The effects of gamma-hydroxybutyrate on the sleep of narcolepsy patients: a double-blind study.

The effects of gamma-hydroxybutyrate (GHB: 25 mg/kg h.s. and 3 h later) vs. placebo on objectively evaluated nighttime sleep and daytime sleepiness in narcolepsy were evaluated in a double-blind, counterbalanced crossover design. Twenty narcolepsy patients were given an overnight polysomnogram (PSG), followed by a daytime multiple sleep latency test (MSLT) at baseline and on the 1st and 29th days of GHB and placebo treatment. The overnight PSGs indicated that the narcolepsy patients had the following significant results during GHB versus placebo treatment: decreased stage 1 (p = 0.012), increased stage 3 (p = 0.008), increased delta (stage 3 and 4 combined) sleep (p = 0.049), fewer stage shifts (p = 0.002), and fewer awakenings (p = 0.006). Minutes of wakefulness were significantly increased only for the last 2 h of the 8 h sleep period on GHB versus placebo (p = 0.019), which is beyond the time of GHB's direct influence. The MSLTs indicated that the narcolepsy patients had a marginally increased sleep latency mean during GHB versus placebo treatment (p = 0.074) and significantly increased total stage 0 (wakefulness) on day 29 of GHB versus day 29 of placebo treatment (p = 0.038). Female narcolepsy patients had significantly fewer naps with REM sleep (REM naps) on day 29 of GHB vs. day 29 of placebo treatment (p = 0.020). The therapeutic effect of GHB in narcolepsy patients, i.e., decreases cataplexy, appears to be due to its improving nocturnal sleep quality, since its half-life is only 1.5 to 2 h. It is conjectured that GHB, an endogenous neurochemical, may be a sleep neurotransmitter or neuromodulator, since GHB rapidly induces sleep, and increases sleep continuity and delta sleep without suppressing REM sleep in both normals and narcolepsy patients.

Efficacy of gamma-hydroxybutyrate versus placebo in treating narcolepsy-cataplexy: double-blind subjective measures.

The efficacy of gamma-hydroxybutyrate (GHB) versus placebo for treating narcolepsy was evaluated in 20 patients with narcolepsy, 10 men and 10 women, using a double-blind counterbalanced crossover design. Each patient completed a daily sleep-wake log and questionnaire during a 14-day baseline, a 29-day placebo period, a 29-day GHB period (50 mg GHB/kg/night given 25 mg/kg h.s. and 25 mg/kg 3 hr later), and a 6-day washout period after each treatment. Cataplexy frequency was significantly lower during GHB treatment than during placebo treatment (p = 0.022). Compared to baseline values, the number of cataplexy attacks per day declined by 52% and 69% during GHB treatment weeks 1 and 4, respectively. The number of subjective arousals from sleep was less with GHB than with placebo (p = 0.035), and the number of sleep attacks was not significantly different during GHB versus placebo treatment. GHB did not have a significant effect on subjective estimates of sleep onset latency, total sleep time, Stanford Sleepiness Scale ratings at morning wake-up, methylphenidate usage, or the number of naps per day. The results indicate that GHB is efficacious for reducing the frequency of cataplexy attacks and subjective nocturnal arousals in patients with narcolepsy within the first 4 weeks of treatment.

Effect of three alcohol doses on breathing during sleep in 30-49 year old nonobese snorers and nonsnorers.

To test the effect of alcohol ingestion and snoring on sleep-disordered breathing (SDB), the sleep and respiration of 31 nonobese healthy males ages 30-49 (15 snorers, 16 nonsnorers) were studied overnight after alcohol ingestion. Subjects received placebo, 0.32, 0.65, and 0.81 g alcohol/kg body weight prior to their evening bedtime, with each dose given on one of four nonconsecutive nights in a repeated-measures counterbalanced design. On each night, respiration was assessed by recording respiratory effort from intercostal surface electromyography (EMG), ventilation from oral and nasal thermistors, and arterial oxygen saturation (SaO2) from an ear oximeter (BIOX III). Snorers had significantly: (a) more total SDB, (b) more obstructive sleep apnea (OSA), and (c) lower minimum SaO2 than nonsnorers after the placebo and each alcohol dose. Snorers had more hypoxic events than nonsnorers after each alcohol dose but not after placebo. Increasing alcohol dose caused a statistically significant (p = 0.0004) decrease in minimum SaO2 in snorers only, but this decrease was small and probably not clinically important. Alcohol did not cause significant increases in SDB and hypoxic events, and did not have different effects on SDB and hypoxic events for snorers versus nonsnorers. Because this experiment included only nonobese 30-49-year-old males, these results do not imply that alcohol has no significant effects on obese subjects or those older than 50.

Sleep apnea in epistaxis patients treated with nasal packs.

The presence of anterior and posterior nasal packs in patients with epistaxis is known to be associated with cardiorespiratory problems and sometimes death, although the mechanism has not been well understood. To determine the incidence and severity of obstructive sleep apnea in patients with epistaxis treated with both anterior and posterior nasal packs, we obtained polysomnograms on twelve patients while the packs were in place. Ten of these patients demonstrated obstructive sleep apnea. The apnea index (apneas/hour sleep) ranged from 1 to 83, with a mean of 29; the hypopnea index (hypopneas/hour sleep) ranged from 9 to 33, with a mean of 20; and the lowest oxygen saturation (SaO2) ranged from 17% to 91%, with a mean of 77%. Ten patients returned for another polysomnogram after removal of the packs. These baseline studies showed improvement in the apnea index and in the lowest SaO2 in all patients, although four patients still demonstrated at least mild obstructive sleep apnea. This study demonstrates that nasal packs used for the treatment of epistaxis may induce obstructive sleep apnea or markedly exacerbate underlying obstructive sleep apnea and, therefore, contribute to the sudden deaths that have been reported in epistaxis patients.

Muscle activity in the legs (MAL) associated with frequent arousals in narcoleptics, nocturnal myoclonus and obstructive sleep apnea (OSA) patients.

"Muscle activity in the legs (MAL)" is an extension of the classification, nocturnal myoclonus, to include all phasic muscle activity in the legs during sleep, irrespective of the repetitiveness, periodicity, or minimum duration of the muscle events. This report examined the number of MAL events and, especially, MAL events associated with arousals (MAL arousals) and awakenings (MAL awakenings) in the clinical records of 9 narcoleptics, 42 obstructive sleep apnea (OSA) patients, and 12 nocturnal myoclonus patients. The mean MAL arousals/hr for narcoleptics, OSA patients, and nocturnal myoclonus patients were 20.5, 3.0, and 12.9, respectively; the mean MAL awakenings/hr were 2.5, 0.2, and 1.3, respectively. Both the narcoleptics and nocturnal myoclonus patients had significantly more MAL arousals/hr and MAL awakenings/hr of sleep than OSA patients. Nonetheless, 62% of the OSA patients had greater than or equal to 1 MAL arousal/hr. Narcoleptics had significantly more MAL awakenings/hr than nocturnal myoclonus patients; narcoleptics also had more MAL arousals/hr of sleep than nocturnal myoclonus patients, but this difference was not significant. Most, 89%, of the narcoleptics, 22% of the OSA patients, and 100% of the nocturnal myoclonus patients had greater than or equal to 5 MAL arousals/hr of sleep. These findings suggest that there may be a relationship between the pathogenesis of MAL, narcolepsy, and OSA.

Postoperative evaluation of sleep apnea after uvulopalatopharyngoplasty.

Uvulopalatopharyngoplasty (UPPP) is an operation that is frequently performed for the treatment of obstructive sleep apnea (OSA). While UPPP usually eliminates or decreases snoring and often reduces excessive daytime sleepiness, the decrease in the number of episodes of apnea and hypopnea, and the improvement in oxygen saturation (SaO2) have been less predictable. We compared preoperative and postoperative polysomnography (PSG) in 27 patients with OSA and found that no single PSG parameter could accurately reflect the changes in respiration seen after UPPP. We suggest that a combination of indices including the apnea index, the apnea and hypopnea index, the frequency and severity of decreases in SaO2, and the lowest SaO2 be used to assess the effect of UPPP. Using this combination we determined that 30% of our patients were markedly improved, 33% were somewhat improved, and 37% were unimproved. To rely solely on the patient's subjective improvement often results in overestimating the therapeutic results of surgery, whereas to rely only on one PSG parameter may underestimate or overestimate the degree of improvement.

Sleep apnea and the Arnold-Chiari malformation.

We present a polysomnogram-documented report of central sleep apnea (427 events) and moderately severe decreases in arterial oxygen saturation (to 81%) associated with the Arnold-Chiari malformation (ACM). Daytime hypersomnolence and other symptoms had significantly impaired our patient's work performance. After surgical correction of the ACM, there was marked improvement in symptomatology. A post-surgery polysomnogram revealed marked improvement in the number of central apneas (74 events) and only mild decreases in oxygen saturation (to 94%).

Interanimal transferability of taste aversion learning for 0.1% saccharin.

Three experiments were performed to assess the interanimal transferability of conditioned taste aversion to 0.1% saccharin. Two experiments used an intracerebrospinal fluid (subdural) route for administering brain extracts and a third used an intraperitoneal (IP) route. As assessed by repeated measurements ANOVA, saccharin consumption was significantly lower during extinction of conditioned aversion for experimental recipients (ER) receiving extracts from aversively conditioned donors, than that of control recipients (CR), receiving extracts from unconditioned donors in one subdural experiment, F(21, 189) = 1.61, p less than 0.05. In the IP experiment the results were in the same direction, though not significant, F(34, 238) = 1.39, p less than 0.1. Results of the other subdural experiment are discussed. It is concluded that these experiments with the conditioned taste aversion paradigm have potential as a model for investigations of behavioral interanimal transfer (BIT) and for neuromolecular research aimed at identification of associated putative neurochemical(s) and the elaboration of their mechanism of action.

The narcoleptic approach paradigm (NAP) for the direct study of dreams and dream sleep functions.

A new sleep research paradigm, the Narcoleptic Approach Paradigm (NAP), was developed to enable direct psychological and physiological investigations of isolated dream sleep (also called rapid eye movement or REM sleep) and nondream sleep (non-REM or NREM). Essential to NAP is the cooperation of individuals with narcolepsy, who frequently have REM sleep onset. Narcoleptic animals may also be used for more convenient and extensive physiological NAP investigations. Several cogent psychological and physiological design variations of the general NAP model are outlined and one investigation successfully utilizing NAP is described to illustrate its power, sensitivity and broad use in neuroscientific sleep research.

Increased severity of obstructive sleep apnea after bedtime alcohol ingestion: diagnostic potential and proposed mechanism of action.

To assess the effect of 3 oz of 80-proof alcohol on the frequency and severity of obstructive sleep apnea (OSA), we studied six OSA patients and six healthy subjects on 2 nights. During the 1st night, when no alcohol was given, five patients demonstrated mild and one severe OSA episodes associated with a decline in arterial oxygen saturation to at least 92% (hypoxic event). On the 2nd night after ingesting 3 oz of alcohol just prior to bedtime, all the patients demonstrated a significant increase in the number and/or severity of hypoxic events compared with the no-alcohol night. Furthermore, the most severe hypoxic events occurred within 80 to 160 min after sleep onset, a significantly shorter latency after sleep onset than on the no-alcohol night. In contrast, the healthy subjects had no incidents of hypoxic events or breathing abnormalities during sleep after ingesting 0.8 gm/kg of alcohol. Possible mechanisms for these results are discussed. An OSA provocation test using alcohol is proposed during a 2nd night of evaluation for patients with mild to moderate or intermittent OSA conditions, but not for patients demonstrating severe hypoxic events or with alcohol intolerance. The alcohol provocation test would serve to determine the influence of alcohol on the frequency and severity of hypoxic events, providing the patient with a measure of the adverse effects of social drinking on their condition.

An etiology of narcolepsy-cataplexy and a proposed cataplexy neuromechanism.

Narcolepsy-cataplexy is an idiopathic sleep disorder that reflects a complex neuropathology. Surveys and physiological investigations indicate that genetic and stress factors are involved in its onset and that stress is associated with symptomatic fluctuations and exacerbations of its clinical course. This paper summarizes the literature regarding the evolution, characteristics and treatment of the disorder. A comprehensive etiology is advanced, integrating neurophysiological and psychological factors specific to narcolepsy-cataplexy with recent advances in blood pressure regulation. Moreover, a testable neuromechanism of cataplexy is proposed, based on longitudinal effects of chronic drowsiness, the strong hypnogenic effect obtained by carotid sinus stimulation, an experimental animal model of narcolepsy-cataplexy, the adaptive characteristics of baroreceptors and, finally, the interconnections between CNS sleep and blood pressure regulators of the brain stem. Through better understanding of the causes and mechanisms of narcolepsy-cataplexy, more effective treatments and preventive measures can be developed, high risk populations identified, and, perhaps, a cure found. Suggestions for future physiological and epidemiological research are made.