Transcranial midbrain sonography in narcoleptic subjects with and without concomitant REM sleep behaviour disorder

Substantia nigra (SN) hyperechogenicity—a sonographic vulnerability marker for Parkinson’s disease (PD)—has been recently described in patients with idiopathic REM sleep behaviour disorder (RBD). It is not known whether subjects with narcolepsy (who frequently have associated RBD) also show SN hyperechogenicity. The aim of this study was to (1) evaluate SN echogenicity in narcolepsy and (2) determine whether transcranial sonography (TCS) differs in narcoleptic subjects with and without RBD. A total of 16 patients with narcolepsy–cataplexy (7 had a concomitant, video-polysomnographically based diagnosis of RBD) were examined with TCS by two investigators blinded to the clinical data. The size of the SN echogenic area in both subgroups was within the range previously described for healthy subjects. The brainstem raphe, however, was reduced in five of seven narcoleptic subjects with RBD, whereas only two of nine narcoleptic subjects without RBD exhibited this TCS finding. We conclude that evaluation of SN echogenicity does not discriminate between both subgroups. The absence of SN hyperechogenicity in narcoleptic patients with RBD supports the hypothesis that SN hyperechogenicity in patients with presumed idiopathic RBD is an additional risk marker for subsequent evolvement of PD rather than an RBD-immanent finding. Reduced echogenicity of the brainstem raphe might indicate an involvement of the serotonergic system in narcoleptic subjects with RBD. W.H. Oertel and G. Mayer contributed equally to this work.     

Specificity of direct transition from wake to REM sleep in orexin/ataxin-3 transgenic narcoleptic mice

To create operational criteria for polygraphic assessments of direct transitions from wake to REM sleep (DREM), as a murine analog of human cataplexy, we have analyzed DREM episodes in congenic lines of orexin/ataxin-3 transgenic [TG] mice and wild-type littermates. The sleep stage of each 10-second epoch was visually scored using our standard criteria. Specificity of DREM for narcoleptic TG mice and sensitivity to detect DREM was evaluated using different DREM criteria. We found that DREM transitions by 10-second epoch scoring are not specific for narcoleptic TG mice and also occur in WT mice during light period. These wake-to-REM transitions in WT mice (also seen in TG mice during light period) were characteristically different from DREM transitions in TG mice during dark period; they tended to occur as brief bouts of wakefulness interrupting extended episodes of REM sleep, suggesting that these transitions do not represent abnormal manifestations of REM sleep. We therefore defined the DREM transitions by requiring a minimum number of preceding wake epochs. Requiring no fewer than four consecutive epochs of wakefulness produced the best combination of specificity (95.9%) and sensitivity (66.0%). By definition, DREM in dark-period is 100% specific to narcolepsy and was 95.9% specific overall. In addition, we found that desipramine, a trycyclic anticataplectic, potently reduces DREM, while two wake-promoting compounds have moderate (d-amphetamine) and no (modafinil) effect on DREM; the effects mirror the anticataplectic effects of these compounds reported in canine and human narcolepsy. Our definition of DREM in murine narcolepsy may provide good electrophysiological measures for cataplexy-equivalent episodes.     

Validation of semiautomatic scoring of REM sleep without atonia in patients with RBD

Objective/BackgroundTo evaluate REM sleep without atonia (RSWA) in REM sleep behavior disorder (RBD) several automatic algorithms have been developed. We aimed to validate our algorithm (Mayer et al., 2008) in order to assess the following: (1). capability of the algorithm to differentiate between RBD, night terror (NT), somnambulism (SW), Restless legs syndrome (RLS), and obstructive sleep apnea (OSA), (2). the cut-off values for short (SMI) and long muscle activity (LMI), (3). which muscles qualify best for differential diagnosis, and (4). the comparability of RSWA and registered movements between automatic and visual analysis of videometry.Patients/MethodsRSWA was automatically scored according to Mayer et al., 2008 in polysomnographies of 20 RBD, 10 SW/NT, 10 RLS and 10 OSA patients. Receiver operating characteristic (ROC) curves were used to determine the sensitivity and specificity of SMI and LMI. Independent samples were calculated with t-tests. Boxplots were used for group comparison. The comparison between motor events by manual scoring and automatic analysis were performed with “Visual Basic for Applications” (VBA) for every hundredth second.ResultsOur method discriminates RBD from SW/NT, OSA and RLS with a sensitivity of 72.5% and a specificity of 86.7%. Automatic scoring identifies more movements than visual video scoring. Mentalis muscle discriminates the sleep disorders best, followed by FDS, which was only recorded in SW/NT. Cut-off values for RSWA are comparable to those found by other groups.ConclusionThe semi-automatic RSWA scoring method is capable to confirm RBD and to discriminate it with moderate sensitivity from other sleep disorders.     

Subtle gait changes in patients with REM sleep behavior disorder

Many people with rapid eye movement (REM) sleep behavior disorder (RBD) have an underlying synucleinopathy, the most common of which is Lewy body disease. Identifying additional abnormal clinical features may help in identifying those at greater risk of evolving to a more severe syndrome. Because gait disorders are common in the synucleinopathies, early abnormalities in gait in those with RBD could help in identifying those at increased risk of developing overt parkinsonism and/or cognitive impairment. We identified 42 probable RBD subjects and 492 controls using the Mayo Sleep Questionnaire and assessed gait velocity, cadence, and stride dynamics with an automated gait analysis system. Cases and controls were similar in age (79.9 ± 4.7 and 80.1 ± 4.7, P = 0.74), Unified Parkinson's Disease Rating Scale Part III (UPDRS) score (3.3 ± 5.5 and 1.9 ± 4.1, P = 0.21) and Mini–Mental State Examination scores (27.2 ± 1.9 and 27.7 ± 1.6, P = 0.10). A diagnosis of probable RBD was associated with decreased velocity (?7.9 cm/s; 95% confidence interval [CI], ?13.8 to ?2.0; P < 0.01), cadence (?4.4 steps/min; 95% CI, ?7.6 to ?1.3; P < 0.01), significantly increased double limb support variability (30%; 95% CI, 6–60; P = 0.01), and greater stride time variability (29%; 95% CI, 2–63; P = 0.03) and swing time variability (46%; 95% CI, 15–84; P < 0.01). Probable RBD is associated with subtle gait changes prior to overt clinical parkinsonism. Diagnosis of probable RBD supplemented by gait analysis may help as a screening tool for disorders of α‐synuclein. © 2013 International Parkinson and Movement Disorder Society     

Quipazine has a biphasic effect on slow wave sleep and reduces REM sleep rebound in REM sleep deprived rats

Rats implanted with electrodes for polygraphic recording were deprived of REM sleep for 24 hr. Following REM sleep deprivation animals were injected with quipazine maleate (7.5 mg/kg IP) and were polygraphically recorded for 48 hr. The results show that quipazine reduces REM sleep rebound and that it has a biphasic effect on slow-wave sleep: initial 6 hr suppression is followed by a delayed increase in the second 24 hr recording period. The initial suppression of slow-wave sleep we attribute to the stimulation of central serotonergic receptors while the effect on REM sleep rebound may result from quipazine's action on central catecholamines.     

发作性睡病夜间睡眠结构特征的探讨

目的了解发作性睡病患者夜间睡眠结构特点。方法对10例符合发作性睡病国际睡眠疾病分类最低诊断标准的发作性睡病患者和13例正常对照者连续进行两夜夜间多导睡眠图监测,比较两组各项睡眠参数,并分析发作性睡病患者的夜间睡眠结构特点。结果发作性睡病组患者的夜间睡眠潜伏期和快速眼动睡眠潜伏期缩短(P<0．01),在整个睡眠过程中睡眠始发快速眼动时段出现比例明显升高(P<0．01),唤醒指数和睡眠纺锤波密度增高(P<0．05),睡眠转换次数和清醒次数及S1期睡眠比例增加(P<0．01),S2期和S3 S4期比例减少(P<0．01),快速眼动密度增加(P<0．01);全夜快速眼动睡眠时段持续时间无逐渐延长趋势。与对照组受试者睡眠生理参数相比,差异具有显著性意义(P<0．05或P< 0．01)。结论发作性睡病患者夜间睡眠结构的特征为快速眼动活动增强,睡眠维持机制紊乱,中枢唤醒水平降低。     

47例REM睡眠行为障碍分析

目的 分析REM睡眠行为障碍的临床表现,探讨其病因、发病机制和治疗方法 .方法 回顾性分析47例REM睡眠行为障碍患者的病历资料.结果 47例患者均为中、老年人,均在熟睡过程中突然出现表现多样的行为障碍,多导睡眠图均为REM睡眠期出现肌弛缓现象消失而伴随肌电活动;病因为5例为帕金森病,3例为酒精戒断,1例为脑外伤,2例多系统萎缩,4例为药物滥用,32例为原发性;治疗应用氯硝西泮,或/和卡马西平、左旋多巴,所有患者有效.结论 REM睡眠行为障碍病因复杂、临床表现多样,经过合理药物、心理治疗,可以取得理想的治疗效果.     

Cholinergically induced REM sleep triggers Fos-like immunoreactivity in dorsolateral pontine regions associated with REM sleep

We sought to determine the presence of Fos-like immunoreactive (Fos-LI) cells in the pontine brainstem following cholinergically induced sustained rapid-eye movement (REMc) sleep in cats. Microinjections (0.25 μl) of vehicle ( N = 2) or carbachol (2.0 μg/0.25 μl; N = 4) were made into the medical pontine reticular formation. Carbachol produced a state with all the signs of natural REM sleep and with durations of 15.2–57.8 min. Compared with vehicle control animals, carbachol treated animals showed a significantly higher number of Fos-LI cells in pontine regions implicated in REM sleep generation, with longer REMc bouts associated with more Fos-LI cells than the short-duration bout. Regions with REMc-associated Fos-LI increases included: the lateral dorsal tegmental (LDT) and pedunculopontine tegmental (PPT) nuclei, where some Fos-LI cells were immunohistochemically identified as cholinergic; the locus coeruleus, where some of the Fos-LI cells were identified to be catecholaminergic; the dorsal raphe and the pontine reticular formation. These findings suggest immediate early gene activation is associated with the ubiquitous biological state of REM sleep.     

The prospective memory of patients with idiopathic REM sleep behavior disorder

BackgroundIdiopathic rapid eye movement sleep behavior disorder (iRBD) likely represents the prodromal stage of synucleinopathy. The present study was to investigate if there was prospective memory (PM) impairment and the relationship between different PM tasks and traditional cognitive tests in patients with iRBD.MethodsA total of 28 patients with iRBD, 25 with Parkinson's disease (PD) and 21 healthy controls were included. The Cambridge Prospective Memory Test (CAMPROMPT) was used to measure the PM including time-based (TBPM) and event-based PM (EBPM). Standard cognitive tests were administered to all participants.ResultsEBPM scores were lower only in patients with iRBD, while the obvious PM abnormalities were found in patients with PD. The patients with iRBD and PD performed worse on delayed recall of the Rey Auditory Verbal Learning Test (RAVLT) and copy of the Rey–Osterrieth complex figure (ROCF). The EBPM correlated with attention, executive function, and immediate memory besides working memory in patients with iRBD. The PM tasks involved in more memory functions in PD patients.ConclusionsThe patients with iRBD were impaired on both episodic memory and EBPM tasks that correlated with attention, executive function, and immediate memory. The PM abnormality was an early cognitive change in iRBD to which more attention should be paid more attention.     

Effects of rapid eye movement (REM) sleep deprivation on pain sensitivity in the rat

The relationship between pain and sleep seems to be reciprocal: if pain may interrupt or disturb sleep, poor sleep can also influence pain perception. However the influence of sleep disturbances on pain sensitivity remain poorly investigated. The aim of this study was to assess the effect of REM sleep deprivation on the reaction of rats subjected to different noxious stimuli. In each experiment 16 Wistar male rats were randomly assigned to two groups: controls (n=8), and REM sleep deprived rats (n=8). REM sleep deprivation was elicited using the ‘inverted flower pot’ technique. Four different experiments were performed to assess the sensitivity to mechanical (vocalization threshold in paw pressure), thermal (tail withdrawal latency in hot water immersion), electrical (envelope of 2nd peep in tail shock test) and chemical (analgesic behavior in formalin test) noxious stimuli. All experiments were performed over a 5-day period with baseline (day 1, day 2) in a dry environment and REM sleep deprivation (day 3, day 4 and day 5) in a wet environment. Under wet conditions, vocalization threshold in the paw pressure test (−20%, P=0.005), and tail withdrawal latency in the hot water immersion test (−21%, P=0.006) were significantly lower, and the envelope of 2nd peep in the tail electrical shock was significantly greater (+78%, P=0.009), in REM sleep deprived rats compared to controls. However, under wet conditions the mean duration of nociceptive behaviors in the formalin test did not differ between the two groups. In conclusion, REM sleep deprivation induces a significant increase in the behavioral responses to noxious mechanical, thermal and electrical stimuli in rats.     

Systematic video-analysis of motor events during REM sleep in idiopathic REM sleep behavior disorder,follow-up and DAT-SPECT

Abnormal motor manifestations in REM sleep are the most visible feature of idiopathic REM sleep behavior disorder (iRBD), which precedes the overt alpha-synucleinopathy. The aim of this study was to perform a systematic visual analysis of the motor events (ME) captured during video-polysomnography, and clarify their relation to the disease severity.Thirty-four iRBD patients (5 women, 29 men; age 67.7 ± 7.2) with a mean follow-up duration 2.9 ± 1.1 years. and 33 controls (10 women, 23 men; age 61.5 ± 8.2) were examined. The ME captured during REM sleep were classified into four categories, previously defined by Frauscher et al. according to clinical severity: minor/simple jerks, major, complex and violent.An average frequency of 110.8 ± 75.2 ME per hour were identified in iRBD, 7.5 ± 11.6 in the controls (p < 0.001). Of these ME, 68.4% were classified as minor/simple jerks, 9.3% as major, 21.7% as complex and 0.7% as violent. The ME frequency was negatively associated with tracer binding on dopamine transporter single-photon emission computed tomography (DAT-SPECT); the association was stronger for caudate nucleus compared to putamen. During follow-up seven patients (24.1%) phenoconverted, yielding a yearly phenoconversion rate 8.3%. Violent ME were associated with increased hazard ratio for phenoconversion in frequency (p = 0.012) and total duration (p = 0.007).Patients with higher amounts of violent ME had a greater risk of phenoconversion; therefore, their role as a predictor should be considered. Additionally, ME were associated with nigrostriatal degeneration, according to DAT-SPECT. These findings indicate that the degree of the clinical severity of motor manifestations in iRBD reflects the severity of the disease.     

Longitudinal changes in cognition in early Parkinson's disease patients with REM sleep behavior disorder

IntroductionCognitive decline is common in Parkinson's disease (PD), and identifying patients at highest risk for it is essential. We aimed to examine the effect of possible REM sleep behavior disorder (pRBD) on rate of cognitive decline in early PD, for both global cognition and in specific cognitive domains.MethodsParkinson's Progression Markers Initiative (PPMI) is a multi-site, international study of PD patients untreated at enrollment. pRBD was assessed with the REM sleep behavior disorder questionnaire (RBDSQ). Global cognition was assessed at baseline and annually using the Montreal Cognitive Assessment (MoCA) and a cognitive battery. Linear mixed effects models were used to examine the relationship between pRBD (RBDSQ ≥ 6) and rate of change in cognitive variables. Age, sex, years of education, and baseline motor and cognitive scores were included as covariates.ResultsThe baseline sample consisted of 423 individuals with PD, mean age 61.7 years and 65.5% male. Data was available on 389, 366, and 196 participants at 1-year, 2-year, and 3-year follow-up respectively. Possible RBD occurred in 108 (25.5%) at baseline. In multivariate analyses, baseline RBD was associated with greater annual rate of decline in MoCA score (β = −0.34, 95%CI −0.54, −0.13, p < 0.001), Symbol Digit Modalities Test (β = −0.69, 95%CI −1.3, −0.09, p = 0.024), and Hopkins Verbal Learning Test-Revised, delayed free recall (β = −0.21, 95%CI −0.41, −0.013, p = 0.037).ConclusionsPossible RBD is common in early PD and predicts future cognitive decline, particularly in attention and memory domains.     

The role of pedunculopontine nucleus in isolated REM sleep behavior disorder and REM sleep without atonia

IntroductionThe aim of this study was to analyze the functions of pedunculopontine nucleus (PPN) in isolated REM sleep behavior disorder (iRBD) and REM sleep without atonia (RSWA) to investigate the role of PPN in dream-enacting motor behaviors in RBD. We evaluated the activity of PPN through the prepulse modulation (PPM) together with other brainstem reflexes to investigate the differences in changes at brainstem.MethodsWe included nine patients with isolated RSWA and 10 patients with iRBD. For diagnosis, all patients underwent polysomnography. None of the patients had parkinsonism or dementia. We also included 17 healthy participants with similar age and sex. Blink reflex (BR), PPM of BR, recovery excitability of BR, and auditory startle reflex (ASR) were recorded in all participants.ResultsThere was a prepulse inhibition deficit in iRBD and RSWA groups compared to healthy subjects. The BR-R2 recovery at 200 ms interval was also higher in patients with iRBD and RSWA. In ASR recordings, the response probabilities were higher in the RBD group compared to RSWA and control groups.ConclusionThe PPM was abnormal in both iRBD and RSWA whereas ASR was enhanced in iRBD. We suggest that there are certain similarities and differences in the pathophysiologies of iRBD and RSWA.     

REM sleep behaviour disorder in the elderly

REM sleep behaviour disorder is a recently described parasomnia characterized by a history of excessive motor activities during sleep and is associated with pathological absence of muscle atonia during REM sleep. There is very limited literature on the condition. Two out of 349 elderly patients referred to a psychogeriatric unit were identified to have REM sleep behaviour disorder. These two patients are presented to illustrate the clinical features of the condition. Both of them showed a good response to clonazepam treatment. © 1997 John Wiley & Sons, Ltd.     

REM sleep behaviour disorder treated with melatonin in a patient with Alzheimer's disease

We report a case of a 68-year-old man with probable Alzheimer's disease who developed rapid eye movement (REM) sleep behaviour disorder. This was confirmed with polysomnography but the patient also had some sleep apnea, which prevented the use of clonazepam for treatment. Melatonin was successfully used as an alternative treatment.     

发作性睡病的临床特征与多次睡眠潜伏期试验对照研究

目的:探讨多次睡眠潜伏期试验(MSLT)对发作性睡病的诊断价值。方法:总结3 6例发作性睡病患者的临床特征,并进行白天5次MSLT和整夜多导睡眠图(PSG)描记,分析平均睡眠潜伏期(sleeplatency ,SL)、睡眠初次出现REM (sleeponsetrapideyemovementperiods ,SOREMP)次数及夜间睡眠相关参数和3 4名正常对照组进行比较。结果:3 6例均有白日过度嗜睡(10 0 % ) ,2 5例伴猝倒(69.44 .% ) ,16例伴入睡前幻觉(4 4 .44 % ) ,8例伴睡眠瘫痪(2 2 .2 2 % ) ,7例典型的睡眠四联征(19.44 % )。白天5次MSLT显示:2 8例发作性睡病患者SL <5min +SOREMP≥2次(77.78% ) ,SL(4 .12±2 .0 4)缩短和SOREMP≥2 (3 .2 8±0 .67)次,与正常对照组相比有显著性差异(P <0 .0 1)。整夜PSG结果显示:发作性睡病组总睡眠时间(3 3 5 .82±3 4.0 9)min、REM潜伏期缩短(17.19±7.14 )min ,和正常对照组相比有显著性差异(P <0 .0 1)。结论:发作性睡病具有睡眠潜伏期缩短和REM睡眠提前的特征,MSLT对发作性睡病的诊断和鉴别诊断具有重要价值。     

快速动眼睡眠行为障碍症10例报告

目的 介绍快速眼动(REM)睡眠行为障碍症(RBD)的临床表现，探讨其原因和可能的发病机制。方法 对由多导睡眠图确诊的10例RBD患者进行回顾性分析。结果 10例患者发病年龄均为中老年人，男性9例，表现睡梦中出现粗暴动作、喊叫和其他行为异常，其中4例为帕金森病患者，2例多系统萎缩，1例脑外伤，3例原因不明；睡前服用氯硝安定可控制发作。全部多导睡眠图(PSG)均为REM睡眠期肌弛缓现象消失而伴随肌电活动。结论 对睡眠中出现的异常行为特别是粗暴动作者．应考虑本病的可能，PSG有助确诊并与癫痫鉴别，氯硝安定治疗有效?     

Enhancement of acetylcholine release during REM sleep in the caudomedial medulla as measured by in vivo microdialysis

Previous studies in our laboratory have found that muscle atonia could be triggered by two distinct areas of the medial medulla, a caudal region, corresponding to the nucleus paramedianus (NPM) and a rostral region, corresponding to the nucleus magnocellularis (NMC). The former region is responsive to acetylcholine (ACh) and the latter region is responsive to glutamate. In this study we have measured the endogenous ACh release across the sleep-wake cycle in these two areas with the microdialysis technique in unanesthetized, freely moving cats. We found that ACh release in NPM was state-dependent and was about 30% higher ( P0.001) during rapid eye movement (REM) sleep than during slow-wave sleep and wakefulness. However, ACh release in NMC was not selectively elevated in REM sleep. The enhancement of ACh release in NPM during REM sleep supports our hypothesis that ACh release onto cholinoceptive neurons in this area mediates the muscle atonia of REM sleep.