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J Neurol (2007) 254 [Suppl 4]: IV/8–IV/14 DOI 10.1007/s00415-007-4003-0

Naoko Tachibana

■ Abstract REM sleep behaviour disorder (RBD) is a parasomnia that is characterized by dreamenacting behaviours associated with REM sleep without atonia

N. Tachibana, MD, PhD (쾷) Dept. of Brain Pathophysiology Human Brain Research Center Kyoto University Graduate School of Medicine Shougoin, Sakyo Kyoto, 606-8507, Japan Tel.: +81-75/751-3695 Fax: +81-75/751-3202 E-Mail: [email protected]

REM sleep behaviour disorder in Parkinson’s disease

(RWA). As experimental animal models for RBD/RWA have been produced by bilateral pontine tegmentum lesions, a proportion of RBD might be explained by a similar location of lesions in the brainstem. RBD attracts the attention of neurologists as well as sleep specialists because RBD often coexists with or precedes neurodegenerative diseases, especially synucleinopathies (Parkinson’s disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy). In addition, apparent idiopathic RBD has various non-motor abnormali-

JON 4003

Introduction REM sleep behaviour disorder (RBD) is a parasomnia related to REM sleep that is characterized by nocturnal behaviours in which patients appear to “act out their dreams” [1, 2]. The symptoms vary from vocalizations and/or simple limb jerks to complex motor and/or ambulatory behaviour that is sometimes so violent that injury to the patient and bed partner can occur. One of the defining features of REM sleep is skeletal muscle atonia, which is believed to prevent us from physical enacting of dreams. However, in RBD patients, this active paralysis during REM sleep is impaired. Although RBD has been a fascinating disorder to sleep researchers and sleep specialists as a window to observe dreams, until recently, it has generally not been a main subject of interest for neurologists. This situation is changing rapidly, since some studies collecting data from a large case series showed that almost half of the RBD cases were associated with neuro-

ties that are also seen in PD or DLB. These findings indicate that RBD/RWA could be one of the early markers of PD or DLB; however, the precise pathophysiological mechanisms of RBD are still unclear, and more collaborative work between movement disorder specialists, sleep specialists, and neuropathologists is required. ■ Key words REM sleep · REM sleep behaviour disorder · REM sleep without atonia · Parkinson’s disease · synucleinopathy

logical diseases, especially so-called synucleinopathies such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) [23, 31]. Movement disorder specialists have also come to be interested in RBD, especially after follow-up studies disclosed that a proportion of apparent idiopathic RBD patients developed parkinsonian syndrome during the years of follow-up [15, 32, 33]. This eventually led to the search for early markers of PD in patients with idiopathic RBD. Evidence is accumulating that poor performance on colour discrimination [25], olfactory function [10, 25], and motor speed [25], and reduced cardiac 123Imetaiodobenzylguanidine uptake occur in apparent idiopathic RBD patients [22], all of which have been reported in the early stage of PD. Some characteristic measurements from single photon-emission computed tomography (SPECT) studies and EEG recordings in PD or DLB patients (such as reduced striatal presynaptic dopamine transporters [8], and reduction of cortical EEG activity, particularly in the occipital regions [9]) have been also demonstrated in idiopathic RBD.

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In this review, the history of discovering RBD in relation to its experimental animal model is described [16, 28]. As the new diagnostic criteria for RBD require documentation of REM sleep without atonia (RWA) [1], which is regarded as a polysomnographical hallmark of RBD, a plausible mechanism of RWA is also discussed. Although it is an intriguing hypothesis that RBD may be a prodromal symptom of PD and its related disorders, whether RBD/RWA is a preclinical symptom/finding of a certain type of neurodegenerative disease remains unclear.

The discovery of RBD Schenck and his colleagues were the first to report RBD in 1986 [30]. This first report described four men, aged 67–72 years, presenting with histories of injuring themselves or their spouses through dream-enacted aggressive behaviours. Polysomnography (PSG) ruled out seizure disorders; instead, variable loss of chin muscle atonia was recorded with increased EMG twitches in the limb muscles during REM sleep associated with behaviours.Although there were no associated psychiatric disorders, all four patients had some neurological diseases including olivo-ponto-cerebellar degeneration, Guillain-Barré syndrome, subarachnoid haemorrhage, and atypical dementia. Prior to this period, some Japanese groups had described an RBD-like state in patients with delirium tremens (DT) associated with the peculiar state called “Stage 1-REM with tonic EMG (Stage 1-REM)” [14], which was also documented in withdrawal from meprobamate [36], pentazocine [38], and barbiturate [35]. However, this state does not seem to be the complete equivalent to chronic RBD seen in neurodegenerative diseases in that the symptoms are limited within the Table 1 Diagnostic criteria of REM sleep behaviour disorder (ICSD-R 1997). The minimal diagnostic criteria are B plus C

range of several days or a week until the withdrawal state resolves. In addition, REM/NREM cycling of these patients is very much impaired, suggesting its pathophysiology is more extensive than disrupted REM-mediated muscle atonia. Although RBD has been operationally classified into acute and chronic RBD [20] – the former mostly covers drug-induced states and the latter socalled idiopathic RBD and RBD associated with various neurological diseases – whether RBD can be defined as a disorder rather than a syndrome is still controversial [39]. Therefore, we should bear in mind that RBD was identified as a new category of parasomnia that occurs exclusively during REM sleep with no impaired consciousness or orientation after awakening, and that, at that time,‘delirious’ behaviours in withdrawal states described by Japanese groups were not considered completely identical with this new category.

Diagnostic criteria of RBD As similar cases accumulated, RBD was incorporated as a parasomnia in the International Classification of Sleep Disorders (ICSD) in 1990, which was revised in 1997 [2] (Table 1). These diagnostic criteria had minimum items, requiring only clinical symptoms without PSG or video documentation. The minimum criteria were sometimes problematic for non-sleep specialists who are unfamiliar with the clinical characteristics of RBD, as taking histories of patients’ nocturnal behaviour is dependent on information from bed partners when patients themselves do not recall dreams well. This has been especially the case in Japan, where it is not culturally unusual for a couple to sleep in separate bedrooms. The first ICSD was revised recently and, in the ICSDII published in 2005, the diagnostic criteria for RBD require documentation of the presence of RWA by PSG [1]

A. The patient has a complaint of violent or injurious behaviour during sleeping. B. Limb or body movement is associated with dream mentation. C. At least one of the following occurs: – harmful or potentially harmful sleep behaviour; – dreams appear to be ”acted out”; – sleep behaviours disrupt sleep continuity. D. Polysomnographic monitoring demonstrates at least one of the following: – excessive augmentation of chin electromyography (EMG) tone; – excessive chin and limb phasic EMG twitching, irrespective of chin EMG activity and one or more of the clinical features during REM sleep: – excessive limb or body jerking; – complex, vigorous or violent behaviours; – absence of epileptic activity in association with the disorder. E. The symptoms are not associated with mental disorders but may be associated with neurological disorders. F. Other sleep disorders (e. g., sleep terrors or sleepwalking) can be present but are not the cause of the behaviour.

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(Table 2). The standard PSG recording follows the method established by Rechitschaffen and Kales in 1968 [26], including the surface EMG recording of the submental muscles; RWA is empirically defined as excessive amounts of sustained or intermittent elevation of submental EMG tone or excessive phasic submental EMG twitching with the other features of REM sleep (i. e. desynchronized EEG and rapid eye movements) (Fig. 1). However, there has been no standardized rule for scoring the stage of RWA, and on some occasions, RBD patients demonstrate behaviours with chin muscle atonia, but with phasic muscle twitching of the limbs (Fig. 2). This seems to be one of the reasons for allowing EMG recording from alternative muscle groups (i. e. the upper or lower limbs) in the diagnostic criteria. Therefore, we need to develop a standard scoring method for RWA, Table 2 Diagnostic criteria of REM sleep behaviour disorder (ICSD-R 2005)

and we need to determine which muscle EMG recordings are sufficient for the purpose of scoring RWA.

The similarity between RBD in humans and ‘oneiric behaviours’ in pontine-lesioned animals Long before the discovery of RBD, Jouvet’s group had caused cats to show ‘oneiric behaviours’ during REM sleep. The cats with bilateral mediodorsal pontine tegmental lesions lost REM sleep-mediated atonia [16]. The group later reported a series of stereotyped behaviours in their experimental cats such as: violent and abrupt jerks; vertical leaps; visual orientation; exploration; stalking, with almost complete immobility; predatory aggression devoid of emotion; and aggressive

A. Presence of REM sleep without atonia: the EMG finding of excessive amounts of sustained or intermittent elevation of submental EMG tone or excessive phasic submental or (upper or lower) limb EMG twitching. B. At least one of the following is present: i. Sleep-related injurious, potentially injurious, or disruptive behaviours by history ii. Abnormal REM sleep behaviours documented during polysomnographic monitoring C. Absence of EEG epileptiform activity during REM sleep unless RBD can be clearly distinguished from any concurrent REM sleep-related seizure disorder. D. The sleep disturbance is not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder.

C3-A2 C4-A1 O1-A2 O2-A1 L-EOG R-EOG

chin EMG

L-TA

R-TA 1 sec

scale bar = 50µV

Fig. 1 Stage RWA seen in an idiopathic RBD patient. The recording shows sustained elevation of submental EMG concomitant with phasic EMG elevation. EEG bears the characteristic feature of REM sleep, low voltage activity with mixed frequency, and EOG demonstrates clusters of rapid eye movements. TA tibialis anterior

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C3-A2 C4-A1 O1-A2 O2-A1 L-EOG R-EOG chin EMG

L-TA

R-TA

1 Sec

scale bar = 50µV

Fig. 2 Polygraphic record of an idiopathic RBD patient showing REM sleep with chin muscle atonia and excessive limb muscle twitching. TA tibialis anterior

attack with emotion against an imaginary enemy. They concluded that these behaviours always appeared during unequivocal REM sleep, as this sleep state retained the other characteristics of REM sleep including cortical EEG activation, ponto-geniculo-occipital (PGO) waves, and relaxation of the nictitating membranes, and, at the same time, the periodic cycling of NREM-REM was preserved [28]. Through the observation of these oneiric cats with specific lesions, the mechanisms responsible for REM sleep-related atonia were considered to originate in the peri-locus coeruleus (LC)-alpha nucleus and adjacent LC-alpha nucleus of the pontine tegmentum, which excite neurons of the nucleus reticularis magnocellularis in the medulla. From here, descending inhibitory projections reach the spinal alpha motoneurons, resulting in hyperpolarization and resultant muscle atonia [27]. Later, Morrison’s group also identified four categories of oneiric behaviours in pontine-lesioned cats, which were dependent on the location and size of the lesions. They were: 1) twitching and jerking limited to the limbs or trunk; 2) head lifting with forelimb support with orienting and exploratory behaviours; 3) stalking imaginary prey and episodic attacking behaviours; and 4) quadrupedal locomotion [13]. From their experiments, they concluded that loss of REM atonia alone is insufficient to generate behaviours, and that the inhibi-

tion of motor pattern generators in the mesencephalic locomotor region played an important role in releasing behaviours during REM sleep. In addition, recently Saper’s group identified the direct spinal projection from the ventral sublaterodorsal nucleus (vSLD) in rats. Lesions of the vSLD caused episodes of RWA associated with muscle jerks and full lunging movements, and even some complex behaviours such as walking, apparently while in REM sleep [19]. Since the vSLD in rats is equivalent to the subcoeruleus area or peri-LC alpha in cats, RBD could exist across the species [12]. In line with this evidence, there seems to be a vital spot in the brainstem to generate RBD in humans, if the region is precisely damaged. Although there has been only one published case of RBD with an isolated brainstem vascular lesion [18], neurodegenerative diseases that could affect the dorsomedial pontine tegmentum regions and/or the pontomedullary or pontospinal pathways mediating REM sleep atonia have the potential to develop RBD.

RBD/RWA in synucleinopathies According to the two large case series [23, 31], almost half of RBD cases are associated with various neurolog-

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ical disorders, especially neurodegenerative diseases. Dating back to 1981, three patients with Shy-Drager syndrome were polysomnographically proven to have RBDlike behaviours during Stage 1-REM [34]. Although the authors described the behaviour as delirious, it seems to be regarded as RBD seen in MSA. In 1997, two studies showed that about 90 % of patients with MSA had RBD/RWA, based on polysomnographic recording as well as clinical features [24, 37]. This high percentage of association could reflect diffuse brainstem pathology in MSA. Subsequently, a more extensive study has focused on patients with parkinsonism and/or cognitive impairment, comparing the frequency of suspected and PSGconfirmed RBD among subjects with synucleinopathies, MSA, PD, or DLB and among subjects with non-synucleinopathies, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), mild cognitive impairment (MCI), primary progressive aphasia (PPA), and posterior cortical atrophy (PCA) [5]. The authors concluded that patients with the synucleinopathies were more likely to have probable and PSGconfirmed RBD than subjects with the non-synucleinopathies. RBD is so common in patients with DLB that the diagnostic criteria for DLB recently included co-existence of RBD as a suggestive feature [4, 21]. In PD, the frequency of association with RBD ranges from 15 % to 34 % based on clinical symptoms of RBD [7, 29], and muscle tone abnormalities during REM sleep were documented by PSG in up to 58 % of PD patients [11]. However, RBD is not totally specific for synucleinopathies, as a few reports described RBD in tauopathies such as PSP [3] and CBD [17]. Although no detailed clinicopathological studies have been performed to see the affected and spared areas related to REM sleep-mediated atonia in any neurological disorder in which RBD was present [39], RBD is more likely to be dependent on the site of the lesions than the nature of neuropathology, based on the results of animal experiments.

Is RBD/RWA a preclinical symptom/finding of Parkinson’s disease? The first prospective study to follow up patients with idiopathic RBD was done by Schenck’s group, and showed that 11 of 29 (38 %) male RBD patients developed parkinsonism at a mean interval of 12.7 years after the

onset of RBD [32]. Two of 11 parkinsonian RBD patients were diagnosed as having MSA later. This study was updated with an additional 7 years of follow-up; in total, 17 of 26 (65.4 %) idiopathic RBD patients originally enrolled eventually developed a parkinsonian disorder and/or a dementia, after an average interval of 13 years from RBD onset [33]. The second prospective study showed similar findings [15], reporting that 20 of 44 (45 %) idiopathic RBD patients (mean age, 74.1 years; 39 males) developed a neurological disorder after a mean of 11.5 years from the reported onset of RBD. Emerging disorders were PD in 9 patients, DLB in 6, MSA with predominant cerebellar syndrome in one, and MCI in four in whom visuospatial dysfunction was prominent. The longer the follow-up interval was, the greater became the probability of finding a neurological disease. A pathophysiological explanation for the high conversion from idiopathic RBD to PD or DLB is possible on the basis of Braak’s hypothesis [6]. His group identified an extensive and stereotyped pattern of ascendant progression in PD. Lewy body pathology begins in the anterior olfactory nucleus and in the lower brainstem nuclei (Stage 1), affecting olfactory and autonomic functions initially, and progresses rostrally to affect the upper brainstem areas, such as LC and pedunculopontine nucleus (Stage 2). Classic motor symptoms of parkinsonism occur when the substantia nigra (Stage 3) is affected, and finally the cerebral cortex is affected. Combining this hypothesis with the data from RBD animal models, at least a proportion of patients with apparent idiopathic RBD may be in a preclinical stage (Stage 2) of PD, and it is possible that they will develop PD in the future with various latencies. Therefore, close follow-up of idiopathic RBD patients could enable us to detect synucleinopathies. Early detection of neurodegenerative disease is of great interest for neurologists because early intervention with effective neuroprotective drugs could be possible once this kind of drug becomes available. However, our knowledge of neuroanatomy related to sleep and its disorders is mainly based on animal studies, and how the pathological process of neurodegenerative diseases is involved in sleep remains hypothetical. Therefore, neurologists, neuropathologists, and sleep specialists need to collaborate in following up RBD patients to confirm whether they are at higher risk for developing a neurodegenerative disease, and ultimately to disclose the neuropathology of RBD.

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