Comparison of the clinical features of rapid eye movement sleep behavior disorder in patients with Parkinson's disease and multiple system atrophy
Takashi Nomura, MD, PhD, Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, 36-1 Nishicho, Yonago 683-8504, Japan. Email: firstname.lastname@example.org
Aims: The aim of this study was to evaluate differences in the clinical presentation and polysomnographic characteristics of rapid eye movement sleep behavior disorder (RBD) between patients with Parkinson's disease (PD) and those with multiple system atrophy (MSA).
Methods: We conducted clinical interviews examining RBD symptoms, including violent and non-violent behaviors, in 49 patients with PD and 16 patients with MSA (as well as their bed partners) and performed polysomnography on all subject patients.
Results: Twenty-seven patients with PD (55.1%) and 11 patients with MSA (68.8%) had rapid eye movement sleep without atonia (RWA) on polysomnogram. The relative amounts of RWA were quite similar between the two groups. For most of the RWA-positive patients in both groups, RBD symptoms remained non-violent or silent. RBD symptoms in PD patients seemed to increase with the course of PD, while most of the RBD symptoms in the MSA patients occurred just prior to or at the onset of MSA and then disappeared within a short period.
Conclusion: Although PD and MSA frequently accompany RWA, RBD symptoms often remain non-violent or silent. Differences in the course of RBD symptoms in patients with PD and MSA may reflect the difference in the degeneration process of the two disorders.
RAPID EYE MOVEMENT (REM) sleep behavior disorder (RBD) is characterized by vigorous and injurious behaviors related to vivid, action-filled, and violent dreams during nocturnal REM sleep and REM sleep without atonia (RWA).1 Diagnosis and treatment of this disorder is one of the most important issues in the field of sleep psychiatry. According to the second edition of the International Classification of Sleep Disorders (ICSD), a clinical diagnosis of RBD can only be made when a patient displays violent, potentially violent or sleep-disruptive dream-enactment behavior along with RWA, as determined by a polysomnogram (PSG).2
RBD has been reported to occur in alpha-synucleinopathies, including Parkinson's disease (PD)3 and multiple system atrophy (MSA).4 The brainstem regions responsible for the occurrence of RBD are also known to be involved in the primary pathology of both PD and MSA.5 Longitudinal studies have shown that 17.7–65% of patients with RBD develop PD over a period of 5–20 years.6–9 For MSA, 69–100% of patients have also been reported to have RBD symptoms, which especially occur before onset of the disorder.4,10–12 These data strongly suggest that RBD symptoms may precede PD and MSA.8,9 Moreover, both PD and MSA frequently complicate RBD symptoms after the onset of these disorders.11,12 However, courses and symptomatic characteristics of RBD in patients with PD and MSA have not been elucidated, although such information could provide important clues for understanding the correlations between RBD and alpha-synucleinopathies. Such knowledge could also be helpful for physicians in preparing a treatment plan for RBD symptoms in patients with PD and MSA. In order to help clarify these issues, we investigated the clinical features, PSG findings, and courses of RBD symptoms in patients with PD and MSA.
This study was approved by the ethics committees of Tottori University, and informed consent was obtained from all of the subjects taking part in the study. Consecutive patients with PD and MSA who were hospitalized at the Department of Neurology of Tottori University from July 2004 to May 2008 were targeted. Patients taking sedative drugs and/or antidepressants, or those with no bed partners were excluded. Forty-nine patients with PD (mean age 70.3 ± 11.2 years, 21 male and 28 female) and 16 patients with MSA (60.2 ± 6.9 years, eight male and eight female) were examined. PD patients were diagnosed according to the standard criteria for the diagnosis of PD.13 The PD patients had all been receiving oral dopaminergic agents for 6.8 ± 6.4 years, and their levodopa dose equivalent14 was 347 ± 203 mg/day. The mean Hoehn and Yahr stage for the patients was 2.7 ± 0.9. Fifteen of the 49 PD patients reported having visual hallucinations that occurred mainly during the nocturnal period. MSA patients were diagnosed according to the standard criteria for the diagnosis of MSA.15 The 16 MSA subjects consisted of 12 patients with MSA-C which was defined as predominant cerebellar symptoms and four with MSA-P which was defined as predominant parkinsonism symptoms.16 The mean duration of MSA morbidity was 4.7 ± 2.4 years. Twelve of the MSA patients were treated with thyrotropin-releasing hormone (TRH) analogues, and six were taking 85.6 ± 140.0 mg/day levodopa dose equivalent of dopaminergic agents. None of the patients with MSA reported having hallucinations.
Overnight PSG recordings were performed on all the patients and included the following: electroencephalography (EEG) with four-channel scalp EEG montages (C3, C4, O1, and O2 referred to the contralateral ear), electrooculography, electromyography (EMG) (submental, left lower limb and right lower limb), oronasal airflow monitoring using thermistors, measurements of thoracic and abdominal respiratory movements with a strain gauge, transcutaneous oxygen saturation, and electrocardiography. Sleep stages were scored according to the established criteria of Rechtschaffen and Kales.17 During REM sleep, the presence of submental phasic EMG activity (3-s mini-epochs containing phasic twitches exceeding 4 times the background EMG activity) or submental tonic EMG activity (more than half of a 30-s epoch of duration) was used to determine the stage of RWA.18 Periodic limb movements in sleep (PLMS) were scored following the new standards for recording and scoring periodic limb movement,19 and the PLMS index (PLMI) was calculated. Abnormal breathing events during sleep were defined as apnea or hypopnea,20 and the apnea–hypopnea index (AHI) was estimated.21 Arousals were scored visually according to standard criteria.22
Within 1 month prior to the PSG recordings, patients and their bed partners were retrospectively interviewed by a physician specializing in sleep disorders. The interviews focused especially on dream enactment behavior or vocalization while dreaming. Patients were diagnosed as having violent RBD if they exhibited RWA on PSG and reports of dream enactment-related problematic behaviors from interviews according to criteria from the second edition of the ICSD.2 If patients had RWA and talked aloud in their sleep while dreaming but did not display violent behavior, they were defined as having non-violent RBD according to the criteria created by Oudiette et al.23 Four patients with PD (PD4, 6, 11 and 18) and one patient with MSA (MSA9) took clonazepam at the time of investigation without aiming to treat RBD, except for PD6, who suffered from severe RBD symptoms. However, none of these patients reported that their RBD symptoms improved after starting clonazepam treatment.
We compared the PSG findings and the history of violent and non-violent RBD between patients with PD and MSA. Thereafter, we calculated both the cross-sectional prevalence and the lifetime prevalence of RBD (including both violent and non-violent RBD symptoms) at the time of investigation in the PD and MSA groups. Regarding lifetime prevalence, the number of patients with experiences related to each RBD symptom category (regardless of presence/absence of symptoms at the time of investigation) was calculated as a percentage of total patients in both groups.
A χ2-test followed by rest error test was used to compare categorical variables. Comparisons of continuous variables between the two groups were made using the Mann–Whitney U-test. A comparison of the amount of RWA in patients with violent RBD, non-violent RBD, and no RBD symptoms between the two patient groups was examined using the Kruskal–Wallis test. Data are presented as the mean ± SD unless otherwise indicated. Statistical significance was defined as P < 0.05 (spss, ver. 11.5J, spss Japan, 2002).
Twenty-seven patients (55.1%) in the PD group and 11 patients (68.8%) in the MSA group had RWA on PSG at the time of the investigation. The rate of RWA was not different between the two patient groups. However, the amount of RWA relative to total sleep time in the MSA group was greater than that observed in the PD group. PLMI scores in the MSA group were also significantly higher than those from the PD group. The proportion of MSA patients with a PLMI of 15 or more was also higher compared to PD patients. There were no significant differences in the other parameters between the two groups (Table 1).
Table 1. Comparison of polysomnography findings between PD and MSA
|Total sleep time (min)||296 ± 86||252 ± 89||0.163|
|REM sleep/total sleep time (%)||8.5 ± 6.4||8.1 ± 4.2||0.629|
|RWA/total sleep time (%)||0.6 ± 1.0||1.1 ± 2.9||0.042|
|Proportion of patients with RWA (%)||55.1||68.8||0.319|
|AHI (/h)||13.1 ± 14.4||22.5 ± 24.8||0.378|
|PLMI (/h)||10.0 ± 25.9||68.2 ± 105.4||0.005|
|Proportion of patients with 15/h or more PLMS (%)||16.3||39.1||0.001|
Proportion of patients with RBD symptoms and course of symptoms in PD and MSA patients
In 27 PD patients with RWA, seven patients (25.9%) had violent RBD symptoms, 10 patients (37.0%) had non-violent RBD symptoms, and 10 patients (37.0%) reported no RBD symptoms at the time of the investigation. From these findings, we estimated the frequency of patients with violent RBD as 14.3% (7/49) for the PD patients. When non-violent RBD symptoms were included, the prevalence of RBD symptoms increased to 34.7% (17/49). In 22 PD patients without RWA, a false positivity of RBD was recognized in two patients who had experienced non-violent RBD-like symptoms once before the onset of PD.
Regarding sex distribution, PD patients with violent RBD symptoms included three men and four women, while patients with non-violent RBD symptoms included three men and seven women. Thus, there was no difference in sex distribution between the patients with violent RBD symptoms and those with non-violent RBD symptoms (χ2-test t, P = 0.642).
There was no difference in the proportion of RWA to total sleep time among the PD patients with violent RBD (1.39 ± 1.20%), non-violent RBD (1.08 ± 1.08%), or those without RBD symptoms (1.26 ± 1.21%) (P = 0.932), despite the ratio of RWA to total sleep time being higher in the patients with violent RBD than in those with non-violent RBD.
Five of the 27 PD patients with RWA (18.5%) reported having RBD symptoms before the onset of motor symptoms (PD3, 10, 12, 14, 16) (Fig. 1). In one case (PD10), symptoms of possible non-violent RBD began occurring 15 years prior to the onset of motor symptoms, and the patient developed violent RBD about 5 years after the onset. However, all other patients with non-violent symptoms did not experience a progression to more violent symptoms.
As shown in Figure 1, the number of patients with RBD symptoms seemed to increase along with prolongation of PD morbidity. Natural disappearance of symptoms was not reported for this group except for the two patients (PD2, 24) whose violent RBD symptoms disappeared within 1 year after the onset of PD. Thus, the lifetime prevalence of violent RBD was estimated at 18.4% (9/49), that of non-violent RBD at 20.4% (10/49), and that of total RBD symptoms at 38.8% (19/49) in this patient population.
There was a significant difference in the number of patients experiencing visual hallucinations between the groups with and without RBD symptoms (10/17 vs 5/32, P = 0.002). Ten out of 15 PD patients who were having hallucinations (66.7%) developed clear symptoms after the appearance of RBD symptoms. In addition, in the two cases mentioned above (PD2, 24), nocturnal visual hallucinations disappeared almost simultaneously with the disappearance of RBD symptoms.
Among 11 MSA patients with RWA, one patient (9.1%) had violent RBD symptoms and three patients (27.3%) had non-violent RBD symptoms at the time of the investigation. Thus, the cross-sectional prevalence of patients with violent RBD in the MSA patients at the time of the investigation was 6.3% (1/16). When non-violent RBD symptoms were included, the prevalence of RBD symptoms increased to 25.0% (4/16). Among five patients without RWA, a false positivity of RBD was recognized in three patients (two cases reported having violent RBD-like symptoms and one reported having non-violent RBD-like symptoms).
Among the MSA patients with RWA there was no difference in the proportion of RWA to total sleep for those with violent RBD (0.4%), non-violent RBD (4.0 ± 5.0%), and no RBD symptoms (4.5 ± 3.92%) (P = 0.231).
Seven out of 11 MSA patients with RWA (MSA2, 4, 5, 6, 7, 8, 10) clearly reported the development of RBD symptoms before the onset of MSA, but only one patient (MSA9) experienced symptoms after the onset of the disorder (Fig. 2). In four of the eight patients with experiences of RBD symptoms (MSA2, 5, 6, 7), the symptoms disappeared within 3 years after the onset of MSA, while symptoms were still present in the other four patients (MSA4, 8, 9, 10) at the time of the investigation. The lifetime prevalence for violent RBD symptoms was estimated at 18.8% (3/16), that of non-violent RBD at 31.3% (5/16), and that of total RBD symptoms at 50.0% (8/16) in this MSA patient population.
Regarding sex, the one MSA patient who had violent RBD symptoms at the time of the survey was male, while the three MSA patients having non-violent RBD symptoms were female. Regarding the lifetime prevalence of RBD symptoms, MSA patients with a history of violent symptoms included two men and one woman, and MSA patients with non-violent RBD symptoms also included two men and three women.
Comparison between PD and MSA (Table 2)
Table 2. Correlations between occurrence of RBD-related symptoms and motor symptoms, and existence of RWA
|Patients with RWA who showed RBD-related symptoms before the onset of motor symptoms||5 (10.2)||7 (43.8)*|
|Patients with RWA who showed RBD-related symptoms after the onset of motor symptoms||14 (28.6)||1 (6.3)|
|Patients with clinically silent RWA||8 (16.3)||3 (18.7)|
|Patients without RWA||22 (44.9)||5 (31.3)|
Five PD patients (10.2%) and seven MSA patients (43.8%) with RWA experienced RBD symptoms before the onset of motor symptoms. On the other hand, 14 PD patients (28.6%) and only one MSA patient (6.3%) reported having RBD symptoms after the onset of motor symptoms. Eight patients with PD (16.3%) and three patients with MSA (18.7%) reported no experience of RBD symptoms in their clinical histories despite the clear existence of RWA on PSG. Twenty-two patients with PD (44.9%) and five patients with MSA (31.3%) had no RWA. The distribution of patients divided by both the existence of RWA and the period of appearance of RBD symptoms for these two groups were significantly different (P = 0.014). The rest error test revealed that the MSA group had a larger number of patients with RBD symptoms that appeared before the onset of motor symptoms compared with the PD group.
Our results showed that both PD and MSA patients frequently show RWA on PSG, which is consistent with results from previous studies.10,24,25 However, in this study, the calculated lifetime prevalence of violent RBD symptoms was 18.4% in the PD group and 18.8% in the MSA group, both of which were remarkably lower than rates previously reported.4,7,10,11 The reason for this phenomenon is unclear. However, considering that the higher prevalence of RBD reported in previous studies (especially in PD patients) was diagnosed after relatively long periods of the disorder, the short PD morbidity length in our subject population might contribute to the observed lower prevalence rate of RBD. In addition, an unexpectedly high number of patients with PD and MSA reported experiencing non-violent RBD symptoms. After combining patients with violent RBD and those with non-violent RBD, the prevalence of RBD seems to not be so low relative to previous reports.
A study by Iranzo et al. showed that subjects with MSA or PD had a lower severity of RBD than those with idiopathic RBD.24 Frauscher et al. also reported that RBD patients with parkinsonian symptoms show few motor events and violent episodes on PSG.26 Taking these reports and our present results together, it is possible that RBD symptoms in a significant number of PD and MSA patients remain mild. However, a future follow-up study will determine whether non-violent RBD symptoms in our subject patients progress to violent RBD symptoms.
Interestingly, in our study there was no difference in the rate of RWA among patients with violent RBD, patients with non-violent RBD, and those without RBD symptoms in either MSA or PD patients. This result might indicate that RBD pathology remains mild or clinically silent in MSA and PD regardless of the amount of RWA. Thus, it could be possible that the existence of RWA is necessary, but hardly sufficient, for the appearance of clinical RBD.
Generally, patients with idiopathic RBD are predominantly male.1,2 However, the patients with MSA and PD having RBD in this study did not show a male predominance. This finding is consistent with previous reports on PD patients with RBD.27,28 Taking this into account, there may exist differential gender distribution characteristics between idiopathic RBD and secondary RBD complicated with α-synucleinopathies.
Some studies have indicated that many patients with idiopathic RBD develop α-synucleinopathies.8 This concept corroborates the proposed staging for the neuropathological process of PD outlined by Braak et al.29 However, a majority of our PD patients reported having RBD symptoms after the onset of motor symptoms, and only less than 20% of them reported that their RBD symptoms occurred prior to the onset of motor symptoms. The reason for this phenomenon is unclear. However, it might be possible that PD patients who develop from ‘idiopathic RBD’ constitute only a small percentage of the total PD population.
In the PD group, the number of patients with nocturnal visual hallucinations was significantly larger in those with RBD symptoms than in those without. Interestingly, some cases showed the disappearance of violent RBD symptoms in conjunction with the disappearance of visual hallucinations. Although a causal correlation between RBD and hallucinations remains controversial,27 these findings corroborate our previous report30 as well as reports by Arnulf et al.31 and Sinforiani et al.28 suggesting that there is a pathophysiological correlation between visual hallucination and RBD in PD patients.
Patients with MSA had a significantly higher rate of RWA as well as higher PLMI scores than those with PD. This finding is consistent with the result reported by Iranzo et al.24 However, it is noteworthy that RBD symptoms in this patient group displayed a limited appearance in the period shortly before the onset of other neurological symptoms, but mostly disappeared within a few years after the onset of neurological symptoms. The neurodegeneration of MSA is known to spread more rapidly and widely compared with PD.5 Considering this characteristic, it is possible that RBD symptoms in MSA patients could disappear upon worsening of their neurological condition due to progressive degeneration of the neuronal structures in the brain stem responsible for the occurrence of RBD. In addition, severe motor symptoms in patients with advanced MSA might mask RBD symptoms. We found that the number of MSA patients with RBD symptoms did not increase with the course of the disease. This finding could be in line with a previous report in which RBD episodes of MSA patients diminished along with the occurrence of status dissociatus over the course of the disease.32 Thus, we speculate that RBD symptoms in patients with MSA are likely to disappear with aggravation of MSA.
With respect to PD, Lavault et al. reported the fluctuation and disappearance of RBD symptoms in some patients with the disorder.27 However, considering the report by Gjerstadt et al. in which the frequency of RBD in PD increased over 8 years of follow-up investigation,33 a longer-term follow up might be necessary to evaluate changes in RBD status throughout the disease course of PD.
The present study has several limitations. First, especially with regard to MSA, our study was conducted on only a small number of patients, which might have led to a sampling bias. Second, we could not use video PSG and this methodological inadequacy might have led to some misidentification of RBD symptoms.
Our study could not yield compelling evidence that the synuclein pathology described in Braak Stage 2 provides a neural substrate for RBD.34 However, patients with both MSA and PD frequently have RWA on PSG even though RBD symptoms remain mild or silent in a majority of these patients. The course of RBD symptoms can differ between PD and MSA, possibly reflecting neuropathological differences and severity of motor symptoms. Future studies, including interviews and polysomnographic evaluations of patients with MSA and PD, will be necessary to draw better conclusions regarding these issues.
This work was supported in part by the Research Committee for Ataxic Diseases, the Ministry of Health and Welfare, Japan.