Melatonin secretion and sleep disorders in patients with spinal cord injuries.

STUDY DESIGN: Prospective observational study. OBJECTIVES: To evaluate melatonin secretion, daytime sleepiness and sleep disorders in patients with spinal cord injuries (SCI), and their association with lesion level. SETTING: Specialized neuro rehabilitation hospital in France METHODS: Prospective observational study of patients aged over 18 hospitalized in for spinal cord injury. Sleep quality was measured with the Pittsburgh Sleep Quality Index (PQSI), daytime sleepiness with the Epworth Sleepiness scale (ESS), and melatonin secretion by 24 h urinary dosage of 6-sulphatoxy-melatonin. RESULTS: 213 patients were screened, 21 patients were included: 17 complete (AIS A) and 4 lesions (AIS B), 76% of traumatic origin with 12 tetraplegic and 9 paraplegic, mean 10 (range 0.5-40) years after injury. Mean age was 46.8 ± 14.7 years, mean BMI 23.56 ± 4.1 and men outnumbered women (15 vs 6). Melatonin secretion was analyzed by 24 h secretion and by secretion profile. Comparing retained vs abolished secretion, only 23% (4/17) of patients with a lesion above T8 retained melatonin secretion, compared to 80% (4/5) with a lesion below T8 (p = 0.022). Non significant differences were found in secretion profile in patients who retained secretion: no patient with a lesion above T8 had a normal secretion profile compared to 50% with a lesion below T8 and in the impact of partial vs total lesions above T8 in whom 17% (2/12) of complete ASIA-A lesions and 50% (2/4) of incomplete lesions retained secretion. CONCLUSION: Lesions of the spinal cord above T8 are strongly associated with abolition of melatonin secretion.

Melatonin (MEL) and its use in circadian rhythm sleep-wake disorders: Recommendations of the French Medical and Research Sleep Society (SFRMS).

The French society of medical research on sleep (SFRMS) appointed a group of experts to conduct a consensus conference in order to study the indications and prescription status of exogenous melatonin (MEL). Eleven sleep physicians/researchers investigated in subgroups the use of MEL in different domains of healthcare in line with their subspecialties (circadian sleep/wake rhythm disorders, psychiatric disorders, neurological disorders, pediatric and neurodevelopmental disorders). In this article we present a summary of the main conclusions of the expert group on MEL therapy in circadian sleep/wake rhythm disorders such us delayed sleep-wake disorder, non-24-hour sleep wake rhythm disorder and jet lag.

Melatonin (MEL) and its use in neurological diseases and insomnia: Recommendations of the French Medical and Research Sleep Society (SFRMS).

The French Medicine and Research Sleep Society had organized a consensus conference about sleep/wake circadian rhythms and their disorders. During this conference a subgroup of 11 sleep doctors/researchers looked specifically at the use of MEL in different pathologies. This article gives a summary of the main results of MEL therapy in some neurological diseases and insomnia approved by this consensus group. Exogenous MEL, which crosses the blood-brain barrier, has been used as a treatment in its two available forms: an immediate release form that principally shows a chronobiotic action and a long release form that mimics the physiological MEL secretion rhythm and is used to replace reduced physiological secretion. MEL secretion decreases frequently with age, mostly in elderly insomniacs and dementia patients. Results of level A studies show that MEL therapy, used as an add-on treatment, has beneficial effects in mild cognitive impairment (MCI) and Alzheimer patients with sleep disorders in improving sleep quality and in regulating the sleep/wake rhythm. MEL has to be prescribed as early as possible and for a long period, at a dose of 2 to 5 or 10 mg. It may have a beneficial effect on cognitive function in MCI but shows no effect in moderate to severe Alzheimer's disease. It should be emphasized that there are no serious side effects with MEL treatment. In these diseases, light therapy used 12 hours before melatonin treatment has a positive synergic effect. In REM sleep behavior disorder, immediate release MEL should be prescribed first as its side effect profile is much better than clonazepam shortly before bedtime. MEL has a good efficacy on clinical symptoms and PSG REM sleep without atonia episodes and is well tolerated. In Parkinson disease with sleep disorders and without REM sleep behavior disorder, MEL seems to improve subjective sleep quality but no conclusions can be drawn. There is insufficient scientific proof for using MEL as a prophylactic treatment in primary headache, migraine and cluster headache. In epileptic patients, MEL can be safely used to regulate the sleep/wake rhythm and to improve insomnia but more randomized controlled studies are necessary. In primary or no-comorbid insomnia, only a 2 mg dose of slow release MEL, 1 to 2 hours before bedtime, over a period of 3 to 12 weeks, is recommended. It decreases sleep onset latency, improves quality of sleep, morning alertness and quality of life without serious side effects and without withdrawal symptoms.

[Melatonin: Physiological and pharmacological aspects related to sleep: The interest of a prolonged-release formulation (Circadin®) in insomnia]. / Mélatonine : aspects physiologiques et pharmacologiques en relation avec le sommeil, intérêt d'une forme galénique à libération prolongée (Circadin®) dans l'insomnie.

Melatonin is a hormone secreted by the pineal gland. It displays a very marked nycthohemeral rhythm, which is entrained to the light dark cycle. The secretion spreads over 8-10 hours, with a maximum around 3-4 a.m. Melatonin plays the role of an endogenous synchronizer which regulates circadian rhythms, especially the sleep/wake and temperature rhythms. Acute melatonin administration reduces sleep latency, increases theta/alpha power and spindle activity (soporific activity). Fast-release melatonin preparations showed inconstant effects in insomnia. Melatonin displays a short blood half-life, a fast turn over and undergoes a high first-pass hepatic metabolism. More than 80% is excreted exclusively in the urine as 6-sulfatoxymelatonin. The individual's capacity to produce the endogenous hormone, the decline in circadian clock output and the increase in complaints of poor sleep quality at older age led to develop a prolonged-release melatonin preparation to mimic the endogenous secretion in patients. This reviews provides data on physiological and pharmacological melatonin effects related to sleep and summarizes trials published about Circadin® efficacy and tolerance in insomnia. Preliminary therapeutic data on other indications are given. The main clinically relevant benefits are improvements in sleep quality and latency, next-day morning alertness and quality of life. The response develops over several days. An oral 2-mg dose once daily, for 3 months, is generally well tolerated with no rebound, withdrawal or 'hangover' effects and no safety concerns on concomitant therapy with antihypertensive, antidiabetic, lipid-lowering or anti-inflammatory drugs. Untoward effects of hypnotics on cognition, memory, postural stability and sleep structure are not seen with Circadin®. Given as a first-line prescription, with 13 weeks' posology and the lack of rebound effects, Circadin® has the potential to improve quality of life in insomnia patients aged 55 years and older and avoid long-term use of hypnotics.

French consensus. Idiopathic hypersomnia: Investigations and follow-up.

Idiopathic hypersomnia is a rare, central hypersomnia, recently identified and to date of unknown physiopathology. It is characterised by a more or less permanent, excessive daytime sleepiness, associated with long and unrefreshing naps. Night-time sleep is of good quality, excessive in quantity, associated with sleep inertia in the subtype previously described as "with long sleep time". Diagnosis of idiopathic hypersomnia is complex due to the absence of a quantifiable biomarker, the heterogeneous symptoms, which overlap with the clinical picture of type 2 narcolepsy, and its variable evolution over time. Detailed evaluation enables other frequent causes of somnolence, such as depression or sleep deprivation, to be eliminated. Polysomnography and multiple sleep latency tests (MSLT) are essential to rule out other sleep pathologies and to objectify excessive daytime sleepiness. Sometimes the MSLT do not show excessive sleepiness, hence a continued sleep recording of at least 24hours is necessary to show prolonged sleep (>11h/24h). In this article, we propose recommendations for the work-up to be carried out during diagnosis and follow-up for patients suffering from idiopathic hypersomnia.

Association between reported sleep need and sleepiness at the wheel: comparative study on French highways between 1996 and 2011.

OBJECTIVE: To investigate the evolution over 15 years of sleep schedules, sleepiness at the wheel and driving risk among highway drivers. METHODS: Comparative survey including questions on usual sleep schedules and before the trip, sleepiness at the wheel, the Epworth sleepiness scale, Basic Nordic Sleep Questionnaire (BNSQ) and a travel questionnaire. RESULTS: 80% of drivers stopped by the highway patrol agreed to participate in both studies with a total of 3545 drivers in 2011 and 2196 drivers in 1996 interviewed. After standardisation based on sex, age and mean annual driving distance, drivers in 2011 reported shorter sleep time on week days (p<0.0001), and week-ends (p<0.0001) and shorter optimal sleep time (p<0.0001) compared to 1996 drivers. There were more drivers sleepy at the wheel in 2011 than in 1996 (p<0.0001) and 2.5 times more drivers in 2011 than in 1996 had an Epworth sleepiness score >15 indicating severe sleepiness. CONCLUSIONS: Even if drivers in 2011 reported good sleep hygiene prior to a highway journey, drivers have reduced their mean weekly sleep duration over 15 years and have a higher risk of sleepiness at the wheel. Sleep hygiene for automobile drivers remains an important concept to address.

Combined caffeine and bright light reduces dangerous driving in sleep-deprived healthy volunteers: a pilot cross-over randomised controlled trial.

AIM OF THE STUDY: To explore the effects of caffeine and bright light therapy on simulated nighttime driving in sleep-deprived healthy volunteers. PARTICIPANTS AND METHODS: Twelve male healthy volunteers aged 20 to 50 years participated in a randomized cross-over study of simulated nighttime driving at a sleep laboratory, followed by recovery sleep with polysomnography at home. The volunteers received variable combinations of caffeine 200mg (C+), caffeine placebo (C-), bright light 10,000 lux (L+), and bright light placebo<50 lux (L-), in four sessions (C+L+, C+L-, C-L+, C-L-), in random order with a wash-out period of 7 days. Treatments were given at 1 a.m. and testing was performed at 1:30 a.m., 3 a.m., 4 a.m., and 6 a.m. Lane drifting was the primary outcome measure. Other measures were reaction times, self-rated fatigue, sleepiness and recovery sleep. RESULTS: Without treatment, lane drifting increased throughout the night, and objective and subjective vigilance declined. Paired comparisons showed that lane drifting was significantly worse at 6 a.m. and at 4 a.m. than at 1:30 a.m. There was a global treatment effect on lane drifting. Lane drifting at 6 a.m. was significantly decreased with C+L+ compared to C-L-. CONCLUSIONS: Bright light therapy combined with caffeine administered at 1 a.m. decreased lane drifting by healthy volunteers during simulated nighttime driving.

Mood disorders, circadian rhythms, melatonin and melatonin agonists.

Recent advances in the understanding of circadian rhythms have led to an interest in the treatment of major depressive disorder with chronobiotic agents. Many tissues have autonomous circadian rhythms, which are orchestrated by the master clock, situated in the suprachiasmatic nucleus (SNC). Melatonin (N-acetyl-5-hydroxytryptamine) is secreted from the pineal gland during darkness. Melatonin acts mainly on MT1 and MT2 receptors, which are present in the SNC, regulating physiological and neuroendocrine functions, including circadian entrainment, referred to as the chronobiotic effet. Circadian rhythms has been shown to be either misaligned or phase shifted or decreased in amplitude in both acute episodes and relapse of major depressive disorder (MDD) and bipolar disorder. Manipulation of circadian rhythms either using physical treatments (such as high intensity light) or behavioral therapy has shown promise in improving symptoms. Pharmacotherapy using melatonin and pure melatonin receptor agonists, while improving sleep, has not been shown to improve symptoms of depression. A novel antidepressant, agomelatine, combines 5HT2c antagonist and melatonin agonist action, and has shown promise in both acute treatment of MDD and in preventing relapse.

Circadian rhythms, melatonin and depression.

The master biological clock situated in the suprachiasmatic nuclei of the anterior hypothalamus plays a vital role in orchestrating the circadian rhythms of multiple biological processes. Increasing evidence points to a role of the biological clock in the development of depression. In seasonal depression and in bipolar disorders it seems likely that the circadian system plays a vital role in the genesis of the disorder. For major unipolar depressive disorder (MDD) available data suggest a primary involvement of the circadian system but further and larger studies are necessary to conclude. Melatonin and melatonin agonists have chronobiotic effects, which mean that they can readjust the circadian system. Seasonal affective disorders and mood disturbances caused by circadian malfunction are theoretically treatable by manipulating the circadian system using chronobiotic drugs, chronotherapy or bright light therapy. In MDD, melatonin alone has no antidepressant action but novel melatoninergic compounds demonstrate antidepressant properties. Of these, the most advanced is the novel melatonin agonist agomelatine, which combines joint MT1 and MT2 agonism with 5-HT(2C) receptor antagonism. Adding a chronobiotic effect to the inhibition of 5-HT(2C) receptors may explain the rapid impact of agomelatine on depression, since studies showed that agomelatine had an early impact on sleep quality and alertness at awakening. Further studies are necessary in order to better characterize the effect of agomelatine and other novel melatoninergic drugs on the circadian system of MDD patients. In summary, antidepressants with intrinsic chronobiotic properties offer a novel approach to treatment of depression.

Effect of sleeping alone on sleep quality in female bed partners of snorers.

The aim of the present study was to objectively measure the effect of sleeping alone for one night on sleep quality in female bed partners of male snorers. Females complaining of poor sleep due to snoring by their bed partner and having no known hearing loss or snoring were included in a prospective multicentre cross-sectional study. 23 females underwent one polysomnography recording while sleeping with their bed partner and another while sleeping alone. Their sleep parameters were compared between the two nights. We excluded seven couples because the female partner snored for >10% of the sleep time (n = 6) or had obstructive sleep apnoea syndrome (n = 1). In the remaining 16 females, sleep time, sleep efficiency, arousal index and percentages of deep sleep (stages 3-4) and rapid eye movement (REM) sleep were not significantly different between the two nights. Percentages of light sleep (non-REM stage 2) and awakening index were lower when sleeping alone (p = 0.023 and p = 0.046, respectively). Sleep quality was decreased and sleep fragmentation increased in females sleeping with male snorers. Some females had unrecognised snoring. However, our data do not suggest that objective sleep quality improves substantially in the female nonsnoring partner when she sleeps alone for one night.

Is there a link between alertness and fatigue in patients with traumatic brain injury?

OBJECTIVES: Many patients with traumatic brain injury (TBI) report chronic fatigue, and previous studies showed a potential relationship between sleepiness and fatigue in these patients. Our study first looked at the impact of objective and subjective sleepiness on fatigue in patients with TBI. We then investigated how fatigue could affect driving performance in these patients. METHODS: Nocturnal polysomnography, the Fatigue Severity Scale (FSS), the Epworth Sleepiness Scale (ESS), and five 40-minute maintenance of wakefulness tests (MWT) were collected in 36 patients with TBI. Fitness to drive was assessed in a subsample of 22 patients compared to 22 matched controls during an hour simulated driving session. RESULTS: In patients with TBI, FSS, ESS, and mean MWT scores (+/-SD) were 27 +/- 10, 8 +/- 4, and 35 +/- 7 minutes vs 15 +/- 2.5, 5 +/- 3, and 37 +/- 5 minutes in controls. Patients with TBI reported more chronic fatigue (W = 99, p < 0.001) than controls, and, unlike in controls, the level of chronic fatigue was correlated to their MWT scores. Patients' driving performances were worse than the controls' (W = 79, p < 0.001). The best predictive factors of driving performance were fatigue scores and body mass index (multiple R = 0.458, 41.8% of explained variance). CONCLUSION: In patients with TBI, chronic fatigue is significantly related to subjective and objective levels of alertness, even though these levels are not highly pathologic. This might suggest that a small level of sleepiness (i.e., MWT scores between 33 and 39 minutes) worsens fatigue in these patients. Chronic fatigue and body mass index could predict driving simulator performance in patients with TBI.

Effect of intrathecal baclofen on sleep and respiratory function in patients with spasticity.

OBJECTIVE: To prospectively evaluate the effect of pump-infused intrathecal baclofen infusion (ITB) in therapeutic doses on sleep quality and on daytime and nighttime respiratory function in patients with severe spasticity. METHODS: We prospectively evaluated 20 consecutive patients (mean +/- SD age 45 +/- 13 years). We assessed spasticity and obtained polysomnography, pulmonary function tests, and resting energy expenditure measurements 1 week before and at least 8 days after pump implantation. Patients stopped oral baclofen upon pump implantation but continued other medications unchanged. We report descriptive statistics as means +/- SD. RESULTS: Most of the patients had multiple sclerosis (n = 9) or spinal cord injury (n = 8); there was one case each of cerebral palsy, hereditary spastic paraplegia, and Friedreich ataxia. Before and after ITB initiation, mean Ashworth scores were 2.75 +/- 0.85 and 1.15 +/- 0.36, and mean spasm scores were 3.75 +/- 0.55 and 1.00 +/- 0.56. ITB improved total sleep time (p = 0.05) and sleep efficiency (p = 0.01) and reduced periodic leg movements (p = 0.02). ITB did not modify sleep-related respiratory events, lung function tests, CO2 rebreathing response, or resting energy expenditure. CONCLUSION: Compared with oral baclofen, intrathecal baclofen infusion did not affect respiratory function and improved sleep continuity. Intrathecal baclofen infusion in therapeutic doses may act at the spinal level rather than at the supraspinal level.

[Study of the real situation of improvement by Zopiclone in treatment of insomnia among persons working during night shifts]. / Etude en situation réelle de l'amélioration par la Zopiclone des insomnies chez les personnes travaillant en équipes de nuit.

UNLABELLED: We investigated the effect of adapted management of sleep on the duration and quality of sleep in shift workers working the night shift. Twenty-nine shift workers suffering from insomnia were included and treated with zopiclone (7.5mg/day) or placebo according to a random double-blind protocol. Patients completed a sleep diary and a wrist actigraph was used to evaluate episodes of rest/activity. A self-administered subjective sleep questionnaire was filled out just after awakening. Zopicone was found to increase the duration of sleep significantly (p<0.05) over the baseline duration after the first and second night on duty. Subjective estimation of sleep was better in patients taking zopiclone who exhibited a smaller number of shorter awakening episodes. IN CONCLUSION: zopiclone improves the quality and duration of sleep in shift workers suffering from insomnia.

Utility of actigraphy in the diagnosis of obstructive sleep apnea.

STUDY OBJECTIVES: To determine whether adding actimetry to simplified polygraphy (respiratory-parameter monitoring without neurophysiologic variable recording) improves apnea-hypopnea index (AHI) evaluation as compared to simplified polygraphy alone. DESIGN: Comparison of AHI values obtained by all-night polysomnography and by simplified polygraphy with and without actimetry. SETTING: A teaching-hospital sleep laboratory in Garches, France. PATIENTS: 20 adults with suspected obstructive sleep apnea syndrome (OSAS). MEASUREMENTS AND RESULTS: Data were analyzed by two scorers working independently. AHI was calculated as the number of apneas and hypopneas per hour of sleep time (polysomnography: AHI-pg), per hour of time in bed (simplified polygraphy: AHI-tib), and per hour of actimetry-estimated total sleep time (AHI-act). AHI-pg showed that 12 patients had OSAS (AHI>10), which was severe (AHI > or =30) in eight. AHI-act was more closely correlated to AHI-pg (r=0.976) than was AHI-tib (r=0.940). According to the Bland and Altman method, AHI-tib underestimated the AHI in two patients and AHI-act overestimated the AHI in one patient. For the diagnosis of severe OSAS, sensitivity and negative predictive value were 50% and 75% with AHI-tib as compared to 88% and 92.5% with AHI-act. CONCLUSIONS: Actimetry, when added to simplified polygraphy, may assist in the diagnosis of OSAS.

Snoring detection during auto-nasal continuous positive airway pressure.

A bench study using an artificial lung model was performed to evaluate the snoring detection sensitivity of six (commercially available) auto-nasal continuous positive airway pressure (NCPAP) devices. Snoring was simulated by a loudspeaker connected to the lung model and abruptly activated during 1 s of each inspiratory period to induce pressure oscillation. The oscillation frequencies chosen were 30, 60, 90, and 120 Hz. For each frequency, the amplitude of the pressure oscillation produced by the loudspeaker was adjusted to find the threshold at which the auto-nCPAP devices detected snoring. Differences in pressure-amplitude thresholds of up to three-fold were found across auto-nCPAP devices. A randomized clinical study to compare the effects of the least sensitive (Virtuoso LX; Respironics, Nantes, France) and one of the most sensitive, (Goodknight 418A; Malinckrodt, Nancy, France) devices, in two groups of six patients with obstructive sleep apnoea syndrome was then conducted. Goodknight 418A was more sensitive than Virtuoso LX for detecting snoring (mean +/- SD 92 +/- 11% versus 50 +/- 39% respectively, p = 0.03). To conclude, striking differences exist between auto-nasal continuous positive airway pressure devices in sensitivity for detecting snoring.

A cross-sectional study of the health effects of work schedules on 3212 hospital workers in France: implications for the new French work schedules policy.

This study was designed to investigate the effects of work schedules on the health of hospital workers at the Assistance Publique-Hôpitaux de Paris (AP-HP). Out of 40 hospitals, 17 volunteered to participate in this study. The Standard Shiftwork Index and a questionnaire concerning physicians' work schedules were used. Ten thousand questionnaires were distributed anonymously to hospital workers between March and April 1999. Professional categories comprised head nurses, nurses, nursing auxiliaries, hospital agents, midwives and full time physicians. Departments included internal and geriatric medicine, general paediatrics, orthopaedic and general surgery, operating and emergency rooms, and anaesthesiology and intensive care units. 3250 questionnaires were returned. Demographics for the respondents were: 79.2% female, average age 38.1 +/- 9.1 years old. Eleven work schedules were identified. One fourth of the personnel had fixed morning work schedules. The highest level of job satisfaction was found in personnel working in paediatrics while dissatisfaction was strongest in the gerontology and, emergency room personnel. General Health Questionnaire (GHQ) scores were high for head nurses, operating room nurses and junior doctors as well as for personnel with rotating and flexible shifts. This study will be used to make recommendations concerning the reduction of working time for French hospital workers.

[Delayed wakefulness-sleep rhythm syndrome and melatonin. Synthesis of existing studies]. / Syndrome de retard de phase du rythme veille-sommeil et mélatonine. Synthèse des études existantes.

Delayed sleep phase syndrome involves undesirable late bed times and arising times with extreme difficulties in falling asleep and in awakening at a desired clock time. These patients present a delayed circadian system. Chronotherapy and phototherapy are designed to have a training effect on the circadian system. Response to these treatments varies widely and depends on the patient's motivation and associated psychological disorders. Other treatments have been proposed with less evident results. The few studies testing the effect of melatonin in delayed sleep phase syndrome concern a small number of patients and present methodological drawbacks. It can be concluded from these studies however that exogenous melatonin influences endogenous secretion more than other secretion rhythms. The effect on sleep time is significant but clinically moderate. More studies are needed to examine the effect of exogenous melatonin as a treatment strategy in delayed sleep phase syndrome.

[Disorders of wakefulness and sleep in blind patients]. / Troubles de la veille et du sommeil chez l'aveugle.

The goal of this paper was to summarize three studies focused on sleep/wake disorders in blind subjects. The first study was an epidemiology survey performed in 1073 blind subjects in comparison with non-blind controls. The blind had more episodes of insomnia and free running rhythms. They also took more sleeping pills and complained of more daytime somnolence. The seriousness of the sleep disorders was related to the seriousness of the blindness. In the second study, 78 blind children were compared with seeing children. They had more insomnia and more parasomnias but there was not any more free running. Finally, polysomnography was performed in 26 free running blind subjects in comparison with 26 controls. Total sleep time and sleep efficiency were lower in the blind. Sleep latency was increased and REM sleep was disturbed (longer latency and percentage decreases). There was no difference concerning slow wave sleep. Factorial analysis showed that factors such as being born blind, having ocular prosthesis, being single or having children had no influence on sleep. Working did however have an influence.

[Respiratory disorders during sleep and myasthenia]. / Troubles respiratoires pendant le sommeil et myasthénie.

A sleep apnea syndrome is described by several studies in patients with myasthenia gravis. Apnea and hypopnea are mainly not obstructive and occur predominantly in rapid eye movement (REM) sleep. They are associated with oxygen desaturation. Although the sleep apnea index is not correlated with myasthenia gravis severity, it becomes less important as myasthenia gravis improves. Risk factors for the development of sleep apnea in myasthenia gravis patients are age, restrictive pulmonary syndrome, diaphragmatic weakness and daytime alveolar hypoventilation. Sleep apnea are not related to a central cholinergic effect in myasthenia gravis caused either by anticholinesterase used to treat myasthenia gravis or by antibodies to muscle acetylcholine receptors. Indeed acetylcholine receptors in brain are antigenically distinct from acetylcholine receptors in skeletal muscle. Sleep apneas are more likely caused by peripheral mechanisms. Correlation between sleep apnea and total lung capacity as well as the importance of diaphragmatic weakness in myasthenic patients may explain their predominance in REM sleep and their reduction with clinical improvement in the myasthenia gravis.