Prabhjyot Saini

Modulation of Vigilance in the Primary Hypersomnias by Endogenous Enhancement of GABAA Receptors

A component of cerebrospinal fluid in excessively sleepy people activates an inhibitory signaling pathway and mimics the actions of sedative-hypnotics. Awake and Refreshed A spindle prick on the finger, and Princess Aurora couldn’t keep her eyes open; one hundred years later, Sleeping Beauty was awakened with a kiss. But persistent daytime sleepiness—hypersomnolence—is no fairy tale, and neither the cause nor a cure is apparent. Now, Rye et al. begin to illuminate, in patients with primary hypersomnias, the neurobiology that underlies sleepiness of unknown etiology. A disabling condition, primary hypersomnia is characterized by lethargy, trance-like states, and “sleep drunkenness” even after prolonged, deep, nonrestorative sleep. The authors showed that cerebrospinal fluid (CSF) from these hypersomnolent subjects contains a small (500 to 3000 daltons) trypsin-sensitive substance that stimulates the in vitro function of selected γ-aminobutyric acid (GABA) receptors only in the presence of GABA—an inhibitory neurotransmitter that stimulates GABA receptors, quells consciousness, and induces sleep. GABA receptors are known to bind a class of psychoactive sedating drugs called benzodiazepines (BZDs). Hypersomnolent CSF samples mimicked the effects of BZD on GABA receptors but did not compete with BZD binding in human brain tissue, suggesting that the newly identified substance functions by a distinct mechanism. Furthermore, the BZD receptor antagonist flumazenil reversed hypersomnolent-CSF activation of GABA signaling, even though the drug is known to be a competitive antagonist of BZD and blocks BZD action by binding to the classical BZD-binding domain of GABA receptors. Most importantly, flumazenil restored vigilance in some hypersomnolent subjects. Together, these mechanistic studies pinpoint a potential new neuropharmacological pathway for a 25-year-old drug. The current study suggests that one of the “spindle pricks” that puts hypersomnolent subjects to sleep is a substance in CSF that augments inhibitory GABA signaling. A deeper understanding of the neurobiology of primary hypersomnia should help scientists discover new “kisses” that restore wakefulness—in fewer than 100 years. 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 GABAA 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 GABAA 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 GABAA receptors and negligible for α4 subunit–containing ones. CSF samples from hypersomnolent patients also modestly enhanced benzodiazepine (BZD)–insensitive GABAA 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 GABAA receptors and to lack intrinsic activity—nevertheless reversed enhancement of GABAA 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.

Improvement in daytime sleepiness with clarithromycin in patients with GABA-related hypersomnia: Clinical experience

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.

Clarithromycin in γ-aminobutyric acid-Related hypersomnolence: A randomized, crossover trial.

Some central hypersomnolence syndromes are associated with a positive allosteric modulator of γ‐aminobutyric acid (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.

Hypersomnia: Evaluation, Treatment, and Social and Economic Aspects

Most central disorders of hypersomnolence are conditions with poorly understood pathophysiologies, making their identification, treatment, and management challenging for sleep clinicians. The most challenging to diagnose and treat is idiopathic hypersomnia. There are no FDA-approved treatments, and off-label usage of narcolepsy treatments seldom provide benefit. Patients are largely left on their own to alleviate the compound effects of this disorder on their quality of life. This review covers the major points regarding clinical features and diagnosis of idiopathic hypersomnia, reviews current evidence supporting the available treatment options, and discusses the psychosocial impact and effects of idiopathic hypersomnia.

Hypocretin measurement: shelf age of radioimmunoassay kit, but not freezer time, influences assay variability

Abstract The hypothalamic peptide hypocretin 1 (orexin A) may be assayed in cerebrospinal fluid to diagnose narcolepsy type 1. This testing is not commercially available, and factors contributing to assay variability have not previously been comprehensively explored. In the present study, cerebrospinal fluid hypocretin concentrations were determined in duplicate in 155 patient samples, across a range of sleep disorders. Intra-assay variability of these measures was analyzed. Inter-assay correlation between samples tested at Emory and at Stanford was high (r = 0.79, p < 0.0001). Intra-assay correlation between samples tested in duplicate in our center was also high (r = 0.88, p < 0.0001); intra-assay variability, expressed as the difference between values as a percentage of the higher value, was low at 9.4% (SD = 7.9%). Although both time the sample spent in the freezer (r = 0.16, p = 0.04) and age of the kit used for assay (t = 3.64, p = 0.0004) were significant predictors of intra-kit variability in univariate analyses, only age of kit was significant in multivariate linear regression (F = 4.93, p = 0.03). Age of radioimmunoassay kit affects intra-kit variability of measured hypocretin values, such that kits closer to expiration exhibit significantly more variability.

Rigor, reproducibility, and in vitro cerebrospinal fluid assays: The devil in the details

Rigor, Reproducibility, and In Vitro Cerebrospinal Fluid Assays: The Devil in the Details Olivia A. Moody, BA, Sahil Talwar, PhD, Meagan A. Jenkins, PhD, Amanda A. Freeman, PhD, Lynn Marie Trotti, MD, MSc, Paul S. Garc ıa, MD, PhD, Donald Bliwise, PhD, Joseph W. Lynch, Brad Cherson, RPh, Eric M. Hernandez, MD, PhD, Neil Feldman, MD, Prabhjyot Saini, MSc, David B. Rye, MD, PhD, and Andrew Jenkins, PhD

Clarithromycin in GABA-related Hypersomnolence: A Randomized, Crossover Trial

Some central hypersomnolence syndromes are associated with a positive allosteric modulator of γ‐aminobutyric acid (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.

Systemic exertion intolerance disease/chronic fatigue syndrome is common in sleep centre patients with hypersomnolence: A retrospective pilot study

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.

Rigor, Reproducibility and in vitro CSF assays: The Devil in the Details

Rigor, Reproducibility, and In Vitro Cerebrospinal Fluid Assays: The Devil in the Details Olivia A. Moody, BA, Sahil Talwar, PhD, Meagan A. Jenkins, PhD, Amanda A. Freeman, PhD, Lynn Marie Trotti, MD, MSc, Paul S. Garc ıa, MD, PhD, Donald Bliwise, PhD, Joseph W. Lynch, Brad Cherson, RPh, Eric M. Hernandez, MD, PhD, Neil Feldman, MD, Prabhjyot Saini, MSc, David B. Rye, MD, PhD, and Andrew Jenkins, PhD

Clarithromycin in γ-aminobutyric acid-Related hypersomnolence: A randomized, crossover trial: Clarithromycin

Some central hypersomnolence syndromes are associated with a positive allosteric modulator of γ‐aminobutyric acid (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.