several minutes, and in rare instances it lasts for
hours—a condition known as status cataplecticus.2 The
frequency of cataplectic attacks in patients varies from
fewer than one episode per year to several episodes per
day. Many patients with narcolepsy report that sleep loss
and fatigue worsen the frequency of cataplectic attacks,
but studies have not shown a clear link between sleep
patterns (total sleep time, sleep efficiency, percentage of
sleep stages, periodic leg movements and REM behaviour
disorder), EDS and the severity of cataplexy.31 Cataplexy
persists throughout life, although the frequency of
attacks might decrease with age.31 Men often experience
a higher number of cataplectic attacks than do women.31
Near the time of disease onset, children with narco-
lepsy often display abnormal motor behaviour that
does not meet the classic definition of cataplexy.31 Some
children display a complex array of ‘negative’ (that is,
hypotonic) and ‘active’ movements (for example, jaw
opening with tongue protrusion, closure of eyelids and
dyskinetic– dystonic movements) that can occur without
any obvious emotional triggers.32 These symptoms,
however, decrease over a 3year period and evolve into
the classic cataplectic attacks described.33
In clinical practice, cataplexy is mostly diagnosed
on the basis of the patient’s history. Cataplexy is often
documented in verbal reports, videos taken by the
patient’s family or, in some patients, after cataplec-
tic episodes that occur in the presence of a physician.
The clinical description of cataplectic attacks should be
precise to enable classification as ‘typical’ or ‘clear-cut’,
and should include triggering factors, muscles that are
affected, duration and frequency of attacks. In patients
with a potential differential diagnosis, the term ‘atypical’
cataplexy should be used and an assay of orexin levels
in CSF used to verify the diagnosis of orexin deficiency
ornarcolepsy.
Trigger factors
In the International Classification of Sleep Disorders,
narcolepsy is classified as type1 or type2.34 According
to this classification, type1 narcolepsy (narcolepsy with
cataplexy) is defined as EDS that persists for at least
3months, plus at least two of the following: clear-cut
cataplexy, a positive result on the Multiple Sleep Latency
Test (that is, time elapsed from the start of a daytime nap
period to the first signs of sleep of ≤8 min, and two or
more sleep-onset REM periods) or low levels of orexin
in CSF. Type2 narcolepsy (narcolepsy without cataplexy,
which as an entity remains controversial with unknown
prevalence) is diagnosed as EDS that persists for at least
3months and a positive result on the Multiple Sleep
Latency Test, in the presence of normal levels of orexin.
The presence of atypical cataplexy is sometimes reported
in type2 narcolepsy.
More than 90% of patients with narcolepsy and cata-
plexy present with low levels of orexin (<110 pg/ml) in
CSF, which undoubtedly stem from the loss of approxi-
mately 90% of orexin-expressing neurons.2,14,15 By con-
trast, more than 80% of individuals who are healthy or
have atypical cataplexy have normal levels of orexin.35
Importantly, a postmortem study of a patient who exhib-
ited narcolepsy without cataplexy indicated loss of 33%
of orexin-positive cells, largely in the posterior hypo-
thalamus.36 This finding suggests that narcolepsy with
Key points
■Cataplexy is the pathognomonic symptom of narcolepsy, and is characterized
by sudden involuntary loss of skeletal muscle tone during wakefulness, typically
triggered by strong positive emotions
■The pathogenesis of cataplexy in human narcolepsy involves degeneration of
orexin neurons in the hypothalamus; genetically induced orexin deficiency causes
cataplexy in both mice and dogs
■Cataplexy is thought to result from activation during wakefulness of the sleep
circuitry involved in rapid eye movement sleep
■Reduced noradrenergic and increased inhibitory input to motor neurons causes
muscle weakness or paralysis during cataplexy; positive emotions trigger
cataplexy through neuronal pathways in the amygdala and medial prefrontal cortex
■ γ‑Hydroxybutyrate (GHB) and antidepressants are effective treatments for
cataplexy, but most treatments (excluding GHB) are used ‘off‑label’
■Novel and experimental treatments to manage cataplexy are required, including
orexin replacement therapy and immune‑based therapies
REVIEWS
© 2014 Macmillan Publishers Limited. All rights reserved

NATURE REVIEWS
|
NEUROLOGY ADVANCE ONLINE PUBLICATION
|
3
cataplexy only ensues when a patient loses almost all
their orexin-positive cells.14,15,36
The association of H1N1 virus infection or anti-H1N1
vaccination with narcolepsy or narcolepsy with cata-
plexy is well-established.21,23,37 For example, a substan-
tial spike in newly diagnosed cases of narcolepsy or
narcolepsy with cataplexy in children and adolescents
who were exposed to the H1N1 virus or the vaccine
has been recorded.21,23,37 A study of patients with narco-
lepsy revealed the presence of CD4+ Tcells that were
reactive to orexin and might also be reactive to a similar
epitope on the H1N1 virus.38 The presence of high titres
a
b
Cataplexy onset
EOGD
EOGG
EMG1
Fp2-O2
Fp1-O1
Fp2-C4
C4-O2
Fp1-C3
C3-O1
Fp2-T4
C4-T4
O2-T4
FP1-T3
C3-T3
O1-T3
ECG
EOGD
EOGG
EMG
Fp2-O2
Fp1-O1
Fp2-C4
C4-O2
Fp1-C3
C3-O1
Fp2-T4
C4-T4
O2-T4
FP1-T3
C3-T3
O1-T3
ECG
Figure 1 | Video‑polysomnographic recording of a patient during a cataplectic attack with loss of muscle tone. Video clips
were taken sequentially over a period of a | 2 min and b | 30 s. The patient presents with sustained loss of muscle tone
thatalternates with brief enhanced EMG activity leading to a flapping up‑and‑down motion of the body segments. These
movements were reported as voluntary by the patient, who was trying to fight against the repetitive postural losses. The
patient was fully conscious during the entire episode. Note that the EEG is characterized by low voltage frequencies
(alphaand theta) and a decrease in heart rate during the brief suppressions of EMG activity. Abbreviations: ECG,
electrocardiogram; EMG, electromyogram; EOGD, right electrooculogram; EOGG, left electrooculogram. Written consent
forpublication was obtained from the patient.
REVIEWS
© 2014 Macmillan Publishers Limited. All rights reserved

4
|
ADVANCE ONLINE PUBLICATION www.nature.com/nrneurol
of antibodies against streptolysin O and Tribbles homo-
logue2 (TRB-2, a protein that is abundant in orexin
neurons) near the onset of narcolepsy also suggests
an auto immune basis for the disease and the potential
for immunotherapy by generating crossreactive anti-
bodies.39,40 However, autoantibodies against TRB-2 in
mice and other species might be a consequence rather
than a cause of orexin neuron damage.
A link between cataplexy and emotion
A cataplectic attack is generally triggered by strong
positive emotions such as excited laughter, repartee
(for example, making a clever remark), elation, or sur-
prise (for example, unexpectedly meeting a friend).25
Infrequently, they are associated with negative emotions
such as frustration or anger or, even more rarely, by stress,
fear or physical effort.2,25,41 Although a certain intensity of
positive emotion is required to trigger a catapletic attack,
nearly half of all patients experience spontaneous attacks
that have no identifiable trigger.25,32,42
Benign muscle weakness, especially in the lower limbs,
often occurs in healthy people when they laugh, hence
the expression ‘weak with laughter’.43 This muscle weak-
ness is linked to suppression of the Hoffmann reflex,
which occurs during normal laughter in healthy indi-
viduals.44 Orexin neurons are active in the response
to strong emotions; therefore, loss of orexin-positive
neurons in patients who have narcolepsy or narcolepsy
with cataplexy hypothetically destabilizes the motor
control system within the brainstem such that posi-
tive emotions trigger severe muscle weakness or total
motorparalysis.8,45
Evidence exists that patients with cataplexy have
altered neuronal responses to positive emotions. For
example, neurophysiological data show that process-
ing of humorous stimuli is temporally disturbed in
patients with narcolepsy or narcolepsy and cataplexy.46
Neuroimaging studies show that patients with narco-
lepsy have a reduced threshold for neuronal activation
in the amygdala (a brain region that has a key role in
the regulation of emotional activity) in response to
both humorous and reward stimuli compared with con-
trols.47,48 In addition, functional neuroimaging studies
describe changes in brain perfusion49 and glucose
metabolism50 during cataplexy in humans. A PET study
revealed increased metabolic activity during cataplexy
in the bilateral precentral and postcentral gyri and
primary somatosensory cortex, and a marked decrease
in activity in the hypothalamus.50 A study using single-
photon emission CT indicated hyperperfusion in the
right amygdala, bilateral cingulate gyri, basal ganglia,
thalamus, premotor cortex, sensorimotor cortex, right
insula, and brainstem, and hypoperfusion in the pre-
frontal cortex and occipital lobe, during cataplexy.49,50
Abnormal functioning of the amygdala during cataplexy
might stem from orexin deficiency, because the release
of orexin from neurons is maximal when healthy indi-
viduals are experiencing positive emotions.51 Animal
studies also indicate that cataplexy is associated with
abnormal function of the amygdala. Postmortem data
show marked axonal degeneration in the amygdala of
narcoleptic dogs, and electrophysiological recordings
demonstrate that individual cells in the amygdala have
increased firing rates during cataplexy.52,53
Animal models
Genetic studies in narcoleptic dogs and mice have pro-
vided valuable insights into the pathophysiology of cata-
plexy. Genetic deletion of Hcrt, which encodes orexin,
in mice and the consequent degeneration of orexin-
expressing neurons induces a behavioural pheno type
that recapitulates the cardinal features of human narco-
lepsy, including cataplexy, sleepiness and disturbed REM
sleep.10,11,13 In dogs, introduction of exon skipping into
the Hcrt-R2 gene causes a narcoleptic phenotype, includ-
ing cataplexy.12,53 These findings not only corroborate
human data showing that narcolepsy or narcolepsy and
cataplexy is the result of abnormal functioning of the
orexin system (Figure2), but also suggest that the orexin
system is important in promoting arousal, controlling
REM sleep, and regulating postural muscle tone.45,53
Cataplectic attacks in Hcrt–/– mice seem remarkably
similar to those in human cataplexy (Table1). Attacks
are characterized by the rapid onset of skeletal muscle
paralysis during wakefulness, resulting in abrupt pos-
tural collapse that terminates purposeful behaviour
(Supplementary Video 2 online).8 Mice seem to be awake
during attacks, because they respond to visual stimuli,
and their EEG activity is similar to the spectrum of
waking EEG activity seen during cataplectic episodes
in children.13,54 Most cataplectic attacks in Hcrt–/– mice
range from 15 s to 2 min, with a mean duration of about
LH
Orexin
Muscle
Amygdala
Excitatory
Disinhibition
Inhibitory
Positive
emotions
mPFC
SubC
vlPAG
LPT LC Cataplexy
MM Motor
neurons
Figure 2 | Hypothetical circuits and pathways controlling cataplexy in the rodent
brain. Activation during wakefulness of neural circuits involved in REM sleep
paralysis is thought to underlie cataplexy, and is probably triggered by a two‑part
brainstem circuit—the SubC and MM connection. Glutamatergic neurons in the
SubC trigger REM paralysis by activating GABAergic or glycinergic cells in the MM,
which in turn project to and inhibit skeletal motor neurons. When a positive
emotion is experienced, GABAergic neurons in the CeA switch on and inhibit cells
in the LC, vlPAG and LPT. The LC–vlPAG–LPT circuit normally prevents muscle
paralysis during wakefulness by suppressing the activity of SubC neurons.
GABAergic CeA neurons inhibit neurons in the LC–vlPAG–LPT circuit, which in turn
disinhibits the SubC to motor neuron circuit, triggering muscle paralysis and
cataplexy. Muscle paralysis in cataplexy is also enabled by loss of noradrenergic
input from LC neurons, which are inhibited during cataplexy. In healthy individuals,
orexin‑expressing neuronal activity cancels out the inhibitory effect of amygdalar
neurons. Abbreviations: CeA, central amygdala; GABA, γ‑aminobutyric acid; LC,
locus coeruleus; LH, lateral hypothalamus; LPT, lateral pontine tegmentum; MM,
medial medulla; mPFC, medial prefrontal cortex; REM, rapid eye movement; SubC,
subcoereulus; vlPAG, ventrolateral periaqueductal grey.
REVIEWS
© 2014 Macmillan Publishers Limited. All rights reserved

NATURE REVIEWS
|
NEUROLOGY ADVANCE ONLINE PUBLICATION
|
5
60 s, similar to human cataplexy. Cataplectic attacks
end with rapid restoration of muscle tone and resump-
tion of normal waking behaviour, as they do in patients
withnarcolepsy.
As in humans with narcolepsy, cataplectic attacks in
narcoleptic dogs and mice can be triggered by posi-
tive emotional stimuli. In narcoleptic dogs, cataplexy is
triggered by palatable foods, play or sex, and in narco-
leptic mice it is triggered by reward stimuli such as
social reunion, running in wheels and palatable food
(Supplementary Video 3 online).55,56 The frequency of
cataplectic attacks is significantly increased when Hcr t–/–
mice are given access to running wheels and chocolate,
which are both reward stimuli for mice.41,57 EEG record-
ings in narcoleptic mice show that cataplexy begins with
a brief phase of wakefulness, followed by high-amplitude
irregular theta activity and then by short 1–2 s bursts of
high-amplitude, regular (~7 Hz), hypersynchronous
paroxysmal theta activity.54 Intracranial EEG recordings
also show that this activity involves the medial pre frontal
cortex, a region associated with reward-driven motor
impulses.54 Interestingly, hypersynchronous paroxysmal
theta activity (~4 Hz) is also observed at the onset of cata-
plexy in children with narcolepsy. These bursts of activity
might represent medial prefrontal cortical activity, but
the clinical relevance of this finding is unclear.54
Neurobiology
A longstanding hypothesis in sleep medicine is that cata-
plexy results from the intrusion of REM sleep paralysis
into wakefulness.2,4,58 This idea stems from the obser-
vation that cataplexy and REM sleep paralysis have a
common neural mechanism.59 For example, tricyclic
antidepressants , which are used to alleviate cataplexy,
also suppress REM sleep, and rapid withdrawal of these
drugs causes a rebound of either cataplexy or REM
sleep.2,60 Deep tendon and monosynaptic Hoffmann
reflex activity are absent during both cataplexy and
REM sleep.2,4,44 Neuroimaging studies of patients with
narcolepsy and electrophysiological recordings from
isolated cells in narcoleptic dogs show that the brain-
stem circuitry involved in REM sleep might have similar
activity during both REM sleep and cataplectic epi-
sodes.49,52 The underlying cause of clinical cataplexy
is a reduction in skeletal motor neuron activity, which
results from increased inhibitory and reduced excitatory
signalling in the brain.41,58 Inhibitory signals are pro-
duced by γ-aminobutyric acid-releasing (GABAergic)
and glycinergic neurons in the medial medulla, which
are intensely activated during cataplexy and REM sleep,
but not during normal waking.55,61,62 Simultaneously,
pontine grey neurons, which are responsible for atonia
both in cataplexy and in REM sleep, activate GABAergic
neurons, which in turn inhibit noradrenergic neurons in
the locus coeruleus (Figure2).63 The cessation of firing
of noradrenergic neurons stops the release of noradrena-
line to motor neurons and results in their disfacilitation.8
The two processes cause reduced motor neuron activity
and a decrease in, or elimination of, tone in the postural
muscles (Figure2).58,64
The close association between the occurrence of cata-
plexy and orexin deficiency in patients with narcolepsy
and animal models of narcolepsy suggests that orexin
has a key role in the pathophysiology of cataplexy.2
The strength of the excitatory projections from orexin
neurons to the noradrenergic neurons in the locus coer-
uleus is thought to prevent cataplexy in healthy individ-
uals.65,66 In patients with narcolepsy or narcolepsy and
cataplexy, however, orexin deficiency reduces normal
levels of noradrenergic neuronal activity, which closely
correlates with cataplectic attacks in Hcrt–/– mice, and
dogs with narcolepsy.8,66 Drugs that increase noradrena-
line levels in the CNS are effective in alleviating cataplexy
in humans, dogs and mice.8,26,65 A study demonstrated
that the frequency of cataplectic attacks was reduced
when orexin receptors were restored to serotonergic
neurons in the dorsal raphe of mice lacking orexin
receptors, which suggests the serotonin signalling system
Table 1 | Cataplexy in humans and animal models
Features Human Mouse* Dog‡
Behavioural Postural collapse, jaw sagging,
weak knees
Postural collapse, falling prone
oronto their sides
Postural collapse, weakness
Level of
consciousness
Awake (memory of episode) Probably awake (response to
visual stimuli intact)
Awake (response to visual stimuli
intact)
Triggers Strong positive emotions
(forexample, laughter, joking,
elation)
Emotionally rewarding behaviours
(for example, eating palatable
food, running, social interaction)
Emotionally rewarding behaviours
(forexample, eating palatable food,
running, social interaction)
Duration of
cataplectic attach
Brief (seconds to minutes) Brief (seconds to minutes) Brief (seconds to minutes)
Cortical EEG Mixture of waking and
REM‑sleep‑like EEG
Mixture of waking and
REM‑sleep‑like EEG
Mixture of waking and REM‑sleep‑like
EEG
Muscle tone Muscle paralysis or weakness;
loss of EMG activity
Muscle paralysis; loss of EMG
activity
Muscle paralysis; loss of EMG activity
Therapy Suppressed by monoamine
reuptake blockers (for example,
antidepressants) and GHB
Suppressed by monoamine
reuptake blockers (for example,
antidepressants) and GHB
Suppressed by monoamine reuptake
blockers (for example, antidepressants)
but no response to GHB
*Hcrt–/– mouse model. ‡Disruption of Hcr tr2. Abbreviations: EMG, electromyogram; GHB, γ‑hydroxybutyrate; REM, rapid eye movement.
REVIEWS
© 2014 Macmillan Publishers Limited. All rights reserved

6
|
ADVANCE ONLINE PUBLICATION www.nature.com/nrneurol
could also be involved in cataplexy.67 Previous work has
shown that activity of serotonergic neurons in the dorsal
raphe does not change during cataplexy, in contrast to
noradrenergic neurons in the locus coeruleus.65,68
Orexin A and orexin B are two different peptides
produced by 70,000–80,000 neurons in the healthy
hypothalamus in humans. Orexin neurons not only
strongly innervate and directly excite noradrener-
gic, dopaminergic, serotonergic, histaminergic and
cholinergic neurons, but also modulate the release
of glutamate and other amino acid transmitters.69,70
Behavioural studies revealed that orexin is released at
high levels during active waking, at intermediate or
low levels in quiet but alert waking periods and during
REM sleep, and at minimal levels in non-REM sleep.71,72
Electrophysiological recording of neuronal unit activ-
ity in narcoleptic dogs shows that most of the brain
regions involved in the generation of REM sleep atonia
are alsoinvolved in episodes of cataplexy.52,55,68,73 Thus,
at the neuronal level, these findings support the concept
of cataplexy as an intrusion of REM sleep paralysis into
wakefulness. Cataplexy is not identical to REM sleep,
however, the main difference being the maintenance
of consciousness. Preservation of activity of histamin-
ergic neurons during cataplexy but not in REM sleep
suggests a function for histamine in maintaining wake-
fulness during cataplectic episodes.66 Orexin neuron
activity and orexin release are absent during conditions
of quiet waking and drowsiness, but the cessation of
this neuronal activity is not sufficient enough to cause
cataplexy under normal physiological conditions; thus,
the absence of orexin neurons in narcolepsy or narco-
lepsy and cataplexy might be associated with other ana-
tomicaland physiological changes in the brain, perhaps
secondary to orexin malfunction.74–76 Accordingly, two
studies of histaminergic neurons in human narcolepsy
or narco lepsy and cataplexy indicated an increase in
numbers of these neurons, but this result differs from
results in animal models.77,78 The relationship between
changes in histaminergic neuronal numbers, cataplexy
and other symptoms of narcolepsy across different
species is unclear.
The amygdala has an important role in the process-
ing of emotional stimuli79 and, therefore, might also be
important in triggering cataplexy. Clinical and basic
research studies show that changes in neuronal activity
in the amygdala are associated with cataplexy. Functional
neuroimaging shows increased activity in the amygdala
while patients watch humorous photographic images,
and electrophysiological recordings from isolated cells
in narcoleptic dogs demonstrate that activity of certain
amygdalar neurons is closely associated with cataplec-
tic attacks.52,80 Another study indicates that bilateral
lesionsof the amygdala significantly reduce the fre-
quency ofcataplectic attacks in Hcrt –/– mice.41 A popula-
tion of GABAergic neurons in the amygdala innervates
the locus coeruleus, lateral pontine tegmentum (LPT)
and ventro lateral periaqueductal grey (vlPAG), the
functions of which are to support muscle tone during
wakefulness.41 Lesions in the LPT and vlPAG in rodents
cause sporadic bouts of muscle paralysis during wakeful-
ness that resemble cataplectic attacks, and inactivity of
locus coeruleus neurons is associated with muscle atonia
during cataplexy.8,66,81,82 In patients experiencing positive
emotions, therefore, GABAergic neurons in the amyg-
dala might become active and in turn inhibit the activity
of cells in the locus coeruleus, LPT and vlPAG that would
normally maintain waking postural tone.
The medial prefrontal cortex (mPFC) also has a role
in triggering cataplexy. Ingestion of palatable foods (for
example, chocolate), which trigger cataplexy in Hcrt–/–
mice, also activates neurons in the mPFC, and inhibition
of mPFC neurons markedly reduces cataplectic attacks
associated with positive emotional stimuli.83 In addition,
neurons in the mPFC innervate the amygdala and lateral
hypothalamus, which contain neurons that are active
during cataplexy and might innervate brainstem regions
involved in the regulation of muscle tone.
Treatment
The inhibitory effect of various antidepressants on the
adrenergic system is supported by invivo and invitro
studies.84 The dopaminergic system is involved in the
regulation of cataplexy via the D2-like receptor inmouse
models of narcolepsy. The frequency of cataplectic
attacks in these mice increases after D2-like recep-
tor activation, and decreases after receptor blockade.85
Cholinergic systems are also thought to be important in
the regulation of cataplexy in animal models, with stim-
ulation of the cholinergic system severely aggravating
canine cataplexy.86
The effectiveness of drugs used to treat cataplexy is
difficult to evaluate, as the methods employed to assess
the frequency and intensity of attacks—for example,
recall history, scale, diaries or video recordings—vary
from one study to another. Some patients might exhibit
a decrease in frequency and severity of cataplectic attacks
with disease duration. Behavioural measures such as cog-
nitive behavioural therapy might be of interest for some
patients to enable them to either control their emotion or
learn to avoid situations that trigger cataplectic attacks,
but this approach is not usually sufficiently effective to
be considered as a recommended treatment.
Antidepressants
Antidepressants and γ-hydroxybutyrate (GHB, also
known as sodium oxybate) are reportedly the most effec-
tive drugs to treat cataplexy (Table2).87 Neither tricyclic
agents nor selective serotonin reuptake inhibitors (SSRIs)
or selective norepinephrine reuptake inhibitors (SNRIs)
are approved by the European Medicines Agency or the
FDA for the treatment of cataplexy in children or adults.
This practice is based only on expert opinion, as no
studies demonstrating efficacy and safety of these drugs
for this indication have been carried out.
Tricyclic agents, which were the first drugs used to
treat cataplexy,87,88 are nonspecific monoamine reuptake
inhibitors that increase the availability of serotonin,
noradrenaline and, in some cases, dopamine.88 Some
tricyclic agents also have anticholinergic properties,
REVIEWS
© 2014 Macmillan Publishers Limited. All rights reserved

NATURE REVIEWS
|
NEUROLOGY ADVANCE ONLINE PUBLICATION
|
7
which might contribute to their anticataplectic effect.
Clomipramine is the most widely used tricyclic agent
to treat cataplexy.87 Often, these agents have an effect
on cataplexy within 48 h at doses below those required
to treat depression, but tolerance frequently develops.
Cataplexy rebound, or status cataplecticus, which is
defined by an increase in the number of attacks and
the severity of cataplexy, typically occurs if antidepres-
sant intake, especially tricyclic agents, is interrupted or
abruptly halted.
Monoamine oxidase inhibitors (MAOIs) increase
the availability of the monoamine neurotransmitters,
for example, dopamine, noradrenaline and serotonin.
Studies have indicated that MAOIs (specifically, sele-
giline hydrochloride) strongly suppress REM sleep and
reduce the frequency of cataplectic attacks, but these
drugs are now rarely used because they are associated
with serious adverse effects.87
SSRIs (fluoxetine, paroxetine and citalopram),
although less effective than tricyclic antidepressants in
decreasing the frequency of cataplectic attacks, are widely
used for this purpose, and the frequency of associ ated
adverse effects is lower than for tricyclic agents. SSRIs,
and SNRIs (such as venlafaxine, duloxetine and milnacip-
ran), are the antidepressants most widely used to treat
cataplexy, particularly venlafaxine as it is effective within
48 h.87 Due to the short duration of action of venlafaxine,
the extended-release form seems to be preferable, start-
ing at a low dose (37.5 mg) but higher doses are often
needed (75–300 mg). Venlafaxine is not recommended
for treatment in pregnant women with narcolepsy, but
has an acceptable tolerance profile for use in children.89,90
The differential efficacy of venlafaxine on either ‘nega-
tive’ (hypotonia) or ‘active’ motor components during
cataplexy is unknown. Other SNRIs, such as duloxetine
and milnacipran, or noradrenaline reuptake inhibitors,
such as viloxazine, reboxetine, atomoxetine and bupro-
pion, seem to be promising treatments in decreasing the
frequency of cataplectic attacks, are well tolerated, and
have a mild stimulant effect.91,92
γ‑Hydroxybutyrate
GHB is a natural metabolite of γ-aminobutyrate and func-
tions as a neurotransmitter at the GHB receptor (GHBR;
also known as solute carrier family 52, riboflavin trans-
porter, member 2) at physiological concentrations and as a
GABA receptor agonist at pharmacological concentrations,
and also modulates dopaminergicsignalling.93
GHB is effective at reducing both the frequency and
intensity of cataplectic attacks, as well as restoring noc-
turnal sleep continuity and reducing EDS in patients
with narcolepsy or narcolepsy and cataplexy.93–95 Despite
a half-life of only 40–60 min, its clinical benefit persists
well beyond this period, and with nightly use the benefit
is significant after 4weeks, highest after 8weeks, and
maintained during long-term therapy.94,95 GHB also has
an acceptable tolerance profile for treatment of children;
however, as for venlafaxine, its relative efficacy on negative
versus active components of cataplexy is unknown.89 It ca n
also be used with antidepressant or stimulant therapy, but
should not be used in conjunction with alcohol.95 Unlike
antidepressants, interruptionof treatment with GHB does
not result in a rebound ofcataplexy. One major issue with
the use of GHB is its nonmedical use, as it is sometimes
used in athletes for performance enhancement owing to
its metabolic effects. Safety data and clinical experience of
GHB therapy indicate that the potential for misuse is low
in patients withnarcolepsy.95,96,97
Effects of stimulants
Drugs that increase adrenergic and dopaminergic
signalling, such as amphetamines, methylphenidate
hydro chlor ide and mazindol (but not modafinil), also
decrease the frequency of cataplectic attacks. Although
rarely used in practice, mazindol is a tricyclic, anorec-
tic, nonamphetamine that is a very effective stimulant
(half-life 10 h) and is also effective in the treatment of
cataplexy.95 A careful cardiological follow-up is required
Table 2 | Therapies for cataplexy
Mode of action Treatment Dose
First line
GABAB agonist that
modulates dopamine
neurotransmission
GHB 6–9 g per night*
Norepinephrine and
serotonin reuptake
inhibitor
Venlafaxine 37.5–300.0 mg
perday
Selective serotonin
reuptake inhibitors
Fluoxetine
Citalopram
20–60 g per day
20–40 mg per day
Tricyclic
antidepressants
Clomipramine
Protriptyline
10–20 mg per day
5–10 mg per day
Second line
Tricyclic
antidepressants
Clomipramine
Protriptyline
30–100 mg per day
20–80 mg per day
Norepinephrine and
serotonin reuptake
inhibitor
Duloxetine 30–120 mg per day
Norepinephrine
reuptake inhibitors
Reboxetine
Atomoxetine
2–10 mg per day
2–10 mg per day
Third line
Tricyclic, anorectic,
nonamphetamine
stimulant
Mazindol 1–4 mg per day
Monoamine oxidase
inhibitor
Selegiline 20–40 mg per day
Future therapies
GABAB agonist GHB
slow‑release
6–9 g per night*
NA Immune‑based
therapy at
disease onset
Intravenous
immunoglobulin,
plasmapheresis or
monoclonal antibodies
NA Orexin,
orexinagonists
or orexin‑
expressing cell
transplantation
NA
*GHB is the first and only medication indicated for cataplexy. Abbreviations:
GABAB, γ‑aminobutyric acid type B receptor; GHB, γ‑hydroxybutyrate; NA, not
applicable.
REVIEWS
© 2014 Macmillan Publishers Limited. All rights reserved

8
|
ADVANCE ONLINE PUBLICATION www.nature.com/nrneurol
with mazindol and amphetamines. Mazindol has less
potential for misuse and development of tolerance than
amphetamines in patients with narcolepsy.
Future therapeutic management
Orexin deficiency underlies the pathophysiology of cata-
plexy; therefore, orexin replacement therapy could be
an effective strategy. In humans, the use of orexin-based
treatment has been disappointing; however, there has
been some success with this approach in treating cata-
plexy in dogs.98,99 Intraventricular delivery of orexinA
has potential efficacy, but is probably inappropriate for
long-term therapy. Intranasal delivery to bypass the
blood–brain barrier is a noninvasive method to deliver
orexin to the brain. This method has been shown to
improve cognition and olfactory performance and stabi-
lize sleep in rhesus monkeys and patients with narco-
lepsy or narcolepsy and cataplexy, but has not been tested
for its effects on cataplexy alone.100–103 Synthetic orexin
receptor agonists might be another treatment option.
Transplantation of orexin neurons might, theoretically,
provide a cure for patients with narcolepsy, even if the
results of neuronal transplantation in other diseases have
been disappointing, with graft rejection and low survival
rates of the implant.104,105
The activation of histaminergic neurons by an inverse
agonist of the histamine H3 receptor, which is presyn-
aptic and enhances histamine release, is a promising
therapy. One of these compounds, pitolisant, improved
wakefulness in normal animals, blocked abnormal tran-
sition from wakefulness to REM sleep in Hcrt–/– mice,
and decreased sleepiness and might have the potential to
treat cataplectic attacks in patients with narcolepsy.106,107
Finally, on the basis of the immune-mediated hypoth-
esis for the loss of orexin neurons, we suggest that
immuno therapies at disease onset might modify the
long-term disease outcome if the ‘autoimmune’ process
that targets orexin neurons is not too advanced and
can be partially reversed. Corticosteroids, intravenous
immunoglobulin, plasmapheresis, immunoadsorption
and alemtuzumab have all been tested in the treatment of
cataplexy, with variable efficacy.108–112 In one patient who
had undetect able levels of orexin in the CSF, intravenous
immunoglobulin treatment only 15days after disease
onset resulted in clinical improvement of cataplexy and
biological normalization of CSF orexin A levels.113 At the
onset of narcolepsy, high doses of immunomodulators
might downregulate T-cell functions and pathogenic
cytokines and interfere with autoantigen recognition
through HLA-DQB1*06:02 expression during induc-
tion therapy.114 Well-designed trials of immunotherapies
in patients at the onset of disease are needed; however,
an improved understanding of the pathophysiology of
orexin neuron loss is also required to develop effective
treatment strategies.
Conclusions
Cataplexy is the pathognomonic symptom of narcolepsy,
but is underdiagnosed as a symptom as it varies pheno-
typically in terms of age of onset, affected muscle group,
trigger factors, frequency and intensity. Cataplexy results
from the inappropriate activation during wakefulness of
the brainstem circuits that normally generate muscle
atonia during REM sleep. The pathological intrusion
of REM sleep paralysis into wakefulness occurs almost
exclusively when orexin neurons are depleted. Neurons
expressing orexin normally serve to drive and synchro-
nize the activity of monoaminergic and cholinergic
neuro nal systems. The loss of an excitatory noradrener-
gic drive onto motor neurons underlies the loss of pos-
tural muscle tone during cataplexy. Involvement of the
amygdala and medial prefrontal cortex is highlighted by
the triggering of cataplectic attacks by emotional stimuli
and processing thereof.
To overcome the consequences of narcolepsy and
cataplexy, early diagnosis and treatment of patients are
essential. Despite a major advance in our understand-
ing of the neurobiology of narcolepsy–cataplexy, there
is no cure. Current therapeutic management is only
sympto matic, with widespread use of antidepressants
and GHB to reduce the frequency of cataplectic attacks.
The discovery of orexin deficiency in humans has ledto
a new diagnostic test for narcolepsy and might lead
toorexin replacement therapy. Future therapeutic targets
must be focused on immunotherapies at early stages in
the disease to prevent the loss of orexin neurons and
diseaseprogression.
Review criteria
Articles were identified from publications listed in English
on PubMed from January 1970 to October 2013. The
following keywords were used alone and in combination:
“narcolepsy”, “cataplexy”, “REM sleep”, “atonia”,
“motoneuron”, “amygdala”, “emotions”, “hypocretin”,
“orexin”, “dog”, “mouse”, “mice”, “brainstem”, “locus
coeruleus”, “noradrenergic”, “arousal” and “neurobiology”.
Publications were also identified through the authors’
collections of scientific literature.
1. American Academy of Sleep Medicine. The
international classification of sleep disorders,
revised. Diagnostic and coding manual.
European Society of Sleep Technology [online],
http://www.esst.org/adds/ICSD.pdf (2001).
2. Dauvilliers, Y., Arnulf, I. & Mignot, E. Narcolepsy
with cataplexy. Lancet 369, 499–511 (2007).
3. Overeem, S., Mignot, E., van Dijk, J.G. &
Lammers, G.J. Narcolepsy: clinical features,
new pathophysiologic insights, and future
perspectives. J. Clin. Neurophysiol. 18, 78–105
(2001).
4. Dauvilliers, Y., Billiard, M. & Montplaisir, J. Clinical
aspects and pathophysiology of narcolepsy. Clin.
Neurophysiol. 114, 2000–2017 (2003).
5. Dauvilliers, Y. etal. Age at onset of narcolepsy in
two large populations of patients in France and
Quebec. Neurology 57, 2029–2033 (2001).
6. Daniels, E., King, M.A., Smith, I.E. &
Shneerson, J.M. Health‑related quality of life
innarcolepsy. J. Sleep Res. 10, 75–81 (2001).
7. Beusterien, K.M. etal. Health‑related quality
oflife effects of modafinil for treatment of
narcolepsy. Sleep 22, 757–765 (1999).
8. Burgess, C.R. & Peever, J.H. A noradrenergic
mechanism functions to couple motor behavior
with arousal state. Curr. Biol. 23, 1719–1725
(2013).
9. Siegel, J.M. Functional implications of sleep
development. PLoS Biol. 3, e178 (2005).
10. Chemelli, R.M. etal. Narcolepsy in orexin
knockout mice: molecular genetics of sleep
regulation. Cell 98, 437–451 (1999).
11. Hara, J. etal. Genetic ablation of orexin neurons
in mice results in narcolepsy, hypophagia, and
obesity. Neuron 30, 345–354 (2001).
REVIEWS
© 2014 Macmillan Publishers Limited. All rights reserved

NATURE REVIEWS
|
NEUROLOGY ADVANCE ONLINE PUBLICATION
|
9
12. Lin, L. etal. The sleep disorder canine narcolepsy
is caused by a mutation in the hypocretin (orexin)
receptor 2 gene. Cell 98, 365–376 (1999).
13. Willie, J.T. etal. Distinct narcolepsy syndromes
in Orexin receptor‑2 and Orexin null mice:
molecular genetic dissection of non‑REM and
REM sleep regulatory processes. Neuron 38,
715–730 (2003).
14. Peyron, C. etal. A mutation in a case of early
onset narcolepsy and a generalized absence of
hypocretin peptides in human narcoleptic brains.
Nat. Med. 6, 991–997 (2000).
15. Thannickal, T.C. etal. Reduced number of
hypocretin neurons in human narcolepsy.
Neuron27, 469–474 (2000).
16. Mignot, E. etal. The role of cerebrospinal fluid
hypocretin measurement in the diagnosis of
narcolepsy and other hypersomnias. Arch.
Neurol. 59, 1553–1562 (2002).
17. Mignot, E. etal. Complex HLA‑DR and ‑DQ
interactions confer risk of narcolepsy‑cataplexy
in three ethnic groups. Am. J. Hum. Genet. 68,
686–699 (2001).
18. Faraco, J. etal. ImmunoChip study implicates
antigen presentation to Tcells in narcolepsy.
PLoS Genet. 9, e1003270 (2013).
19. Hallmayer, J. etal. Narcolepsy is strongly
associated with the T‑cell receptor alpha locus.
Nat. Genet. 41, 708–711 (2009).
20. Kornum, B.R. etal. Common variants in P2RY11
are associated with narcolepsy. Nat. Genet. 43,
66–71.
21. Dauvilliers, Y. etal. Increased risk of narcolepsy
in children and adults after pandemic H1N1
vaccination in France. Brain 136, 2486–2496
(2013).
22. Hor, H. etal. Genome‑wide association study
identifies new HLA class II haplotypes strongly
protective against narcolepsy. Nat. Genet. 42,
786–789.
23. Partinen, M. etal. Increased incidence and
clinical picture of childhood narcolepsy following
the 2009 H1N1 pandemic vaccination campaign
in Finland. PLoS ONE 7, e33723 (2012).
24. Luca, G. etal. Clinical, polysomnographic and
genome‑wide association analyses of narcolepsy
with cataplexy: a European Narcolepsy Network
study. J. Sleep Res. 22, 482–495 (2013).
25. Overeem, S. etal. The clinical features of
cataplexy: a questionnaire study in narcolepsy
patients with and without hypocretin‑1
deficiency. Sleep Med. 12, 12–18.
26. Nishino, S. & Mignot, E. Narcolepsy and
cataplexy. Handb. Clin. Neurol. 99, 783–814
(2011).
27. Sturzenegger, C. & Bassetti, C.L. The clinical
spectrum of narcolepsy with cataplexy:
areappraisal. J. Sleep Res. 13, 395–406 (2004).
28. Mayer, G. The neurophysiology of cataplexy
[German]. Nervenarzt 76, 1464–1469 (2005).
29. Vetrugno, R. etal. Behavioural and
neurophysiological correlates of human
cataplexy: a video‑polygraphic study. Clin.
Neurophysiol. 121, 153–162 (2010).
30. Billiard, M., Besset, A. & Cadilhac, J. in Sleep/
Wake Disorders: Natural History, Epidemiology
and Long‑Term Evolution (eds C. Guilleminault &
E. Lugaresi) 171–185 (Raven Press, 1983).
31. Mattarozzi, K. etal. Clinical, behavioural and
polysomnographic correlates of cataplexy in
patients with narcolepsy/cataplexy. Sleep Med.
9, 425–433 (2008).
32. Plazzi, G. etal. Complex movement disorders at
disease onset in childhood narcolepsy with
cataplexy. Brain 134, 3480–3492 (2011).
33. Pizza, F. etal. Clinical and polysomnographic
course of childhood narcolepsy with cataplexy.
Brain 136, 3787–3795 (2013).
34. American Academy of Sleep Medicine. The
International Classification of Sleep Disorders
—Third Edition (ICSD‑3). AASM Resource Library
[online], (2014).
35. Andlauer, O. etal. Predictors of hypocretin
(orexin) deficiency in narcolepsy without
cataplexy. Sleep 35, 1247–1255F (2012).
36. Thannickal, T.C., Nienhuis, R. & Siegel, J.M.
Localized loss of hypocretin (orexin) cells in
narcolepsy without cataplexy. Sleep 32,
993–998 (2009).
37. Han, F. etal. Narcolepsy onset is seasonal and
increased following the 2009 H1N1 pandemic
inChina. Ann. Neurol. 70, 410–417 (2011).
38. De la Herran‑Arita, A.K. etal. CD4+ Tcell
autoimmunity to hypocretin/orexin and cross‑
reactivity to a 2009 H1N1 influenza A epitope
innarcolepsy. Sci. Transl. Med. 5, 216ra176
(2013).
39. Aran, A. etal. Elevated anti‑streptococcal
antibodies in patients with recent narcolepsy
onset. Sleep 32, 979–983 (2009).
40. Cvetkovic‑Lopes, V. etal. Elevated Tribbles
homolog 2‑specific antibody levels in narcolepsy
patients. J. Clin. Invest. 120, 713–719 (2010).
41. Burgess, C.R., Oishi, Y., Mochizuki, T.,
Peever,J.H. & Scammell, T.E. Amygdala lesions
reduce cataplexy in orexin knock‑out mice.
J.Neurosci. 33, 9734–9742 (2013).
42. Plazzi, G. etal. Narcolepsy with cataplexy
associated with holoprosencephaly
misdiagnosed as epileptic drop attacks.
Mov.Disord. 25, 780–782.
43. Overeem, S., Lammers, G.J. & van Dijk, J.G.
Weak with laughter. Lancet 354, 838 (1999).
44. Overeem, S., Reijntjes, R., Huyser, W.,
Lammers,G.J. & van Dijk, J.G. Corticospinal
excitability during laughter: implications for
cataplexy and the comparison with REM sleep
atonia. J. Sleep Res. 13, 257–264 (2004).
45. Siegel, J.M. & Boehmer, L.N. Narcolepsy and
the hypocretin system—where motion meets
emotion. Nat. Clin. Pract. Neurol. 2, 548–556
(2006).
46. Mensen, A., Poryazova, R., Schwartz, S. &
Khatami, R. Humor as a reward mechanism:
event‑related potentials in the healthy and
diseased brain. PLoS ONE 9, e85978 (2014).
47. Reiss, A.L. etal. Anomalous hypothalamic
responses to humor in cataplexy. PLoS ONE 3,
e2225 (2008).
48. Ponz, A. etal. Abnormal activity in reward brain
circuits in human narcolepsy with cataplexy.
Ann.Neurol. 67, 190–200 (2010).
49. Hong, S.B., Tae, W.S. & Joo, E.Y. Cerebral
perfusion changes during cataplexy in narcolepsy
patients. Neurology 66, 1747–1749 (2006).
50. Dauvilliers, Y. etal. A brain PET study in patients
with narcolepsy‑cataplexy. J. Neurol. Neurosurg.
Psychiatry 81, 344–348 (2010).
51. Blouin, A.M. etal. Human hypocretin and
melanin‑concentrating hormone levels are linked
to emotion and social interaction. Nat. Commun.
4, 1547 (2013).
52. Gulyani, S., Wu, M.F., Nienhuis, R., John, J. &
Siegel, J.M. Cataplexy‑related neurons in the
amygdala of the narcoleptic dog. Neuroscience
112, 355–365 (2002).
53. Siegel, J.M. Narcolepsy: a key role for
hypocretins (orexins). Cell 98, 409–412 (1999).
54. Vassalli, A. etal. Electroencephalogram
paroxysmal theta characterizes cataplexy in
mice and children. Brain 136, 1592–1608
(2013).
55. Siegel, J.M. etal. Neuronal activity in
narcolepsy: identification of cataplexy‑related
cells in the medial medulla. Science 252,
1315–1318 (1991).
56. Espana, R.A., McCormack, S.L., Mochizuki, T. &
Scammell, T.E. Running promotes wakefulness
and increases cataplexy in orexin knockout
mice. Sleep 30, 1417–1425 (2007).
57. Clark, E.L., Baumann, C.R., Cano, G.,
Scammell, T.E. & Mochizuki, T. Feeding‑elicited
cataplexy in orexin knockout mice. Neuroscience
161, 970–977 (2009).
58. Peever, J. Control of motoneuron function and
muscle tone during REM sleep, REM sleep
behavior disorder and cataplexy/narcolepsy.
Arch. Ital. Biol. 149, 454–466 (2011).
59. Luppi, P.H. etal. The neuronal network
responsible for paradoxical sleep and its
dysfunctions causing narcolepsy and rapid eye
movement (REM) behavior disorder. Sleep Med.
Rev. 15, 153–163 (2011).
60. Ristanovic, R.K., Liang, H., Hornfeldt, C.S.
&Lai, C. Exacerbation of cataplexy following
gradual withdrawal of antidepressants:
manifestation of probable protracted rebound
cataplexy. Sleep Med. 10, 416–421 (2009).
61. Kodama, T., Lai, Y.Y. & Siegel, J.M. Changes in
inhibitory amino acid release linked to pontine‑
induced atonia: an invivo microdialysis study.
J.Neurosci. 23, 1548–1554 (2003).
62. Lai, Y.Y. & Siegel, J.M. Medullary regions
mediating atonia. J. Neurosci. 8, 4790–4796
(1988).
63. Mileykovskiy, B.Y., Kiyashchenko, L.I.,
Kodama,T., Lai, Y.Y. & Siegel, J.M. Activation of
pontine and medullary motor inhibitory regions
reduces discharge in neurons located in the
locus coeruleus and the anatomical equivalent
of the midbrain locomotor region. J. Neurosci. 20,
8551–8558 (2000).
64. Brooks, P.L. & Peever, J.H. Identification of
thetransmitter and receptor mechanisms
responsible for REM sleep paralysis. J.Neurosci.
32, 9785–9795 (2012).
65. Wu, M.F. etal. Locus coeruleus neurons:
cessation of activity during cataplexy.
Neuroscience 91, 1389–1399 (1999).
66. John, J., Wu, M.F., Boehmer, L.N. & Siegel, J.M.
Cataplexy‑active neurons in the hypothalamus:
implications for the role of histamine in sleep and
waking behavior. Neuron 42, 619–634 (2004).
67. Hasegawa, E., Yanagisawa, M., Sakurai, T. &
Mieda, M. Orexin neurons suppress narcolepsy
via 2 distinct efferent pathways. J. Clin. Invest.
124, 604–616 (2014).
68. Wu, M.F. etal. Activity of dorsal raphe cells
across the sleep‑waking cycle and during
cataplexy in narcoleptic dogs. J. Physiol. 554,
202–215 (2004).
69. Peyron, C. etal. Neurons containing hypocretin
(orexin) project to multiple neuronal systems.
J.Neurosci. 18, 9996–10015 (1998).
70. Peever, J.H., Lai, Y.Y. & Siegel, J.M. Excitatory
effects of hypocretin‑1 (orexin‑A) in the
trigeminalmotor nucleus are reversed by NMDA
antagonism. J. Neurophysiol. 89, 2591–2600
(2003).
71. Lee, M.G., Hassani, O.K. & Jones, B.E.
Discharge of identified orexin/hypocretin
neurons across the sleep‑waking cycle.
J.Neurosci. 25, 6716–6720 (2005).
72. Mileykovskiy, B.Y., Kiyashchenko, L.I. &
Siegel,J.M. Behavioral correlates of activity in
identified hypocretin/orexin neurons. Neuron 46,
787–798 (2005).
73. Siegel, J.M. etal. Activity of medial mesopontine
units during cataplexy and sleep‑waking states
in the narcoleptic dog. J. Neurosci. 12,
1640–1646 (1992).
74. Siegel, J.M. etal. Neuronal degeneration in
canine narcolepsy. J. Neurosci. 19, 248–257
(1999).
REVIEWS
© 2014 Macmillan Publishers Limited. All rights reserved

10
|
ADVANCE ONLINE PUBLICATION www.nature.com/nrneurol
75. Wu, M.F., Nienhuis, R., Maidment, N., Lam, H.A.
& Siegel, J.M. Role of the hypocretin (orexin)
receptor 2 (Hcrt‑r2) in the regulation of
hypocretin level and cataplexy. J. Neurosci. 31,
6305–6310 (2011).
76. Grimaldi, D., Silvani, A., Benarroch, E.E. &
Cortelli, P. Orexin/hypocretin system and
autonomic control: new insights and clinical
correlations. Neurology 82, 271–278 (2014).
77. John, J. etal. Greatly increased numbers of
histamine cells in human narcolepsy with
cataplexy. Ann. Neurol. 74, 786–793 (2013).
78. Valko, P.O. etal. Increase of histaminergic
tuberomammillary neurons in narcolepsy.
Ann.Neurol. 74, 794–804 (2013).
79. LeDoux, J. The amygdala. Curr. B iol. 17,
R868–R874 (2007).
80. Schwartz, S. etal. Abnormal activity in
hypothalamus and amygdala during humour
processing in human narcolepsy with cataplexy.
Brain 131, 514–522 (2008).
81. Lu, J., Sherman, D., Devor, M. & Saper, C.B.
Aputative flip‑flop switch for control of REM
sleep. Nature 441, 589–594 (2006).
82. Kaur, S. etal. Hypocretin‑2 saporin lesions of
theventrolateral periaquaductal gray (vlPAG)
increase REM sleep in hypocretin knockout
mice. PLoS ONE 4, e6346 (2009).
83. Covington, H.E. 3rd etal. Antidepressant effect
of optogenetic stimulation of the medial
prefrontal cortex. J. Neurosci. 30, 16082–16090
(2010).
84. Nishino, S. & Mignot, E. Pharmacological
aspects of human and canine narcolepsy.
Prog.Neurobiol. 52, 27–78 (1997).
85. Burgess, C.R., Tse, G., Gillis, L. & Peever, J.H.
Dopaminergic regulation of sleep and cataplexy
in a murine model of narcolepsy. Sleep 33,
1295–1304 (2010).
86. Reid, M.S. etal. Neuropharmacological
characterization of basal forebrain cholinergic
stimulated cataplexy in narcoleptic canines.
Exp.Neurol. 151, 89–104 (1998).
87. Billiard, M. etal. EFNS guidelines on
management of narcolepsy. Eur. J. Neurol. 13,
1035–1048 (2006).
88. Parkes, J.D. & Schachter, M. Clomipramine and
clonazepam in cataplexy. Lancet 2, 1085–1086
(1979).
89. Aran, A. etal. Clinical and therapeutic aspects
of childhood narcolepsy‑cataplexy:
aretrospective study of 51 children. Sleep 33,
1457–1464.
90. Ratkiewicz, M. & Splaingard, M. Treatment of
cataplexy in a three‑year‑old using venlafaxine.
J.Clin. Sleep Med. 9, 1341–1342 (2013).
91. Larrosa, O., de la Llave, Y., Bario, S., Granizo, J.J.
& Garcia‑Borreguero, D. Stimulant and
anticataplectic effects of reboxetine in patients
with narcolepsy: a pilot study. Sleep 24,
282–285 (2001).
92. Niederhofer, H. Atomoxetine also effective in
patients suffering from narcolepsy? Sleep 28,
1189 (2005).
93. Pistis, M. etal. γ‑hydroxybutyric acid (GHB) and
the mesoaccumbens reward circuit: evidence for
GABAB receptor‑mediated effects. Neuroscience
131, 465–474 (2005).
94. [No authors listed]. A randomized, double blind,
placebo‑controlled multicenter trial comparing
the effects of three doses of orally administered
sodium oxybate with placebo for the treatment
of narcolepsy. Sleep 25, 42–49 (2002).
95. Alshaikh, M.K. etal. Sodium oxybate for
narcolepsy with cataplexy: systematic review
and meta‑analysis. J. Clin. Sleep Med. 8,
451–458 (2012).
96. Wang, Y.G., Swick, T.J., Carter, L.P., Thorpy, M.J. &
Benowitz, N.L. Safety overview of postmarketing
and clinical experience of sodium oxybate
(Xyrem): abuse, misuse, dependence, and
diversion. J. Clin. Sleep Med. 5, 365–371 (2009).
97. Wang, Y.G., Swick, T.J., Carter, L.P., Thorpy, M.J.
& Benowitz, N.L. Sodium oxybate: updates and
correction to previously published safety data.
J.Clin. Sleep Med. 7, 415–416 (2011).
98. Kastin, A.J. & Kerstrom, V. Orexin A but not
orexin B rapidly enters brain from blood by
simple diffusion. J. Pharmacol. Exp. Ther. 289,
219–223 (1999).
99. John, J., Wu, M.F. & Siegel, J.M. Systemic
administration of hypocretin‑1 reduces cataplexy
and normalizes sleep and waking durations in
narcoleptic dogs. Sleep Res. Online 3, 23–28
(2000).
100. Deadwyler, S.A., Porrino, L., Siegel, J.M. &
Hampson, R.E. Systemic and nasal delivery
oforexin‑A (hypocretin‑1) reduces the effects of
sleep deprivation on cognitive performance in
nonhuman primates. J. Neurosci. 27,
14239–14247 (2007).
101. Baier, P.C. etal. Olfactory dysfunction in patients
with narcolepsy with cataplexy is restored by
intranasal orexin A (hypocretin‑1). Brain 131,
2734–2741 (2008).
102. Baier, P.C. etal. Effects of intranasal
hypocretin‑1 (orexin A) on sleep in narcolepsy
with cataplexy. Sleep Med. 12, 941–946 (2011).
103. Weinhold, S.L. etal. The effect of intranasal
orexin‑A (hypocretin‑1) on sleep, wakefulness
and attention in narcolepsy with cataplexy.
Behav. Brain Res. 262, 8–13 (2014).
104. Kantor, S. etal. Orexin gene therapy restores
thetiming and maintenance of wakefulness in
narcoleptic mice. Sleep 36, 1129–1138 (2013).
105. Arias‑Carrion, O. etal. Transplantation of
hypocretin neurons into the pontine reticular
formation: preliminary results. Sleep 27,
1465–1470 (2004).
106. Dauvilliers, Y. etal. Pitolisant versus placebo or
modafinil in patients with narcolepsy: a double‑
blind, randomised trial. Lancet Neurol. 12,
1068–1075 (2013).
107. Lin, J.S. etal. An inverse agonist of the
histamine H3 receptor improves wakefulness
innarcolepsy: studies in orexin–/– mice and
patients. Neurobiol. Dis. 30, 74–83 (2008).
108. Dauvilliers, Y., Carlander, B., Rivier, F.,
Touchon,J. & Tafti, M. Successful management
of cataplexy with intravenous immunoglobulins
at narcolepsy onset. Ann. Neurol. 56, 905–908
(2004).
109. Lecendreux, M., Maret, S., Bassetti, C.,
Mouren,M.C. & Tafti, M. Clinical efficacy of
high‑dose intravenous immunoglobulins near the
onset of narcolepsy in a 10‑year‑old boy. J. Sleep
Res. 12, 347–348 (2003).
110. Plazzi, G. etal. Intravenous high‑dose
immunoglobulin treatment in recent onset
childhood narcolepsy with cataplexy. J. Neurol.
255, 1549–1554 (2008).
111. Chen, W., Black, J., Call, P. & Mignot, E.
Late‑onset narcolepsy presenting as rapidly
progressing muscle weakness: response to
plasmapheresis. Ann. Neurol. 58, 489–490
(2005).
112. Donjacour, C.E. & Lammers, G.J. A remarkable
effect of alemtuzumab in a patient suffering
fromnarcolepsy with cataplexy. J. Sleep Res. 21,
479–480 (2012).
113. Dauvilliers, Y., Abril, B., Mas, E., Michel, F.
&Tafti,M. Normalization of hypocretin‑1 in
narcolepsy after intravenous immunoglobulin
treatment. Neurology 73, 1333–1334 (2009).
114. Dauvilliers, Y. etal. Cerebrospinal fluid and
serum cytokine profiles in narcolepsy with
cataplexy: a case–control study. Brain Behav.
Immun. 37, 260–266 (2014).
Author contributions
Y.D. researched data for the article. Y.D., J.M.S. and
J.H.P. wrote the article and substantially contributed
to discussion of the content. Y.D., J.M.S., R.L., Z.A.T.
and J.H.P. reviewed and/or edited the manuscript
before submission.
Supplementary information is linked to the online
version of the paper at www.nature.com/nrneurol.
REVIEWS
© 2014 Macmillan Publishers Limited. All rights reserved