Sleep Medicine Reviews 29 (2016) 23e33

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Sleep Medicine Reviews

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CLINICAL REVIEW

Idiopathic hypersomnia
Michel Billiard a, *, Karel Sonka b, 1
a
Department of Neurology, Gui de Chauliac Hospital, 80 Avenue Augustin Fliche, 34295 Montpellier, Cedex 5, France
b
Department of Neurology, First Faculty of Medicine, Charles University in Prague, Katerinska 30, 1200 Prague, Czech Republic

a r t i c l e i n f o s u m m a r y

Article history: Idiopathic hypersomnia continues to evolve from the concept of “sleep drunkenness” introduced by
Received 3 December 2014 Bedrich Roth in Prague in 1956 and the description of idiopathic hypersomnia with two forms, pol-
Received in revised form ysymptomatic and monosymptomatic, by the same Bedrich Roth in 1976. The diagnostic criteria of
24 August 2015
idiopathic hypersomnia have varied with the successive revisions of the International classifications of
Accepted 24 August 2015
Available online 3 September 2015
sleep disorders, including the recent 3rd edition. No epidemiological studies have been conducted so
far. Disease onset occurs most often during adolescence or young adulthood. A familial background is
often present but rigorous studies are still lacking. The key manifestation is hypersomnolence. It is
Keywords:
Idiopathic hypersomnia
often accompanied by sleep of long duration and debilitating sleep inertia. Polysomnography (PSG)
Hypersomnolence followed by a multiple sleep latency test (MSLT) is mandatory, as well as a 24 h PSG or a 2-wk
Diagnostic criteria actigraphy in association with a sleep log to ensure a total 24-h sleep time longer than or equal to 66O
Neurochemistry minutes, when the mean sleep latency on the MSLT is longer than 8 min. Yet, MSLT is neither sensitive
Genetics nor specific and the polysomnographic diagnostic criteria require continuous readjustment and bio-
Immunology logic markers are still lacking. Idiopathic hypersomnia is most often a chronic condition though
Homeostatic and circadian regulation spontaneous remission may occur. The condition is disabling, sometimes even more so than narco-
Treatment
lepsy type 1 or 2. Based on neurochemical, genetic and immunological analyses as well as on explo-
ration of the homeostatic and circadian processes of sleep, various pathophysiological hypotheses have
been proposed. Differential diagnosis involves a number of diseases and it is not yet clear whether
idiopathic hypersomnia and narcolepsy type 2 are not the same condition. Until now, the treatment of
idiopathic hypersomnia has mirrored that of the sleepiness of narcolepsy type 1 or 2. The first ran-
domized, double-blind, placebo-controlled trials of modafinil have just been published, as well as a
double-blind, placebo-controlled trial of clarithromycine, a negative allosteric modulator of the g-
aminobutyric acid-A receptor.
© 2015 Elsevier Ltd. All rights reserved.

Introduction
In contrast to narcolepsy first described in 1877 [1] and named
in 1880 [2], and to KleineeLevin syndrome first described in 1925
[3] and named in 1942 [4], the identification of idiopathic hyper-
somnia is much more recent, starting with the first description of
sleep drunkenness in 1956 [5] and culminating in the coinage of
the term idiopathic hypersomnia and the initial description of
the condition in 1976 [6]. Thereafter, diagnostic criteria of idio-
pathic hypersomnia have been published in the International
* Corresponding author. Tel.: þ33 6 75 028 364.
E-mail addresses: mbilliard@orange.fr (M. Billiard),
(K. Sonka).
1
Tel.: þ420 224 965 568x50; fax: þ420 224 922 678.
classification of sleep disorders (ICSD) [7] and revised in two later
editions, the International classification of sleep disorders, second
edition (ICSD-2) [8] and the International classification of sleep
disorders, third edition (ICSD-3) [9]. Yet the clinician is still chal-
lenged by the absence of pathognomonic clinical features such
as cataplexy in narcolepsy type 1 or the episodic hypersomnia
associated with at least one of the following: cognitive dysfunc-
tion, altered perception, eating disorder or disinhibited behavior,
typical of the Kleine-Levin syndrome, the inaccuracy of the “gold
standard” multiple sleep latency test (MSLT) and the absence of a
biologic marker. Moreover, an animal model is lacking, the path-
ophysiology is poorly understood, and the treatment is still bor-
rowed from narcolepsy type 1 or 2. In this chapter we aim at
ksonka@lf1.cuni.cz formulating an appraisal of where the field is and where it should
be heading.

http://dx.doi.org/10.1016/j.smrv.2015.08.007
1087-0792/© 2015 Elsevier Ltd. All rights reserved.
24 M. Billiard, K. Sonka / Sleep Medicine Reviews 29 (2016) 23e33
Abbreviations
ADHD attention deficit/hyperactivity disorder
CAP cycling alternating pattern
CGI clinical global impression
CPAP continuous positive airway pressure
CHKB choline kinase beta
CPT1B carnitine palmitoyl transferase
CSF cerebrospinal fluid
DAT dopamine transporter
DM1 myotonic dystrophy type 1
DSM-IV-TR Diagnostic and statistical manual of mental
disorders, 4th edition, text revision
DSM-5 Diagnostic and statistical manual of mental disorders,
5th edition
EEG electroencephalogram
EQS excessive quantity of sleep
ESS Epworth sleepiness scale
GABA g aminobutyric acid
HLA human leucocyte antigen
ICSD International classification of sleep disorders
ICSD-2 International classification of sleep disorders, 2nd
edition
ICSD-3 International classification of sleep disorders, 3rd
edition
IgG immunoglobulin G
Historical account
The concept of idiopathic hypersomnia takes its roots in the
description by Roth of “sleep drunkenness”, a major difficulty in
awakening [5]. One year later, the same author published a book
entitled “Narcolepsy and hypersomnia, from the aspect of physiology
of sleep” [10], in which he distinguished, solely on clinical grounds,
155 patients with narcolepsy and 93 with hypersomnia, and among
those, 50 with functional hypersomnia, 29 with organic hyper-
somnia and 14 with independent “post-dormital” drunkenness. In
1960, Vogel showed that narcoleptic patients fall directly into REM
sleep, paving the way to a more accurate distinction of these
different forms of hypersomnolence [11]. In 1966, Dement et al.
accordingly wrote that “those patients without cataplexy or sleep
paralysis who also fail to show sleep-onset REM periods in labo-
ratory tests probably do not have narcolepsy and should be rele-
gated to another diagnostic category [12], a statement reminiscent
of the much earlier clinical one by Levin: “I shall restrict the term
narcolepsy or Gelineau's syndrome to those cases that present both
sleep attacks and cataplexy … Patients with attacks of sleep are
common, whereas patients with attacks of sleep and cataplexy are
relatively rare, and it would seem wise, for the present, to regard
the latter as a separate group” [13]. In 1967, Berti-Ceroni et al.
proposed the term “essential narcolepsy” for this category of pa-
tients [14] and in 1968, Passouant et al. proposed the term “NREM
narcolepsy” [15]. Later, Roth et al. published an article entitled
“Hypersomnia with sleep drunkenness” based on 48 patients from
the Department of Neurology in Prague and 11 that he had
personally examined at the University of Chicago Sleep Laboratory
[16]. These patients usually reported that their night sleep was
extremely deep and the majority of them (51 of 58) suffered from
diurnal hypersomnia, meaning too much daytime sleep. A total
of 36 polygraphic recordings, approximately one hour in duration,
were performed in 16 patients, during the day, in Prague. None of
these patients showed sleep-onset REM periods (SOREMPs). Eleven
MSL mean sleep latency
MSLT multiple sleep latency test
MWT maintenance of wakefulness test
OSAS obstructive sleep apnea syndrome
PLM periodic limb movements
PSG polysomnography
REM rapid eye movement
RERAs respiratory effort related arousals
rs Ref SNP
SOREMPs sleep-onset REM periods
SNP single nucleotide polymorphism
SWA slow wave activity
T-MHA tele-methylhistamine
TCRA T-cell receptor alpha
Glossary of terms
Hypersomnolence as captured in the Diagnostic and statistical
manual of mental disorders, 5th edition
(DSM-5) focuses on excessive daytime
sleepiness
Hypersomnia as defined in the International classification of
sleep disorders, 3rd edition (ICSD-3) focuses upon
duration of sleep, hence the diagnostic terms
“idiopathic hypersomnia” or “post-traumatic
hypersomnia”
patients from the Chicago Sleep Laboratory were monitored for two
nights each, again without any SOREMPs [17]. Finally, in a landmark
article published in 1976, Roth reported 642 personally-observed
cases of narcolepsy and hypersomnia and coined the term “Idio-
pathic hypersomnia” [6]. Two forms were proposed: a poly-
symptomatic form characterized by excessive diurnal sleep of
one to several hours duration, prolonged night sleep of a
12e18 h duration and great difficulty upon awakening in the
morning, and a monosymptomatic form characterized by the most
prominent and often unique manifestation of excessive diurnal
sleep of one to several hours duration, however not as irresistible as
in narcolepsy [6]. In 1979, the Diagnostic classification of sleep and
arousal disorders referred to “Idiopathic CNS hypersomnolence” as a
disorder of excessive somnolence “characterized by recurrent
daytime sleepiness, but “sleep attacks” do not occur because the
sleepiness is not as irresistible as in narcolepsy” [18]. In keeping
with Dement's statement (see above) and results of previous
polygraphic recordings in Chicago [17] and in Prague [16], the
Diagnostic classification of sleep and arousal disorders mentioned
that polysomnography (PSG) should fail to uncover SOREMPs. In
addition, it included a reference to the MSLT, several years before
the publication of the “guidelines for the MSLT: a standard measure
of sleepiness” [19], indicating that “sleep latencies are usually very
short in the daytime (MSLT) as well as at bedtime [18]. In 1990, the
ICSD referred to “Idiopathic hypersomnia” as an “intrinsic sleep dis-
order” [7]. It also pointed that PSG should rule out SOREMPs; with
regard to the MSLT it stated: “The MSLT usually demonstrates a
sleep latency of less than 10 min”. Of note, neither of these classi-
fications maintained the division of idiopathic hypersomnia into
two forms, as proposed earlier by Roth [6]. In 1997, Bassetti and
Aldrich proposed three forms of idiopathic hypersomnia: “classic”,
referring to patients who tended to have sleepiness that was not
overwhelming, to take long non-refreshing naps up to a
4 h duration, to have prolonged night-time sleep and to have dif-
ficulty in awakening in the morning; “narcoleptic-like”, referring to
 M. Billiard, K. Sonka / Sleep Medicine Reviews 29 (2016) 23e33
patients with overwhelming hypersomnolence, who took short
refreshing naps and awakened without difficulties and “mixed”,
referring to patients with clinical features intermediate between
the two other groups [20]. In 1998, Billiard et al. suggested
returning to Roth's initial distinction and proposed the terms
“complete” and “incomplete” forms [21]. Thereafter, the ICSD-2
returned to two forms of idiopathic hypersomnia, namely idio-
pathic hypersomnia with and without long sleep time. The form
with long sleep time was clinically characterized by excessive
daytime sleepiness, prolonged nocturnal sleep time (more than
10 h) and great difficulty waking up or sleep drunkenness, either in
the morning or at the end of naps, and additionally polysomno-
graphically characterized by a major sleep period prolonged to
more than 10 h in duration, a mean sleep latency (MSL) of less than
8 min and fewer than 2 SOREMPs on the MSLT. The form without
long sleep time was clinically characterized by excessive daytime
sleepiness and normal nocturnal sleep (6e10 h in duration) and
polysomnographically by a major sleep period of normal duration
(6e10 h) and, similarly, a MSL of less than 8 min and fewer than 2
SOREMPs on the MSLT [8].
However, the distinction between idiopathic hypersomnia with
and without long sleep time was later challenged by the absence of
symptoms specific to one subgroup (e.g., great difficulty waking up
or sleep drunkenness were found in both subgroups, albeit less
frequently in the form without long sleep time) [22,23]. In addition,
the validity of SOREMPs during the MSLT in diagnosing narcolepsy
without cataplexy [24] or narcolepsy (without affiliation status)
[25], was brought into question, as well as the validity of MSL
during the MSLT in diagnosing idiopathic hypersomnia [22,23].
Indeed, 32 of 72 patients with idiopathic hypersomnia had a MSL of
8 min or more in one study [22] and 22 of 75 a MSL of more than
10 min and 7 a MSL between 8 and 10 min in a second study [23].
Moreover, a study identifying patients with idiopathic hyper-
somnia, narcolepsy without cataplexy and physiologic hyper-
somnia who had undergone two diagnostic MSLT at 2.5 mo to 16.9
y (average 4.2 ± 3.8 y) has shown the poor test-retest reliability of
the MSLT [26]. A change in diagnosis occurred in 6 of 14 subjects
with an initial diagnosis of idiopathic hypersomnia, with five pa-
tients changing to a final diagnosis of physiological hypersomnia
(MSL  8 min) and one patient changing to a final diagnosis of
narcolepsy without cataplexy (n of SOREMs  2). Conversely, three
patients with an initial diagnosis of narcolepsy without cataplexy
were rediagnosed with idiopathic hypersomnia (n of SOR-
EMPs < 2) and two subjects with physiologic hypersomnia to
idiopathic hypersomnia (MSL < 8 min).
Thus, the newly released ICSD-3 has abandoned the division
between idiopathic hypersomnia with and without long sleep time
for clinical reasons and has profoundly revised the polysomno-
graphic criteria of idiopathic hypersomnia [9].
Epidemiology
The exact prevalence of idiopathic hypersomnia remains un-
known due to uncertainties in the diagnostic criteria resulting in an
absence of robust epidemiological studies. Ratios of idiopathic
hypersomnia to narcolepsy, with and without cataplexy, and to
narcolepsy (without affiliation status) in cohorts of patients pub-
lished by different sleep disorders centers are available. However,
these ratios range from 5.0% [27] to 47.2% [6], obviously reflecting
referral and reporting biases. Onset of the condition is most often
during adolescence or young adulthood. According to some co-
horts, there is a higher prevalence of idiopathic hypersomnia in
women [20,27,28].
Apart from these evaluations, a recent study has proposed the
concept of “excessive quantity of sleep” (EQS), defined as a main
25
sleep period or 24-h sleep duration greater than or equal to nine
hours, accompanied by complaints of impaired functioning or
distress due to excessive sleep [29]. This study used the Sleep-Eval
expert system to ask questions on living and sleeping habits, health,
and mental and organic disorders according to the Diagnostic and
statistical manual of mental disorders, 4th edition, text revision
(DSM-IV-TR) [30], in a non-selected population sample of 15,929
individuals aged 18e102 y. EQS was observed in 1.6% (1.4e1.8%) of
the sample and the prevalence of DSM-IV-TR hypersomnia disorder
was 0.5% (0.4e0.6%), suggesting idiopathic hypersomnia is poten-
tially more common than previously said to be. The same conclu-
sion was reached by Mignot et al. [24] who showed that 23.38% of
men and 22.18% of women in the Wisconsin sleep cohort exhibited
a MSL of <8 min and by Singh et al. [25] who showed a rate of
MSL < 8 min of 33.2% for a group of 539 subjects composed of 333
randomly selected from the general population, enriched with 206
with complaints of sleepiness.
Predisposing and precipitating factors
A familial background is found in a high proportion of probands,
almost similar in different series (Table 1), although more rigorous
studies with clinical interviews and sleep studies in relatives are
warranted.
Precipitating factors such as head trauma, viral illness and
general anaesthesia have been reported but no definitive link has
been proven.
Clinical features
Hypersomnolence is the key manifestation of idiopathic
hypersomnia and is generally considered less irresistible than in
narcolepsy type 1. Naps are few, long and non-refreshing in half to
three quarters of patients [9]. Night sleep is abnormally long in at
least a third of patients [9]. Awakening in the morning or at the
end of naps may be difficult or may present as sleep drunkenness,
e.g., severe sleep inertia consisting of difficulty in coming to
complete wakefulness accompanied by confusion, disorientation,
poor motor coordination and repeated returns to sleep [16].
Manifestations of autonomic dysfunction such as headache,
orthostatic disturbance, cold extremities, feeling of faintness,
temperature dysregulation, palpitations and digestive problems
are sometimes present. In addition, subjective symptoms such as
being more alert in the evening than in the morning, difficulty
focusing more than one hour, complaints of attention and mem-
ory deficits, mental fatigability and hyperactivity helping to resist
sleepiness have recently been reported [34]. Altogether, the
phenotype of idiopathic hypersomnia is not unitary, hence the
successive suggestions of nosological separation of the condition
into two or three forms.
Laboratory tests
According to ICSD-3 [9], two polysomnographic diagnostic
criteria must be met to confirm a clinical diagnosis of idiopathic
hypersomnia:
1) An MSLT performed according to standard techniques shows
fewer than two SOREMPs or no SOREMP if the REM latency on
the preceding polysomnogram was less than or equal to
15 min.
2) The presence of at least one of the following
1) The MSLT shows a mean sleep latency of < or ¼ 8 min
2) Total 24-h sleep time is  660 min (typically 12e14 h) on 24-
h polysomnographic monitoring (performed after correction
26 M. Billiard, K. Sonka / Sleep Medicine Reviews 29 (2016) 23e33

Table 1
Heredofamilial occurrence of idiopathic hypersomnia in various series. Note the similar proportion of probands with a positive family history of idiopathic hypersomnia in each
series.

Authors Number of probands Number and percent of probands with a positive

family history of idiopathic hypersomnia

Nevsimalova-Bruhova and Roth, 1972 [31] 23 9 (39.1%)

Roth, 1980 [32] 167 45 (26.9%)
Billiard and Dauvilliers, 2001 [33] 35 13 (37.1%)
Anderson et al., 2007 [22] 66 20 (30.0%)
Ali et al., 2009 [28] 49 18 (37.7%)

of chronic sleep deprivation) or by wrist actigraphy in asso-
ciation with a sleep log (averaged over at least seven days
with unrestricted sleep).
Thus, the distinction between idiopathic hypersomnia with and
without long sleep time has been formally removed. However, the
authors of the ICSD-3 recognize that nocturnal sleep is of abnor-
mally long duration in at least one third of patients and admit that
some patients with idiopathic hypersomnia may have a mean sleep
latency 8 min on the MSLT and a total 24-h sleep time less than
660 min, while others may show a mean sleep latency >8 min on
the MSLT and a total 24-h sleep time 660 min, which underlines
that the MSLT is non-specific vis a vis criteria for hypersomnia
[24,25]. This is clear evidence of the insufficiency of polysomno-
graphic tests and of the need for alternative behavioral metrics and
biological markers.
In addition to these diagnostic criteria, several authors have
reported alteration of slow wave sleep duration, REM sleep dura-
tion and number of arousals per hour in comparison with controls
or narcolepsy patients with or without cataplexy (Table 2).
Furthermore, investigation of nocturnal sleep abnormalities in 19
patients with idiopathic hypersomnia in comparison with 13
normal subjects and 17 patients with narcolepsy with cataplexy,
showed that idiopathic hypersomnia and narcolepsy with cata-
plexy patients slept more than normal subjects, and that idiopathic
hypersomnia patients showed the highest levels of sleep frag-
mentation (e.g., awakenings), associated with a cycling alternating
pattern (CAP) rate higher than in narcolepsy with cataplexy pa-
tients during lighter sleep stages and lower than in normal subjects
during slow wave sleep respectively [40].
Episodes of obstructive sleep apnea should theoretically be
fewer than 5 per hour and respiratory-effort related arousals
(RERAs) fewer than 10. If not, a continuous positive airway pressure
(CPAP) trial should be performed: if there is no change, the
diagnosis of idiopathic hypersomnia is confirmed. Periodic limb
movements (PLM) should be fewer than 15 per hour, although PLM
(without related arousals) are a debated cause of sleepiness [42].
A very recent article has demonstrated the reliability of actig-
raphy in distinguishing the features of estimated daytime and
nighttime sleep between patients with narcolepsy type 1 and
idiopathic hypersomnia, and age and sex matched healthy controls
[43].
In addition, psychiatric evaluation should be performed in
subjects suspected of having a psychiatric disorder, mainly bipolar
disorder II, major depressive disorder or schizoaffective disorder,
and neuroimaging in the presence of neurological signs.
Course and complications
Once established, idiopathic hypersomnia is usually stable and
long lasting. However fluctuations in disease severity may be
observed as documented by changes in MSLT results over multiple-
year intervals [26] and spontaneous remissions reported in several
series [20e22,44].
Initially, complications of idiopathic hypersomnia may appear
similar to those of narcolepsy type 1 or 2, including poor perfor-
mance at school and work, sleep during recreational activities and a
higher incidence of car accidents. However, some idiopathic
hypersomnia patients have unique and often debilitating com-
plaints including: arriving late to work, receiving negative com-
ments from their employer and often being dismissed as a
consequence; poor tolerance by family members of the lengthy
time they spend in bed; absence of benefit from night sleep and
from naps, to the extent that these patients never feel refreshed and
difficulty in awakening often resistant to stimulant medications
[45]. Furthermore, a recent study has shown that patients with

Table 2
Sleep architecture in idiopathic hypersomnia in comparison with narcolepsy and normal controls in various series. SWS, slow wave sleep; IH, idiopathic hypersomnia; LST, long
sleep time; N, narcolepsy; NC, narcolepsy with cataplexy; n.s., non significant.

Disease under study SWS duration REM sleep duration Arousals (per hour)

Versus controls Versus N Versus controls Versus N Versus controls Versus N

IH Baker et al. [35] e Longer e ns e e

IH Aldrich [36]
IH Bassetti and Aldrich [20]
IH Sforza et al. [37]
IH Vgontzas et al. [38]
IH Anderson et al. [22]
IH Vernet et al. [23]
IH e 48 h monitoring Vernet
et al. [34]
IH w/out LST Takei et al. [39]
IH w/out LST Pizza et al. [40]
IH with LST Drakatos et al. [41]
e Versus N n.s.
e Versus N n.s. e Versus N n.s. versus NC n.s. e Versus N n.s. versus NC fewer
versus NC n.s.
Shorter e Longer e e e
n.s. e n.s. e e e
e Longer e e e e
Shorter e Longer e Fewer
n.s. n.s. Fewer
e Versus NC n.s. e Versus NC n.s. e Versus NC fewer
n.s. Versus NC n.s. n.s. Versus NC n.s. fewer Versus NC more
e Versus NC n.s. e Versus NC n.s. versus N n.s. e Versus NC fewer versus N n.s.
versus N n.s.
 M. Billiard, K. Sonka / Sleep Medicine Reviews 29 (2016) 23e33
narcolepsy with cataplexy, narcolepsy without cataplexy and
idiopathic hypersomnia without long sleep time had significantly
lower scores for most SF-36 domains compared with Japanese
normative data [46].
Pathophysiology
Several non-mutually exclusive hypotheses have been proposed
but the outcome is not definitive.
Neurochemistry
More than 40 y ago, Petitjean and Jouvet reported hypersomnia
with a proportional increase of NREM and REM sleep suggestive of
idiopathic hypersomnia, following destruction of norepinephrine
neurons in the rostral third of the locus coeruleus complex or of
the norepinephrine bundle at the level of the isthmus in a feline
model [47]. Subsequently a series of studies measuring mono-
amine metabolites in the cerebrospinal fluid (CSF) of idiopathic
hypersomnia patients were performed in the 1980s. However
biological methods for measuring monoamine metabolites have
been criticized and none of these studies has ever been replicated.
More recently, it has been shown by different groups that CSF
hypocretin-1 concentrations are normal in patients with idiopathic
hypersomnia [48e50]. On the other hand, reduced CSF histamine
levels have been observed in hypocretin-deficient narcolepsy with
cataplexy, in hypocretin non-deficient narcolepsy and in idiopathic
hypersomnia, while those in obstructive sleep apnea syndrome
were not altered [51]. This led to the suggestion that CSF histamine
is a biomarker reflecting the degree of hypersomnia of central
origin. However, using a new validated method of CSF histamine
and tele-methylhistamine (t-MHA) measurement [52], Dauvilliers
et al. did not find any CSF histamine and t-MHA level differences
between the various etiologies of central hypersomnia (narcolepsy
with and without cataplexy, idiopathic hypersomnia), unspecified
excessive daytime sleepiness and neurological controls [53]. Thus,
they concluded that measurements of both histamine and t-MHA
are not useful in assessing the etiology or severity of central
hypersomnias.
A promising perspective comes from a recent experiment
showing that, in the presence of 10 mM g-aminobutyric acid
(GABA), CSF from hypersomnolent subjects (excluding known
causes of sleepiness) stimulated GABAA receptor function in vitro,
relative to the stimulation obtained with CSF from control subjects
(p < 0.0001) [54]. Remarkably, the authors could show, in a mo-
lecular sizing experiment followed by a molecular and then
neutralizing experiment, that the bioactive CSF component had a
mass of 500e3000 Da and was neutralized by trypsin.
Genetics
As indicated earlier (Table 1) approximately one third of pro-
bands have a positive family history of idiopathic hypersomnia.
Recently, a report of three adolescent-onset cases of idiopathic
hypersomnia assessed clinically and by use of ad libitum PSG was
published, arguing for a genetic origin in this family [55]. The
pedigree was compatible with autosomal dominant inheritance.
Incidentally, no report of twins affected with idiopathic hyper-
somnia has ever been published. Following these observations,
there was initial interest in potential human leucocyte antigen
(HLA) markers in idiopathic hypersomnia [20,56,57], but no
consistent findings have emerged. In 2008, a genome-wide asso-
ciation study using 500 K single-nucleotide polymorphism (SNP)
microarrays in 222 Japanese individuals with narcolepsy with
cataplexy and 190 Japanese controls led to the discovery of a Ref
SNP (rs) 5770917 located between carnitine palmitoyltransferase
1B (CPT1B) and choline kinase beta (CHKB) as a novel genetic
27
marker of susceptibility for narcolepsy with cataplexy [58], which
was not found in the Chinese population [59]. In 2009, a similar
study conducted in Caucasians with replication in three ethnic
groups found an association between narcolepsy and poly-
morphism in the T-cell receptor alpha (TCRA) locus with highest
significance at rs 1,154,155 [60]. In line with these studies, genome-
wide analyses have been conducted in Japanese patients with
essential hypersomnia, a condition defined by pure clinical diag-
nostic criteria: 1) recurrent daytime sleep episodes that occur
basically every day over a period of at least six months, 2) absence
of cataplexy, 3) the condition does not meet the diagnostic criteria
of any other disorder causing excessive daytime sleepiness, such as
sleep apnea syndrome [61]. One study showed that SNP rs 5770917
located between CPTIB and CHKB, and HLA-DRB1*1501-
DQB1*0602 haplotype independently confer susceptibility to
essential hypersomnia [62], while another study showed that SNP
rs 1154155 located in TCRA confers susceptibility to essential
hypersomnia with HLA-DRB1*1501-DQB1*0602 haplotype [63].
Immunology
Tanaka and Honda assessed immunoglobulin G (IgG) profiles in
narcolepsy with cataplexy patients positive for the HLA-DQB1*0602
allele, idiopathic hypersomnia patients and healthy controls [64].
The distribution of serum IgG significantly differed among narco-
lepsy with cataplexy patients, idiopathic hypersomnia patients and
healthy controls. Decreased IgG1 and IgG2 levels, stable expression
of IgG3 and an increase in the proportion of IgG4 was found in
narcolepsy with cataplexy patients, in contrast with an IgG1/IgG2
imbalance, a decrease of IgG2 and an increase of IgG3 and IgG4 levels
in idiopathic hypersomnia patients, in favor of immunological dif-
ferences between the two conditions. Moreover, the significant in-
crease in the IgG1/IgG2 ratio in idiopathic hypersomnia patients
suggested type 1 helper T-cell involvement in idiopathic hyper-
somnia. However, no other clinical or biological studies have sup-
ported an immunopathological process in idiopathic hypersomnia.
Homeostatic and circadian regulation
In a study comparing the level of slow wave activity (SWA) in
the first two NREM-REM sleep cycles, this level was significantly
lower in idiopathic hypersomnia patients than in controls [37].
Thus, patients with idiopathic hypersomnia may need a prolonged
sleep time due to lower intensity of NREM sleep. Two other studies
compared the sleep spindle index in idiopathic hypersomnia and
controls [65] and in idiopathic hypersomnia and narcolepsy
(without affiliation status), [66]. They documented an increased
spindle index predominating by the end of night sleep in idiopathic
hypersomnia, which may explain the symptoms of major difficulty
awakening and “sleep drunkenness”.
In addition, a disturbed circadian rhythm has been hypothe-
sized on the basis of a phase delay in the rhythm of melatonin and
cortisol secretions in 15 patients with idiopathic hypersomnia
with long sleep time [67]. In a more recent study, Horne and
€
Ostberg scores were lower in idiopathic hypersomnia patients
than in controls, consistent with a delayed sleep phase in idio-
pathic hypersomnia [23]. Moreover, an investigation of the diurnal
dynamics of circadian clock gene expression in dermal fibroblasts
of idiopathic hypersomnia patients, in comparison with those of
healthy controls, has shown that the amplitude of the rhythmi-
cally expressed genes BMAL1, PER1 and PER2 was significantly
dampened in dermal fibroblasts of idiopathic hypersomnia pa-
tients, suggesting aberrant dynamics in the circadian clock of
idiopathic hypersomnia patients [68] (Fig. 1). However, at the
present state of knowledge, it is difficult to say which of the two
conditions exists first and which causal relationship they may
have.
Fig. 1. Expression of circadian clock genes in dermal fibroblasts of healthy controls and idiopathic hypersomnia patients. Borrowed from Lippert J, Halfter H, Heidbreder A et al.
Altered dynamics in the circadian oscillation of clock genes in dermal fibroblasts of patients suffering from idiopathic hypersomnia. PLoS One 2014; 9: e85255 [61]. Blue dots indicate
actual measurements, the colored lines represent the gene expression profile relative to 18SrRNA in the shape of a sine curve to prove circadian gene expression in all examined cell
lines. The broken black line indicates the best fit sine curve defined as the average value of the three rhythmic functions fitted to the data. Numbers in parenthesis beside the figures
indicate the time points used for prediction and numbers at the right indicate root-mean-square errors (MSE). (For interpretation of the references to color in this figure legend, the
reader is referred to the web version of this article.)
 M. Billiard, K. Sonka / Sleep Medicine Reviews 29 (2016) 23e33
Differential diagnosis
The differentiation of idiopathic hypersomnia from other con-
ditions is rarely straightforward. Thus, in several countries, evalu-
ation is performed in reference centers with specialized clinicians
and access to long term PSG or actigraphic monitoring.
Idiopathic hypersomnia may be confused with obstructive
sleep apnea syndrome (OSAS), especially when respiratory-related
arousals (RERAs) (rather than apneas or hypopneas) are present. In
case of any doubt a short-term CPAP trial should be performed.
Among hypersomnias of central origin, the main issue is the
distinction between idiopathic hypersomnia and narcolepsy type 2.
If one considers ICSD-3 diagnostic criteria of both conditions, there
is much more in common between idiopathic hypersomnia and
narcolepsy type 2 than differences [9]. Clinical criteria A and B of
idiopathic hypersomnia and A and C of narcolepsy type 2 are
similar, and MSLT criteria C and D1 of idiopathic hypersomnia and B
of narcolepsy type 2 only differ by the number of SOREMPs on the
MSLT, fewer than two in the former and two or more in the latter, a
rather subtle difference if one considers that the number of SOR-
EMPs may vary from one MSLT to another in a same individual [25].
Moreover, we have recently shown, by means of a cluster analysis,
that narcolepsy without cataplexy and idiopathic hypersomnia
without long sleep time belong to the same cluster [69].
Narcolepsy (without affiliation status) with long sleep time is a
special case that shares many clinical and polysomnographic sim-
ilarities with classical narcolepsy (without affiliation status), but is
remarkable by longer sleep time during the night and day and
higher sleep efficiency [70]. In this article the authors did not
mention how many of their narcoleptic patients were type 1 and
type 2, and of the 23 narcoleptics with long sleep time only three
had “core narcolepsy” (narcolepsy type 1), suggesting that the ma-
jority of the long sleepers had narcolepsy type 2, a condition with
more commonality than differences with idiopathic hypersomnia
(see above).
Hypersomnia may be associated with a psychiatric disorder.
According to the Diagnostic and statistical manual of mental dis-
orders, 5th edition (DSM-5), hypersomnia is an optional clinical
diagnostic criterion of several mental disorders: bipolar 1 disorder
and more typically bipolar 2 disorder in the spectrum of bipolar and
related disorders, major depressive disorder, persistent depressive
disorder, premenstrual dysphoric disorder in the spectrum of
depressive disorders, and schizoaffective disorder in the spectrum
of schizophrenia and other psychotic disorders [71]. In general,
patients complain about intractable excessive daytime sleepiness
and usually rank very high on the Epworth sleepiness scale (ESS).
However, the degree of sleepiness varies with days, night sleep
tends to be of poor quality and above all, objective hypersomno-
lence has never been evidenced on the MSLT, except in 5 of 25
patients with bipolar disorder [72]. Of note, an optional feature of
depression with atypical features is “an extended period of night-
time sleep or daytime napping that totals at least 10 h of sleep” (or
at least 2 h more than when not depressed) [71], something close to
the ICSD-3 660 min of idiopathic hypersomnia.
Post-traumatic hypersomnia, a condition including both hyper-
somnia (increased sleep need per 24 h) and hypersomnolence
[73], may mimic idiopathic hypersomnia. Past medical history
with notion of an initial coma following head trauma is of
major value. Imaging studies may reveal various findings: lesions
affecting the hypothalamic region, brainstem, midbrain or pontine
tegmentum, or more often an absence of any significant lesion
[74,75].
Hypersomnolence affects 16e50% of patients with Parkinson's
disease [76] and up to 28% of patients with multiple system atrophy
[77], but hypersomnolence may precede the occurrence of the
29
principal neurologic features of both of these neurological condi-
tions by several years. An inverse correlation between ESS scores
and mean dopamine transporter (DAT) binding has been reported
in the striatum, in Parkinson's disease patients with Hoehn and
Yahr stage 2 [78].
Myotonic dystrophy type 1 (DM1) is the most common adult-
onset form of muscular dystrophy. According to Laberge et al. hy-
persomnolence is present in 33.1% of DM1 patients [79]. DM1
related hypersomnolence consists in a persistent sleepiness unaf-
fected by naps, the latter being long and unrefreshing. Differential
diagnosis with idiopathic hypersomnia is based on the presence of
weakness of limb, facial and respiratory muscles, myotonia, car-
diomyopathy, endocrine abnormalities, frontal balding, neuropsy-
chological deficits and cataract.
Hypersomnia following a viral infection such as viral pneu-

monia, infectious mononucleosis, hepatitis B virus or Guillain-Barre
syndrome, usually develops within weeks or months following
infection, with the subject complaining of residual fatigue, hyper-
somnolence and abnormally long sleep. Prognosis is favorable
though recovery may take months to years [80].
Delayed sleep phase syndrome should be considered given the
major difficulty in awakening in the morning. Since idiopathic
hypersomnia patients feel at their best during the evening hours
and consider themselves as evening types [67], have low Horne-
€
Ostberg scores [23], and show a phase delay of the melatonin and
cortisol rhythms [67] one may even question whether the two
conditions are recognizable as unique.
Chronic fatigue syndrome is characterized by persistent or re-
lapsing fatigue that does not resolve with sleep or rest. The
disabling fatigue is accompanied by joint and muscle pain, head-
ache, poor concentration, impaired short term memory, disturbed
sleep, recurrent subjective feverish feelings and sore throat [81].
PSG shows reduced sleep efficiency and may include alpha-
intrusion into sleep electroencephalogram (EEG) [82].
Insufficient sleep syndrome is associated with hypersomno-
lence predominating in the afternoon and in the evening, impaired
concentration and lower energy level [83]. A detailed history of the
subject's current sleep schedule is needed as well as extending
sleep time for a minimum of two weeks, to see whether the pro-
cedure is followed by a decrease in sleepiness.
A long sleeper is an individual who consistently sleeps more in
24 h than does the typical person of his or her age group. For
adults, the usually accepted figure is 10 h or more, but many
epidemiological studies have used sleep times of 8e10 h [9].
The main difference from idiopathic hypersomnia is the absence
of complaint of diurnal hypersomnolence or difficulty in awak-
ening as long as sufficient sleep is obtained to fulfill the subject's
needs [9].
However, the differentiation of a genuine long sleeper from a
patient with idiopathic hypersomnia may be difficult in different
situations: in the child or adolescent because the normal contin-
uum of sleep duration is somewhat higher in this age group than
in adults; in patients with atypical depression or bipolar 2 disor-
der staying long hours in bed without sleeping deeply and in
case of subjects with excessive nocturnal sleep and daytime hy-
persomnolence due to sedative medication or substance. A
consistent daily pattern, documented by a carefully kept sleep log
(preferably confirmed by actigraphy) showing ten or more hours
of sleep per night over a minimum of two weeks is desirable for
the identification of the long sleeper.
Recently, emphasis has been put on the frequent presence of
fatigue upon awakening and hypersomnolence in sleepwalkers, in
the absence of any concomitant sleep disorder [84,85].
Finally, there are conditions such as hypothyroidism [86], iron
deficiency [87] or vitamine D storage insufficiency [88] which have
30 M. Billiard, K. Sonka / Sleep Medicine Reviews 29 (2016) 23e33
been suggested as possible causes of hypersomnolence or fatigue,
but still lack comprehensive characterization inclusive of objective
measurements of sleep propensity and vigilance.
Treatment
Behavioral treatment
Behavioral treatment of idiopathic hypersomnia is not as suc-
cessful as in narcolepsy with or without cataplexy. Naps are non-
refreshing in 46e78% of patients [9] and extension of sleep time
for several days to saturate the patient's need for sleep does not
bring relief in the long term.
Conventional pharmacological options
Although the type of hypersomnolence is not the same in nar-
colepsy type 1 and idiopathic hypersomnia, the same pharmaco-
logical options, stimulants (amphetamines and methylphenidate),
and wakefulness promoting agents (modafinil and armodafinil) are
used in both conditions.
The first trial with modafinil in idiopathic hypersomnia was per-
formed as an open-label study in 1988 [89].18 patients participated in
the study. Modafinil was administered in the morning and at noon.
The dose varied from 200 to 500 mg/day according to patient weight
and the severity of symptoms. The number of daytime drowsiness
and sleep episodes was significantly reduced in 15 patients.
It then took twenty more years for further retrospective
studies to be performed, one on 61 patients with idiopathic
hypersomnia followed for 3.8 ± 2.1 y [22] and another on 85 pa-
tients with idiopathic hypersomnia followed for 2.4 ± 4.7 y [28]. In
the first study, 54 patients were treated with modafinil and 39
(72.2%) remained on this drug alone. Of these 39, 24 (44%) were
good responders, 8 (14.8%) switched to dexamphetamine due to
side effects and 7 (12.9%) reported lack of efficacy. The most
common side effects were transient nausea and headache, often
alleviated by dose reduction and more cautious dose escalation.
Among those who switched to dexamphetamine, 5 (62%) were
good responders and 3 (37%) poor responders [22]. In the second
study 50 patients were treated with modafinil and 61 with
methylphenidate. Of the 50 patients that received modafinil
mono-treatment, only 25 (50%) remained on drug, 18 of them
(36%) reporting complete response, 4 (8%) partial response and 3
(6%) no benefit. Of the 61 subjects treated with methylphenidate,
40 (66%) remained on drug, 25 of them (41%) reporting complete
response, 13 (21%) partial response and 2 (3%) poor response [28].
The main side effects were headache with modafinil, palpitations
and nervousness with methylphenidate.
A later study involved a consecutive cohort of 104 patients with
idiopathic hypersomnia and 126 patients with narcolepsy with
cataplexy from four different university hospitals [90]. Modafinil
produced a similar ESS change in idiopathic hypersomnia patients
(2.6 ± 5.1) and in narcolepsy with cataplexy patients (3 ± 5.1)
and a similar benefit as estimated by patients and clinicians in
idiopathic hypersomnia patients (6.9 ± 2.7) as well as in narcolepsy
with cataplexy patients (6.5 ± 2.5). Loss of efficacy and habituation
were rare in both groups. Of note, idiopathic hypersomnia patients
reported similar but more frequent adverse effects with modafinil
than narcolepsy patients.
A further study evaluated quality of life, ESS scores, and items
concerning psychosocial and environmental variables in patients
with narcolepsy with cataplexy (83 on psychostimulants and 28
drug-naïve), patients with narcolepsy without cataplexy (48 on
psychostimulants and 27 drug-naïve), and patients with idiopathic
hypersomnia without long sleep time (54 on psychostimulants and
82 drug-naïve), comparing these patient groups with Japanese
normative data [46]. All three diagnostic groups had significantly
lower scores for most SF-36 domains compared with Japanese
normative data, and ESS scores were significantly reduced with
treatment.
Recently, two randomized, double-blind, placebo-controlled
trials have been performed.
The first, a multicenter study, was performed in 31 adult pa-
tients with idiopathic hypersomnia without long sleep time, 14
on modafinil and 17 on placebo [91]. Modafinil 200 mg given
in the morning improved ESS and clinical global impression
(CGI) compared to placebo and led to a non-significant increase
in MSL on the maintenance of wakefulness test (MWT). The
second, a crossover study, was conducted in 13 narcolepsy pa-
tients (seven with cataplexy) and 14 idiopathic hypersomnia
patients receiving modafinil (400 mg) or placebo. Modafinil
improved driving performance judged by the mean number of
inappropriate line crossings and standard deviation of lateral
position of the vehicle compared to placebo, as well as MSL on
the MWT [92].
Another treatment, mazindol (a tricyclic, non-amphetamine
stimulant) was evaluated by a retrospective analysis of 37 idio-
pathic hypersomnia patients refractory to modafinil, methylpheni-
date and sodium oxybate, at three different university hospitals [93].
Patients received an average dose of 3.6 mg/day. The benefit on
sleepiness as determined by the difference between the final ESS
score and the ESS score before starting treatment was 4.8 ± 4.7
(p < 0.0001). Treatment was discontinued in six patients (16%), due to
lack of efficacy in five patients (13.5%) and to adverse effects in four
(11%).
Antidepressants like bupropion or protriptyline that have
insomnia as a side effect may be efficient. The same applies to the
non-amphetamine attention-deficit/hyperactivity disorder (ADHD)
drug atomoxetine.
Anecdotally, but of interest considering possible alteration of
circadian regulation, improvement in half of 10 idiopathic hyper-
somnia patients treated with melatonin (2 mg of the slow release
form at bedtime) has been reported [94].
Sleep inertia is often a problematic issue. Considering this, a
report by Bagai and Malow of a 17-y-old male with a presumed
diagnosis of narcolepsy type 2 is worth mentioning [95]. The
subject had a one year history of difficulty awakening and was
successfully treated by a nicotine patch (14 mg) applied to his arm
by his parents, approximately 20 min before the desired wake
time.
Additionally, rapid attenuation of post-nap sleep inertia has
been observed in healthy non-smoking subjects who were
administered gum containing 100 mg of caffeine immediately after
awakening [96].
Newer therapies
Flumazenil is an antagonist of the sedative-hypnotic action
of benzodiazepines, at the classical benzodiazepine-binding domain
in GABAA receptors. Its first use in idiopathic hypersomnia was
suggested by the nearly complete reversal of the effect of CSF of
hypersomnolent patients on GABAA R-mediated chloride currents
in vitro by co-application of 10 mM GABA [54]. Subsequently, flu-
mazenil improved psychomotor vigilance and subjective alertness
in seven hypersomnolent patients, two with a diagnosis of idio-
pathic hypersomnia, two with a diagnosis of narcolepsy without
cataplexy and three habitually long sleepers, a result questioning
the utility of diagnostic classification for treatment [54].
More recently, a patient with idiopathic hypersomnia was
successfully treated with a 96-h continuous low dose subcu-
taneous infusion followed by a slow-release flumazenil implant,
opening the path for determining most efficacious treatment
[97].
 M. Billiard, K. Sonka / Sleep Medicine Reviews 29 (2016) 23e33
The main limitation of flumazenil is bioavailability and a num-
ber of potential side effects have been reported such as dizziness,
nausea, headache, anxiety, confusion and hyperphagia.
Clarithromycin, another negative allosteric modulator of
the GABAA receptor was first tested in a group of 39 “hyper-
somnolent patients” [98]. Subjective improvement was reported
in 34. Of these 34 patients, 23 chose to use clarithromycin on a
long-term basis: 16 on a daily basis, four on an intermittent basis,
while three discontinued use after a mean of 5 mo. Very recently,
a 5-wk, randomized, placebo-controlled, double-blind, crossover
trial of clarithromycine 500 mg performed in 20 patients with
hypersomnolence syndromes (excluding narcolepsy type 1) and
evidence of abnormal CSF potentiation of GABAA receptors,
showed a significant improvement of subjective measures of
sleepiness (ESS and Stanford sleepiness scale) [99].
Levothyroxine 25 mcg/day, was orally administered to nine pa-
tients with idiopathic hypersomnia with long sleep time [100].
Mean total sleep time was 12.9 ± 0.3 h and ESS score 17.8 ± 1.4
before treatment. After treatment, mean total sleep times were
9.1 ± 0.7 and 8.5 ± 8.5 h at 4 and 8 wk respectively, and mean ESS
scores 8.8 ± 2.3 and 7.4 ± 2.8 at 4 and 8 wk respectively. No adverse
effects were noted. One patient dropped out of the study in the
second week due to poor effect.
Sodium oxybate is now extensively used in narcolepsy type 1,
but has not yet been evaluated in idiopathic hypersomnia.
Pitolisant, a histamine H3 inverse agonist, has been effective in
patients with narcolepsy with cataplexy [101]. A very recent
retrospective analysis of 65 patients with idiopathic hypersomnia
evaluated the benefits and risks of pitolisant [102]. The median ESS
decreased from 17 (15.5e18.5) to 14 (12e17) and by more than 3 in
35.4% of patients, while the most frequent side-effects included
gastrointestinal pain in 15.4% of patients, increased appetite and
weight gain in 14.1%, headache in 12.8%, insomnia in 11.5% and
anxiety in 9%.
To sum up, a number of either conventional or newer drugs
have been studied. However, only three double-blind, placebo-
controlled trials are available, two with modafinil and one with
clarithromycine, mainly based on subjective measures of sleepi-
ness, with the exception of a MWT in the case of modafinil.
Subjective measures of sleepiness were improved while MSL on
the MWT was significantly increased in only one trial.
Conclusion
In the absence of specific polysomnographic diagnostic criteria
and consistent biologic markers, the question as to whether
idiopathic hypersomnia exists sui generis as an extreme normal
variant or with its own unique biological underpinning remains
open. Pathophysiology of idiopathic hypersomnia is still in in-
fancy, but recent neurochemical approaches seem promising.
Among other approaches, genetic studies including linkage ana-
lyses in multiplex families and genome-wide association studies
in large populations of patients deserve to be extended as well as
interrogating circadian genes as candidates for a disturbed circa-
dian rhythm in idiopathic hypersomnia. Current treatments of
idiopathic hypersomnia still mirror those of hypersomnolence in
narcolepsy types 1 and 2. Retrospective studies of the effects of
modafinil and methylphenidate have shown positive results in a
modest majority of patients, but also partial results or no benefit
at all in other patients. Very recent randomized, double-blind,
placebo-controlled clinical trials of modafinil have shown signif-
icant improvements in tested patients. Yet, some patients do not
benefit from the available drugs, hence the potential interest of
newer treatments, especially an histamine H3 inverse agonist,
pitolisant, which has shown promising results in a retrospective
31
study and clarithromycin, a medication acting through an
endogenous enhancement of GABAA receptors, which has shown a
significant improvement of subjective measures of sleepiness in a
double-blind, placebo-controlled trial, in patients with hyper-
somolence and evidence of abnormal CSF potentiation of GABAA
receptors. Both these treatments pave the way for more specific
treatments of idiopathic hypersomnia.
Search strategies and selection criteria
References for this review were identified through searches of
the PubMed database with the terms “Idiopathic hypersomnia”,
“hypersomnia”, “idiopathic CNS hypersomnolence”, “sleep drunk-
enness”. The final reference list was generated on the basis of his-
toric impact, originality and relevance to the broad scope of this
review.
Practice points
1) A key step in the diagnosis of idiopathic hypersomnia is
to exclude other causes of hypersomnolence. Many
sleep disorders can mimic hypersomnia.
2) Current neurophysiological diagnostic criteria including
an MSLT showing fewer than two SOREMPs, and a mean
sleep latency 8 min or a total 24-h sleep time
660 min on 24-h polysomnographic monitoring do not
appear to have specific value, hence the importance of
abnormally long sleep time and severe sleep inertia
when present and the role of clinical judgment.
3) Differential diagnosis with obstructive sleep apnea syn-
drome, in a patient presenting apneas or RERAs, cannot
be made without a short-term CPAP trial.
4) Differential diagnosis with insufficient sleep syndrome
and long sleeper cannot be made without a 14 d wrist
actigraphy associated with sleep log.
5) Even if not active in all patients, modafinil appears
beneficial in a modest majority of patients.
Research agenda
1) Current neurochemical research on the deficiency of an
arousal system or the presence of a molecule facilitating
GABA's actions by way of the GABAA receptor's BZD
binding domain should be pursued and reinforced.
2) The neurophysiologic underpinnings of sleep inertia
should be investigated in laboratory animals as well as in
humans using neuroimaging modalities to capture its
functional anatomy.
3) Family studies of idiopathic hypersomnia should be
based on systematic clinical interview, and when
possible, on neurophysiological investigations.
4) Linkage analyses in multiplex families are warranted to
test the likelihood of the cosegragation of a genetic
marker with idiopathic hypersomnia and genome-wide
association studies in extended populations of patients
to search for genetic markers.
5) Randomized, double-blind, placebo controlled studies of
pitolisant are urgently needed in patients with idiopathic
hypersomnia.
32 M. Billiard, K. Sonka / Sleep Medicine Reviews 29 (2016) 23e33
Contributors
MB wrote all drafts and KS reviewed and edited all drafts.
Conflicts of interest
We declare that we have no conflict of interest.
Acknowledgments
KS is supported by the Charles University grant PRVOUK P26/
LF1/4 and by the Czech Ministry of Health grant NT13238-4.
The authors thank Dr Aron Rulseh for English editing.
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