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Patients with obstructive sleep apnea/hypopnea syndrome can experience residual daytime sleepiness despite regular use of nasal continuous positive airway pressure therapy. This randomized, double-blind, placebo-controlled, parallel group study assessed the efficacy and safety of modafinil for the treatment of residual daytime sleepiness in such patients. Patients received modafinil (n = 77) (200 mg/d, Week 1; 400 mg/d, Weeks 2 to 4) or matching placebo (n = 80) once daily for 4 wk. Modafinil significantly improved daytime sleepiness, with significantly greater mean changes from baseline in Epworth Sleepiness Scale scores at Weeks 1 and 4 (p0.001) and in multiple sleep latency times (MSLT) at Week 4 (p0.05). The percentage of patients with normalized daytime sleepiness (Epworth score10) was significantly higher with modafinil (51%) than with placebo (27%) (p0.01), but not for MSLT (10 min; 29% versus 25%). Headache (modafinil, 23%; placebo, 11%; p = 0.044) and nervousness (modafinil, 12%; placebo, 3%; p = 0.024) were the most common adverse events. During modafinil or placebo treatment, the mean duration of nCPAP use was 6.2 h/night, with no significant change from baseline observed between groups. Modafinil may be a useful adjunct treatment for the management of residual daytime sleepiness in patients with obstructive sleep apnea/hypopnea syndrome who are regular users of nasal continuous positive airway pressure therapy.

Excessive daytime sleepiness (EDS) is a common and debilitating symptom of narcolepsy and other sleep disorders. Modafinil is a novel stimulant which effectively treats EDS, yet lacks many of the undesirable side-effects commonly encountered with currently available compounds. The specific mode of action of modafinil is not well understood, but it may promote sleep by indirectly influencing adrenergic or GABAergic neurotransmission. Modafinil-induced wakefulness is not associated with rebound hypersomnolence or the potential for abuse as is often encountered with other stimulants such as amphetamines. At typical therapeutic doses, modafinil may produce dry mouth but generally has a low incidence of minor side-effects. Many preclinical and clinical studies have demonstrated the effectiveness of modafinil in promoting wakefulness and vigilance in normal subjects and in those with EDS. Modafinil significantly improves the EDS of narcolepsy and also may improve the EDS of idiopathic hypersomnia and obstructive sleep apnoea. Modafinil's low prevalence of side-effects, minimal potential for abuse, and lack of rebound hypersomnia indicate that it has potential to become a widely prescribed drug for the treatment of narcolepsy.

Background and Objective: Laser-assisted uvulopalatoplasty (LAUP) is being used increasingly as a surgical treatment for snoring and obstructive sleep apnea (OSA). There is limited evidence for the success of LAUP in eliminating OSA. This study assesses the efficacy of LAUP in eliminating snoring and OSA and addresses which patients may be the best candidates for LAUP treatment. Study Design/Materials and Methods: From January 1994 to January 1996, 297 patients were evaluated for snoring, with 190 (64%) exhibiting some degree of OSA documented by a PSG: 41/ 190 (22%) mild OSA; 33/190 (17%) moderate OSA; 85/190 (45%) severe OSA; 31/190 (16%) severity unknown. Ninety patients (90/ 297) have undergone LAUP treatment: 58/90 (64%) with OSA and 32/90 (36%) with snoring only. Results: Our results indicate a significant reduction of snoring in patients without OSA, but diminishing success in patients with increasing degrees of OSA. Additionally, LAUP was not efficacious in treating OSA: pre-op respiratory disturbance index (RDI) of 10.8 vs. post-op RDI of 19.5 for mild OSA (P = 0.14); pre-op RDI of 22.9 vs. post-op RDI of 25.4 for moderate OSA (P = 0.43); pre-op RDI of 56.8 vs. post-op RDI of 46.3 (P < 0.05), which is statistically but not clinically significant (i.e., RDI remained in the severe range). Conclusion: We conclude that LAUP is an effective treatment for nonapneic snoring, but does not provide sufficient resolution of OSA, and based on our results, LAUP should be considered as an adjunctive therapy rather than a sole treatment for OSA in most cases.

We previously observed tht low oral doses of melatonin given at noon increase blood melatonin concentrations to those normally occurring nocturnally and facilitate sleep onset, as assessed using and involuntary muscle relaxation test. In this study we examined the induction of polysomnographically recorded sleep by similar doses given later in the evening, close to the times of endogenous melatonin release and habitual sleep onset. Volunteers received the hormone (oral doses of 0.3 or 1.0 mg) or placebo at 6, 8, or 9 PM. Latencies to sleep onset, to stage 2 sleep, and to rapid eye movement (REM) sleep were measured polysomnographically. Either dose given at any of the three time points decreased sleep onset latency and latency to stage 2 sleep. Melatonin did not suppress REM sleep or delay its onset. Most volunteers could clearly distinguish between the effects of melatonin and those of placebo when the hormone was tested at 6 or 8 PM. Neither melatonin dose induced "hangover" effects, as assessed with mood and performance tests administered on the morning after treatment. These data provide new evidence that nocturnal melatonin secretion may be involved in physiologic sleep onset and that exogenous melatonin may be useful in treating insomnia.

A recent publication suggested that hypocretin (Hcrt, orexin) may mediate the neuropathological process leading to Alzheimer's disease (AD) and that antagonism of hypocretin receptors decreases this process. Narcoleptics have an approximately 90% loss of Hcrt neurons and commensurate reductions in the levels of Hcrt in their cerebrospinal fluid beginning at disease onset, usually before the age of 30. If Hcrt mediates the disease process, narcoleptics should be protected against AD. We examined the postmortem neuropathology and clinical records of 12 sequentially encountered cases of human narcolepsy. We found that AD was present in 4 of these narcoleptics, a prevalence that is similar to that of the general population.

The classification of sleep disorders is based both on clinical and neurophysiological criteria and is undergoing constant refinement. Sleep disorders can be caused by either a primary disorder of a mechanism controlling sleep or inadequate function of an end organ, such as the upper airways and lungs. Understanding the physiology and pattern of normal sleep is an important foundation for interpreting the clinical symptoms, signs, and neurophysiological abnormalities observed in patients with sleep disorders. The term polysomnography refers to the simultaneous recording of multiple sleep parameters, including a limited electroencephalogram, respiratory parameters, chest excursion, limb movements, and the electrocardiogram. Polysomnography is important for assessing a variety of sleep disturbances, including disorders such as sleep-related breathing disorders (including obstructive sleep apnea), rapid eye movement behavior disorder, and periodic movements of sleep. The multiple sleep latency test and maintenance of wakefulness test are studies that are especially useful in the evaluation of narcolepsy and other hypersomnias.

Sleep is an active, clinically important behavior that is associated with important physiologic changes in most organ systems. These changes have a temporal organization that is under cerebral influence. Sleep disorders may represent a primary disorder of mechanisms regulating sleep or failure of a specific organ system manifesting in a unique way during sleep. Sleep complaints should not be ignored or treated empirically with pharmacologic agents. More often than not, disordered sleep is a symptom of underlying disease.

Interleukin-2 is an effective agent against renal cell carcinoma and melanoma, but it has been associated with autoimmune sequelae such as hypothyroidism and vitiligo. A 64-year-old man with non-insulin-dependent diabetes and metastatic renal cell carcinoma developed insulin-dependent diabetes after his first cycle of therapy with high-dose (HD) interleukin-2. After additional therapy with interleukin-2, the patient developed generalized myasthenia gravis (MG) and polymyositis, both of which responded to treatment with corticosteroids and plasmapheresis. To investigate the role of IL-2 in the development of these autoimmune complications, autoantibody titers were assayed from serum obtained before and after IL-2 treatment and after treatment with corticosteroids plus plasmapheresis. Before IL-2 treatment, the patient had antibodies directed against insulin, islet cell antigens, and striated muscle. Acetylcholine receptor antibody levels were normal before starting IL-2. After treatment with IL-2, the patient developed acetylcholine receptor binding antibodies and exhibited an increase in the striated muscle antibody titer from 1:40 to 1:160. Recovery from the MG and polymyositis was associated with substantial decreases in the acetylcholine receptor and striated muscle antibody titers. These findings suggest that HD IL-2 accelerated the progression of latent autoimmune diabetes and myositis in this patient whose tolerance to islet cell antigens and striated muscle had already been broken and precipitated a break in tolerance to the acetylcholine receptor resulting in the development of MG. This case demonstrates the importance of prompt recognition of IL-2-induced MG and shows how this complication can be successfully managed with aggressive therapy.

The neuroexcitatory peptide hypocretin and its receptors are central to the pathophysiology of both human and animal models of the disease. In this study of American and Icelandic patients with narcolepsy, the authors found no significant association between narcolepsy and single-nucleotide polymorphisms in the genes for hypocretin or its two known receptors, hypocretin receptor-1 and hypocretin receptor-2.

A quiet magnetic resonance (MR) imaging technique for detecting changes in cerebral activity functions is presented. This single-shot method, functional Burst imaging (FBI), combines elements of Burst imaging with an offset technique known as asymmetric spin echo (ASE). The FBI sequence has the unique feature of being nearly silent, because of the low number of gradient switching steps involved. Furthermore, this approach has the key advantage that it can be implemented on conventional MR systems. Established auditory and visual paradigms were used to evaluate whether FBI can detect changes in cerebral activity using a 1.5 Tesla MR system. In a second set of experiments, the FBI technique was used to evaluate cerebral activity changes during different sleep stages in humans. The results obtained demonstrate that the FBI sequence provides an alternative approach for functional imaging of brain activity in primary and secondary sensory areas of the human brain. Furthermore, in using this quiet MR technique, it was possible to scan continuously during different stages of human sleep without acoustic noise perturbation.

Sleep latency changes following behavioral interventions for sleep-onset insomnia are only moderate because the majority of insomniacs do not achieve good sleeper status at posttreatment. This study evaluated the efficacy of a multifactor behavioral intervention consisting of stimulus control and relaxation-response training (n = 10) compared to stimulus control alone (n = 10) for sleep-onset insomnia. Only the multifactor subjects' mean posttest sleep latency fell within the good sleeper range. They also exhibited a 77% improvement on mean sleep-onset latency compared to the stimulus control group (63%). Thus a multifactor intervention may be more effective than stimulus control alone for treatment of sleep-onset insomnia.

• Thirty-two patients with amyotrophic lateral sclerosis were studied with somatosensory evoked potentials (SEPs), visual evoked potentials, and brain-stem auditory evoked potentials. H-reflexes were used to screen for abnormalities of peripheral nerve conduction. Nineteen patients (59%) showed an abnormality of lower extremity SEPs. In 13 patients (40%) the delay was of central origin, while in six patients (19%) peripheral conduction delay was possible. Abnormality of upper limb SEPs was seen in 11 patients (34%), all but two of whom had abnormal lower limb SEPs as well. Four patients (12%) had abnormal brain-stem auditory evoked potentials, all of whom had abnormal SEPs from upper and lower limbs. Four patients had abnormal visual evoked potentials, which in three patients were of minor degree. These results give physiologic evidence to suggest that abnormalities in amyotrophic lateral sclerosis occur outside the motor system.

Patients with cerebellar deficits made elbow flexion movements as rapidly as possible for three different angular distances. Electromyographic activity of biceps and triceps and the kinematics of the movements were analysed. Results were compared with those of normal subjects making both rapid and slow movements. In the patients, the first agonist burst of the biceps was frequently prolonged regardless of the distance or speed of the movement. The most striking kinematic abnormality was prolonged acceleration time. The pattern of acceleration time exceeding deceleration time was common in patients but uncommon in normal subjects. The best kinematic correlate of the duration of the first agonist burst was acceleration time. Altered production of appropriate acceleration may therefore be an important abnormality in cerebellar dysfunction for attempted rapid voluntary movements.