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Hypersomnia: Etiologies

Chapter · December 2017

DOI: 10.1016/B978-0-12-809324-5.01050-6

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From During, E., Dimitriu, A., Guilleminault, C. Hypersomnia: Etiologies. In Reference

Module in Neuroscience and Biobehavioral Psychology, Elsevier, 2017. ISBN 9780128093245
ISBN: 9780128093245
© 2017 Elsevier Inc. All rights reserved.
Elsevier
 Author's personal copy
Hypersomnia: Etiologies q
E During, Stanford University, Stanford, CA, United States; and Stanford Sleep Medicine Center, Redwood City, CA, United States
A Dimitriu, Stanford University, Stanford, CA, United States
C Guilleminault, Stanford University, Stanford, CA, United States; and Stanford Sleep Medicine Center, Redwood City, CA,
United States
Ó 2017 Elsevier Inc. All rights reserved.
Introduction
Observational Studies/Case Series
EEG/Sleep Architecture Abnormalities
Neurotransmitters in Hypersomnia
Circadian Dysfunction
Conclusion
Further Reading
Glossary
g-Aminobutyric acid (GABA) The major inhibitory
neurotransmitter of the central nervous system.
Ascending reticular activating system (ARAS) A netlike
arrangement of largely monoaminergic neurons and nuclei
located in the pons, midbrain, and diencephalon
(thalamus and hypothalamus), sending projections to the
basal forebrain and cortical areas, involved in maintenance
of wakefulness.
Brainstem Posterior part of the central nervous system
adjoining and continuous with the spinal cord.
Anatomically composed of the medulla oblongata, pons,
and midbrain.
Cataplexy A sudden and transient episode of loss of muscle
tone, often triggered by emotions, and commonly seen in
narcolepsy.
Circadian rhythm An approximate 24-h cycle of rhythmic
biological, physiological, and physical behavior exhibited
by living things on Earth.
Electroencephalogram (EEG) A graphical record of the
electrical activity of the braindalso a common component
of the polysomnogram.
Epworth sleepiness scale (ESS) A questionnaire that
measures subjective sleepiness.
Histamine In the central nervous system, a wake-
promoting amine known to decrease during sleep.
Hypocretin Also known as orexin, a neuropeptide secreted
by the lateral hypothalamus and implicated in the
maintenance of wakefulness, regulation of hunger and fat
metabolism.
Idiopathic hypersomnia A condition of excessive daytime
sleepiness with no known cause, usually marked by
unrefreshing nighttime sleep and naps.
Idiopathic Relating to a disease for which the cause is
unknown.
q
Change History: February 2016. Updated the text, Glossary, Further Reading, and added Table 1 and Table 2.
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4
5
7
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Mean sleep latency (MSL) The mean amount of time from
light out until sleep onset, calculated with all sleep onset
latency values of the four or five opportunities to sleep
performed during the MSLT.
Melatonin A hormone secreted by the pineal gland in
mammals, usually during the dark cycle, which is believed
to be responsible for regulation of day/night behavioral
rhythms.
Multiple sleep latency test (MSLT) A test to measure
overall sleepiness in an individual, in which four or five
opportunities are given for a patient to fall asleep for
20 min. Polysomnographic recording is performed during
this time to measure sleep quality and measure sleep stages
and rapid eye movement sleep (REM) sleep.
Multiple system atrophy A rare neurodegenerative disease
causing parkinsonism and prominent autonomic
dysfunction.
Narcolepsy A condition related to an intrusion of REM into
wakefulness, characterized by excessive daytime sleepiness,
disorganization of the normal nocturnal sleep architecture,
sudden attacks of loss of muscle tone (cataplexy) triggered
by emotions, sleep-related hallucinations and sleep
paralysis.
Non-REM sleep (NREM) A reference to any stage of sleep
other than REM sleep, including stages 1–4 (called N1 to
N4).
Polysomnogram (PSG) A diagnostic test performed in sleep
labs that measures a variety of physical and neurological
activities, including brain activity, respiratory and cardiac
parameters, oxygen levels, eye movements, and muscle tone.
Rapid eye movement (REM) sleep A stage of sleep which
generally occurs about 90 min after sleep onset (sooner in
narcolepsy) accompanied by dreaming, rapid eye
movements and loss of muscle tone.
http://dx.doi.org/10.1016/B978-0-12-809324-5.01050-6 1
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2 Hypersomnia: Etiologies

Sleep efficiency The fraction of time spent asleep divided
by the total amount of time spent in bed.
Sleep spindles Short (0.5–3 s) bursts of 11–16 Hz activity
measured on EEG in stage 2 (N2) and slow-wave sleep
(SWS). Represent a inhibitory loop between pacemaking
GABAergic reticular thalamic activity and corticothalamic
projections. Involved in memory consolidation and sleep
stability.
Slow-wave activity (SWA) A reference to the brainwave
activity commonly seen in N3 sleep (formerly know as
stage 3 and 4), consisting of EEG activity from 0.5 to 2 Hz
and peak-to-peak amplitude >75 mV.
Upper airway resistance syndrome (UARS) Sleep disorder
characterized by increased airway resistance and excessive
respiratory effort leading to repeated arousals, often
causing daytime fatigue and sleepiness.

Introduction

The term “hypersomnia” has been used in sleep medicine to describe a group of disorders characterized by an increased propensity
to sleep, which central feature is excessive daytime sleepiness (EDS), associated or not with prolonged nocturnal sleep time. EDS,
also called “hypersomnolence,” is a common symptom that needs to be distinguished from daytime fatigue and from increased
sleep time. Its causes range from insufficient quantity and decreased quality of sleep related to underlying disorders fragmenting
sleep, to circadian rhythm abnormalities. The International Classification of Sleep Disorders (ICSD-3) includes “central disorders
of hypersomnolence,” a group that comprises eight disorders or situations resulting in EDS ( Table 1). This group includes well-
defined conditions such as narcolepsy type 1 (formerly known as “narcolepsy with cataplexy”), Kleine-Levin Syndrome (character-
ized by episodes of transient EDS associated with neuropsychiatric changes) and specific circumstances in which hypersomnolence
is a consequence of behavioral, psychiatric, medical or pharmacological factors. It also comprises narcolepsy type 2 (formerly
known as “narcolepsy without cataplexy”) and idiopathic hypersomnia (IH), two syndromes with nearly identical symptoms, there-
fore difficult to delineate in practice. Their distinguishing feature is REM propensity as measured by PSG followed by MSLT, a marker
influenced by other factors such as medications (antidepressants are usually REM suppressing, while their discontinuation cause
REM rebound) and variations in sleep schedule, particularly shift work and chronic sleep deprivation (REM promoting). Further-
more, Trotti and al. have demonstrated that the MSLT has a low test-retest reliability, resulting in changes in diagnosis in as many as
half of patients. The differential diagnosis between IH and narcolepsy type 2 will thus be one the focuses of this discussion. The
difficulty to distinguish IH from other disorders causing EDS is complicated by the fact that IH lacks a positive definition or specific
criteria; it rather presents with suggestive but inconsistent symptoms. In that respect, it may not only represent a diagnosis of exclu-
sion but a heterogeneous disorder. A good understanding of central and systemic disorders, as well as situations likely to cause EDS
is therefore paramount.
When a patient presents with hypersomnia, one should always evaluate for an underlying disorder fragmenting sleep such as
obstructive sleep apnea (OSA), upper airway resistance syndrome (UARS), restless leg syndrome or periodic limb movements
(PLM) during sleep, as well as fragmentation of sleep due to pain, insufficient nocturnal sleep time (“insufficient sleep syndrome”),
chronic fatigue syndrome or psychiatric conditions such as depressive or conversion disorder. Medical conditions causing hyper-
somnolence can be conceptualized as either: (1) systemic processes affecting the central nervous system (CNS) as a whole in its
ability to maintain wakefulness, such as seen in metabolic (hepatic, uremic encephalopathy), genetic (fragile X, Prader–Willi, Moe-
bius syndrome), or endocrine (hypothyroidism) disorders, or (2) focal lesions of the ascending reticular activating system (ARAS),
which can occur in neurodegenerative conditions (Parkinson’s disease, multiple system atrophy), strokes, inflammatory (neuro-
myelitis optica, neurosarcoidosis), proliferative (tumors) or infectious conditions involving the upper brainstem or diencephalon.
Guilleminault et al. have also described hypersomnia following head trauma and viral illness.
Bedrich Roth first described IH in 1969 as distinct from narcolepsy with or without cataplexy after analysis of 642 patients over
a 30-year period. He found 174 subjects to have deep unrefreshing nocturnal sleep with long unrefreshing daytime naps. He defined

Table 1 Central disorders of hypersomnolence listed

in the ICSD-3

Narcolepsy type 1 (with cataplexy)

Narcolepsy type 2 (without cataplexy)
Idiopathic hypersomnia
Kleine-Levin syndrome
Hypersomnia due to a medical disorder
Hypersomnia due to a medication or substance
Hypersomnia associated with a psychiatric condition
Insufficient sleep syndrome

International Classification of Sleep Disorders, third ed.

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Hypersomnia: Etiologies 3

Table 2 Criteria for idiopathic hypersomnia

Criteria A–F must be met:

A. Daily periods of irrepressible need to sleep or daytime lapses into sleep
occurring for at least 3 months.
B. Cataplexy is absent.
Note: sleep paralysis or hypnagogic hallucinations can be reported.
C. MSLT shows no more than one SOREMP (including a SOREMP <15 mn on
the preceding PSG)
D. The presence of at least one of the following:
1. The MSLT shows a MSL of
8 min.
2. Total 24-h sleep time is  11 h (typically 12–14 h) on 24-h PSG
monitoring (performed after correction of chronic sleep deprivation), or
by wrist actigraphy in association with a sleep log (averaged over at least
seven days with unrestricted sleep).
Note: criteria D may not be fulfilled if other criteria are met. A repeat MSLT is
advised if suspicion for IH remains high.
E. Insufficient sleep syndrome is ruled out (if deemed necessary, by lack of
improvement of sleepiness after an adequate trial of increased nocturnal
time in bed, preferably confirmed by at least a week of wrist actigraphy).
F. The hypersomnolence and/or MSLT findings are not better explained by
another sleep disorder, other medical or psychiatric disorder, or use of
drugs or medications.
Additional supportive features:
a. Sleep inertia (irritability, confusion, automatic behaviors) or long (over an
hour) unrefreshing naps
b. Sleep efficiency >90% on PSG
c. coexistence of autonomic symptoms (orthostatic symptoms, temperature
dysregulation, Raynaud-type peripheral vascular complaints, headaches)

Adapted from ICSD-3.

two types of patients with variants of this syndrome: the monosymptomatic type, who suffered from EDS alone, and the polysymp-
tomatic type, who reported EDS, prolonged sleep duration and “sleep drunkenness.” He also noted a family history in one third of
patients and described a lack of response to treatment in most cases.
Based on this landmark study, the second international classification of sleep disorders (ICSD-2) distinguished in 2005 two
subtypes of IH: “IH with long sleep time” (in patients reporting over 10 h of nocturnal sleep time) and “IH without long sleep
time” (6–10 h of nocturnal sleep time), however this distinction was later abandoned by the third edition of the classification
(ICSD-3) released in 2014. The ICSD-3 rather proposes a set of characteristic features and two core “objective” criteria: (1)
absence of propensity to enter REM early in sleep during PSG and MSLT, and (2) short sleep latency during MSLT or evidence
of increased sleep duration exceeding 11 h per day ( Table 2).
Having ruled out known medical and psychiatric causes of hypersomnia, what commonly remains is a conundrum for most
physicians and patients, with a markedly sleepy patient who suffers from unrefreshing sleep and sleep inertia (“drunkenness”).
The following is a systematic analysis of the possible causes of this disorder, comprised of
l Observational studiesdcase reports
l Electroencephalographic (EEG)/sleep architecture abnormalities
l Dysfunction of sleep and wake regulating monoamines
l Circadian rhythm dysfunction

Observational Studies/Case Series

To better understand the various possible etiologies underlying IH, several large case series have been executed.
In a recent study by Vernet and Arnulf, subjects were selected with the diagnosis of IH. Seventy-five patients were selected and 30
healthy, age- and sex-matched controls were included in a 48-h trial, which included face-to-face interviews, questionnaires, human
leukocyte antigen (HLA) genotyping, PSG, and MSLT, followed by 24-h ad libitum sleep monitoring.
As expected, hypersomniacs had high Epworth Sleepiness Scale (ESS) scores, with 89% > 10. They had no cataplexy and no
more hallucinations than controls, but 28% had sleep paralysisda common symptom in patients with narcolepsy, 36% had sleep
drunkenness, and 46% reported unrefreshing naps. Hypersomniacs also rated slightly higher on depression and anxiety scores
compared to controls. On HLA typing, there was no difference in DQB1*06:02 commonly associated with narcolepsy, and there
was no difference in 122 other alleles of HLA-DRB1 and DQB1, with the exception of DRB1*11, which occurred with a twice lower

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4 Hypersomnia: Etiologies

frequency in hypersomniacs than in controls (P ¼ .05). Consistent with these findings, Billiard et al. have reported: “Despite some
reports that suggest an increased frequency in HLA-Cw2 and DR5 in idiopathic hypersomnia subjects, HLA typing is of no help in
the positive diagnosis of idiopathic hypersomnia.”
Comparing hypersomniacs with long and short sleep duration (nocturnal sleep >600 min and <600 min, respectively), there
was no symptomatic (EDS, fatigue, sleep drunkenness) or HLA DQB1*06:02 genotype differences between groups; the only statis-
tical difference was found in age and BMI, long sleepers being younger (29 vs. 40 years of age) and with a lower body mass index
(BMI) (23 vs. 26 kg m2) than short sleepers.
As expected, over a 24-h period, hypersomniacs had a longer total sleep time than controls, reflecting both increased nocturnal
and diurnal total sleep time. There was however no difference in sleep onset latency or sleep efficiency in hypersomniacs. More inter-
estingly, during nocturnal PSG recording, hypersomniacs more frequently had slow-wave sleep (SWS) episodes at the end of the
night, with 61% of patients having an SWS episode after 6 a.m., compared to 37% in controls.
On MSLT, as a group, hypersomniacs were shown to have a twice shorter MSL than controls, although as many as 39% of hyper-
somniacs had an MSL greater than 8 min.
Given the absence of weight differences when comparing hypersomniacs and controls, the authors of this study hypothesized
that the hypothalamic area responsible for eating and metabolism (including hypocretin/orexin neurons) were not dysfunctional in
this group. Hypersomniacs were rather more likely to show elements of a delayed sleep phase, indicating some degree of circadian
dysregulation. Finally, MSLT data revealed that hypersomniacs do not fall asleep as quickly as narcoleptic patients, but rather have
much greater difficulty waking spontaneously after sleep and that there may be a delayed circadian component contributing to this,
which will be covered later in this article.
In an earlier study by Bassetti and Aldrich in 1997, a series of 42 patients with a known diagnosis of IH were examined. Demo-
graphics, PSG, and MSLT data were reviewed. The authors found that hypersomniacs had a mean age of onset of 19  8 years and
almost all patients reported trouble driving and problems in work and social life due to their sleepiness. Sixty percent took one or
more involuntary naps per day, lasting >30 min, that were unrefreshing in 77% of cases. About a half described restless sleep with
frequent arousals and 55% had problems with awakening but only 21% complained of sleep drunkenness. Lifetime prevalence of
psychiatric symptoms was 57%, and common associated medical conditions included hypothyroidism (10%), recurrent infections
(10%), and obesity (25%). Apart from short sleep latency (6.4  5.7 min), polysomnographic data were unremarkable. MSL
during the MSLT was in the pathological range (4.3  2.1 min), but significantly higher than in the comparison group of narcolep-
tics with or without cataplexy (2.8  1.1 and 2.2  1.2 min, respectively). An identifiable cause of hypersomnia was observed in 10
out of 42 subjects (24%) of which 4 reported onset after a viral illness, 3 related to head trauma, and 3 with prominent psychiatric
complaints, with no improvement with stimulants and improvement with antidepressants. On a 3-year follow-up, a satisfactory
subjective response to treatment with stimulants (50% improvement in subjective sleepiness or normalization of ESS) was ob-
tained in 18 out of 25 patients (72%) while the MSLT remained abnormal. A “spontaneous improvement” was noted in the
EDS symptoms in 9 out of 35 (26%) of patients followed for >1 year, including all four subjects who reported symptom onset
after viral illness.
In another, more recent retrospective study of 77 patients with IH, Anderson et al. examined the PSG characteristics of patients
with this disorder and compared them to a 63 patients with narcolepsy with or without cataplexy. They found a similar early age of
onset in both groups with a mean age of 16.6  9.4 years, with no precipitant in a majority of cases. Then mean length of sleep was
reported at 9.2  1.8 h. Sleep drunkenness was noted in 52% of patients with IH as compared to 36% found in the Vernet and
Arnulf study. All patients but one reported taking naps with 87% lasting longer than 60 min on 5 or more days of each week
and 78% reported these to be unrefreshing. Two thirds of patients reported a family history of similar problems, and in eight cases,
more than one family member was affected. HLA-DQB1*06:02 carrier frequency in hypersomnia patients was 18% as opposed to
98% in the narcoleptic group, and a carrier frequency of 10% was noted for the Cw2 antigen among the hypersomniacs tested. Over-
night PSG showed a short MSL of 11.5  8.2 min, higher sleep efficiency (94.3%), and higher proportion of SWS in IH compared to
narcolepsy (22.9%  8.7% of total sleep time vs. 17.6% 7.1%). On MSLT, the MSL for hypersomniacs (8.3  3.1 min) was signif-
icantly longer than for the narcolepsy group (4.1  2.6 min). The authors noted that the single most useful factor in the clinical
history to distinguish hypersomnia from narcolepsy was nap duration >60 min, which in this study had an 87% sensitivity and
specificity.

EEG/Sleep Architecture Abnormalities

Consistent with the EEG findings in numerous studies that followed, Roth initially described IH to be a consequence of NREM
dysfunction.
Per the case series by Vernet and Arnulf, the main finding on PSG in IH was delayed SWS with higher proportion of N3 and N4
stages toward the end of the night. By contrast, there were minimal differences between normal and hypersomniac patients with
respect to REM latency and the amount of REM over the course of the night. Anderson et al. did comment on decreased sleep
latency, increased mean SWS, and high mean sleep efficiency distinguishing hypersomniacs from narcoleptic patients. In another
PSG comparison between patients with hypersomnia and narcolepsy, Baker et al. concluded that IH patients have longer and more
consolidated sleep at night. As compared with narcoleptic patients, they have longer total sleep time, significantly less wakefulness
after sleep onset, more pronounced in the first and second third of the night with less stage 1 NREM and more stage 3 and 4 NREM

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Hypersomnia: Etiologies 5

sleep, with more NREM sleep in the second third of the night. The authors also concluded that the urge to sleep is far more resistible
in IH than in narcolepsy.
MSLT findings have been consistent with no abnormality in SOREMPs, but decreased sleep latencies, twice shorter than normals,
though longer than those observed in narcoleptic patients. Komada et al. confirmed similar findings in their study, where they noted
that both subjective and objective sleepiness measured by ESS and MSLT, are milder in patients with IH than in narcoleptics, and
confirmed no abnormality in SOREMPs in the hypersomnia group. Interestingly, preservation of normal diurnal variation in sleep-
iness as measured by MSLT on a third nap scheduled at 14:00 (shorter MSL) was noted in hypersomniac patients, while no relative
increased sleepiness was noted in narcolepsy patients. Vernet and Arnulf also comment in their study on the paradoxical finding that
patients with long sleep times actually had longer sleep latencies in their MSLT seriesdsupporting the theory that these patients
have difficulty waking updmore so than excessive propensity to fall asleep, and consistent with the pathognomonic “sleep drunk-
enness” first described by Roth in the polysymptomatic group. The general consensus with respect to MSLT findings has been that IH
is a milder disease than narcolepsy with a preservation of diurnal rhythm, and longer sleep latencies on MSLT than narcolepsy,
though still shorter latencies than controls.
Because of the subtle differences found on PSG and MSLT in IH patients, ad libitum 24-h PSG has been suggested as the optimal
method of diagnosing hypersomnia, initially by Billiard and in the case series by Vernet and Arnulf. 24-h total sleep time >660 min
has since then become a core criteria for IH in the ICSD-3.
Several studies have attempted to identify quantitative differences in the sleep of IH patients using spectral analysis of nocturnal
EEG. Sforza et al. found decreased slow-wave activity (SWA, also called “delta power”), more pronounced in the first two NREM
periods of the night, suggesting reduced sleep pressure in these patientsdpossibly as a function of decreased process S. Despite
the decreased amount of SWA, these patients did show a normal exponential decay in SWA, indicating some preservation of homeo-
static regulatory mechanisms. The authors hypothesized that IH patients may need to sleep longer to make up for decreased SWA
levels, or that there was a decreased amplitude in their circadian rhythms.
With the notion that sleep spindles reflect thalamic gatekeeping, or the inhibition of sensory inflow to the cortex during NREM
sleep, Bové et al. examined the density of sleep spindles in a small group of IH patients compared with narcolepsy patients and
controls. Sleep spindle density was found to be about twice as higher in patients with IH compared to controls whereas patients
with narcolepsy were in an intermediate range. Also noted in this study was a statistically significant increase in sleep spindle density
not only in the beginning but at the end of the night compared to controls, supporting the hypothesis of a weak awakening system
and consistent with patient reports of deep sleep and difficulty in waking. The authors also point to the increase in sleep spindles
seen with benzodiazepine use, and hypothesize that a low density of sleep spindles may be necessary toward the morning hours for
a rapid transition to the waking state.
The cyclic alternating pattern (CAP) has been described by Terzano as a feature of sleep microstructure and sleep stability.
Although CAP was initially conceptualized as an arousal phenomenon, the A1 subtype of CAP (synchronized EEG patterns such
as sequences of K-complexes or delta bursts in NREM sleep) has become recognized as an attempt by the brain to preserve sleep
and part of the progression into SWS, while the A2 and A3 subtypes (desynchronized EEG patterns with alpha or fast beta activity
(>16 Hz) alone in the case of A3, or preceded by slow high-voltage waves in the case of A2) have become a marker of central
nervous system arousal. In a study of CAP rates including 30 patients with UARS and 30 controls, other than increased rate of
A2 and A3 CAP which can be interpreted as increased sleep fragmentation in the UARS group, Guilleminault et al. found after anal-
ysis of all participants data regardless of their condition that the rate of CAP in NREM sleep correlated with ESS and Fatigue Severity
Scale (r ¼ 0.38 and 0.51, respectively). Additionally, they found a specific correlation between A2 index and Fatigue Severity Scale
(r ¼ 0.29, P ¼ .05) whereas an inverse correlation was found between A1 index and these two scales. The authors concluded that
CAP-based analysis may be a more sensitive method than standard sleep scoring. Given the decreased SWA activity noted by Sforza
et al. in hypersomnia patients, an analysis of NREM microstructure with respect to CAP would seem logical in this population.
However, at the time of this writing, there are no analyses of CAP in patients with IHdthough this would appear to be paramount
to a more complete understanding of the pathophysiology of this disorder.

Neurotransmitters in Hypersomnia

Bassetti and Aldrich in 1997 attributed hypersomnia and atypical depression to diencephalic dysfunction, with facilitation of NREM
sleep consistent with a dysfunction of the arousal systems, first proposed by Roth, et al.
The first animal model of this disorder was achieved by Petitjean and Jouvet, with a lesion to the dorsal noradrenergic bundle in
the isthmus of the cat brain, resulting in hypersomnia and an increase in 5HT synthesis. With the proximity of these lesions to the
locus coeruleus, a possible role for norepinephrine in this disorder becomes evident. Faull et al. initially looked at cerebrospinal
fluid (CSF) levels of monoamine metabolites including homovanillic acid (HVA), 3-methoxy-4-hydroxyphenyl-ethylene glycol
(MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) and initially noted no difference
in metabolite levels in narcoleptic and hypersomnia groups. Reevaluation of the data revealed a dopamine system desynchronized
from the norepinephrine and serotonin systems in narcoleptics. In hypersomnia patients, the norepinephrine system was noted to
be desynchronized from the dopamine and serotonin systems, supporting the belief that narcolepsy was a result of dopaminergic
dysfunction, while IH was the result of norepinephrine dysfunction.

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6 Hypersomnia: Etiologies

While hypocretin/orexin has been implicated as a fundamental overseer of the flip-flop switch between sleep and wake, more
recent studies have implicated the possibility of an equally important role for histamine in maintaining arousal. A study by
Huang et al. investigated the interplay between hypocretin/orexin in histamine receptor (H1) knockout mice. Interestingly, in
comparison to the wild type, the knockout mice exhibited no difference in sleep and wake patterns. Substantial decreases in
NREM and REM were noted in wild-type mice following hypocretin infusion, while knockout mice showed no response. Consis-
tent with this theory has been the finding that H1 receptor gene knockout mice are resistant to the wake-promoting effects of
hypocretin. Interestingly, more specific investigations of H1 knockout mice have revealed a pattern of behavior quite similar
to hypersomnia in humans. Inouye et al. revealed significantly decreased exploratory behavior in mutant mice and evidence
of circadian dysregulation. Yanai et al. noted a decrease in open field ambulation and decreased rate of defensive response to
intruders. In accord with the findings by Faull et al., brain content monoamine analysis by Yanai et al. noted an increase in
the ratio of 5-hydroxyindoleacetic acid and 5-hydroxytryptamine (5-HT), indicating increased 5-HT turnover rates, in the H1
knockout mice.
In a recent study by Nishino et al., it was found that CSF histamine levels were significantly diminished in narcoleptic patients
with and without low CSF hypocretin. The authors report: “As histamine is a wake-promoting amine known to decrease during
sleep, decreased histamine could either passively reflect or partially mediate daytime sleepiness in these pathologies.”
Whether CSF histamine is a mediator or a reflection of sleepiness, further studies under more controlled conditions are needed to
explore whether histamine level changes are of clinical significance. A notable example of its use would be in the differentiation of
idiopathic hypersomnia and narcolepsy without cataplexy with hypersomnia secondary to depression or insufficient sleep, as ther-
apeutic strategies are dramatically different. It is also possible that histamine levels are a useful, objective marker of the severity of
centrally mediated somnolence.
In a companion paper, Kanbayashi et al. specifically examined the CSF histamine content of patients with IH, with normal
CSF hypocretin measurements. The conclusions mirror those of Nishino et al., in the finding of significantly decreased hista-
mine levels. In a supporting study, the administration of H3 receptor antagonists in rats was shown to result in increased CSF
histamine concentrations, demonstrating that CSF histamine content could accurately reflect central histaminergic activity.
The function of histamine is summarized in a paper by Brown et al. in which it is linked to arousal, anxiety, and activation
of the sympathetic nervous system, with highest rates of firing during wake, and lowest rates of firing during REM sleep. Also
mentioned is the function of the H3 presynaptic autoreceptor, with the role of inhibiting histamine release, which provides
a target for wake-promoting agents. The H3 antagonist pitolisant has been used in France in selected narcolepsy and IH
patients since 2010. Although shown to significantly improve subjective sleepiness in narcolepsy patients (Dauvilliers
et al.), its efficacy has been modest and inconsistent in patients with IH (Leu-Semenescu et al.). Based on the minimal
involvement of histamine in REM sleep and its maximal role in arousal with similar CSF monoamine profiles between
H1 knockout mice and hypersomnia patients, this neurotransmitter may still remain pivotal to the understanding of IH
and atypical depression.
In addition to stimulants (modafinil and armodafinil), g-aminobutyric acid (GABA)–benzodiazepine receptor antagonists
may provide a new direction for the treatment of hypersomnia. A study by Rye et al. suggests enhanced GABAA signaling
(þ84%  40.7% vs. þ35.8%  7.5% in controls) in response to in vivo addition of GABA in the CSF of a small group of
patients with hypersomnia (narcolepsy without cataplexy as defined by MSLT, or patients with persistent EDS despite reported
nocturnal TST > 10 h); enhancement showing to be reversed after addition of flumazenil, a GABAA receptor antagonist. A clin-
ical in vivo challenge with intravenous administration of flumazenil in seven selected patients including patients with IH
showed significantly decreased lapses in attention and subjective sleepiness as well as objective improvement in performance
on psychomotor vigilance task. The authors conclude that flumazenil, although thought to be a pure GABAA receptor antag-
onist lacking intrinsic activity, may act in some hypersomniac patients on a naturally occurring CSF constituent acting as
a positive allosteric modulator of synaptic GABAA receptors. This discovery paved the way for a clinical trial conducted by
Trotti et al. using clarithromycin, another GABAA negative allosteric modulator. Comparing the effect of clarithromycin versus
placebo in 20 patients with hypersomnia (patients with IH, narcolepsy without cataplexy, or subjective unexplained EDS) in
a randomized, double-blind, cross-over study comparing the effect of 14 day use of clarithromycin versus placebo, the authors
found significant improvement in subjective sleepiness, despite no evidence of an objective benefit per psychomotor vigilance
tests.
In addition to GABAA signaling, other possible pathways involved in IH may involve GABAB and dopaminergic transmission
as suggested by recent evidence of a clinical benefit of sodium oxybate (SXB)–sodium salt of g-hydroxybutyrate (GHB), in IH
patients. A retrospective study in 46 patients with IH treated empirically with SXB conducted by Leu-Semenescu and al. found
a 3-point decrease in the ESS. In addition, half of the patients with IH reported shortened nighttime sleep duration and two thirds
of them reported a reduction of their severe morning inertia with doses lower compared to those used in a group of narcolepsy
type 1 patients (highest total night dose of 4.4 g vs. 6.6 g, respectively). These clinical effects could be related to a restorative effect
of SXB on SWA, shown to be decreased in IH patients in Sforza’s spectral analysis study, while findings of decreased nighttime
sleep duration and decreased subsequent sleep inertia could be related to the biphasic action of SXB on cerebral dopaminergic
activity–an initial phase of dopaminergic terminal hyperpolarization being followed by the release of newly synthesized dopa-
mine (Maitre).

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Hypersomnia: Etiologies 7

Circadian Dysfunction

In the controlled case series published by Vernet and Arnulf, finding of increased amount of SWS in the last hours of the night as
well as lower score on the Horne-Ostberg questionnaire (“evening type”) in hypersomniacs versus controls were indicators of
a delayed sleep-phase in these patients.
In a rare analysis, while exploring the role of circadian dysregulation in IH, Nevsimalova et al. compared salivary cortisol and
melatonin levels over a 24-h period in 15 patients with the polysymptomatic form of hypersomnia against 15 controls. In patients
with IH, a significant phase delay in the evening melatonin rise and decline times was noted. Evening melatonin rise occurred 2 h
later than in controls, while subsequent phase of melatonin decline occurred about 3 h later. They also reported an insignificant
lengthening of the melatonin signal, and a lower concentration of melatonin in the IH versus control group. In the morning,
the IH group demonstrated a 1-h delay in cortisol rise time, compared to controls. One of the conclusions of this study is that
the sleep drunkenness seen in the morning in IH patients may be due to a prolonged and phase-delayed melatonin signal. The
authors cite this phase delay as an explanation for why IH patients may have a tendency to be night owls and suggest a role for
melatonin in the treatment of this disorder.

Conclusion

Hypersomnia can be caused by a variety of medical and/or psychiatric conditions in addition to sleep disorders causing sleep frag-
mentation. Once all other causes of hypersomnia have been ruled out and in the absence of cataplexy, PSG followed by MSLT is the
only test available to distinguish narcolepsy type 2 from IH by measuring REM propensity. However, many variables affect REM
sleep and up to 4% of the general population have an MSLT fulfilling criteria for narcolepsy. In addition, the low test-retest reli-
ability of the MSLT increases the risk of misdiagnosis and misclassification, further obscuring the boundary between IH and narco-
lepsy without cataplexy. Research aims at developing more specific markers to differentiate these conditions. Current evidence
suggests that IH may selectively affect slow-wave sleep distribution and delta power, with delayed slow-wave sleep and decreased
SWA across the sleep cycle with a possible compensatory increased daytime sleep drive. This is in accordance with finding of delayed
circadian secretion of melatonin in IH patients. While IH presents with clear derangement in histamine function and recent research
suggests the presence of a positive allosteric modulator of GABAA receptors in the CSF of these patients, similar results are found in
patients with narcolepsy. One study suggests a specific involvement of the dopamine system in narcolepsy and norepinephrine
system in IH. Further research is needed to extend these findings. It is still unclear whether IH is the consequence of a single pathway
defect or the expression of a broader neural network failure. As new disorders affecting the sleep and arousal systems may be discov-
ered, narcolepsy type 2 and IH could represent two final common pathways, one resulting in REM sleep and the other in NREM
sleep dysregulation. With many developing explanations for IH, it is likely that in the next several years we will see a decrease in
the number of truly “idiopathic” cases and an increase in the number of therapeutic options for EDS and sleep instability.

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