French consensus. Idiopathic hypersomnia: Investigations and follow-up

French consensus. Idiopathic hypersomnia: Investigations and follow-up

NEUROL-1693; No. of Pages 6 revue neurologique xxx (2016) xxx–xxx Available online at ScienceDirect Sleep disorders in neurol...

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NEUROL-1693; No. of Pages 6 revue neurologique xxx (2016) xxx–xxx

Available online at


Sleep disorders in neurology

French consensus. Idiopathic hypersomnia: Investigations and follow-up S. Leu-Semenescu a,b,c, M.-A. Quera-Salva d, Y. Dauvilliers a,e,f,* a

Centre de re´fe´rence nationale narcolepsie et hypersomnie idiopathique, 34295 Montpellier cedex 5, France Service de pathologies du sommeil, GH Pitie´-Salpeˆtrie`re/Charles-Foix, AP–HP, 75013 Paris, France c Inserm U 1127, CNRS UMR 7225, centre de recherche de l’institut du cerveau et de la moelle e´pinie`re, UPMC-Paris 6, 75013 Paris, France d EA 4047, CIC 1429, AP–HP, unite´ des troubles du sommeil et de l’e´veil, centre de re´fe´rence narcolepsie-hypersomnies hoˆpital Raymond-Poincare´, 92380 Garches, France e Unite´ des troubles du sommeil et de l’e´veil, service de neurologie, hoˆpital Gui-De-Chauliac, 80, avenue AugustinFliche, 34295 Montpellier cedex 5, France f Inserm U1061, 34295 Montpellier, France b

info article


Article history:

Idiopathic hypersomnia is a rare, central hypersomnia, recently identified and to date of

Received 31 August 2016

unknown physiopathology. It is characterised by a more or less permanent, excessive

Accepted 20 September 2016

daytime sleepiness, associated with long and unrefreshing naps. Night-time sleep is of

Available online xxx

good quality, excessive in quantity, associated with sleep inertia in the subtype previously described as ‘‘with long sleep time’’. Diagnosis of idiopathic hypersomnia is complex due to


the absence of a quantifiable biomarker, the heterogeneous symptoms, which overlap with

Idiopathic hypersomnia

the clinical picture of type 2 narcolepsy, and its variable evolution over time. Detailed

Excessive sleepiness

evaluation enables other frequent causes of somnolence, such as depression or sleep

Continuous polysomnography

deprivation, to be eliminated. Polysomnography and multiple sleep latency tests (MSLT)


are essential to rule out other sleep pathologies and to objectify excessive daytime sleepi-


ness. Sometimes the MSLT do not show excessive sleepiness, hence a continued sleep recording of at least 24 hours is necessary to show prolonged sleep (> 11 h/24 h). In this


article, we propose recommendations for the work-up to be carried out during diagnosis and follow-up for patients suffering from idiopathic hypersomnia. # 2016 Elsevier Masson SAS. All rights reserved.



Idiopathic hypersomnia (IH) is a rare, central hypersomnia identified more recently than narcolepsy. While there are no epidemiologic studies to date, it seems to be rarer than type 1 narcolepsy. Clinical experience suggests a higher incidence

in women than men [1–4]. Family forms are sometimes observed. The age at onset of the disease is often under 30, with symptoms sometimes present since childhood. However, IH is only exceptionally diagnosed in children. IH is a heterogeneous disease whose physiopathology remains unknown. Several hypotheses have been proposed concerning possible circadian or homeostatic deregulation, or

* Corresponding author. Service de neurologie, hoˆpital Gui-de-Chauliac, 80, avenue Augustin-Fliche, 34295 Montpellier cedex 5, France. E-mail address: [email protected] (Y. Dauvilliers). 0035-3787/# 2016 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Leu-Semenescu S, et al. French consensus. Idiopathic hypersomnia: Investigations and follow-up. Revue neurologique (2016),

NEUROL-1693; No. of Pages 6


revue neurologique xxx (2016) xxx–xxx

deficiency of certain arousal systems. No genetic factor has been identified. To date, there is still no biomarker specific to IH [5,6]. Recently, a dysfunction of the GABAergic signalling pathway has been identified [7]. However, no component active in the CSF has been found in these patients, and no difference from other forms of central hypersomnia, nor correlation between the potentiation of GABA and the degree of abnormality in vigilance measurements has been shown. Moreover, these results have not been replicated in a recent study [8]. The diagnosis of certainty of IH is often difficult compared to the diagnosis of type 1 narcolepsy, due to the absence of a biomarker and specific clinical signs. Two IH phenotypes were initially described: one with and the other without prolonged night-time sleep. The subtype with long sleep time was characterised by a more or less permanent daytime sleepiness, the subject complaining of being rarely completely awake. Night-time sleep was of good quality and of long duration with little wake after sleep onset, but was associated with difficulties in waking up marked by sleep inertia sometimes of long duration. The form without long sleep time was characterised by sleep attacks during the day of variable duration, sometimes refreshing and by nighttime sleep of normal quantity (more than 6 hours and less than 10 hours) and quality without sleep inertia [9]. These two phenotypes were sometimes associated with each other and have finally been pooled in the current revision of the classification of sleep disorders (ICSD-3) [10]. IH shows frequent variation in phenotype with a continuum possible between the form without and with long sleep time, but also with type 2 narcolepsy, notably for the form previously called without long sleep time. In fact, only the presence of one sleep onset REM period differentiates between them, and this is an unstable biomarker, which is not always reproducible from one recording to the next in a given subject [11]. The symptoms of IH may be severe and chronic, requiring long-term treatment. Nevertheless, these symptoms can disappear over time (in up to 50 % of patients), change in severity or even being included into one disease category to another. Consequently, clinicians must regularly re-evaluate the presence and severity of the symptoms, the diagnosis and management.


Diagnosis of idiopathic hypersomnia


Diagnostic criteria

The diagnosis of IH must be established according to ICSD3 criteria [10]. The presence of all of the following criteria is necessary:

 the presence, over at least the past three months, of an excessive sleepiness, an irrepressible need to sleep or daytime lapses into sleep, without cataplexy;  the polysomnography and the multiple sleep latency test (MSLT) will objectify no more than one sleep onset REM period;  excessive daytime sleepiness must be objectified by mean sleep latency on the MSLT of  8 minutes and/or total sleep

time of  11 hours over 24 hours on a continued 24-hour polysomnographic recording after correction of chronic sleep deprivation. Investigations must be conducted in a Narcolepsy-Hypersomnia Reference or Competence centre (or other affiliated centre). The international classification also proposes that the prolonged sleep time can be demonstrated by a wrist worn actigraph and sleep diary over the 7 nights preceding the polysomnography without sleep restriction. This recommendation is not retained in the French expert consensus;  investigations must be carried out after having excluded sleep deprivation. Its absence will be confirmed by the persistence of excessive sleepiness after a period of sleep extension, preferably confirmed by a week of actigraphy;  excessive sleepiness and investigation results of the examinations must not be explained more clearly by another sleep disorder, other medical or psychiatric disorder or use of drugs or medications.


Clinical evaluation

Diagnosis is made at the end of a detailed work-up. This must evaluate the excessive sleepiness, the quality of night-time sleep and eliminate other causes of excessive sleepiness. There is no specific excessive sleepiness phenotype to IH, nevertheless the clinical phenotype previously described as with long sleep time has distinct clinical features. Sleepiness is often perceived as permanent and the subject complains of seldom feeling fully alert. Reported night-time sleep is often of long duration (always more than 9 hours or even 10 or 11 hours) and good quality with few night-time arousals. Marked sleep inertia is often present and is defined by an important reduction in vigilance during the minutes or hours following the morning arousal. It can manifest in difficulty waking up in the morning, an excessive time necessary to feel fully operational or through sleep drunkenness associated with mental confusion. Daytime naps are long, lasting up to several hours with marked difficulty to wake-up [12]. However, these night-time and daytime sleep characteristics are neither specific to nor constant in IH with long sleep time. The workup must eliminate the presence of cataplexy, and look for signs associated with narcolepsy such as hypnagogic hallucinations or sleep paralysis, rarely present in IH. The clinical evaluation must first and foremost eliminate chronic sleep deprivation. Sleep needs vary greatly from one subject to another or even in the same subject over the years and also depend on environmental factors. Sleep duration is often very different on weeknights and weekend nights showing a real need for recovery. Extension of sleep time is currently recommended preferably confirmed by a week of actigraphy in order to confirm the persistence of excessive sleepiness despite a documented increase in time spent in bed. Excessive daytime sleepiness (EDS) should not be reversible with an increase in night-time sleep time, and if it is, it is likely that the subject is a long sleeper deprived of sleep due to socioprofessional constraints. Even if necessary, increasing sleep time is not always easy to carry out in practice, especially over a long period. The clinical interview must eliminate circadian rhythm disturbances, endocrine or neurological disorders (in particular

Please cite this article in press as: Leu-Semenescu S, et al. French consensus. Idiopathic hypersomnia: Investigations and follow-up. Revue neurologique (2016),

NEUROL-1693; No. of Pages 6


Fig. 1 – Decision tree for the diagnosis of idiopathic hypersomnia.

revue neurologique xxx (2016) xxx–xxx

Please cite this article in press as: Leu-Semenescu S, et al. French consensus. Idiopathic hypersomnia: Investigations and follow-up. Revue neurologique (2016),

NEUROL-1693; No. of Pages 6


revue neurologique xxx (2016) xxx–xxx

vascular, tumoral, infectious, and neurodegenerative lesions affecting the arousal circuits), the substance abuse or the use of sedating medication. The most difficult differential diagnosis concerns depression, for which excessive sleepiness is a frequent symptom. Subjects suffering from IH, probably due to the disease-related handicap, can present depressive symptoms that are not necessarily the cause of excessive sleepiness. Within the context of a suspicion of IH in the presence of symptoms of depression, it is important to study the date of onset of the different symptoms, the evolution of excessive sleepiness depending on mood and the effect of the various treatments of depression on excessive sleepiness and vice versa [13]. In the case of doubt, an evaluation by a psychiatrist or a therapeutic test with antidepressants may be necessary before continuing investigations.



Ideally a 7-day actigraphy during a constraint-free period will rule out sleep deprivation and may suggest a diagnosis of IH if night and daytime sleep is longer than 11 out of 24 hours. However, actigraphy is not enough to diagnose IH since it does not objectively analyse the difference between sleep and wake alternation but only between activity-rest periods. The recommended investigations should ideally include polysomnography with MSLT immediately followed by polysomnography over a minimum of 24 hours ‘‘ad libitum’’ (Fig. 1). Withdrawal from psychotropic drugs must be carried out before the recording. Withdrawal duration will depend on the half-life of the medication and its active metabolic, with at least 5 half-lives being recommended to avoid withdrawal symptoms or iatrogenic rebound of slow wave or REM sleep. If stopping psychotropic drugs is not possible due to an unstabilised underlying pathology, the diagnosis of hypersomnia cannot be fully confirmed. Polysomnography needs to show a nigh-time sleep of more than 6 hours, with sleep efficiency often greater than 90 %. It will eliminate excessive sleep fragmentation characterised by overly frequent arousals and micro-arousals (> 15/h), the presence of respiratory events (> 15/h), and overly frequent periodic leg movements (> 15/h). The MSLT can confirm a diagnosis of IH if the mean sleep latency is below or equal to 8 minutes with no more than one sleep onset REM period (on the night recording or the MSLT). However, normal values on the MSLT do not exclude diagnosis of IH. In the case of the subtype with long sleep time, the mean sleep latency is over 10 minutes in more than half of cases, justifying a continuous 24-hour polysomnography [9]. This recording can establish the diagnosis of IH in the absence of a mean sleep latency of less than 8 minutes on the MSLT. Experts recommend that tests are conducted in a Narcolepsy-Hypersomnia Reference or Competence centre or at least in an affiliated centre in collaboration with one of these centres recorded in the patient’s medical notes. The 24-hour continuous recording post PSG-MSLT can be made difficult by logistical constraints leading to recordings of only 16–18 hours. We recommend that the continuous sleep recording should be at least 24 hours in order to be valid in this

context. Insofar as possible the procedure should be standardised, concerning the time spent in bed during the recording, the activities authorised (TV, computer, physical activity) as well as the ambient light and stimulants taken (coffee, tobacco). Lastly, these results (total sleep time recorded) can be modulated by the sleep duration obtained on each MSLT sessions conducted the previous day, as this can modify sleep homeostasis and the 16-hour of wake required prior to a nighttime sleep recording. Consequently, we recommend ideally and insofar as possible, a recording of 24 hours or more (i.e. 32 hours including 2 nights and one day recorded continuously) after a polysomnography and MSLTs which should be stopped as soon as the subject lapses into sleep to respect homeostasis (16 hours of wake prior to PSG), in a strict bedrest, without environmental stimulants. The finding of an 11-hour sleep time or more over the 24 hour recording enables confirmation of a long sleep time and the diagnosis of IH if the clinical criteria required are present. IH often develops during adolescence. If the total sleep time over 24 hours is used to confirm the diagnosis of IH in children or adolescents, normal values need to be adapted to take into account sleep duration variations associated with developmental stages. Based on the clinical context (late age at onset, associated headache, clinical picture. . .), a biological work-up (blood or urine) to look for an inflammatory or infectious syndrome, an endocrine pathology, toxins or even a brain MRI to look for lesions could be indicated. HLA typing in the context of a suspicion of IH is not useful, nor is hypocretin-1 dosing in the cerebrospinal fluid (CSF).


Management of atypical symptoms or results

The demonstration of a mean sleep latency on the MSLT of  8 minutes associated with one (day or night) sleep onset REM period, should prompt the clinician to look for sleep deprivation, cataplexy, hypnagogic hallucinations, sleep paralysis, or even carry out HLA DQB1*06:02 typing due to the possible continuum between IH and type 2 narcolepsy. In this particular case, the indications of CSF hypocretin1 measurement can be discussed, which will help in differential diagnosis of narcolepsy and the chronic prognosis in the case of lowered hypocretin-1 (Fig. 1). The presence of sleep fragmentation without respiratory events or periodic leg movements can be linked to a first night effect. The recording must be repeated. In the case of an apnea/hypopnea index higher than 15, a therapeutic test is recommended (e.g. with continued positive airway pressure [CPAP]) followed by repeating the tests under treatment if excessive sleepiness persists. Based on the results and clinical context, a diagnosis of IH or residual sleepiness post-sleep apnea syndrome correctly treated with CPAP will be made [14]. In the case of mean sleep latency on the MSLT above 12 minutes, a 24-hour PSG (if not done during the 48 hour work-up) is indicated based on the clinical context. However, the repetition of the MSLT within this context is indicated if the clinical complaint is significant and persists as normal mean sleep latency on MSLT can be seen in the context of hospitalisation-related stress.

Please cite this article in press as: Leu-Semenescu S, et al. French consensus. Idiopathic hypersomnia: Investigations and follow-up. Revue neurologique (2016),

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A 24-hour sleep recording that demonstrates night-time sleep longer than 11 hours but without daytime naps suggests recovery from sleep deprivation or a long sleeper. A night-time sleep longer than 11 hours can also be associated with a very small quantity of sleep the following night as having previously exhausted the need to sleep, thus complicating the final diagnosis of IH. If the clinical diagnosis of suspicion of IH persists after having excluded all the other causes of excessive sleepiness, mean sleep latency on the MSLT higher than 8 minutes, with less than 11 hours of sleep on the 24-hour recording, redoing the investigations after a period of time is indicated. The reproducibility of the results of the PSG-MSLT recording has been shown to be close to 50 % in IH when investigations are repeated after 4 years in a clinical study [15]. To date there is no data on the test-retest reliability of the 24-hours recording in IH.


a Reference rare diseases centre is strongly recommended. The following elements must be assessed at each visit:  the patient’s acceptance of the disease;  the effectiveness of the treatment proposed via a detailed clinical interview looking at the frequency and severity of symptoms as well as the results of validated psychometric tools;  the residual handicap related to the pathology should be routinely evaluated;  the overall tolerance, specifically cardiovascular tolerance of treatment according to the recommendations established for each drug.

 patient education about the disease, its prognosis and treatment, as well as explanation about current knowledge of the condition;  an offer of psychological support;  information about the need for regular evaluation of the effectiveness and safety of treatment;  information about the risks of sleepiness while driving in reference to the Ministerial Decree of 18 December 2015. It is recommended that patients do not drive during the investigations, initiation and adaptation of treatment;  information must be provided about the need to re-evaluate the disease without stimulant treatment after a few years;  giving the Narcolepsy-Hypersomnolence Reference/Competence centres information leaflet;  the contact details of the Patients’ Association (ANC).

Further investigations will depend on the eventual appearance of comorbidities, screened by the clinical examination. A neuropsychological consultation, or a psychiatric consultation could be requested in the case of anxiety, mood problems, or a marked cognitive deficit. Concerning driving, patients should be advised not to drive during the treatment adaptation period. The risk at the wheel is evaluated during the clinical interview looking for irrepressible sleepiness while driving, inappropriate lane crossing due to sleepiness, the occurrence of accidents, and by the Maintenance of Wakefulness test (MWT). These tests should be offered in the months following the stabilisation of the treatment in order to evaluate residual sleepiness on stimulant treatment according to the Ministerial Decree of 18 December 2015. These tests must be carried out in a Narcolepsy-Hypersomnia Reference centre. A latency of less than 19 minutes on the MWT signifies a real risk of accident. In order to minimise risk, the sleep latency of each test must be above 33 minutes (ideally no lapses into sleep) and the patient should not report episodes of sleepiness leading to inappropriate lane changes. This evaluation is necessary due to the risk of accidents which is reduced with optimised treatment [16]. Clinical monitoring by the Narcolepsy-Hypersomnia Reference Centre and the renewal of the licence must be conducted every year by an approved driving licence physician. Moreover, MWTs must be conducted regularly (in practise every 5 years) for non-professional drivers or earlier if stimulant treatment is modified. Professional drivers should redo their MWT if possible every year as stipulated by the driving aptitude decree. Patients must present the MWT results to the approved physician who renews the validity of the driving licence. The follow-up appointment is also the occasion to discuss the socioprofessional aspects of the disease-related handicap and the administrative arrangements such as registering with a chronic disease or formal recognition of the handicap. In the framework of follow-up on patients suffering from IH, it is recommended to repeat comprehensive investigations after withdrawal from the stimulant treatment 5 years following the initial diagnosis in order to confirm the persistence of the disease.




Work-up prior to treatment

When the IH diagnosis has been made, pharmacologic treatment is usually prescribed and a work-up must be completed in order to choose the treatment offering the best benefit–risk ratio for the patient. Firstly, the initial clinical interview should evaluate the severity of each symptom of IH and its impact, based on the patient’s lifestyle and their professional obligations. The patient’s history should include the search for cardiovascular, metabolic, endocrine and neuropsychiatric comorbidities. The presence of certain comorbidities will guide the physician towards an appropriate choice of treatment. Measurement of blood pressure (or even an ambulatory 24hour blood pressure measurement if needed) and an electrocardiogram are necessary before starting stimulant treatment. The procedure of announcing the diagnosis to patients must be done with care and should include:


A follow-up consultation looking at the effectiveness and tolerance of the treatment is recommended every 6 months with a sleep specialist or a neurologist. An annual follow-up in


IH is a diagnosis of elimination, a heterogeneous disease of unknown physiopathology and uncertain evolution. There is no specific biomarker for the disease. Repeating the initial

Please cite this article in press as: Leu-Semenescu S, et al. French consensus. Idiopathic hypersomnia: Investigations and follow-up. Revue neurologique (2016),

NEUROL-1693; No. of Pages 6


revue neurologique xxx (2016) xxx–xxx

investigations is necessary for these patients within the 5 years following the initial diagnosis. Follow-up in a reference centre is necessary for epidemiological reasons (with a patient register), for clinical reasons to standardise and optimise the treatment and lastly for research purposes in order to improve knowledge of the disease.

Disclosure of interest Smaranda Leu-Semenescu: Investigator and conference for UCB pharma and Bioprojet. Maria-Antonia Quera-Salva: investigator with Bioprojet Ltd, Vanda. Fondation Vinci and Fondation des « Gueules Casse´s » research funds. Yves Dauvilliers: expertise activity and conference for UCB Pharma, JAZZ, Bioprojet, Flamel, NLS-pharma, and Theranexus.


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Please cite this article in press as: Leu-Semenescu S, et al. French consensus. Idiopathic hypersomnia: Investigations and follow-up. Revue neurologique (2016),