The neurobiology of narcolepsy.

Narcolepsy is characterized by excessive sleepiness and abnormal manifestations of rapid eye movement (REM) sleep. Neurochemical studies of human and canine narcolepsy have demonstrated disturbed monoaminergic and cholinergic function and suggest that deficits of noradrenaline availability in specific brain regions may account for much of its disordered pathophysiology. Genetic susceptibility to narcolepsy is closely linked to a specific region of the major histocompatibility complex on chromosome 6 and an important direction for future research will be to unravel the relationship between this gene region and the neurochemical abnormalities of narcolepsy.

Are morning headaches part of obstructive sleep apnea syndrome?

To determine whether morning headaches are a consistent symptom in sleep apnea, we reviewed clinical and polysomnographic data of 304 patients with sleep apnea and compared the findings with normal control subjects and with three other groups of patients seen at a sleep disorders center. Eighteen percent of patients with sleep apnea had frequent morning headaches compared with 21% to 38% in the other groups of patients and 6% of control subjects. In patients with sleep apnea, morning headaches were most common in those with mild predominantly nonobstructive apnea. Polysomnographic characteristics of patients with moderate to severe sleep apnea did not significantly differ between patients with frequent headaches and those without such headaches. Frequent morning headaches are a nonspecific symptom in patients with sleep disorders and are not a consistent or reliable symptom of sleep apnea syndrome.

The effect of diazepam sedation on cerebral glucose metabolism in Alzheimer's disease as measured using positron emission tomography.

The effect of sedation induced by intravenous diazepam on cerebral glucose metabolic activity was examined with [18F]2-fluoro-2-deoxy-D-glucose (FDG) and positron emission tomography (PET) in five patients with probable Alzheimer's disease. Each subject was studied on 2 separate days: on one occasion at rest with eyes patched and ears open, and on the second when sedated with intravenous diazepam titrated to maintain stage II sleep by clinical and EEG criteria. Similar patterns of glucose uptake were observed in both the presence and the absence of sedation, but overall glucose utilization was depressed an average of 20% and was closely correlated with the amount of diazepam administered prior to the injection of FDG. The predominant temporoparietal hypometabolism and relative sparing of frontal metabolism observed in this disease are therefore not explained by differences in anxiety or activity level in this patient group. Utilization of diazepam sedation for PET study appears to be safe and may permit the study of patients otherwise unable to cooperate with FDG-PET procedures.

Insomnia, self-medication, and relapse to alcoholism.

OBJECTIVE: This study was an investigation of the frequencies of insomnia and its self-medication with alcohol in a group of alcoholic patients, as well as the relationship of these variables to alcoholic relapse. METHOD: The subjects were 172 men and women receiving treatment for alcohol dependence. They completed a sleep questionnaire, measures of alcohol problem severity and depression severity, and polysomnography after at least 2 weeks of abstinence. RESULTS: On the basis of eight items from the Sleep Disorders Questionnaire, 61% of the subjects were classified as having symptomatic insomnia during the 6 months before treatment entry. Compared to patients without insomnia, patients with insomnia were more likely to report frequent alcohol use for sleep (55% versus 28%), had significantly worse polysomnographic measures of sleep continuity, and had more severe alcohol dependence and depression. Among 74 alcoholics who were followed a mean of 5 months after treatment, 60% with baseline insomnia versus 30% without baseline insomnia relapsed to any use of alcohol, a significant difference. Insomnia remained a robust predictor of relapse after application of logistic regression analysis to control for other variables. A history of self-medicating insomnia with alcohol did not significantly predict subsequent relapse. CONCLUSIONS: The majority of alcoholic patients entering treatment reported insomnia symptoms. Given the potential link between insomnia and relapse, routine questions about sleep in clinical and research settings are warranted.

Intracerebral hemorrhage complicating intravenous tissue plasminogen activator treatment.

Tissue plasminogen activator's thrombolytic action is relatively specific for fibrin; however, systemic bleeding can occur in patients, especially when heparin is simultaneously administered. We describe two cases of intracerebral hemorrhage from a cohort of 450 patients (0.44%) treated at one institution with tissue plasminogen activator and heparin for acute myocardial infarction. A pooled worldwide review of 5258 cases from several clinical protocols for treatment of acute myocardial infarction, using tissue plasminogen activator from one source, revealed a similar overall incidence of 0.68%. The incidence of intracerebral hemorrhage may be reduced by lowering the total dose of tissue plasminogen activator or by reducing the infusion rate and duration. The incidence of central nervous system hemorrhage with tissue plasminogen activator is within the range reported with streptokinase, but because equal coronary artery thrombolytic doses are not known, no definitive comparison is possible.

Narcolepsy.

Narcolepsy is a chronic neurologic disorder characterized by excessive daytime sleepiness, cataplexy, and premature onset of rapid eye movement sleep. It can be differentiated from other disorders causing daytime drowsiness by its clinical symptoms and by sleep laboratory studies. The disorder usually begins in adolescence and remains present throughout life. Genetic susceptibility to narcolepsy is closely associated with specific HLAs that indicate the existence of a gene in the region of the major histocompatibility complex on chromosome 6 that increases susceptibility to narcolepsy. Neurochemical studies of human and canine narcolepsy have demonstrated disturbed monoaminergic and cholinergic function that may account for impaired regulation of rapid eye movement sleep, but the link between these abnormalities and the genetic factors is still unknown. Treatment of sleepiness with stimulants and cataplexy with tricyclic antidepressants leads to substantial improvement but does not fully resolve symptoms in most patients.

Diagnostic aspects of narcolepsy.

The diagnostic criteria for narcolepsy continue to evolve as more is learned about the features of this and other sleep disorders. A variety of symptoms have been said to distinguish narcolepsy from other sleep disorders, including cataplexy, character of daytime sleepiness, sleep paralysis, hypnagogic hallucinations, and automatic behavior. Other diagnostic assessments, such as determination of human leukocyte antigen (HLA) haplotype and findings of sleep laboratory assessments, also contribute to the differential diagnosis. As diagnostic and analytic techniques have become more sophisticated, however, it has become apparent that many of the characteristic features of narcolepsy--including the HLA-DR2 haplotype, sleep-onset REM sleep, and short sleep latency--may also be present in other sleep disorders. Although unambiguous cataplexy does not occur with other sleep disorders and is therefore a valuable symptom for diagnosis, it may occur with a few other neurologic disorders. Furthermore, the clinical assessment of cataplexy-like symptoms is not always straightforward. Current evidence suggests there is a fairly well-defined syndrome of narcolepsy-cataplexy that is highly associated with specific HLA markers and REM sleep abnormalities. On the other hand, there is substantial clinical overlap between narcolepsy without cataplexy and idiopathic hypersomnia. Patients with features of narcolepsy who do not have definite cataplexy and patients with features of idiopathic hypersomnia must be assessed thoroughly because of the possibility that other sleep disorders are the cause of the symptoms.

The clinical spectrum of narcolepsy and idiopathic hypersomnia.

To better define the clinical spectra of narcolepsy and idiopathic hypersomnia, we retrospectively compared clinical and polygraphic findings and questionnaire results in groups of subjects with narcolepsy with or without cataplexy, idiopathic hypersomnia, insufficient sleep syndrome, mild sleep apnea, and excessive daytime sleepiness not otherwise specified. Sleep paralysis and sleep-related hallucinations were most frequent in narcolepsy-cataplexy, but their frequency did not differ between narcolepsy without cataplexy and idiopathic hypersomnia. Mean durations of nocturnal sleep, daytime naps, and morning grogginess were not increased in idiopathic hypersomnia compared with other groups. Among subjects without cataplexy, symptoms of sleep paralysis and sleep-related hallucinations were equally common in subjects with and without frequent sleep-onset REM periods. These findings suggest that the occurrence of these symptoms in subjects without classical narcolepsy-cataplexy is a function of factors other than a propensity for early onset of REM sleep and indicate a need to reevaluate diagnostic criteria for narcolepsy and idiopathic hypersomnia.

Narcolepsy associated with lesions of the diencephalon.

Although symptomatic narcolepsy, or narcolepsy due to identifiable brain lesions, was once thought to be common, there are few well-documented reported cases since the discovery of the association of REM sleep abnormalities with narcolepsy. Even fewer such reports have been accompanied by human leukocyte antigen (HLA) testing. We report 3 patients who fulfill criteria for symptomatic narcolepsy, 1 with a craniopharyngioma, the 2nd with a hypothalamic syndrome of unknown etiology, and the 3rd with obstructive hydrocephalus and a sarcoid granuloma in the region of the 3rd ventricle. The first 2 were positive for HLA-DR2 while the 3rd was negative for the HLA-DR2 and HLA-DQwl antigens. These findings suggest that diencephalic lesions can be associated with signs and symptoms of narcolepsy that are clinically indistinguishable from those of idiopathic narcolepsy, and that the HLA-DR2 antigen is not required in all cases of symptomatic narcolepsy.

Diagnostic value of video-EEG polysomnography.

To investigate the diagnostic value of video-EEG polysomnography (VPSG), we reviewed our experience in 122 patients with suspected parasomnias who underwent one or two nights of VPSG. Of 86 patients without known epilepsy, VPSG provided useful diagnostic information for 41 (69%) of those with a history of prominent motor activity during sleep and for 11 (41%) of those with a history of minor motor activity during sleep. Two children and one adult with clinical histories suggestive of sleep terrors had unequivocal partial seizures during VPSG. Of 36 patients with known epilepsy, VPSG was useful diagnostically in 28 (78%). VPSG is superior to standard polysomnography for the evaluation of parasomnias because of the increased capability to identify and localize EEG abnormalities and to correlate behavior with EEG and polysomnography. VPSG may also be a suitable alternative to intensive inpatient monitoring for some patients with known or suspected epilepsy who have frequent undiagnosed nocturnal spells.

The Epworth Sleepiness Scale may not reflect objective measures of sleepiness or sleep apnea.

OBJECTIVE: To assess the validity of the Epworth Sleepiness Scale score (ES) as a measure of sleepiness among patients suspected or confirmed to have obstructive sleep apnea syndrome. BACKGROUND: The ES is used with increasing frequency as a measure of excessive daytime sleepiness in part because several studies suggested that the ES correlates with mean sleep latency (MSL) on the Multiple Sleep Latency Test and with severity of sleep apnea among patients with that disorder. However, associations identified between the ES and other measures were not strong or consistent. METHODS: The authors used regression models and retrospective data from a relatively large series of 237 patients to restudy how ES relates to MSL, to a simple self-rating of problem sleepiness (available for 141 patients), and to two polysomnographic measures of sleep apnea severity: the number of apneas or hypopneas per hour of sleep and the minimum recorded oxygen saturation. RESULTS: The ES had a statistically significant association with self-rated problem sleepiness but not with MSL or measures of sleep apnea severity. Male gender, adjusted for potential confounding variables, had considerably more influence on the ES than did MSL or measures of sleep apnea severity. CONCLUSIONS: Our data suggest that the subjectively derived ES cannot be used as a surrogate for the objectively determined MSL.

Dopamine-receptor autoradiography of human narcoleptic brain.

Although the pathology of human narcolepsy is unknown, studies of human and canine narcolepsy have suggested that dopamine metabolism may be disturbed. We used quantitative autoradiography to assess dopamine D1- and D2-receptor binding in basal ganglia and amygdala of five narcoleptic and 17 control human brains. In caudate, narcoleptic brains had a statistically significant increase of 57% in D1-receptor binding, and large but not significant increases of 54% in medial globus pallidus D1 binding, 63% in caudate D2-receptor binding, 95% in lateral globus pallidus D2 binding, and 93% in lateral amygdala D2 binding. We found no major changes in the putamen or in the basal or accessory basal nuclei of the amygdala. These results suggest that narcolepsy is associated with upregulation of dopamine receptors in specific areas of the brain, although medications used prior to death may have contributed to the findings.

Familial recurrent Bell's palsy with ocular motor palsies.

We studied a family in which the father and 7 of 10 children had episodes of Bell's palsy. Five of the eight affected family members also had ocular motor palsies. Facial nerve and blink reflex studies in four affected siblings demonstrated asymmetrically reduced amplitude of evoked responses without delayed conduction. EMG revealed signs of chronic denervation and reinnervation in all four patients; two had synkinesis. Three siblings had diabetes mellitus, but with no clinically evident polyneuropathy.

Sleep apnea in patients with transient ischemic attack and stroke: a prospective study of 59 patients.

Although sleep apnea (SA) appears to be a cardiovascular risk factor, little is known about its frequency in patients with transient ischemic attack (TIA) and stroke. We prospectively studied 59 subjects (26 women and 33 men; mean age, 62 years) with stroke (n = 36) or TIA (n = 23) with the use of a standard protocol that included assessment of snoring and daytime sleepiness (Epworth Sleepiness Score [ESS]), a validated SA score (Sleep Disorders Questionnaire [SDQ-SA]), and a severity of stroke score (Scandinavian Stroke Scale [SSS]). SA was considered clinically probable (P-SA) when habitual snoring was associated with an ESS of > 10 or when SDQ-SA score was > or = 32 in women and > or = 36 in men. Polysomnography (PSG) was obtained in 36 subjects (group 1) a mean of 12 days after TIA or stroke. In 23 subjects (group 2), PSG was not available (n = 11), refused (n = 10), or inadequate (n = 2). Clinical and PSG data were compared with those obtained in 19 age- and gender-matched control subjects. Groups 1 and 2 were similar in mean age (61 versus 64 years), type of event (36% versus 44% TIA), reported habitual snoring (58% versus 52%), and P-SA (58% versus 50%). PSG showed SA (Apnea-Hypopnea Index [AHI], > or = 10) in 25 of 36 subjects (69%). The proportion of subjects with SA was similar in the TIA and stroke groups (69% versus 70%) and was well above the frequency found in our control group (15%). An AHI of > or = 20 and a minimal oxygen saturation of < 85% were each found in 20 of 36 subjects (55%). Gender and age did not correlate with severity of SA. Subjects with habitual snoring, P-SA, or severe stroke (SSS of < 30) had a significantly higher AHI (p < 0.05). The sensitivity of P-SA for SA was 64%, and the specificity was 67%. We conclude that SA has a high frequency in patients in the acute phase of TIA and stroke and SA cannot be predicted reliably on clinical grounds alone but is more likely in patients with habitual snoring, abnormal SDQ-SA, or severe stroke.

Usefulness of polysomnography in epilepsy patients.

We reviewed the records of 63 adult epilepsy patients who underwent polysomnograms in our laboratory since 1985 to determine the indications for polysomnography and the results of testing. Reasons for referral included excessive daytime sleepiness, suspected obstructive sleep apnea (OSA), and characterization of nocturnal spells. The most common polysomnographic diagnosis was OSA, although we also found narcolepsy, insufficient sleep syndrome with possible idiopathic hypersomnolence, and previously unrecognized nocturnal seizures. We treated OSA with continuous positive airway pressure in 28 patients, 15 of whom were using the device at follow-up appointments. The majority of patients treated for OSA or other disorders reported an improvement in sleepiness or seizure control. Polysomnography, when indicated, is beneficial in epilepsy patients.

Failure of cholinergic agonist RS-86 to improve cognition and movement in PSP despite effects on sleep.

Postmortem studies of patients with progressive supranuclear palsy (PSP) have demonstrated loss of cholinergic neurons in the striatum, nucleus basalis of Meynert, and the pedunculopontine nucleus. These findings suggest that cholinergic drugs might be an effective treatment for this disease. We studied the efficacy of RS-86, a direct cholinergic agonist, upon motor abilities, eye movements, and psychometric performance in 10 patients with PSP during a 9-week placebo-controlled, double-blinded, crossover trial. Glycopyrrolate, a peripheral anticholinergic drug, was given throughout the trial to minimize cholinergic side effects. We used changes in rapid eye movement (REM) sleep to assess the degree of cholinergic activation achieved by treatment. Despite the enhancement of cholinergic activity in the CNS as indicated by increases in REM sleep latency and REM sleep time, RS-86 did not improve motor signs, eye movements, or cognition. Pharmacologic replacement of the cholinergic deficits in PSP does not result in significant clinical benefit.

Decreased striatal dopaminergic innervation in REM sleep behavior disorder.

REM sleep behavior disorder (RBD) is a possible herald of neurodegenerative disorders with parkinsonism. The authors determined the density of striatal dopaminergic terminals with [11C]dihydrotetrabenazine PET in six elderly subjects with chronic idiopathic RBD and 19 age-appropriate controls. In subjects with RBD, there were significant reductions in striatal [11C]dihydrotetrabenazine binding, particularly in the posterior putamen.

Automobile accidents in patients with sleep disorders.

Sleep-related motor vehicle accidents are a serious safety hazard both for the driver who falls asleep and for others on the road. Sleep disorders may be significant contributing factor in some of these accidents. We reviewed data on sleep-related accidents from 70 control subjects and 424 adults with four categories of sleep disorders: sleep apnea, narcolepsy, other disorders of excessive sleepiness, and sleep disorders without excessive sleepiness. The proportion of individuals with sleep-related accidents was 1.5-4 times greater in the hypersomnolent patient groups than in the control group. In patients with hypersomnia, the incidence of sleep-related accidents per year of excessive sleepiness was 3-7%. Although the proportion of patients with sleep-related accidents was highest in narcoleptics, apneics were involved in more sleep-related accidents because of their greater number. Apneics and nacroleptics accounted for 71% of all sleep-related accidents. The proportion of severe apneics who had sleep-related accidents was almost twice that of patients with mild or moderate apnea. Mean sleep latency by Multiple Sleep Latency Test did not differ significantly in patients with accidents and those without. Patients with a wide variety of sleep disorders appear to be at increased risk for sleep-related accidents. The severity and duration of hypersomnia are probably not the only factors that contribute to that risk. These findings have implications for the management of patients with sleep disorders.

Characteristics of apneas and hypopneas during sleep and relation to excessive daytime sleepiness.

STUDY OBJECTIVES: One of the most important symptoms in patients evaluated for possible obstructive sleep apnea syndrome is excessive daytime sleepiness, but the measures of apnea severity and of sleepiness used most commonly have not generally shown strong associations. We explored whether information recorded during standard polysomnography, other than the overall rate of apneas and hypopneas per hour of sleep (AHI), might help explain the measured severity of sleepiness. DESIGN: Observational SETTING: A clinical sleep laboratory in a university hospital PATIENTS: N = 1,146 patients evaluated for suspected sleep-disordered breathing with nocturnal polysomnograms and multiple sleep latency tests. RESULTS: The AHI during supine sleep (recorded in a subgroup of n = 169 subjects), the rate of apneas (n = 1,146), and the rate of obstructive apneas (n = 1,146) were particularly useful in explaining variation in measured levels sleepiness; rates of hypopneas and central apneas were less useful (n = 1,146). In addition, the minimum recorded oxygen saturation (n = 1,097) was as important as the AHI to the level of sleepiness. CONCLUSIONS: In an attempt to explain excessive daytime sleepiness among patients evaluated for sleep-disordered breathing, additional insight is provided by observation of supine sleep during polysomnography, by emphasis on apneas rather than hypopneas, by emphasis on obstructive rather than central events, and by consideration of the minimum oxygen saturation.

Exacerbation of human cataplexy by prazosin.

A middle-aged woman with narcolepsy developed a pronounced exacerbation of cataplexy within 3 days of beginning treatment for hypertension with prazosin, an alpha 1-adrenoceptor antagonist. At times, episodes of cataplexy were virtually continuous (status cataplecticus), and there was only partial amelioration with tricyclic antidepressants. Cataplexy improved when prazosin was discontinued. These findings are similar to the reported effects of prazosin on cataplexy in narcoleptic dogs; they support a role for altered alpha 1-adrenoceptor function in narcolepsy.