Geert Mayer

The REM sleep behavior disorder screening questionnaire--a new diagnostic instrument.

Many patients with assumed idiopathic REM sleep behavior disorder (RBD) may actually represent an early clinical manifestation of an evolving neurodegenerative disorder, such as the α‐synucleinopathies, Parkinsons disease or multiple system atrophy. Early detection of these patients is clinically relevant for long‐term prospective as well as future neuroprotective studies. For this purpose, we validated a 10‐item patient self‐rating questionnaire (maximum total score 13 points) covering the clinical features of RBD. The RBD screening questionnaire (RBDSQ) was applied to 54 patients with polysomnographically confirmed RBD (29 men; mean age 53.7 ± 15.8 years), 160 control subjects (81 men; mean age 50.8 ± 15.5 years) in whom RBD was excluded by history and polysomnography (PSG, control group 1) and 133 unselected healthy subjects (58 men; mean age 46.9 ± 12.3 years; no PSG, control group 2). In most subjects (n = 153) of control group 1, other sleep‐wake disturbances were present. The mean RBDSQ score in the RBD group was 9.5 ± 2.8 points compared with 4.6 ± 3.0 points in control group 1 (P < 0.0001). Considering an RBDSQ score of five points as a positive test result, we found a sensitivity of 0.96 and a specificity of 0.56. The RBDSQ poorly discriminated patients with the most challenging differential diagnoses such as sleepwalking or epilepsy. In control group 2, the mean RBDSQ score (2.02 ± 1.78) was significantly lower than in the RBD group (P < 0.0005), revealing a specificity of 0.92. Due to its high sensitivity, the RBDSQ appears to be particularly useful as a screening tool.

Narcolepsy is strongly associated with the T-cell receptor alpha locus

Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs and mice, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P < 10−21, 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders; thus, narcolepsy will provide new insights on how HLA–TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders.

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.

Kleine-Levin syndrome: An autoimmune hypothesis based on clinical and genetic analyses

Background: Kleine-Levin syndrome (KLS) is a rare disorder of unknown etiology. Pathophysiologic hypotheses include a hypothalamic dysfunction and abnormalities in the central serotonin and dopamine metabolism. Several clinical symptoms also suggest an underlying autoimmune process. Objective: To systematically investigate patients with KLS with reference to the available hypotheses. Methods: The authors collected clinical, polysomnographic, CSF, CT, and MRI records and analyzed gene polymorphisms of HLA-DQB1, tryptophan hydroxylase (TpH), and catechol-O-methyltransferase (COMT) in 30 unrelated patients with KLS and their families. The genotype data were contrasted with data from a normal control population. Results: Only human leukocyte antigen (HLA)-DQB1*0201 allele frequency was significantly increased in patients with KLS. Three patients with KLS but none of the control subjects were DQB1*0201 homozygous. Two affected subjects from the same family were DQB1*0201 homozygous. In 17 DQB1*0201 heterozygous parents, 11 (64.7%) had transmitted this allele, suggesting a preferential transmission. Conclusion: These findings, together with the young age at onset, the recurrence of symptoms, and the frequent infectious precipitating factors, suggest an autoimmune etiology for Kleine-Levin syndrome.

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.

Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15–25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 × 10−8). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 × 10−43) and DRB1*1301-DQB1*0603 (P < 3 × 10−7). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 × 10−14). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.

ImmunoChip Study Implicates Antigen Presentation to T Cells in Narcolepsy

Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.

HLA and genetic susceptibility to sleepwalking

HLA-DQB1 typing was performed in 60 Caucasian subjects with sleepwalking (SW) disorder and their families and 60 ethnically matched subjects without any diagnosed sleep disorder. A total of 21 sleepwalkers (35.0%) were DQB1*0501 positive vs eight (13.3%) controls (P=0.0056; odds ratio=3.5, 95% CI=1.4–8.7). The family data for all HLA subtypes were further assessed for allelic association with SW using the transmission–disequilibrium test. A significant excess transmission was observed for DQB1*05 and *04 alleles in familial cases, strongly suggesting that a DQB1 polymorphic amino acid might be more tightly associated than any single allele. Sequence screening revealed that Ser74 in the second exon shared by all DQB1*05 and *04 was 20 times transmitted against 4 times non-transmitted (P=0.001) in familial cases of SW. Thus, together with narcolepsy and REM sleep behavior disorder, these findings suggest that specific DQB1 genes are implicated in disorders of motor control during sleep.

Rapid eye movement sleep behavior disorder: Devising controlled active treatment studies for symptomatic and neuroprotective therapy-a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group

OBJECTIVES We aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD. METHODS The consensus statement was generated during the fourth IRBD-SG symposium in Marburg, Germany in 2011. The IRBD-SG identified essential methodologic components for a randomized trial in RBD, including potential screening and diagnostic criteria, inclusion and exclusion criteria, primary and secondary outcomes for symptomatic therapy trials (particularly for melatonin and clonazepam), and potential primary and secondary outcomes for eventual trials with disease-modifying and neuroprotective agents. The latter trials are considered urgent, given the high conversion rate from idiopathic RBD (iRBD) to Parkinsonian disorders (i.e., PD, dementia with Lewy bodies [DLB], multiple system atrophy [MSA]). RESULTS Six inclusion criteria were identified for symptomatic therapy and neuroprotective trials: (1) diagnosis of RBD needs to satisfy the International Classification of Sleep Disorders, second edition, (ICSD-2) criteria; (2) minimum frequency of RBD episodes should preferably be ⩾2 times weekly to allow for assessment of change; (3) if the PD-RBD target population is included, it should be in the early stages of PD defined as Hoehn and Yahr stages 1-3 in Off (untreated); (4) iRBD patients with soft neurologic dysfunction and with operational criteria established by the consensus of study investigators; (5) patients with mild cognitive impairment (MCI); and (6) optimally treated comorbid OSA. Twenty-four exclusion criteria were identified. The primary outcome measure for RBD treatment trials was determined to be the Clinical Global Impression (CGI) efficacy index, consisting of a four-point scale with a four-point side-effect scale. Assessment of video-polysomnographic (vPSG) changes holds promise but is costly and needs further elaboration. Secondary outcome measures include sleep diaries; sleepiness scales; PD sleep scale 2 (PDSS-2); serial motor examinations; cognitive indices; mood and anxiety indices; assessment of frequency of falls, gait impairment, and apathy; fatigue severity scale; and actigraphy and customized bed alarm systems. Consensus also was established for evaluating the clinical and vPSG aspects of RBD. End points for neuroprotective trials in RBD, taking lessons from research in PD, should be focused on the ultimate goal of determining the performance of disease-modifying agents. To date no compound with convincing evidence of disease-modifying or neuroprotective efficacy has been identified in PD. Nevertheless, iRBD patients are considered ideal candidates for neuroprotective studies. CONCLUSIONS The IRBD-SG provides an important platform for developing multinational collaborative studies on RBD such as on environmental risk factors for iRBD, as recently reported in a peer-reviewed journal article, and on controlled active treatment studies for symptomatic and neuroprotective therapy that emerged during the 2011 consensus conference in Marburg, Germany, as described in our report.

S3-Leitlinie Nicht erholsamer Schlaf/Schlafstörungen

Somnologie 2017 · 21:2–44 DOI 10.1007/s11818-016-0097-x Online publiziert: 27. Februar 2017