このスライドは第11回ISMSJ学術集会（2019年10月 名古屋）での特別講演内容を，演者のKarel Šonka先生のご厚意にてISMSJ
ホームページ上に公開したものです．無断複製・転載を禁止します．Copyright (C) 2019 Prof. Karel Šonka All Rights Reserved.

Karel ŠONKA
Dept. of Neurology, Charles University, 1st Faculty of Medicine and General University Hospital
PragueIdiopathic hypersomnia 201911th annual meeting of Integrated Sleep Medicine Society Japan
Nagoya, October 12, 20191

Conflict of Interest Disclosures– Authors/Presentersx

The authors do not have any potential conflicts of interest to disclose,OR
The authors wish to disclose the following potential conflicts of interest related to content in thislecture:Type of Potential Conflict

Details of Potential Conflict

Grant/Research Support
Consultant
Speakers’ Bureaus

Financial support
Other
This talk presents material that is related to one or more of these potential conflicts, and the following
objective references are provided as support for this lecture:

1.
2.
3.
2

Short content• Idiopathic hypersomnia concepts• Weakness of ICSD3 diagnostic criteria• Pathophysiology• Diagnosis and severity measurement• Treatment

Department of Neurology and Center of Clinical Neuroscience
First Faculty of Medicine, Charles University and General University Hospital in Prague

3

Idiopathic hypersomnia• Rare disease with „central„ EDS.
• EDS may be unique symptom of IH.
• Clinical picture of EDS in IH has different manifestations.

Department of Neurology and Center of Clinical Neuroscience
First Faculty of Medicine, Charles University and General University Hospital in Prague

4

History of idiopathic hypersomnia concepts

Department of Neurology and Center of Clinical Neuroscience
First Faculty of Medicine, Charles University and General University Hospital in Prague5

First description by Bedřich Roth (1919 – 1989)
in combination with sleep drunkenness

Sleep drunkeness – nosological entity, hypersomnia - its symptom
Department of Neurology and Center of Clinical Neuroscience
First Faculty of Medicine, Charles University and General University Hospital in Prague

Bedrich Roth, 1959

Two forms of postdormitial drunkenness
A sporadic form
Once or a few times in the patient’s life time, on suddenly being
artificially wakened after insufficient sleep

A form with persistent occurrence which occurs
everytime on awakeningnew „clinical entity“

B. Roth, 1957
7

Sleep drunkenness symptoms:

Sleep drunkenness(awakening difficulties)

Fast falling asleep
Deep and uninterruptiblenight sleep
Daytime hypersomnia
B. Roth, 1957

page 2698

Sleep drunkenness symptoms:

Sleep drunkenness(awakening difficulties)

Fast falling asleep
Deep and uninterruptiblenight sleep
Daytime hypersomnia
B. Roth, 1957

page 269
9

History
Existence of the EDS disease different from narcolepsy was mentioned after Roth bysome authors
Dement at al 1966,
Berti-Ceroni et al 1967,
Passouant et al 1968

New term„Hypersomnia with sleep drunkeness“
Roth, Nevšímalová, Rechtschaffen, 1972

10

B. Disorders of Excessice Somnolence
1. Psychophysiological
2. Associated with Psychiatric Disorders
3. Associated with Use of Drugs and Alcohol
4. Associated with Sleep induced Respiratory
Impairment
5. Associated with Sleep-related Myoclonus and RLS
6. Narcolepsy
7. Idiopathic CNS Hypersomnolence
8. Associated with Other Medical, Toxic, andEnvironmental Conditions
9. Associated with Other DOES Conditions
10. No Disorders of Excessice Somnolence Abnormality
11

1976: Second concept of idiopathic hypersomnia:
Two forms of idiopathic hypersomnia

Polysymptomatic form characterized by EDS of one to several
hours duration, prolonged night sleep of a 12-18 h duration andgreat difficulty upon awakening in the morning
Monosymptomatic form characterized by the most prominent andoften unique manifestation of EDS of one to several hours
duration, however not as irresistible as in narcolepsy
12
Bedrich Roth, France, 1976

Bedrich Roth in his laboratory, 1984.

13

Dyssomnias, intrinsic sleep disorders
1
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.

Psychophysiological Insomnia
Sleep State Misperception
Idiopathic Insomnia
Narcolepsy
Recurrent Hypersomnia
Idiopathic Hypersomnia
Posttraumatic Hypersomnia
Obstructive Sleep Apnea Syndrome
Central Sleep Apnea Syndrome
Central Alveolar Hypoventilation Syndrome
Periodic Limb Movement Disorder
Restless Legs Syndrome
Intrinsic Sleep Disorder NOS

Rochester, 1990
14

n = 28, 11 males and 17 femalesn = 23, 9 males and 14 females« Classic » idiopathic hypersomnia
n = 8 (3 males and 5 females)« Narcoleptic » -like idiopathic hypersomnia
n = 9 (5 males and 4 females)« Mixed » idiopathic hypersomnia
n = 11 (3 males and 8 females)« Complete form »n = 13 (4 males and 9 females)« Incomplete form »n = 10 (4 males, 9 females)15

3. Hypersomnias of central origin
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.

Narcolepsy with cataplexy
Narcolepsy without cataplexy
Narcolepsy due to medical condition
Narcolepsy, unspecified
Recurrent hypersomnia
Idiopathic hypersomnia with long sleep time
Idiopathic hypersomnia without long sleep time
Behaviorally induced Insufficient sleep syndrome
Hypersomnia due to medical condition
Hypersomnia due to drug or substanceHypersomnia not due to substance or known
physiological condition (Nonorganic hypersomnia,
NOS)

Westchester, 2005

16

Sleep 200917

Central Disorders of Hypersomnolence
1.
2.
3.
4.
5.
6.
7.

Narcolepsy Type 1
Narcolepsy Type 2
Idiopathic Hypersomnia
Kleine Levin Syndrome
Hypersomnia due to a medical disorder
Hypersomnia Due to a Medication or SubstanceHypersomnia Associated with a Psychiatric
Disorder8. Insufficient Sleep Syndrome
Isolated Symptoms and Normal Variants

Darien, 201418

Idiopathic hypersomnia
alternate name: Idiopathic CNS hypersomnolence
ICSD3 diagnostic criteria (2014)
A. Daily periods of irrepressible need to sleep or daytime lapses into sleep
B. Cataplexy is absent.
C. MSLT + night PSG: < 2 SOREMp
D. The presence of at least one of the following:
1. MSLT: sleep latency of ≤ 8 minutes.
2. Total 24-hour sleep time is ≥ 660 min. on 24-hour PSG or by actigraphy in association with a sleeplog

E. Insufficient sleep syndrome is ruled out.
F. Not better explained …..

19

Present time20

Criticism of IH classification• Patterns of two sleepiness forms are different• Other symptoms are not taken in account• Not based on aetiopathophysiology

21

Questions:(a) Do IH forms represent one entity independent versus NT1 and NT2?
(b) Does exist another grouping of symptom complexes with „central“ EDS.

Cluster analysis was chosen as a statistical method ofpartitioning patients sample into relatively homogenous classes.
22Patients
Retrospective analysis
Adult patients
No treatment, no concomitant sleep disorders
Diagnosis according to ICSD2
IH w/o LST

IH with LST

N with C

N w/o C

(N=25)(N=26)(n=23)(N=22)

10/15

7/19

11/12

13/9

Age at examination (years)

41,1 (9,6)

33,0 (11,4)

43,0 (15,7)

45,9 (17,6)

Age at onset (years)

29,4 (9,9)

20.9 (8,6)

22.5 (10,9)

25,5 (15,9)Disease duration (years)

10,7 (10,5)

13,7 (14,7)

10,1 (8,1)

17,6 (16,0)

Men /Women (#)

23

Preselection of variables by factor analysis
Variable name

Variable type

Unwanted naps (#)

scale

Irresistible naps duration

Scale

Irresistible unwanted naps

NominalGreat difficulty waking up from naps

NominalCataplexyNominalMSLT: mean sleep latency

Scale

MSLT: number of SOREMPs

Scale

Not included: Night PSG results because of different protocols.
Differences between working days and weekends because of lack of data.
The analysis was not focused on finding the most relevant symptoms and features for clustering new groups,
or on excluding any symptoms from the diagnostic criteria.
24

Result:

Cluster 1 – IH w/o LST + N w/o C
Cluster 2 – IH with LST
Cluster 3 - N with C

25

ICSD3 spectra of narcolepsy and idiopathic hypersomnia
NT 1

NT 2

Idiopathic hypersomnia

cataplexy +no cataplexy

MSLT SL (min)

<8

<8

<8

≤ or > 8

MSLT SOREMPs

≥2

≥2

<2

<2

sleep >660
min

Hypocretin
deficientnarcolepsyGroupwaiting for theidentification

True
idiopathic
hypersomnia

MSLT SL (min)<8<8≤ or > 8

MSLT SOREMPs≥2≥ 2 or < 2

<2
26

2015

Japanese drug naïve patients with N with C showed higher comorbidity rates and degree of
PLMS and polysomnographically diagnosable RBD with excessive motor activity compared tothose with N w/o C or IH w/o LST which were very similar.

27

The differenceNT2 versus IH diagnosed by MSLT:
number of SOREMp only!

28

MSLT has demonstrated good sensitivity, specificity, andreliability for NT1 (although between 14%-29% have negative
MSLTs), however the test may be less robust for thedifferentiation of NT2 versus IH.
MSLT has poor reliability in NT2 and IH – the “diagnosis” wasreconfirmed in only 30%-47% upon serial MSLT testing.
- Trotti LM et al. Test-retest reliability of the multiple sleep latency test in narcolepsy without cataplexy andidiopathic hypersomnia. J Clin Sleep Med 2013.
- Šonka K et al. The value of repeated non-confirmatory multiple sleep latency test (MSLT) for the diagnosis of
narcolepsy. Cesk Slov Neurol N 2014.
- Lopez R et al. Test-retest reliability of the multiple sleep latency test in central disorders of hypersomnolence.
Sleep 2017.
- Ruoff C et al. The MSLT is repeatable in narcolepsy type 1 but not narcolepsy type 2: a retrospective patient
study. J Clin Sleep Med 2018.

29

Possible explanations why repeated MSLT in NT2
and IH does not show identical result• The test is inappropriate for NT2 and IH• NT2 and IH are not well defined• NT2 and IH change over time30

IH course – a retrospective study
Patients
IH diagnosed previously
according to ICSD2/3
No other sleep disorders when
diagnosed
Adult age at the diagnosis
Follow-up >1 yearN
44 (17 males, 27 females)Long sleep duration (600 or 660 min): 18 subjects
Age at onset
24.7 (±13.0) y.
Age at diagnosis
37.4 (±11.0)
ESS at diagnosis
14.8 (±4.5)
MSLT latency
6.0 (±2.9)
MSLT 1 SOREM
3 (6%)
Night sleep SOREM
031

IH course – a retrospective study. Results.
Night-time - current status

Day-time - current status

Subj. sleep latency (min)11.0 (±12.8)
Subj. N of awakenings
1.6 (±3.2)
Subj. sleep not interrupted 31 (72%)

EDS everyday 35 (81%)
EDS irresistible 30 (70%)
Nap duration (if any) 55,4 min (±65,9)Life experience:
Morning sleep drunkenness 28 (65%)
Sleep paralysis
13 (30%)Hypnagogic hallucinations 9 (21%)
32

IH course – a retrospective study. Results
Age at follow-up: 42.8 (±12.2) y.
Follow-up duration: 5.4 (±5.2) y.
BMI: 25.8 (±5.8)
Treatment:
Modafinil
Methylphenidate

12 (26,7%)
7 (15,6%)

Antidepressants

6 (13,3%)

Drug effect (life experience):
Modafinil responders
71%
Methylphenidate responders 60%

Improvement:

12 (28%)

EDS subjectively (nearly/completely) disappeared: 4(9%)(2 with LST, 2 without LST)No change over time: 21 (49%)
Worsening:
10 (23%)
Repeated extreme changes of EDS intensity: 1 (2%) excluded
Diagnosis change: 1 subject – rediagnosed with NT2 (new
MSLT) – excluded33

IH course – a retrospective study. Results
Current status
ESS (0-24):
13.5 (±4,9)
FSS (0-60):
43.6 (±16,5)
Sleep Inertia Questionnaire (0-150): 59.5 (±20.1)
BDI:
7.3 (±6.6)
Stai II:
23.9 (±2.3)
Morningness-eveningness (16-86): 48.9 (±10.3)
EuQL:
6.9 (±1.9)
Subj. health esteem (0 – 100):
65.4 (±22.8)

New comorbidities
Depression
11 (26%)RLS
11 (26%), treated 2
Anxiety
6 (14%)
Hyperprolactinemia 2 (5%)
Bipolar
1 (2%)
Dissociative disorders 1 (2%)
Mental anorexia
1 (2%)RBD / violent behavior 0
Sleep apnea?
34

IH course – a retrospective study. Results
Comparison between groups according subjective
severity evolution„Improvement“„no change“„worsening“

ESS

10.2

13.4

16,5

FSS

37.7

40.1

56.6

BDI

3.75

7.94

10.80

Subj. health esteem (0 – 100)

81.5

65.6

54.5

EuQL

6.0

6.6

8.5

No other statistical differences!

35
Statistical difference (p<0.05)

IH course – a retrospective study. Results
Comparison between groups according subjective
severity evolution
ESS
FSS
BDI

„Improvement“„no change“„worsening“

10.2

13.4

16,5

37.7
40.1
56.6
Cook JD et al. Identifying Subtypes of Hypersomnolence Disorder: A
clustering analysis. Sleep Med
3.75in press.
7.94
10.80

A moreseverehypersomnolence
Subj. healthesteem(0 – 100)
81.5 phenotype was
65.6 identified in a54.5
cluster that also had elevated depressive symptoms. This cluster
EuQL endorsed significantly greater6.0
6.6 sleep inertia,8.5
daytime sleepiness,andfunctional impairment, while displaying longer sleep duration andworsestatisticalvigilance.differences!
No other
36
Statistical difference (p<0.05)

Disease course and therapy response

Sleep 2007

No difference between patients with and without improvement andbetween therapy responders and nonresponders

37

Disease course

Sleep 2009

Patients with LST were younger, slimmer, have lower Horne-Ostberg scores, andwould sleep longer on a 24-h basis, with higher sleep efficiency, than patients without LST.

Hypothesis
IH with LTS may be a juvenile form of the same disease, later evolving toward lessnighttime sleep.
In favor of this hypothesis: total sleep time during nighttime and during 24 hours slightly
decreased with increasing age at diagnosis time.
38

Pathophysiology
no hypocretin deficiency(Kanbayashi T et al. Sleep Res. 2002)
no important brain structure impairment
no neurodegeneration
no association with HLA DQB1*0602(Miyagawa T et al. Human Genome Variation 2015)
Genetics:
IH, or another central disorder of hypersomnolence in family history
in 34–38% of IH patients.
39

New aspects of IH pathophysiology••••

Low histamine
Activity modulation at GABA-A receptors
Inflamation /autoimmunity
Circadian system impairment40

Low histamine
Histamin level
dependent on
treatment

41

Enhancement of activity at GABA-A receptors
CSF from patients with IH has been shown to enhance activity at GABA-A receptors invitro, in excess of that of CSF from controls
Rye DB et al. Sci Transl Med. 2012
Symptoms of IH are reversible in some patients with use of GABA-receptor antagonists
or negative allosteric modulators (Clarithromycin and Flumazenil)
Trotti LM et al. Ann Neurol. 2015
Trotti LM et al. J Clin Sleep Med. 201642

Autoimmunity/inflamation

Neurology, 2017

2010

43

Circadian system impairment
mRNA expression of several clock
genes was impaired in fibroblast
cells from IH patientscompared to healthy controls.
Phase delay in the rhythm of melatoninand cortisol secretions in 15 patientswith IH.

Lippert J et al. PLoS ONE, 2014

Clinical Neurophysiology, 201044

Differential diagnosis of IH• Insufficient sleep syndrome• The narcolepsies (type 1 and type 2) versus IH• Delayed sleep phase syndrome• Hypersomnia associated with a psychiatric disorder• Hypersomnia due to a medical disorder45

Quantifying IH symptoms• Sleep duration (actigraphy, sleep log)
• MSLT latency• Sleep Inertia Questionnaire (Kanady JC et al 2015)14 item scale

46

Treatment (off label in EU)
•
•
•
•
•
•
•
•
•

Methylphenidate
Modafinil / armodafinil
Flumazenil
Claritromycin
H3 recetor inversible agonist (pitolisant)Gamma hydroxybutyrate
Solriamfetol (selective dopamine-norepinephrine reuptake inhibitor)
Light
Levothyroxine (Shinno H et al. Sleep Med. 2011)47

Conclusion• „True“ idiopathic hypersomnia is the disease defined by long sleep and eventuallydifficulties of awakening.
• Idiopathic hypersomnia defined by MSLT sleep latency only and NT2 are not wellstudied diseases and perhaps they belongs to one entity or will be grouped in new
way when new pathophysiologic explanation and robust biological marker occur.
• Disease course, responsiveness to the stimulants and sleep comorbidities seem not
to be markers distinguishing between forms of IH but large studies are lacking.

Roth B. Narcolepsy and hypersomnia; review and classification of 642 personally observed cases.
Schweiz Arch Neurol Neurochir Psychiat 1976
48