Yves Dauvilliers

Narcolepsy with cataplexy

Narcolepsy with cataplexy is a disabling sleep disorder affecting 0.02% of adults worldwide. It is characterised by severe, irresistible daytime sleepiness and sudden loss of muscle tone (cataplexy), and can be associated with sleep-onset or sleep-offset paralysis and hallucinations, frequent movement and awakening during sleep, and weight gain. Sleep monitoring during night and day shows rapid sleep onset and abnormal, shortened rapid-eye-movement sleep latencies. The onset of narcolepsy with cataplexy is usually during teenage and young adulthood and persists throughout the lifetime. Pathophysiological studies have shown that the disease is caused by the early loss of neurons in the hypothalamus that produce hypocretin, a wakefulness-associated neurotransmitter present in cerebrospinal fluid. The cause of neural loss could be autoimmune since most patients have the HLA DQB1*0602 allele that predisposes individuals to the disorder. Treatment is with stimulant drugs to suppress daytime sleepiness, antidepressants for cataplexy, and gamma hydroxybutyrate for both symptoms. Because narcolepsy is an under-recognised disease, it is important that general practitioners and other primary health-care workers identify abnormal daytime sleepiness early.

EFNS guidelines on management of narcolepsy.

Management of narcolepsy with or without cataplexy relies on several classes of drugs, namely stimulants for excessive daytime sleepiness and irresistible episodes of sleep, antidepressants for cataplexy and hypnosedative drugs for disturbed nocturnal sleep. In addition, behavioral measures can be of notable value. Guidelines on the management of narcolepsy have already been published. However contemporary guidelines are necessary given the growing use of modafinil to treat excessive daytime sleepiness in Europe within the last 5–10 years, and the decreasing need for amphetamines and amphetamine‐like stimulants; the extensive use of new antidepressants in the treatment of cataplexy, apart from consistent randomized placebo‐controlled clinical trials; and the present re‐emergence of gamma‐hydroxybutyrate under the name sodium oxybate, as a treatment of all major symptoms of narcolepsy. A task force composed of the leading specialists of narcolepsy in Europe has been appointed. This task force conducted an extensive review of pharmacological and behavioral trials available in the literature. All trials were analyzed according to their class evidence. Recommendations concerning the treatment of each single symptom of narcolepsy as well as general recommendations were made. Modafinil is the first‐line pharmacological treatment of excessive daytime sleepiness and irresistible episodes of sleep in association with behavioral measures. However, based on several large randomized controlled trials showing the activity of sodium oxybate, not only on cataplexy but also on excessive daytime sleepiness and irresistible episodes of sleep, there is a growing practice in the USA to use it for the later indications. Given the availability of modafinil and methylphenidate, and the forseen registration of sodium oxybate for narcolepsy (including excessive daytime sleepiness, cataplexy, disturbed nocturnal sleep) in Europe, the place of other compounds will become fairly limited. Since its recent registration cataplexy sodium oxybate has now become the first‐line treatment of cataplexy. Second‐line treatments are antidepressants, either tricyclics or newer antidepressants, the later being increasingly used these past years despite few or no randomized placebo‐controlled clinical trials. As for disturbed nocturnal sleep the best option is still hypnotics until sodium oxybate is registered for narcolepsy. The treatments used for narcolepsy, either pharmacological or behavioral, are diverse. However the quality of the published clinical evidences supporting them varies widely and studies comparing the efficacy of different substances are lacking. Several treatments are used on an empirical basis, specially antidepressants for cataplexy, due to the fact that these medications are already used widely in depressed patients, leaving little motivation from the manufacturers to investigate efficacy in relatively rare indications. Others, in particular the more recently developed substances, such as modafinil or sodium oxybate, are evaluated in large randomized placebo‐controlled trials. Our objective was to reinforce the use of those drugs evaluated in randomized placebo‐controlled trials and to reach a consensus, as much as possible, on the use of other available medications.

Polysomnographic diagnosis of idiopathic REM sleep behavior disorder

The presence of either excessive tonic chin EMG activity during REM sleep, or excessive phasic submental or limb EMG twitching is required to diagnose REM sleep behavior disorder (RBD). The aim was to identify cut‐off values and to assess the sensitivity and specificity of these values taken separately or combined to diagnose idiopathic RBD patients. Eighty patients presenting with a clinical diagnosis of idiopathic RBD and 80 age‐ and gender‐matched normal controls were studied in the sleep laboratory. Receiver operating characteristic curves were drawn to find optimal cut‐off values for three REM sleep EMG parameters. Tonic and phasic EMG activity were measured in the chin, but not in the limbs. Videos were examined during the recording but were not systematically reviewed by the authors. Total correct classification of 81.9% was found for tonic chin EMG density ≥30%; 83.8% for phasic chin EMG density ≥15% and 75.6% for ≥24 leg movements per hour of REM sleep. Five patients did not fulfill any of these three polysomnographic (PSG) criteria. Conversely, one subject of the control group met the PSG criteria for RBD. This study estimates the diagnostic value of a visual scoring method for the diagnosis of idiopathic RBD and establishes cut‐off values to be used in clinical and research set‐ups. For the five RBD patients who did not show chin EMG abnormalities, it cannot be excluded that they had increased phasic EMG activity in the upper limbs and presented visible motor activity.

Pitolisant versus placebo or modafinil in patients with narcolepsy: A double-blind, randomised trial

BACKGROUND Narcolepsy is characterised by excessive daytime sleepiness (EDS) and cataplexy. Histamine neurons are crucial to maintain wakefulness. We assessed the safety and efficacy of pitolisant (previously called BF2.649), a selective histamine H3 receptor inverse agonist that activates these neurons, in patients with narcolepsy. METHODS For this double-blind, randomised, parallel-group controlled trial, we recruited patients with narcolepsy from 32 sleep disorder centres in five European countries. Patients were eligible if they were aged 18 years or older, had not taken psychostimulants for at least 14 days, and had EDS (defined as an Epworth Sleepiness Scale [ESS] score of at least 14). Using a computer-generated randomisation sequence, we randomly allocated patients to receive pitolisant, modafinil, or placebo (1:1:1). Treatment lasted 8 weeks: 3 weeks of flexible dosing according to investigators judgment (10 mg, 20 mg, or 40 mg a day of pitolisant; 100 mg, 200 mg or 400 mg a day of modafinil) followed by 5 weeks of stable dosing. Patients took four tablets a day in a double-dummy design to ensure masking. For the primary analysis, assessed in the intention-to-treat population, we assessed the superiority of pitolisant versus placebo, and the non-inferiority of pitolisant versus modafinil. This trial is registered with ClinicalTrials.gov, number NCT01067222. FINDINGS Between May 26, 2009, and June 30, 2010, we screened 110 patients, 95 of whom were eligible and randomly assigned to treatment: 30 to placebo, 32 to pitolisant, and 33 to modafinil. Over the 8-week treatment period, mean ESS score reductions were -3·4 (SD 4·2) in the placebo group, -5·8 (6·2) in the pitolisant group, and -6·9 (6·2) in the modafinil group. Our primary analysis of between-group differences in mean ESS score at endpoint (adjusted for baseline) showed pitolisant to be superior to placebo (difference -3·0, 95% CI -5·6 to -0·4; p=0·024), but not non-inferior to modafinil (difference 0·12, 95% CI -2·5 to 2·7; p=0·250). We recorded 22 adverse events with pitolisant, 26 with modafinil, and ten with placebo. Six severe adverse events were treatment-related: one with pitolisant (abdominal discomfort) and five with modafinil (abdominal pain, abnormal behaviour, amphetamine-like withdrawal symptoms, lymphoadenopathy, and inner ear disorders). INTERPRETATION Pitolisant at doses up to 40 mg was efficacious on EDS compared with placebo and well tolerated compared with modafinil. If these findings are substantiated in further studies, pitolisant could offer a new treatment option for patients with narcolepsy. FUNDING Bioprojet, France.

MAO-A and COMT polymorphisms and gene effects in narcolepsy.

Narcolepsy presents one of the tightest associations with a specific HLA antigen (DQB1*0602) but there is strong evidence that non-HLA genes also confer susceptibility. Recent observations have implicated the hypocretin/orexin system in narcolepsy in both humans and animals. In addition, the implication of monoaminergic systems in the pathophysiology of narcolepsy is well established and a significant association between the monoamine oxydase-A (MAO-A) gene and human narcolepsy has recently provided a possible genetic link. We investigated polymorphisms of MAO-A and catechol-O-methyltransferase (COMT) in 97 Caucasians with well-defined narcolepsy-cataplexy and sought for genotypic effects on disease symptoms. No evidence of association between genotype or allele frequencies of both MAO-A or COMT gene and narcolepsy was found. However, a sexual dimorphism and a strong effect of COMT genotype on disease severity were found. Women narcoleptics with high COMT activity fell asleep twice as fast as those with low COMT activity during the multiple sleep latency test (MSLT) while the opposite was true for men. COMT genotype also strongly affected the presence of sleep paralysis and the number of REM sleep onsets during the MSLT. In agreement with well-documented pharmacological results in canine narcolepsy, this study reports the first genetic evidence for the critical involvement of the dopaminergic and/or noradrenergic systems in human narcolepsy.

Psychological health in central hypersomnias: The French Harmony Study

Background: A large observational French study of central hypersomnia, including narcolepsy with cataplexy (C+), without cataplexy (C−) and idiopathic hypersomnia (IH), was conducted to clarify the relationships between the severity of the condition, psychological health and treatment response. Methods: 601 consecutive patients over 15 years of age suffering from central hypersomnia were recruited on excessive daytime sleepiness, polysomnography and Multiple Sleep Latency Test (MSLT) results. 517 (47.6% men, 52.4% women) were finally included: 82.0% C+, 13.2% C− and 4.8% IH. Face to face standardised clinical interviews plus questionnaires (Epworth Sleepiness Scale (ESS), short version Beck Depression Inventory (S-BDI), Pittsburgh Sleep Quality Index (PSQI) and 36-item Short Form Health Survey (SF-36)) were performed. Patients affected with a different diagnosis and with and without depressive symptoms were compared. Results: Mean ESS and body mass index were higher in C+ compared with C−/IH patients. Half of the patients (44.9%) had no depressive symptoms while 26.3% had mild, 23.2% moderate and 5.6% severe depressive symptoms. C+ patients had higher S-BDI and PSQI and lower SF-36 scores than C−/IH patients. Depressed patients had higher ESS scores than non-depressed patients, with no difference in age, gender, duration of disease or MSLT parameters. Finally, C+ patients treated with anticataplectic drugs (38.7%) had higher S-BDI and lower SF-36 scores than C+ patients treated with stimulants alone. Conclusion: Our data confirmed the high frequency of depressive symptoms and the major impact of central hypersomnias on health related quality of life, especially in patients with cataplexy. We recommend a more thorough assessment of mood impairment in central hypersomnias, especially in narcolepsy–cataplexy.

Recurrent hypersomnia: a review of 339 cases.

Based on 339 cases this review identifies, quantifies and compares 4 clinical forms of recurrent hypersomnia (1) Kleine-Levin syndrome (KLS) (239 cases), (2) Kleine-Levin syndrome without compulsive eating (KLS WOCE) (54 cases), (3) Menstrual related hypersomnia (MRH) (18 cases) and Recurrent hypersomnia with comorbidity (RHC) (28 cases). A second part of the review considers the main current issues on recurrent hypersomnia: the predisposing factors, including a window on family cases; the pathophysiology based on clinical patterns, neuroimaging data, neuropathological examinations and cerebrospinal fluid (CSF) hypocretin-1 measurements; the issues of recurrence and of a possible disruption of the circadian timing system; the relationships between recurrent hypersomnia and mood disorders; and a note on the atypical Kleine-Levin syndrome. The main outcomes of this study are a clear nosologic distinction of the different forms of recurrent hypersomnia, the finding that the prevalence of familial cases of KLS is in the same range as in narcolepsy, the suggestion of the possible involvement of a large set of cortical and subcortical structures in recurrent hypersomnia and some clues in favour of a relationship between recurrent hypersomnia and mood disorders.

Periodic leg movements during sleep and wakefulness in narcolepsy.

The objectives of the study were to measure the prevalence of periodic leg movements during NREM and REM sleep (PLMS) and while awake (PLMW) and to assess the impact of PLMS on nocturnal sleep and daytime functioning in patients with narcolepsy. One hundred and sixty‐nine patients with narcolepsy and 116 normal controls matched for age and gender were included. Narcoleptics with high and low PLMS indices were compared to assess the impact of PLMS on sleep and Multiple Sleep Latency Test (MSLT) variables. More narcoleptics than controls had a PLMS index greater than 5 per hour of sleep (67% versus 37%) and an index greater than 10 (53% versus 21%). PLMS indices were higher both in NREM and REM sleep in narcoleptic patients, but the between‐group difference was greater for REM sleep. A significant increase of PLMS index was also found with aging in both narcoleptic patients and controls. PLMW indices were also significantly higher in narcoleptic patients. Patients with an elevated index of PLMS had a higher percentage of stage 1 sleep, a lower percentage of REM sleep, a lower REM efficiency and a shorter MSLT latency. The present study demonstrates a high frequency of PLMS and PLMW in narcolepsy, an association between the presence of PLMS and measures of REM sleep and daytime functioning disruption. These results suggest that PLMS represent an intrinsic feature of narcolepsy.

Sexual dimorphism of the catechol-O-methyltransferase gene in narcolepsy is associated with response to modafinil

The gene for catechol-O-methyltransferase (COMT) plays a key modulatory role in dopaminergic and noradrenergic neurotransmission. Recent evidence suggests that modafinil, like other stimulants, might act through the dopaminergic system. We have reported a sexual dimorphism and a strong effect of the COMT genotype on narcolepsy symptoms and hypothesized that response to modafinil treatment may be associated with the COMT genotype. Here we confirm that COMT genotype distribution between men and women narcoleptics is associated with response to modafinil. In addition, the optimal daily dose of modafinil is approximately 100 mg lower in women narcoleptics and lower in all narcoleptics with low activity COMT genotype. Our results suggest that a sexual dimorphism in COMT activity affects the response to modafinil and probably to other dopaminergic stimulants.

Determinants of excessive daytime sleepiness in a French community-dwelling elderly population

Epidemiological studies have suggested that excessive daytime sleepiness (EDS) is associated with depression, but the association between EDS and other psychiatric disorders has not been investigated. The aim of this study was to investigate the association of EDS with a wide range of psychiatric disorders and health‐related conditions in the elderly population. Two thousand two hundred and fifty‐nine non‐institutionalised persons aged 65‐years and over randomly recruited from the Montpellier district, France, completed the Epworth Sleepiness Scale (ESS). Psychiatric status was assessed by the Mini International Neuropsychiatric Interview and demographic and other health information was obtained. This cross‐sectional study was conducted from March 1999 to February 2001. Men were significantly more likely to report EDS (ESS score>10) compared with women (12.0% versus 6.0% respectively). EDS was significantly associated in univariate analyses with chronic diseases, early awakening, snoring, severity of depression and lifetime prevalence of manic and hypomanic episodes. A multivariate analysis revealed that the lifetime prevalence of manic and hypomanic episodes, snoring and gender (male) were independently associated with EDS. No independent association with other psychiatric disorders was found.