The biology underlying excessive daytime sleepiness (hypersomnolence) is incompletely understood. After excluding known causes of sleepiness in 32 hypersomnolent patients, we showed that, in the presence of 10 μM γ-aminobutyric acid (GABA), cerebrospinal fluid (CSF) from these subjects stimulated GABA(A) receptor function in vitro by 84.0 ± 40.7% (SD) relative to the 35.8 ± 7.5% (SD) stimulation obtained with CSF from control subjects (Student's t test, t = 6.47, P < 0.0001); CSF alone had no effect on GABA(A) signaling. The bioactive CSF component had a mass of 500 to 3000 daltons and was neutralized by trypsin. Enhancement was greater for α2 subunit- versus α1 subunit-containing GABA(A) receptors and negligible for α4 subunit-containing ones. CSF samples from hypersomnolent patients also modestly enhanced benzodiazepine (BZD)-insensitive GABA(A) receptors and did not competitively displace BZDs from human brain tissue. Flumazenil--a drug that is generally believed to antagonize the sedative-hypnotic actions of BZDs only at the classical BZD-binding domain in GABA(A) receptors and to lack intrinsic activity--nevertheless reversed enhancement of GABA(A) signaling by hypersomnolent CSF in vitro. Furthermore, flumazenil normalized vigilance in seven hypersomnolent patients. We conclude that a naturally occurring substance in CSF augments inhibitory GABA signaling, thus revealing a new pathophysiology associated with excessive daytime sleepiness.

Objective Some central hypersomnolence syndromes are associated with a positive allosteric modulator of GABA-A receptors in cerebrospinal fluid. Negative allosteric modulators of GABA-A receptors, including clarithromycin, have been reported to reduce sleepiness in these patients. We sought to systematically assess the effects of clarithromycin on objective vigilance and subjective sleepiness. Methods This was a five-week, randomized, placebo-controlled, double-blind, crossover trial of clarithromycin 500 mg with breakfast and lunch, in patients with hypersomnolence syndromes (excluding narcolepsy with cataplexy) and evidence for abnormal cerebrospinal fluid potentiation of GABA-A receptors. The study occurred at a university-affiliated medical center. The primary outcome measure was median reaction time on the psychomotor vigilance task (PVT) at week 2 in each condition. Secondary outcomes included the Epworth Sleepiness Scale, Stanford Sleepiness Scale, Functional Outcomes of Sleep, Pittsburgh Sleep Quality Index, the SF-36, and additional PVT measures. Results Twenty-three patients began treatment. Three patients dropped out, and final analyses were performed on twenty complete cases. Median reaction time was not significantly different between clarithromycin and placebo. Subjective measures of sleepiness were significantly improved on clarithromycin versus placebo. Altered taste perception occurred, but was the only side effect more common on clarithromycin than placebo. No serious adverse events occurred. Interpretation Subjective sleepiness, but not psychomotor vigilance, improved during a two-week course of clarithromycin. Although additional studies are needed, this suggests that clarithromycin may be a reasonable treatment option in patients with treatment-refractory hypersomnolence. This trial was registered at clinicaltrials.gov (NCT01146600) and supported by the American Sleep Medicine Foundation.

We fine mapped the leukocyte antigen (HLA) region in 13,770 Parkinson’s disease (PD) patients, 20,214 proxy-cases, and 490,861 controls of European origin. Four HLA types were associated with PD after correction for multiple comparisons, HLA-DQA1*03:01, HLA-DQB1*03:02, HLA-DRB1*04:01, and HLA-DRB1*04:04. Haplotype analyses followed by amino acid analysis and conditional analyses suggested that the association is protective and primarily driven by three specific amino acid polymorphisms present in most HLA-DRB1*04 subtypes—11V, 13H, and 33H (OR = 0.87, 95% CI: 0.83–0.90, p < 8.23 × 10−9 for all three variants). No other effects were present after adjustment for these amino acids. Our results suggest that specific HLA-DRB1 variants are associated with reduced risk of PD, providing additional evidence for the role of the immune system in PD. Although effect size is small and has no diagnostic significance, understanding the mechanism underlying this association may lead to the identification of new targets for therapeutics development.

The macrolide antibiotic clarithromycin can enhance central nervous system excitability, possibly by antagonism of GABA-A receptors. Enhancement of GABA signaling has recently been demonstrated in a significant proportion of patients with central nervous system hypersomnias, so we sought to determine whether clarithromycin might provide symptomatic benefit in these patients. We performed a retrospective review of all patients treated with clarithromycin for hypersomnia, in whom cerebrospinal fluid enhanced GABA-A receptor activity in vitro in excess of controls, excluding those with hypocretin deficiency or definite cataplexy. Subjective reports of benefit and objective measures of psychomotor vigilance were collected to assess clarithromycin's effects. Clinical and demographic characteristics were compared in responders and non-responders. In total, 53 patients (38 women, mean age 35.2 (SD 12.8 years)) were prescribed clarithromycin. Of these, 34 (64%) reported improvement in daytime sleepiness, while 10 (19%) did not tolerate its side effects, and nine (17%) found it tolerable but without symptomatic benefit. In those who reported subjective benefit, objective corroboration of improved vigilance was evident on the psychomotor vigilance task. Twenty patients (38%) elected to continue clarithromycin therapy. Clarithromycin responders were significantly younger than non-responders. Clarithromycin may be useful in the treatment of hypersomnia associated with enhancement of GABA-A receptor function. Further evaluation of this novel therapy is needed.

Restless legs syndrome (RLS) is a common neurological sensorimotor disorder often described as an unpleasant sensation associated with an urge to move the legs. Here we report findings from a meta-analysis of genome-wide association studies of RLS including 480,982 Caucasians (cases = 10,257) and a follow up sample of 24,977 (cases = 6,651). We confirm 19 of the 20 previously reported RLS sequence variants at 19 loci and report three novel RLS associations; rs112716420-G (OR = 1.25, P = 1.5 × 10−18), rs10068599-T (OR = 1.09, P = 6.9 × 10−10) and rs10769894-A (OR = 0.90, P = 9.4 × 10−14). At four of the 22 RLS loci, cis-eQTL analysis indicates a causal impact on gene expression. Through polygenic risk score for RLS we extended prior epidemiological findings implicating obesity, smoking and high alcohol intake as risk factors for RLS. To improve our understanding, with the purpose of seeking better treatments, more genetics studies yielding deeper insights into the disease biology are needed.

A commentary on this article appears in this issue on page 1321.

No abstract

Symptoms of the central disorders of hypersomnolence extend beyond excessive daytime sleepiness to include non-restorative sleep, fatigue and cognitive dysfunction. They share much in common with myalgic encephalomyelitis/chronic fatigue syndrome, recently renamed systemic exertion intolerance disease, whose additional features include post-exertional malaise and orthostatic intolerance. We sought to determine the frequency and correlates of systemic exertion intolerance disease in a hypersomnolent population. One-hundred and eighty-seven hypersomnolent patients completed questionnaires regarding sleepiness and fatigue; questionnaires and clinical records were used to assess for systemic exertion intolerance disease. Sleep studies, hypocretin and cataplexy were additionally used to assign diagnoses of hypersomnolence disorders or sleep apnea. Included diagnoses were idiopathic hypersomnia (n = 63), narcolepsy type 2 (n = 25), persistent sleepiness after obstructive sleep apnea treatment (n = 25), short habitual sleep duration (n = 41), and sleepiness with normal sleep study (n = 33). Twenty-one percent met systemic exertion intolerance disease criteria, and the frequency of systemic exertion intolerance disease was not different across sleep diagnoses (p = .37). Patients with systemic exertion intolerance disease were no different from those without this diagnosis by gender, age, Epworth Sleepiness Scale, depressive symptoms, or sleep study parameters. The whole cohort reported substantial fatigue on questionnaires, but the systemic exertion intolerance disease group exhibited more profound fatigue and was less likely to respond to traditional wake-promoting agents (88.6% versus 67.7%, p = .01). Systemic exertion intolerance disease appears to be a common co-morbidity in patients with hypersomnolence, which is not specific to hypersomnolence subtype but may portend a poorer prognosis for treatment response.