Effectiveness of Pramipexole, a Dopamine Agonist, on Rapid Eye Movement Sleep Behavior Disorder

Tohoku J. Exp. Med., 2012, 226, 177-181 Effectiveness of Pramipexole on RBD 177

Taeko Sasai,1,2,3 Yuichi Inoue1,2 and Masato Matsuura3

1Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan 2Department of Somnology, Tokyo Medical University, Tokyo, Japan 3 Department of Life Sciences and Bio-informatics, Division of Biomedical Laboratory Sciences, Graduate School of Health Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Rapid eye movement (REM) sleep behavior disorder (RBD) is parasomnia characterized by REM sleep without atonia (RWA) and elaborate motor activity in association with dream mentation. Periodic leg movement during sleep (PLMS) is observed in a large share of patients with RBD, suggesting a common pathology: dopaminergic dysfunction. This study was undertaken to evaluate the effectiveness and mechanism of action of pramipexole, a dopamine agonist, on RBD symptoms. Fifteen patients (57-75 years old) with RBD with a PLMS index of more than 15 events/h shown by nocturnal polysomnography were enrolled. Sleep variables, the score of severity for RBD symptoms, REM density, and PLM index were compared before and after one month or more of consecutive pramipexole treatment. Correlation analysis was conducted between the rate of change in RBD symptoms and the rate of reduction of REM density. Fourteen patients with RBD (80.0%) achieved symptomatic improvement of RBD with pramipexole treatment, which reduced REM density and PLM index during non-REM sleep despite the unchanged amount of RWA. The rate of change in RBD symptoms correlated positively with the rate of REM density reduction. Significant reduction of the PLM index was observed in non-REM sleep but not in REM sleep. Pramipexole can improve RBD symptoms, possibly because of changes in dream contents or its amount manifested as the reduction of REM density. The restricted influence of pramipexole on PLMS only during non-REM sleep suggests that other factors may affect the pathophysiology of PLMS during the REM sleep period in RBD.

Keywords: dopaminergic function; periodic leg movements; pramipexole; REM sleep behavior disorder; REM sleep without atonia Tohoku J. Exp. Med., 2012, 226 (3), 177-181. © 2012 Tohoku University Medical Press

Rapid eye movement (REM) sleep behavior disorder REM sleep periods. Moreover, the pathophysiology of (RBD) is a parasomnia characterized by dream-enacting PLMS in idiopathic RBD remains unsolved. behavior associated with REM sleep without atonia (RWA). Episodes of violent behavior in RBD are mostly asso- Although the pathogenesis of RBD remains unclear, RBD ciated with nightmares. However, no report describes the is frequently associated with α-synucleinopathies including effectiveness of pramipexole for alleviating nightmares in Parkinson disease (PD), dementia with Lewy bodies, and RBD or its relation to REM density, which possibly triggers multiple system atrophy. It has been widely accepted that dream imagery (Ogawa et al. 2005). RBD represents a prodromal phase of these diseases (Olson To elucidate the mechanism of pramipexole action on et al. 2000; Boeve and Saper 2006; Iranzo et al. 2006; the pathogenesis of RBD, we investigated its effects on Postuma et al. 2006). RBD symptoms, with particular attention to REM-related Periodic leg movement during sleep (PLMS) is often parameters and PLMS in this pilot study. comorbid with RBD, suggesting a common pathogenesis of the two disorders. Its frequency in RBD is higher than that Methods seen in the normal population, especially during the REM Subjects sleep period (Fantini et al. 2002). Although two previous This study was approved by the ethical committee of the case series investigated the effectiveness of pramipexole on Neuropsychiatric Research Institute. During August 2006 - December RBD symptoms (Fantini et al. 2003; Schmidt et al. 2006), 2008, 15 consecutive patients (man : woman = 8 : 7, age [range] = these studies did not respectively examine the effect of 65.7 [57-75] years), who were diagnosed with idiopathic RBD pramipexole on PLMS during non-REM (NREM) and according to the International Classification of Sleep Disorders sec- Received December 20, 2011; revision accepted for publication February 3, 2012. doi: 10.1620/tjem.226.177 Correspondence: Taeko Sasai, Japan Somnology Center, Neuropsychiatric Research Institute, 1-17-7 Yoyogi, Shibuya-ku, Tokyo, Japan. e-mail: [email protected]

177 178 T. Sasai et al. ond edition (ICSD-2) published by the American Academy of Sleep of RBD symptoms was calculated by taking the difference in the Medicine (AASM 2005) and who showed a PLMS index of more scores of RBD symptoms obtained before and after medication and than 15 events/h on nocturnal polysomnography (n-PSG), were dividing that difference by the score before medication. PLMS was enrolled in this study. All patients had no other sleep disorder or scored according to the criteria set by AASM (AASM 2007). PLMS symptom suggestive of neurodegenerative disorder and/or dementia. was distinguished carefully from phasic EMG activity on the anterior After diagnosis with PSGs and clinical interviews, the patients began tibialis muscle during stage REM by consideration of the periodicity treatment with pramipexole and underwent a second n-PSG more or amplitude of leg movements. than 3 months after starting the treatment. All the patient subjects were drug naïve before starting the treatment for RBD. All patients Statistical analysis who had taken any concomitant treatments other than pramipexole Using Wilcoxon signed rank tests, scores of RBD symptoms were excluded from this study. and sleep variables before and after treatment were compared. Correlation between the rate of change of the RBD symptoms and the PSG variables rate of reduction of REM density was investigated using Spearman’s Sleep stages were scored according to criteria set by rank correlation coefficient. Rechtschaffen and Kales. The RWA and REM density were scored according to a previously described method (Consens et al. 2005). Results REM density was defined as the ratio of the number of 3-s epochs of Kolmogorov-Smirnov tests revealed that the sleep REM sleep with at least 1 REM divided by the total number of all 3-s variables were not normally distributed. Table 1 shows that epochs with REM sleep. The reduction rate of REM density with the the mean dosage of pramipexole was 0.21 ± 0.09 mg/day. treatment was calculated by dividing the difference in the REM den- sities measured before and after medication by the value of REM The mean duration of the treatment before the second density before medication. The severity of RBD symptoms was n-PSG was 9.1 ± 7.1 months. Subjective assessment assessed according to criteria explained in the revised edition of revealed that 12 patients (80%) achieved clear improvement ICSD-1 (AASM 2001) based on reports of the frequency and intensity with the pramipexole treatment: 50% reduction in the score of vocalization or dream enactment behavior obtained from patients for severity of RBD symptoms. The scores of severity for or their family members. Additionally, we assessed the subjective RBD symptoms after pramipexole treatment were signifi- frequency of nightmares based on their reports. The rate of reduction cantly lower than those before the treatment (Z = −3.376,

Table 1. RBD symptoms before and after treatment with pramipexole.

Dosage of Length of Score of severity for Disappearance Improvement Patient 1) Age Sex pramipexole treatment RBD symptoms of nightmares of nightmares2) no. (mg/day) (months) before treatment after treatment after treatment after treatment 1 69 M 0.125 8 2 1 + 2 72 F 0.250 4 2 2 3 63 F 0.375 21 3 1 + 4 57 M 0.250 25 3 1 + 5 61 F 0.250 17 3 1 + 6 64 F 0.375 13 3 1 + 7 75 M 0.250 4 3 1 + 8 75 M 0.250 6 3 2 9 64 F 0.125 3 3 1 10 63 M 0.125 4 3 2 + 11 63 F 0.125 5 3 1 + 12 69 M 0.125 5 3 1 13 67 F 0.125 3 2 1 + 14 59 M 0.250 3 3 0 + 15 69 M 0.125 6 3 0 + 66.5 ± 5.2 M:F = 8:7 0.2 ± 0.1 8.0 ± 7.0 2.8 ± 0.4 1.1 ± 0.6* RBD, REM sleep behavior disorder. *p < 0.01 compared to the score of severity of RBD symptoms before treatment. 1)Severity of RBD symptoms are scored for 0 = none; 1 = REM sleep behavior occurs less than once per month and causes only mild discomfort for the patient or bed-partner, 2 = REM sleep behavior occurs more than once per month but less than once per week and is usually associated with physical discomfort to the patient or bed-partner, 3 = REM sleep behavior occurs more than once per week and is associated with physical injury to the patient or bed-partner. 2)Improvement of nightmares means 50% or more reduction of frequency of nightmare. Effectiveness of Pramipexole on RBD 179

Table 2. Polysomnograhic variables before and after treatment with pramipexole. before treatment after treatment p total sleep time (minutes) 402.8 ± 63.4 409.0 ± 88.6 n.s. Sleep efficiency (%) 82.5 ± 10.3 79.4 ± 14.1 n.s. Stage 1 (%SPT) 6.8 ± 3.3 7.5 ± 3.4 n.s. Stage 2 (%SPT) 51.8 ± 9.8 52.5 ± 12.3 n.s. Stage 3 + 4 (%SPT) 5.0 ± 5.5 3.0 ± 2.8 n.s. Stage REM (%SPT) 11.3 ± 4.9 14.7 ± 6.8 n.s. RWA (%SPT) 7.7 ± 5.2 5.7 ± 3.8 n.s. RWA (%REM) 39.2 ± 19.3 34.7 ± 21.6 n.s. tonic REM (%/REM) 11.2 ± 8.7 9.8 ± 11.1 n.s. phasic REM (%REM) 28.1 ± 18.9 24.5 ± 21.4 n.s. WASO (%SPT) 17.4 ± 10.3 20.6 ± 14.2 n.s. REM density (%) 23.3 ± 10.0 16.2 ± 8.4 < 0.01 PLMS index (events/hour) 38.4 ± 17.9 19.2 ± 20.7 < 0.01 PLMS arousal index (events/hour) 4.7 ± 5.4 1.5 ± 2.2 < 0.01 PLMS index during NREM sleep (events/hour) 36.0 ± 16.7 11.1 ± 16.4 < 0.01 PLMS index during REM sleep (events/hour) 39.4 ± 31.6 33.5 ± 35.1 n.s.

Values are expressed as mean ± s.d. SPT, sleep period time; REM, rapid eye movement; RWA, REM sleep without atonia; WASO, wake after sleep onset; PLMS, periodic leg movements during sleep. p < 0.01). All the patient subjects complained of frequent (Fantini et al. 2003; Schmidt et al. 2006). Fantini et al. nightmares before treatment. After pramipexole treatment, (2003) reported that 7 of 8 patients reported reduced RBD five patients (33.3%) reported complete disappearance of clinical manifestations after pramipexole treatment. nightmares, the number of patients having nightmares Schmidt et al. (2006) also reported that pramipexole miti- decreased to six patients (40.0%). Consequently, among gated the RBD symptom severity. However, to date, the the 12 patients who achieved clear improvement of RBD mechanism of action of pramipexole on RBD symptoms symptoms, 10 patients (83.3%) reported disappearance or remains unclear. improvement of nightmares. This study is the first to investigate the influence of Regarding n-PSG measures, no significant differences pramipexole on RBD symptoms, PLMS-related variables, in the sleep stage variables, including the amount of RWA, and REM-related PSG variables simultaneously. The were found between those assessed before and after treat- results of our study show that pramipexole treatment ment with pramipexole. However, the REM density after improved RBD symptoms in 80.0% patients, suggesting the treatment was significantly lower than the value before that pramipexole is effective for the treatment of idiopathic the treatment (Z = −2.556, p < 0.01). Among PLMS mea- RBD. Fantini et al. (2003) reported that pramipexole treat- sures, the PLMS index during the sleep period as a whole ment decreased neither the amount of phasic EMG activity (Z = −3.238, p < 0.01), the index during NREM sleep nor the REM density. Consistent with their finding, the period (Z = −3.351, p < 0.01), and the PLMS arousal index amount of RWA did not decrease in this study. Zhang et al. (Z = −3.297, p < 0.01) decreased significantly after the (2008) reported that RBD episodes do not occur commonly treatment. Nevertheless, no significant change in PLMS during one-night PSG monitoring and reported that the index was observed during the REM sleep period (Table 2). occurrence tends to show high night-to-night variation. In Regarding the relation between the RBD symptoms the present study, however, RBD symptoms examined and the REM density, positive correlation was found before and after treatment were evaluated according to between the reduction rate of RBD symptoms and that of reports about RBD symptoms obtained from the patients or REM density with pramipexole treatment (rs = 0.785, p < their family members. The severity was rated according to 0.01) (Fig. 1). the revised edition of ICSD-1. Therefore, the improvement of RBD symptoms after treatment was not explained by the Discussion night-to-night variation of the occurrence of RBD episodes. According to a recent review of the effectiveness of Regarding EMG activity, Zhang et al. reported high correla- interventions in RBD (Aurora et al. 2010), only two reports tions in both tonic and phasic EMG activities between night have described published studies that evaluated the effec- 1 and night 2 (tonic, r = 0.82; phasic, r = 0.83). tiveness of pramipexole treatment on idiopathic RBD Accordingly, no difference in the amount of RWA between 180 T. Sasai et al.

Fig. 1. Correlation between the rate of reduction of RBD symptom scores and REM density following treatment with pramipexole. REM, rapid eye movement; RBD, REM sleep behavior disorder. those measured before and after treatment was thought to ing nightmares, engendering improvement in RBD symp- depend on the night-to-night variation of the amount of toms in patients with idiopathic RBD. In this regard, the RWA; pramipexole cannot influence RWA. effect of pramipexole on idiopathic RBD might differ from Inconsistent with Fantini’s report, a significant that on secondary RBD in PD patients who are already tak- decrease in REM density after treatment with pramipexole ing high-dosage dopaminergic medication (Kumru et al. was observed in this study. The reason for the inconsis- 2008). Effects of pramipexole might differ depending on tency in REM density findings remains unknown. differences in the dosage of dopaminergic medication or in Nevertheless, it is noteworthy that in the present study, the the presence or absence of neurodegenerative disorders changes in RBD symptoms with pramipexole treatment (Aurora et al. 2010). Further study is necessary to clarify were associated significantly with the reduction of REM this issue. density. This study lacked data related to comparison It remains unclear whether dopaminergic dysregula- between RBD patients and the control group. However, tion is involved in PLMS in RBD. Fantini et al. (2003) Tachibana et al. reported previously that RBD patients reported no change in the PLMS index in patients with showed a significantly higher REM density than that of RBD after pramipexole treatment. However, no report in control subjects (Tachibana et al. 1994). Reportedly, neural the relevant literature describes the influence of pramipex- activity in the parieto-occipital visual cortex after the ole on PLMS in RBD during NREM and REM sleep peri- appearance of REMs during the REM sleep period can trig- ods. The results of the present study demonstrated that ger dream imagery (Ogawa et al. 2005; Miyauchi et al. selective improvement of PLMS during NREM sleep 2009). Based on these earlier reports and the results of the period occurs in patients with idiopathic RBD. Bliwise and present study, the improvement in RBD symptoms associ- Rye (2008) reported that, in comparison with healthy con- ated with the reduction of REM density indicates that the trols, higher EMG activity detected by the phasic electro- effectiveness of pramipexole on RBD symptoms depends myographic metric (PEM) rate was observed in patients on a decrease in the vividness or the number of dreams with RBD, especially during REM sleep. In addition, linked closely with REM density. This idea is supported by Huang et al. (2011) reported that excessive electromyo- the fact that 83.3% of patients with clear improvement of graphic activities in RBD patients might ameliorate the RBD symptoms showed the reduction or disappearance of severity of OSA, especially during REM sleep, possibly nightmares after pramipexole treatment. because of activation of upper airway dilator muscles. High doses of dopaminergic drugs are known to These increased muscle activities during REM sleep might induce vivid dreams, nightmares, and RBD in PD patients also be associated with the increased PLMS and its weak (Kulisevsky and Roldan 2004; Gjerstad et al. 2008). In responsiveness to pramipexole treatment during REM sleep contrast, consistent with previous studies (Fantini et al. in RBD patients. Consequently, the difference in the effec- 2003; Schmidt et al. 2006), the results of our study suggest tiveness of pramipexole treatment might indicate that that a low dose of pramipexole can be effective for reduc- PLMS during REM sleep period has a pathology associated Effectiveness of Pramipexole on RBD 181 with a lack of REM sleep motor inhibition probably 60-64. because of brainstem dysfunction (Fantini et al. 2002) Boeve, B.F. & Saper, C.B. (2006) REM sleep behavior disorder: a possible early marker for synucleinopathies. Neurology, 66, rather than dopaminergic dysfunction. 796-797. However, this study presents some limitations. First, Consens, F.B., Chervin, R.D., Koeppe, R.A., Little, R., Liu, S., this study was not a randomized controlled investigation. Junck, L., Angell, K., Heumann, M. & Gilman, S. (2005) Second, the participating subjects were enrolled from one Validation of a polysomnographic score for REM sleep behavior disorder. 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