发作性睡病的延迟诊断及与癫痫的鉴别诊治

发作性睡病是临床少见的睡眠-觉醒节律障碍性疾病,表现为白天反复发作的不可遏制的睡眠,常伴猝倒发作、睡眠瘫痪及入睡前幻觉。临床医师对发作性睡病的认识不足是导致误诊和延迟诊断的主要原因之一。癫痫发作类型复杂多样,与发作性睡病易混淆,二者需相互鉴别,且当二者共患病时,诊断和治疗会更加困难。现通过对发作性睡病的临床特征与延迟诊断原因进行分析,总结发作性睡病与癫痫的鉴别要点及共患病的诊治经验,以提高临床医师对发作性睡病及其与癫痫共患病的认识,改善患者的预后及生活质量。     

Canine cataplexy is preferentially controlled by adrenergic mechanisms: evidence using monoamine selective uptake inhibitors and release enhancers

Narcolepsy is currently treated with antidepressants to control REM-related symptoms such as cataplexy and with amphetamine-like stimulants for the management of sleepiness. Both stimulant and antidepressant drugs presynaptically enhance monoaminergic transmission but both classes of compounds lack pharmacological specificity. In order to determine which monoamine is selectively involved in the therapeutic effect of these compounds, we examined the effects of selective monoamine uptake inhibitors and release enhancers on cataplexy using a canine model of the human disorder. A total of 14 compounds acting on the adrenergic (desipramine, nisoxetine, nortriptyline, tomoxetine, viloxazine), serotoninergic (fenfluramine, fluoxetine, indalpine, paroxetine, zimelidine) and dopaminergic (amfonelic acid, amineptine, bupropion, GBR 12909) systems were tested. Some additional compounds interesting clinically but with less pharmacological selectivity, i.e., cocaine, dextroamphetamine, methylphenidate, nomifensine and pemoline, were also included in the study. All compounds affecting noradrenergic transmission completely suppressed canine cataplexy at low doses in all dogs tested, whereas compounds which predominantly modified serotoninergic and dopaminergic transmission were either inactive or partially active at high doses. Our results demonstrate the preferential involvement of adrenergic systems in the control of cataplexy and, presumably, REM sleep atonia. Our findings also demonstrate that canine narcolepsy is a useful tool in assessing the pharmacological specificity of antidepressant drugs.     

Canine narcolepsy is associated with an elevated number of α2-receptors in the locus coeruleus

α₂-Receptors in the canine brain were pharmacologically characterized using [³H]yohimbine binding. Competition studies revealed a single class of binding sites in frontal cortex but two distinct subtypes in nucleus caudatus. The role of central α₂-receptors in narcolepsy was investigated in 5 normal and 5 narcoleptic Doberman pinschers. Scatchard analysis of [³H]yohimbine binding in different brain areas revealed an increase in the number of α₂-binding sites limited to the locus coeruleus. This suggests that altered autoinhibition of norepinephrine release may be associated with the narcoleptic symptomatology.     

Effects of protriptyline on vigilance and information processing in narcolepsy

Vigilance, memory function, and response latency on the Sternberg short-term memory scanning task were examined in eight narcoleptic patients on and off medication. Off medication, half of the patients demonstrated reduced vigilance and all displayed diminished automatic memory encoding and longer response latencies on the Sternberg memory scanning procedure relative to the treated condition. Protriptyline normalized vigilance in half of the patients, while response latency and automatic information processing significantly improved in all. These findings are discussed with regard to the potential effect of the medication on central nervous system arousal.     

Comparison of the psychosocial effects of epilepsy and narcolepsy/cataplexy: a controlled study

A questionnaire survey compared the psychosocial effects of epilepsy in 60 patients without major organic pathology (selected cases with temporal lobe epilepsy or primary generalized epilepsy) with those of matched (duration of illness, sex) patients with narcolepsy/cataplexy and with those of age- and sex-matched controls. Comparing epileptic patients with controls, we confirmed the well-documented marked deleterious effects of epilepsy upon work, education, occupational and household accidents, recreation, personality, interpersonal relations, and other parameters. Comparisons of epileptic and narcoleptic patients, however, showed that, in general, persons with narcolepsy are even more psychosocially impaired. The narcoleptic patients showed greater frequencies of disease-attributed reduced performance at work, poorer driving records, higher accident rates from smoking, greater problems in planning recreation, and other significant differences. Rather dissimilar profiles of psychosocial impairment were found to characterize the two conditions, and these were largely understandable as a function of their symptoms. The only areas in which epileptic patients showed greater problems than those with narcolepsy were in educational achievement and in ability to maintain a driving license. Most of the intergroup differences remained significant even for smaller groups matched also for age. The somewhat greater psychosocial impact of narcolepsy appears to be due to the continuous excessive daytime sleepiness that persists between the diagnostic attacks, whereas persons with epilepsy are relatively alert between seizures.     

Methylphenidate and brain dopamine neurotoxicity

To further evaluate the dopamine (DA) neurotoxic potential of the widely prescribed psychostimulant, methylphenidate, mice were treated with various doses (range: 10–120 mg/kg) and treatment schedules of methylphenidate (every 2 h×4 or twice daily×4). Higher doses of methylphenidate produced intense stereotypy, as well as short- (5-day), but not long- (2-week), term depletions of striatal DA axonal markers. By contrast, amphetamine caused not only intense stereotypy, but also profound, long-lasting, dose-related DA deficits. These findings indicate that results of studies of amphetamine neurotoxicity using short (5-day) post-drug survival periods are potentially misleading. Further, the present findings confirm and extend previous results indicating that methylphenidate, unlike amphetamine, lacks DA neurotoxic potential, and strongly suggest that DA efflux, although perhaps necessary, is not sufficient for the expression of amphetamine-induced DA neurotoxicity.     

Searching for a marker of REM sleep behavior disorder: submentalis muscle EMG amplitude analysis during sleep in patients with narcolepsy/cataplexy

STUDY OBJECTIVES: To evaluate the amplitude of submentalis muscle EMG activity during sleep in patients with narcolepsy/cataplexy with or without REM sleep behavior disorder (RBD). DESIGN: Observational study with consecutive recruitment. SETTINGS: Sleep laboratory. PATIENTS: Thirty-four patients with narcolepsy/cataplexy and 35 age-matched normal controls. MEASUREMENTS AND RESULTS: Half the patients (17 subjects) had a clinical and video polysomnographic diagnosis of RBD. The average amplitude of the rectified submentalis muscle EMG signal was used to assess muscle atonia, and the new REM sleep Atonia Index was computed. Chin muscle activations were detected and their duration and interval analyzed. REM sleep Atonia Index was lower in both patient groups (with narcolepsy patients with RBD showing the lowest values) with respect to controls, and it did not correlate with age as it did in controls. The total number of chin EMG activations was significantly higher in both patient groups than controls. No significant differences were found between the two groups of patients, although more chin EMG activations were noted in narcolepsy patients with RBD than those without. CONCLUSIONS: Elevated muscle activity during REM sleep is the only polysomnographic marker of RBD. This study shows that polysomnographically evident RBD is present in many patients with narcolepsy/ cataplexy. This condition might be specific to narcolepsy/cataplexy, reflecting a peculiar form of REM sleep related motor dyscontrol (i.e., status dissociatus), paving the way to enacting dream behaviors, and correlated with the specific neurochemical and neuropathological substrate of narcolepsy/cataplexy.     

Hypocretin (orexin) loss in Alzheimer's disease

Sleep disturbances in Alzheimer's disease (AD) patients are associated with the severity of dementia and are often the primary reason for institutionalization. These sleep problems partly resemble core symptoms of narcolepsy, a sleep disorder caused by a general loss of the neurotransmitter hypocretin. AD is a neurodegenerative disorder targeting different brain areas and types of neurons. In this study, we assessed whether the neurodegenerative process of AD also affects hypothalamic hypocretin/orexin neurons. The total number of hypocretin-1 immunoreactive neurons was quantified in postmortem hypothalami of AD patients (n = 10) and matched controls (n = 10). In addition, the hypocretin-1 concentration was measured in postmortem ventricular cerebrospinal fluid of 24 AD patients and 25 controls (including the patients and controls in which the hypothalamic cell counts were performed). The number of hypocretin-1 immunoreactive neurons was significantly decreased by 40% in AD patients (median [25th-75th percentiles]); AD 12,935 neurons (9972-19,051); controls 21,002 neurons (16,439-25,765); p = 0.049). Lower cerebrospinal fluid (CSF) hypocretin-1 levels were found in AD patients compared with controls (AD: 275 pg/mL [197-317]; controls: 320 pg/mL [262-363]; p = 0.038). Two AD patients with documented excessive daytime sleepiness showed the lowest CSF hypocretin-1 concentrations (55 pg/mL and 76 pg/mL). We conclude that the hypocretin system is affected in advanced AD. This is reflected in a 40% decreased cell number, and 14% lower CSF hypocretin-1 levels.     

Measures of functional outcomes,work productivity,and quality of life from a randomized,phase 3 study of solriamfetol in participants with narcolepsy

ObjectiveSolriamfetol (formerly JZP-110), a dopamine/norepinephrine reuptake inhibitor, is approved in the US to improve wakefulness in adults with excessive daytime sleepiness associated with narcolepsy (75–150 mg/d) or obstructive sleep apnea (37.5–150 mg/d). In a randomized, double-blind, placebo-controlled trial in participants with narcolepsy, effects of solriamfetol on functional status, health-related quality of life (HRQoL), and work productivity were evaluated.MethodsParticipants with narcolepsy (N = 239) were randomized to solriamfetol 75, 150, or 300 mg, or placebo for 12 weeks. Outcome measures included the Functional Outcomes of Sleep Questionnaire short version (FOSQ-10), 36-Item Short Form Health Survey version 2 (SF-36v2), and Work Productivity and Activity Impairment questionnaire for Specific Health Problem (WPAI:SHP). A mixed-effects model with repeated measures was used for comparisons vs placebo.ResultsAt week 12, solriamfetol increased FOSQ-10 total score, with greatest mean difference from placebo (95% CI) at 300 mg (1.45 [0.31, 2.59]). On SF-36v2, improvements vs placebo were observed in physical component summary scores (300 mg: 2.22 [0.04, 4.41]) and subscales of role physical, general health, and vitality. On WPAI:SHP, solriamfetol 150 mg reduced overall work impairment vs placebo (−15.5 [−29.52, −1.47]), and 150 and 300 mg reduced activity impairment vs placebo (−10.05 [−19.48, −0.62] and −13.49 [−23.19, −3.78], respectively). Most treatment-emergent adverse events (TEAEs) were mild or moderate in severity. Common TEAEs were headache, nausea, decreased appetite, nasopharyngitis, dry mouth, and anxiety.ConclusionsSolriamfetol improved measures of functional status, HRQoL, and work productivity, particularly at the 150- and 300-mg doses. Most TEAEs were mild to moderate.Trial registrationClinicalTrials.gov identifier NCT02348593, EudraCT number 2014-005487-15.     

2018 worldwide survey of health-care providers caring for patients with narcolepsy: WSS narcolepsy task force

BackgroundThere are limited data available on regional differences in the diagnosis and management of narcolepsy. In order to better understand worldwide trends in clinical assessment and management of narcolepsy, a survey of health-care providers was conducted by the World Sleep Society Narcolepsy task force.MethodsA total of 146 surveys that included items on the diagnosis and management of narcolepsy were completed by practitioners representing 37 countries.ResultsMost of the participants were from Europe, North America, Oceania, Asia and Latin America. A consistent approach to applying the diagnostic criteria of Narcolepsy was documented with the exception of measurement of CSF hypocretin-1, which has limited availability. While the majority of practitioners (58%) reported not using the test, 1% indicated always evaluating CSF hypocretin-1 levels. There was much variability in the availability of currently recommended medications such as sodium oxybate and pitolisant; modafinil and antidepressants were the most commonly used medications. Amphetamines were unavailable in some countries.ConclusionThe results of the study highlight clinical and therapeutic realities confronted by worldwide physicians in the management of narcolepsy. While the diagnostic criteria of narcolepsy rely in part on the quantification of CSF hypocretin-1, few physicians reported having incorporated this test into their routine assessment of the condition. Regional differences in the management of narcolepsy appeared to be related to geographic availability and expense of the therapeutic agents.