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Orthostatic hypotension and cardiac sympathetic denervation in Parkinson disease patients with REM sleep behavioral disorder
Journal of the Neurological Sciences 362 (2016) 59–63
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Orthostatic hypotension and cardiac sympathetic denervation in Parkinson disease patients with REM sleep behavioral disorder Joong-Seok Kim a,⁎, Hyung-Eun Park a, Yoon-Sang Oh b, Si-Hoon Lee a, Jeong-Wook Park c, Byung-chul Son d, Kwang-Soo Lee a a
Department of Neurology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Department of Neurology, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Department of Neurology, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea d Department of Neurosurgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea b c
a r t i c l e
i n f o
Article history: Received 5 August 2015 Received in revised form 5 December 2015 Accepted 12 January 2016 Available online 15 January 2016 Keywords: Parkinson's disease Rapid eye movement sleep behavioral disorder (RBD) Orthostatic hypotension (OH) Cardiac sympathetic denervation 123 I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy
a b s t r a c t Background: Rapid eye movement (REM) sleep behavioral disorder (RBD), orthostatic hypotension (OH), and cardiac sympathetic denervation were commonly observed in PD and are related in both the premotor and motor periods. This study is intended to evaluate if the OH and cardiac sympathetic denervation found in PD are associated with RBD. Methods: Among 94 non-medicated and mild PD patients, 53 had RBD. Orthostatic vital signs and ambulatory 24hour blood pressure values were recorded. 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy as obtained in all patients. The association between orthostatic hypotension, supine hypertension, nocturnal hypertension, non-dipping, myocardial MIBG uptake, and RBD was analyzed. Results: RBD was associated with orthostatic hypotension. Patients with RBD had higher systolic blood pressure changes during orthostasis and lower myocardial MIBG uptake than patients without RBD and controls. Patients with OH also had lower mean H/M ratios those in the non-OH group. Conclusion: This study showed that RBD was closely associated with OH and cardiac sympathetic denervation in patients with early and mild PD. The result also suggests that impaired cardiac sympathetic innervation could be the mechanism behind OH in PD. This association may be closely correlated with Braak alpha-synuclein pathogenetic sequences, which would account for the clinical spectrum of PD. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Rapid eye movement (REM) sleep behavioral disorder (RBD) is one of the commonest non-motor symptoms in Parkinson's disease (PD), affecting 15–60% of patients [1]. While it is not associated with the severity of motor symptoms, it is related to cognitive dysfunction and precedes dementia in PD [2]. RBD is an independent risk factor for the development of PD and may present several years before motor symptoms appear [2,3]. A variety of cardiovascular autonomic abnormalities have been noted in PD, including orthostatic hypotension (OH), supine hypertension (SH), nocturnal hypertension (NH), and absence of normal nocturnal blood pressure (BP) fall (“non-dipping”) [4]. These abnormalities are related to each other. It can occur independently of levodopa treatment and early in the course of disease [5,6]. In addition, ⁎ Corresponding author at: Department of Neurology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea. E-mail address: [email protected] (J.-S. Kim).
http://dx.doi.org/10.1016/j.jns.2016.01.020 0022-510X/© 2016 Elsevier B.V. All rights reserved.
these disturbances appear more frequently as the disease progresses, and it can influence subjective symptoms, quality of life, and disease treatment [7]. Metaiodobenzylguanidine (MIBG) is a physiologic analogue of norepinephrine, and iodine-123 (123I) MIBG cardiac scintigraphy is a noninvasive tool used to estimate myocardial sympathetic denervation [8]. Cardiac MIBG uptake was decreased in patients with Lewy body diseases such as PD and dementia with Lewy bodies (DLB). Therefore, it is useful for early differentiation of PD from atypical Parkinsonism and DLB from Alzheimer's disease. MIBG may also be helpful in the early detection of a subject with premotor PD [8,9]. RBD, autonomic dysfunctions, and cardiac sympathetic denervation were commonly observed in PD [1,3,8–10]. PD patients with clinical RBD had reduced MIBG uptake compared to those with normal REM sleep [10]. The hypothesis tested in this study was that the cardiovascular autonomic dysfunctions and cardiac sympathetic denervation found in early PD are associated with RBD. We assessed whether RBD was related to orthostatic hypotension, supine hypertension, nocturnal hypertension, or non-dipping and cardiac sympathetic denervation in Korean patients with early and mild PD.
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2. Methods 2.1. Subjects The institutional review board of St. Mary's Hospital approved this study's protocol, and each patient provided written informed consent for participation. Ninety-four patients at the Department of Neurology at Seoul St. Mary's Hospital between March 2013 and December 2014 were diagnosed with PD according to the UK brain bank criteria [11]. None of the patients had ever taken anti-Parkinsonian medication. Twenty-five healthy elderly subjects free from Parkinsonism and RBD were enlisted to serve as controls. Clinical information obtained included age, sex, disease duration, history of arterial hypertension, history of diabetes mellitus (DM), history of cigarette smoking, and current medication use. All patients underwent detailed clinical evaluations, including laboratory tests for lipid profiles and serum homocysteine. Exclusion criteria were patients (1) with neurological abnormalities related to atypical PD or secondary Parkinsonism, (2) with a history of diabetic neuropathy or other peripheral/autonomic neuropathy, (3) with a previous relevant cardiac disease, or any abnormalities on routine chest radiography and electrocardiography, (4) taking medications known to influence autonomic functions and drugs reported to influence cardiac MIBG uptake. All patients were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) and the modified Hoehn and Yahr (H&Y) stage. All blood pressure monitoring was performed after discontinuing antihypertensive drugs for more than 7 days. Patients were educated to abstain from drinking alcohol or coffee the day before the study. 2.2. RBD diagnosis Patients were administered the REM sleep behavior disorder screening questionnaire (RBDSQ), a 10-item questionnaire with scores ranging from 0 to 13 [12]. Bed partners were also asked question 1 of the Mayo questionnaire (MQ1) [13]: “Have you ever seen the patient appear to ‘act out his/her dreams’ while sleeping? (punched or flailed arms in the air, shouted or screamed)”. Both the RBDSQ test scores ≥5 and a response of “yes” on the MQ1 were considered consistent with RBD. Single, isolated episodes were disregarded and only recurrent episodes were taken into consideration. Subjects reporting only a single episode of somniloquy and/or vivid dreams were not included in this group. 2.3. Tilt testing Continuous electrocardiographic and noninvasive blood pressure monitoring leads were connected in each patient (YM6000, Mediana Tech, Redmond, WA, USA). After 30 min of supine rest, head-up tilt testing (20 min at 60°) was performed using the Manumed Special Tilt1section (ENRAF NONIUS, Rotterdam, The Netherlands). Blood pressure was measured in the upper limb every 5 min before and 1, 3, 5, 10, 15 and 20 min during tilt, 1 min post-tilt, and as indicated for patient safety. Supine baseline and the lowest tilt values for blood pressure were recorded. For statistical analysis, the lowest values between 3 and 5 min were chosen. Orthostatic hypotension was defined as a fall in BP of at least 20 mm Hg systolic BP and/or 10 mm Hg diastolic BP measured between 2 and 5 min after the tilt [14,15]. Subjects with systolic pressure ≥140 mm Hg or diastolic pressure ≥90 mm Hg were considered to have supine hypertension [16–18]. 2.4. Ambulatory blood pressure monitoring Automated 24-hour BP recording instruments (Mobil-O-Graph NG, I.E.M., Stolberg Germany) with an upper arm cuff were used to measure blood pressure and heart rate every 15 min during the day and every
30 min at night. The accuracy of this device was validated previously [19]. The following parameters were evaluated: average systolic and diastolic blood pressure and heart rate for daytime, nighttime and 24-h periods. Daytime and nighttime blood pressure was defined using narrow clock-time intervals (day from 10.00 to 20.00 and night from midnight to 06.00) [20]. Nocturnal falls in blood pressure and heart rate were calculated as percent changes between daytime and nighttime mean values. Subjects with b10% nocturnal fall in mean blood pressure were considered “non-dippers” [21]. Nocturnal hypertension was defined according to the 2007 European Hypertension Society/European Cardiology Society guidelines (i.e., average nighttime BP ≥ 120/70 mm Hg) [22,23]. 2.5. MIBG scintigraphy MIBG scintigraphy was performed and data was collected for 30 min (early) and 2 h (late) after injecting 111 MBq of 123I-MIBG using a dual head camera (Siemens, Munich Germany), and a static image was obtained with a 128 × 128 matrix. Regions of interest were manually drawn around the heart, mediastinum and thyroid. Tracer uptake was measured within each region of interest to calculate the heart to mediastinum (H/M) ratio. Patients were stratified to normal and low MIBG uptake group according to healthy controls; the range of normal H/M ratio was calculated as above mean (2.26280) − 2 × stanstandard deviation (0.23117) of age-matched normal controls (cutoff value = 1.80046). 2.6. Statistical analysis Statistical analysis was performed with SPSS software version 22.0. Independent sample t-tests or one-way ANOVAs (with Bonferroni post-hoc testing) were used to compare groups and Pearson's χ2 tests were used to compare frequencies for categorical variables. A forward binary logistic regression model was performed to study factors that may contribute to the development of RBD in PD patients. The presence of RBD was considered a dependent variable while age, sex, disease duration, hypertension, diabetes mellitus, nonsmoking, UPDRS score, supine hypertension (or supine SBP), orthostatic hypotension (or ΔSBP during tilt test), nocturnal hypertension (or nighttime SBP), nondipping (percent of dipping), and late H/M ratio were considered covariables. A p-value b 0.05 was considered significant. 3. Results All blood pressure monitoring was performed after discontinuing antihypertensive drugs for 8.5 ± 1.1 days. During the period, no serious clinical problem was observed. Ambulatory blood pressure was recorded without interruption in all subjects with a mean measurement period of 23.1 ± 1.4 h and the average number of measurements obtained during the recording was 67.7 ± 6.7. Among patients with OH, the mean tilting time of tilt before orthostatic symptoms was 3.6 ± 1.2 min. All patients without OH were tested for 20 min of tilt. Among the 94 PD patients, 50 were women (53.2%). Mean age (± SD) was 66.8 ± 10.8 years, and mean disease duration was 1.8 ± 1.4 years. Total UPDRS and H&Y stage scores were 27.3 ± 15.2 and 1.7 ± 0.7, respectively. Compared to controls, the proportion of arterial hypertension and orthostatic hypotension in PD patients was higher (Tables 1 and 2). Fifty-three (56.4%) patients had RBD, based on the both questionnaires. The PD + RBD group and PD–no RBD group were similar in sex, medical history, and severity of PD. The PD + RBD group was older than the PD–no RBD group (Table 1). Patients with PD + RBD had more orthostatic hypotension than the PD–no RBD group and controls (Table 2). The nadir pressure during tilt was lower in the PD + RBD group than in the PD–no RBD group and controls (ΔSBP during tilt, mm Hg; controls vs. no RBD vs. RBD, 3 ± 9 vs. 6 ± 13 vs. 15 ± 13,
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Table 1 Demographics of Parkinson disease's patients with/without REM sleep behavioral disorder and controls.
Age, year, mean ± SDa No. of men, n (%)b Disease duration, year, mean ± SDa Hypertension, n (%)b Diabetes mellitus, n (%)b Current or ex-smoker, n (%)b H&Y stage, mean ± SDa UPDRS, mean ± SDa UPDRS part 1, intellectual UPDRS part 2, ADL UPDRS part 3, motor
PD (n = 94)
Controls (n = 25)
p
No RBD (n = 41)
RBD (n = 53)
p
66.8 ± 10.8 44 (46.8%) 1.8 ± 1.4 38 (40.4%) 15 (16.0%) 24 (25.5%) 1.7 ± 0.7 27.3 ± 15.2 3.0 ± 2.1 8.2 ± 5.9 16.1 ± 9.4
67.4 ± 4.8 6 (24.0%) – 4 (16.0%) 3 (12.0%) 7 (28.0%) – – – – –
0.776 0.040
63.3 ± 12.0 20 (48.8%) 2.1 ± 1.6 14 (34.1%) 8 (19.5%) 11 (26.8%) 1.6 ± 0.6 24.5 ± 10.3 2.4 ± 1.8 7.2 ± 3.9 14.7 ± 6.8
69.5 ± 8.9 24 (45.3%) 1.5 ± 1.2 24 (45.3%) 7 (13.2%) 13 (24.5%) 1.8 ± 0.7 29.5 ± 18.0 3.4 ± 2.2 9.1 ± 7.0 17.2 ± 10.9
0.005 0.736 0.037 0.275 0.408 0.800 0.305 0.118 0.024 0.160 0.203
0.023 0.624 0.803
Abbreviations: H&Y = Hoehn and Yahr, PD = Parkinson's disease, RBD = REM sleep behavioral disorder, UPDRS = Unified Parkinson's Disease Rating Scale. a Analyses were performed by independent sample t-test. b Analyses were performed by χ2 test.
p b 0.001; Fig. 1). In addition, mean supine blood pressure values were mildly elevated in the PD + RBD group compared to those in the PD–no RBD group and controls (supine SBP, mm Hg; controls vs. no RBD vs. RBD, 123 ± 14 vs. 122 ± 16 vs. 130 ± 17, p = 0.040) (supplementary e-table 1 and Fig. 1). Patients with PD + RBD had higher frequency of low MIBG uptake with late H/M ratio ≤ 1.8 than the PD–no RBD group (Table 2). The mean late H/M ratio was lower in patients with PD + RBD than in those with PD–no RBD and controls (controls vs. no RBD vs. RBD, 2.3 ± 0.2 vs. 1.7 ± 0.5 vs. 1.5 ± 0.4, p b 0.001, Fig. 1). Twenty-five (26.6%) patient had OH, with ΔSBP during tilt ≥ 20 mm Hg. The PD + OH group was older than the PD–no OH group (no OH vs. OH, 65.1 ± 11.0 vs. 71.6 ± 8.5, p = 0.009). The PD + OH group and PD–no OH group had similar sex makeup, disease duration, UPDRS and H&Y score, presence of hypertension and DM, and smoking habitus (supplementary e-table 2). Patients with PD + OH tended to have higher orthostatic ΔSBP and lower nocturnal BP dip, higher nighttime SBP and decreased myocardial MIBG uptake than those with PD–no OH and controls (Fig. 2). On forward stepwise binary logistic regression analyses, orthostatic hypotension, increasing age, and relatively shorter disease duration were significantly associated with RBD in PD (Table 3). Hypertension, DM, and increasing UPDRS score were not related to RBD in PD. 4. Discussion Clinical stages preceding motor symptoms of PD have been identified. Accumulating epidemiological and clinical evidence suggest that the non-motor symptoms, including hyposmia, cognitive dysfunction, autonomic failures, depression, anxiety, and sleep disorders (such as RBD), appear as the sole first symptoms of PD [3,24–26]. Reduced MIBG uptake is accepted as a sensitive finding for diagnosing early PD in situ [9]. However, the inter-relation of nonmotor symptoms and imaging markers was not clarified in PD. In this study of patients with mild and untreated PD, RBD was closely associated with orthostatic hypotension and cardiac sympathetic denervation. Orthostatic hypotension in PD was also related to deceased
H/M ratio. Recent study has revealed that failure to increase total peripheral resistance with cardiac denervation during orthostatic stress is associated with systolic blood pressure reduction leading to OH [27]. This finding fits the proposition that sleep and neurocirculatory abnormalities are related to each other. This association may be closely correlated with Braak alpha-synuclein pathogenetic sequences [28,29], which would account for a difference in the degree of cardiac sympathetic denervation and the clinical spectrum of PD. Normal orthostatic blood flow is crucial for maintaining neurovascular compensation and autoregulation, and this function is essential for handling the release of neurotransmitters and hormones [30]. Most arousal and sleep systems and their neurotransmitters are damaged and disturbed in PD brains, including the locus ceruleus (noraderenalin), pedunculopontine nucleus (PPN), basal forebrain (acetylcholine), median raphe (serotonin), and lateral hypothalamus (hypocretin/orexin) [31]. OH frequently develops in PD due to neurogenic dysfunction, reflecting cardiac and extracardiac sympathetic noradrenergic denervation and baroreflex failure [32]. A significant orthostatic blood pressure drop can trigger decreased firing of the arterial baroreceptors [33]. Together with orthostatic hypotension, decreased cardiovagal function can disturb maintenance of neurovascular autoregulation. In line with the Braak schema for the pathogenetic sequence in synucleinopathies [29], PD may feature early involvement of the locus ceruleus, PPN, raphe nucleus, and hypothalamus along with early deposition of alpha-synuclein in the sympathetic noradrenergic nerves of the heart [34,35]. Several clusters of noradrenergic, cholinergic, serotonergic, and orexinergic neurons outflow extensively to each brain area [31]. Impairments of these systems can provoke RBD and orthostatic hypotension. Such dysfunctions could directly lead to cardiac sympathetic denervation (decreasing MIBG uptake). In this study of PD patients, the RBD group was older and shorter disease duration than non RBD group. They had a tendency to have severer motor symptoms. The aging effect on occurrence of RBD in PD has not been widely studied yet. Recent study showed that the older-onset PD had a higher frequency of RBD than young-onset PD
Table 2 Autonomic abnormalities of patients and controls.
Orthostatic hypotension, n (%) Supine hypertension, n (%) Non-dipper, n (%) Nocturnal hypertension, n (%) Low MIBG, n (%)a
PD (n = 94)
Controls (n = 25)
p
No RBD (n = 41)
RBD (n = 53)
p
25 (26.6%) 17 (18.1%) 82 (87.2%) 20 (21.3%) 69 (73.4%)
1 (4.0%) 3 (12.0%) 19 (76.0%) 2 (8.0%) 0 (0%)
0.015 0.470 0.164 0.129 b0.001
3 (7.3%) 5 (12.2%) 38 (92.7%) 8 (19.5%) 24 (58.5%
22 (41.5%) 12 (22.6%) 44 (83.0%) 12 (22.6%) 45 (84.9%)
b0.001 0.192 0.164 0.713 0.004
Abbreviations: PD = Parkinson's disease, RBD = REM sleep behavioral disorders. Analyses were performed by χ2 test. a Low MIBG is defined as the value below mean − (2 × standard deviation) of healthy controls (cutoff value = 1.80046).
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Fig. 1. Mean values (±standard error of the mean [SEM]) for neurocirculatory measures in patients with Parkinson's disease with/without REM sleep behavioral disorder (RBD). (A) Mean systolic blood pressure (SBP) during supine rest before head-up tilting; (B) systolic BP change (ΔSBP) during tilt testing; (C) nighttime systolic BP by ambulatory blood pressure monitoring; (D) nocturnal percent fall in BP; (E) early heartto-mediastinum (H/M) ratio; and (F) late H/M ratio. (**) Group differences are significant at p b 0.01. The RBD group had a higher orthostatic BP change (ΔSBP) and lower H/M ratio than the group without RBD and controls.
[36]. The presence of RBD was associated with the non-tremorpredominant motor subtype of PD and more rapid decline in motor and cognitive dysfunctions [37]. While our study had strengths, it also had some limitations. A major strength was that it enrolled patients with relatively early and mild PD who had never taken dopaminergic medications. Because most anti-Parkinsonian drugs have hemodynamic effects and affect sleep and arousal, our results were less likely to be affected by confounders. Therefore, we can suggest that the association occurred independently of such treatment. However, several limitations should also be considered. First, simple questionnaires were used to detect RBD and polysomnography was not performed. Although the gold standard of RBD diagnosis is polysomnography, a recent report suggested that questionnaire-based diagnosis could herald a sensitivity of 100% and a specificity of 82.4% [13]. Second, the sex distribution between controls and patient group was different. Because the male predominance of RBD was observed in general population and neurodegenerative disorders [38], this difference may be a confounder. This is attributed to several factors, including hormonal and anatomical factors and lifestyle factors such as physical activity, dietary intake, and smoking behavior. Third, the proportion of hypertension was higher in PD patients than controls, and most subjects with hypertension were on anti-hypertensive medications. Care should be taken to interpret the result that RBD patients
Fig. 2. Mean values (±standard error of the mean [SEM]) for neurocirculatory measures in patients with Parkinson's disease (PD) with/without orthostatic hypotension (OH). (A) Mean systolic blood pressure (SBP) during supine rest before head-up tilting; (B) systolic BP change (ΔSBP) during tilt testing; (C) nighttime systolic BP by ambulatory blood pressure monitoring; (D) nocturnal percent fall in BP; (E) early heart-tomediastinum (H/M) ratio; and (F) late H/M ratio. (**) Group differences are significant at p b 0.01. The PD + OH group had a higher orthostatic BP change (ΔSBP) than those with PD–no OH and controls, and the PD group had lower nocturnal BP dip than those with controls. The OH group had lower H/M ratio than the group without OH and controls.
had a higher ΔSBP during tilt than non-RBD patients and controls because the use of anti-hypertensive medication can contribute to orthostatic hypotension. Fourth, other mechanisms that might play Table 3 Binary logistic regression models for clinical, autonomic variables for contributors of REM sleep behavioral disorder in patients with Parkinson's disease. Characteristics
Model 1 Constant Age Disease duration Orthostatic hypotension Non-dipper Model 2 Constant Age Disease duration Orthostatic ΔSBP
B
SE
Wald
−2.271 0.065 −0.521 2.463
1.856 1.479 0.028 5.215 0.201 6.723 0.770 10.230
df p
1 1 1 1
Exp (B)
95% confidence interval
0.221 0.103 0.022 1.067 1.009, 1.128 0.010 0.594 0.400, 0.881 0.001 11.736 2.595, 53.076
−1.546 0.797
3.758 1
0.053
0.213 0.045, 1.017
−3.689 0.064 −0.512 0.061
4.522 5.815 7.231 9.273
0.033 0.016 0.007 0.002
0.025 1.066 1.012, 1.123 0.599 0.412, 0.870 1.063 1.022, 1.106
1.735 0.026 0.191 0.020
1 1 1 1
Abbreviations: SBP = systolic blood pressure. Analysis was performed by forward binary logistic regression tests.
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a pathophysiologic role in OH and cardiac sympathetic denervation were not assessed. Patients with DM can have cardiac autonomic neuropathy and reduced heart uptake of MIBG is a useful marker of cardiac autonomic neuropathy [39]. Although the PD without diabetes group and the PD with diabetes showed similar MIBG uptake (PD–no DM vs. PD + DM, 1.6 ± 0.5 vs. 1.6 ± 0.4, p = 0.815), this could be a potential confounding factor. Finally, the study was performed in a confined geographical region with a relatively homogeneous ethnic background. Further studies are needed in patients of different ethnic origins to generalize to the overall population of PD patients worldwide. In conclusion, our results showed that RBD was closely associated with OH and cardiac sympathetic denervation in patients with early and mild PD. The result also suggests that impaired cardiac sympathetic innervation could be the mechanism behind OH in PD. OH may cause cerebral hypoperfusion, which can disturb normal neurotransmitter and hormone functions associated with sleep and arousal. It is also possible that lesions responsible for RBD may be located or clustered closely to the lesions responsible for the cardiovascular autonomic dysfunctions and cardiac sympathetic denervation. This study suggests that some nonmotor symptoms are related to each other, although further comprehensive works are needed to confirm this association. Conflict of interest The authors have no conflicts of interest or financial support to report. Acknowledgments This study was supported by the Research Fund of Seoul St. Mary's Hospital, The Catholic University of Korea. The authors thank Byung Min Yoo for his excellent statistical assistance on this project. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.jns.2016.01.020. References [1] V.C. De Cock, M. Vidailhet, I. Arnulf, Sleep disturbances in patients with parkinsonism, Nat. Clin. Pract. Neurol. 4 (2008) 254–266. [2] I. Arnulf, REM sleep behavior disorder: motor manifestations and pathophysiology, Mov. Disord. 27 (2012) 677–689. [3] H.M. Lee, S.B. Koh, Many faces of Parkinson's disease: non-motor symptoms of Parkinson's disease, J. Mov. Disord. 8 (2015) 92–97. [4] J.S. Kim, Y.S. Oh, K.S. Lee, Y.I. Kim, D.W. Yang, D.S. Goldstein, Association of cognitive dysfunction with neurocirculatory abnormalities in early Parkinson disease, Neurology 79 (2012) 1323–1331. [5] D.S. Goldstein, B.A. Eldadah, C. Holmes, S. Pechnik, J. Moak, A. Saleem, et al., Neurocirculatory abnormalities in Parkinson disease with orthostatic hypotension: independence from levodopa treatment, Hypertension 46 (2005) 1333–1339. [6] D.S. Goldstein, Orthostatic hypotension as an early finding in Parkinson disease, Clin. Auton. Res. 16 (2006) 46–64. [7] J.M. Senard, S. Rai, M. Lapeyre-Mestre, C. Brefel, O. Rascol, A. Rascol, et al., Prevalence of orthostatic hypotension in Parkinson's disease, J. Neurol. Neurosurg. Psychiatry 63 (1997) 584–589. [8] E.J. Chung, S.J. Kim, 123I-metaiodobenzylguanidine myocardial scintigraphy in Lewy body-related disorders; literature review, J. Mov. Disord. 8 (2015) 55–66. [9] R. Sakakibara, F. Tateno, M. Kishi, Y. Tsuyusaki, H. Terada, T. Inaoka, MIBG myocardial scintigraphy in pre-motor Parkinson's disease: a review, Parkinsonism Relat. Disord. 20 (2014) 267–273. [10] T. Nomura, Y. Inoue, B. Högl, Y. Uemura, M. Kitayama, T. Abe, et al., Relationship between (123)I-MIBG scintigrams and REM sleep behavior disorder in Parkinson's disease, Parkinsonism Relat. Disord. 16 (2010) 683–685. [11] W.R. Gibb, A.J. Lees, The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease, J. Neurol. Neurosurg. Psychiatry 51 (1988) 745–752.
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Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Orthostatic hypotension and cardiac sympathetic denervation in Parkinson disease patients with REM sleep behavioral disorder Joong-Seok Kim a,⁎, Hyung-Eun Park a, Yoon-Sang Oh b, Si-Hoon Lee a, Jeong-Wook Park c, Byung-chul Son d, Kwang-Soo Lee a a
Department of Neurology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Department of Neurology, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Department of Neurology, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea d Department of Neurosurgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea b c
a r t i c l e
i n f o
Article history: Received 5 August 2015 Received in revised form 5 December 2015 Accepted 12 January 2016 Available online 15 January 2016 Keywords: Parkinson's disease Rapid eye movement sleep behavioral disorder (RBD) Orthostatic hypotension (OH) Cardiac sympathetic denervation 123 I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy
a b s t r a c t Background: Rapid eye movement (REM) sleep behavioral disorder (RBD), orthostatic hypotension (OH), and cardiac sympathetic denervation were commonly observed in PD and are related in both the premotor and motor periods. This study is intended to evaluate if the OH and cardiac sympathetic denervation found in PD are associated with RBD. Methods: Among 94 non-medicated and mild PD patients, 53 had RBD. Orthostatic vital signs and ambulatory 24hour blood pressure values were recorded. 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy as obtained in all patients. The association between orthostatic hypotension, supine hypertension, nocturnal hypertension, non-dipping, myocardial MIBG uptake, and RBD was analyzed. Results: RBD was associated with orthostatic hypotension. Patients with RBD had higher systolic blood pressure changes during orthostasis and lower myocardial MIBG uptake than patients without RBD and controls. Patients with OH also had lower mean H/M ratios those in the non-OH group. Conclusion: This study showed that RBD was closely associated with OH and cardiac sympathetic denervation in patients with early and mild PD. The result also suggests that impaired cardiac sympathetic innervation could be the mechanism behind OH in PD. This association may be closely correlated with Braak alpha-synuclein pathogenetic sequences, which would account for the clinical spectrum of PD. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Rapid eye movement (REM) sleep behavioral disorder (RBD) is one of the commonest non-motor symptoms in Parkinson's disease (PD), affecting 15–60% of patients [1]. While it is not associated with the severity of motor symptoms, it is related to cognitive dysfunction and precedes dementia in PD [2]. RBD is an independent risk factor for the development of PD and may present several years before motor symptoms appear [2,3]. A variety of cardiovascular autonomic abnormalities have been noted in PD, including orthostatic hypotension (OH), supine hypertension (SH), nocturnal hypertension (NH), and absence of normal nocturnal blood pressure (BP) fall (“non-dipping”) [4]. These abnormalities are related to each other. It can occur independently of levodopa treatment and early in the course of disease [5,6]. In addition, ⁎ Corresponding author at: Department of Neurology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea. E-mail address: [email protected] (J.-S. Kim).
http://dx.doi.org/10.1016/j.jns.2016.01.020 0022-510X/© 2016 Elsevier B.V. All rights reserved.
these disturbances appear more frequently as the disease progresses, and it can influence subjective symptoms, quality of life, and disease treatment [7]. Metaiodobenzylguanidine (MIBG) is a physiologic analogue of norepinephrine, and iodine-123 (123I) MIBG cardiac scintigraphy is a noninvasive tool used to estimate myocardial sympathetic denervation [8]. Cardiac MIBG uptake was decreased in patients with Lewy body diseases such as PD and dementia with Lewy bodies (DLB). Therefore, it is useful for early differentiation of PD from atypical Parkinsonism and DLB from Alzheimer's disease. MIBG may also be helpful in the early detection of a subject with premotor PD [8,9]. RBD, autonomic dysfunctions, and cardiac sympathetic denervation were commonly observed in PD [1,3,8–10]. PD patients with clinical RBD had reduced MIBG uptake compared to those with normal REM sleep [10]. The hypothesis tested in this study was that the cardiovascular autonomic dysfunctions and cardiac sympathetic denervation found in early PD are associated with RBD. We assessed whether RBD was related to orthostatic hypotension, supine hypertension, nocturnal hypertension, or non-dipping and cardiac sympathetic denervation in Korean patients with early and mild PD.
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2. Methods 2.1. Subjects The institutional review board of St. Mary's Hospital approved this study's protocol, and each patient provided written informed consent for participation. Ninety-four patients at the Department of Neurology at Seoul St. Mary's Hospital between March 2013 and December 2014 were diagnosed with PD according to the UK brain bank criteria [11]. None of the patients had ever taken anti-Parkinsonian medication. Twenty-five healthy elderly subjects free from Parkinsonism and RBD were enlisted to serve as controls. Clinical information obtained included age, sex, disease duration, history of arterial hypertension, history of diabetes mellitus (DM), history of cigarette smoking, and current medication use. All patients underwent detailed clinical evaluations, including laboratory tests for lipid profiles and serum homocysteine. Exclusion criteria were patients (1) with neurological abnormalities related to atypical PD or secondary Parkinsonism, (2) with a history of diabetic neuropathy or other peripheral/autonomic neuropathy, (3) with a previous relevant cardiac disease, or any abnormalities on routine chest radiography and electrocardiography, (4) taking medications known to influence autonomic functions and drugs reported to influence cardiac MIBG uptake. All patients were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) and the modified Hoehn and Yahr (H&Y) stage. All blood pressure monitoring was performed after discontinuing antihypertensive drugs for more than 7 days. Patients were educated to abstain from drinking alcohol or coffee the day before the study. 2.2. RBD diagnosis Patients were administered the REM sleep behavior disorder screening questionnaire (RBDSQ), a 10-item questionnaire with scores ranging from 0 to 13 [12]. Bed partners were also asked question 1 of the Mayo questionnaire (MQ1) [13]: “Have you ever seen the patient appear to ‘act out his/her dreams’ while sleeping? (punched or flailed arms in the air, shouted or screamed)”. Both the RBDSQ test scores ≥5 and a response of “yes” on the MQ1 were considered consistent with RBD. Single, isolated episodes were disregarded and only recurrent episodes were taken into consideration. Subjects reporting only a single episode of somniloquy and/or vivid dreams were not included in this group. 2.3. Tilt testing Continuous electrocardiographic and noninvasive blood pressure monitoring leads were connected in each patient (YM6000, Mediana Tech, Redmond, WA, USA). After 30 min of supine rest, head-up tilt testing (20 min at 60°) was performed using the Manumed Special Tilt1section (ENRAF NONIUS, Rotterdam, The Netherlands). Blood pressure was measured in the upper limb every 5 min before and 1, 3, 5, 10, 15 and 20 min during tilt, 1 min post-tilt, and as indicated for patient safety. Supine baseline and the lowest tilt values for blood pressure were recorded. For statistical analysis, the lowest values between 3 and 5 min were chosen. Orthostatic hypotension was defined as a fall in BP of at least 20 mm Hg systolic BP and/or 10 mm Hg diastolic BP measured between 2 and 5 min after the tilt [14,15]. Subjects with systolic pressure ≥140 mm Hg or diastolic pressure ≥90 mm Hg were considered to have supine hypertension [16–18]. 2.4. Ambulatory blood pressure monitoring Automated 24-hour BP recording instruments (Mobil-O-Graph NG, I.E.M., Stolberg Germany) with an upper arm cuff were used to measure blood pressure and heart rate every 15 min during the day and every
30 min at night. The accuracy of this device was validated previously [19]. The following parameters were evaluated: average systolic and diastolic blood pressure and heart rate for daytime, nighttime and 24-h periods. Daytime and nighttime blood pressure was defined using narrow clock-time intervals (day from 10.00 to 20.00 and night from midnight to 06.00) [20]. Nocturnal falls in blood pressure and heart rate were calculated as percent changes between daytime and nighttime mean values. Subjects with b10% nocturnal fall in mean blood pressure were considered “non-dippers” [21]. Nocturnal hypertension was defined according to the 2007 European Hypertension Society/European Cardiology Society guidelines (i.e., average nighttime BP ≥ 120/70 mm Hg) [22,23]. 2.5. MIBG scintigraphy MIBG scintigraphy was performed and data was collected for 30 min (early) and 2 h (late) after injecting 111 MBq of 123I-MIBG using a dual head camera (Siemens, Munich Germany), and a static image was obtained with a 128 × 128 matrix. Regions of interest were manually drawn around the heart, mediastinum and thyroid. Tracer uptake was measured within each region of interest to calculate the heart to mediastinum (H/M) ratio. Patients were stratified to normal and low MIBG uptake group according to healthy controls; the range of normal H/M ratio was calculated as above mean (2.26280) − 2 × stanstandard deviation (0.23117) of age-matched normal controls (cutoff value = 1.80046). 2.6. Statistical analysis Statistical analysis was performed with SPSS software version 22.0. Independent sample t-tests or one-way ANOVAs (with Bonferroni post-hoc testing) were used to compare groups and Pearson's χ2 tests were used to compare frequencies for categorical variables. A forward binary logistic regression model was performed to study factors that may contribute to the development of RBD in PD patients. The presence of RBD was considered a dependent variable while age, sex, disease duration, hypertension, diabetes mellitus, nonsmoking, UPDRS score, supine hypertension (or supine SBP), orthostatic hypotension (or ΔSBP during tilt test), nocturnal hypertension (or nighttime SBP), nondipping (percent of dipping), and late H/M ratio were considered covariables. A p-value b 0.05 was considered significant. 3. Results All blood pressure monitoring was performed after discontinuing antihypertensive drugs for 8.5 ± 1.1 days. During the period, no serious clinical problem was observed. Ambulatory blood pressure was recorded without interruption in all subjects with a mean measurement period of 23.1 ± 1.4 h and the average number of measurements obtained during the recording was 67.7 ± 6.7. Among patients with OH, the mean tilting time of tilt before orthostatic symptoms was 3.6 ± 1.2 min. All patients without OH were tested for 20 min of tilt. Among the 94 PD patients, 50 were women (53.2%). Mean age (± SD) was 66.8 ± 10.8 years, and mean disease duration was 1.8 ± 1.4 years. Total UPDRS and H&Y stage scores were 27.3 ± 15.2 and 1.7 ± 0.7, respectively. Compared to controls, the proportion of arterial hypertension and orthostatic hypotension in PD patients was higher (Tables 1 and 2). Fifty-three (56.4%) patients had RBD, based on the both questionnaires. The PD + RBD group and PD–no RBD group were similar in sex, medical history, and severity of PD. The PD + RBD group was older than the PD–no RBD group (Table 1). Patients with PD + RBD had more orthostatic hypotension than the PD–no RBD group and controls (Table 2). The nadir pressure during tilt was lower in the PD + RBD group than in the PD–no RBD group and controls (ΔSBP during tilt, mm Hg; controls vs. no RBD vs. RBD, 3 ± 9 vs. 6 ± 13 vs. 15 ± 13,
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Table 1 Demographics of Parkinson disease's patients with/without REM sleep behavioral disorder and controls.
Age, year, mean ± SDa No. of men, n (%)b Disease duration, year, mean ± SDa Hypertension, n (%)b Diabetes mellitus, n (%)b Current or ex-smoker, n (%)b H&Y stage, mean ± SDa UPDRS, mean ± SDa UPDRS part 1, intellectual UPDRS part 2, ADL UPDRS part 3, motor
PD (n = 94)
Controls (n = 25)
p
No RBD (n = 41)
RBD (n = 53)
p
66.8 ± 10.8 44 (46.8%) 1.8 ± 1.4 38 (40.4%) 15 (16.0%) 24 (25.5%) 1.7 ± 0.7 27.3 ± 15.2 3.0 ± 2.1 8.2 ± 5.9 16.1 ± 9.4
67.4 ± 4.8 6 (24.0%) – 4 (16.0%) 3 (12.0%) 7 (28.0%) – – – – –
0.776 0.040
63.3 ± 12.0 20 (48.8%) 2.1 ± 1.6 14 (34.1%) 8 (19.5%) 11 (26.8%) 1.6 ± 0.6 24.5 ± 10.3 2.4 ± 1.8 7.2 ± 3.9 14.7 ± 6.8
69.5 ± 8.9 24 (45.3%) 1.5 ± 1.2 24 (45.3%) 7 (13.2%) 13 (24.5%) 1.8 ± 0.7 29.5 ± 18.0 3.4 ± 2.2 9.1 ± 7.0 17.2 ± 10.9
0.005 0.736 0.037 0.275 0.408 0.800 0.305 0.118 0.024 0.160 0.203
0.023 0.624 0.803
Abbreviations: H&Y = Hoehn and Yahr, PD = Parkinson's disease, RBD = REM sleep behavioral disorder, UPDRS = Unified Parkinson's Disease Rating Scale. a Analyses were performed by independent sample t-test. b Analyses were performed by χ2 test.
p b 0.001; Fig. 1). In addition, mean supine blood pressure values were mildly elevated in the PD + RBD group compared to those in the PD–no RBD group and controls (supine SBP, mm Hg; controls vs. no RBD vs. RBD, 123 ± 14 vs. 122 ± 16 vs. 130 ± 17, p = 0.040) (supplementary e-table 1 and Fig. 1). Patients with PD + RBD had higher frequency of low MIBG uptake with late H/M ratio ≤ 1.8 than the PD–no RBD group (Table 2). The mean late H/M ratio was lower in patients with PD + RBD than in those with PD–no RBD and controls (controls vs. no RBD vs. RBD, 2.3 ± 0.2 vs. 1.7 ± 0.5 vs. 1.5 ± 0.4, p b 0.001, Fig. 1). Twenty-five (26.6%) patient had OH, with ΔSBP during tilt ≥ 20 mm Hg. The PD + OH group was older than the PD–no OH group (no OH vs. OH, 65.1 ± 11.0 vs. 71.6 ± 8.5, p = 0.009). The PD + OH group and PD–no OH group had similar sex makeup, disease duration, UPDRS and H&Y score, presence of hypertension and DM, and smoking habitus (supplementary e-table 2). Patients with PD + OH tended to have higher orthostatic ΔSBP and lower nocturnal BP dip, higher nighttime SBP and decreased myocardial MIBG uptake than those with PD–no OH and controls (Fig. 2). On forward stepwise binary logistic regression analyses, orthostatic hypotension, increasing age, and relatively shorter disease duration were significantly associated with RBD in PD (Table 3). Hypertension, DM, and increasing UPDRS score were not related to RBD in PD. 4. Discussion Clinical stages preceding motor symptoms of PD have been identified. Accumulating epidemiological and clinical evidence suggest that the non-motor symptoms, including hyposmia, cognitive dysfunction, autonomic failures, depression, anxiety, and sleep disorders (such as RBD), appear as the sole first symptoms of PD [3,24–26]. Reduced MIBG uptake is accepted as a sensitive finding for diagnosing early PD in situ [9]. However, the inter-relation of nonmotor symptoms and imaging markers was not clarified in PD. In this study of patients with mild and untreated PD, RBD was closely associated with orthostatic hypotension and cardiac sympathetic denervation. Orthostatic hypotension in PD was also related to deceased
H/M ratio. Recent study has revealed that failure to increase total peripheral resistance with cardiac denervation during orthostatic stress is associated with systolic blood pressure reduction leading to OH [27]. This finding fits the proposition that sleep and neurocirculatory abnormalities are related to each other. This association may be closely correlated with Braak alpha-synuclein pathogenetic sequences [28,29], which would account for a difference in the degree of cardiac sympathetic denervation and the clinical spectrum of PD. Normal orthostatic blood flow is crucial for maintaining neurovascular compensation and autoregulation, and this function is essential for handling the release of neurotransmitters and hormones [30]. Most arousal and sleep systems and their neurotransmitters are damaged and disturbed in PD brains, including the locus ceruleus (noraderenalin), pedunculopontine nucleus (PPN), basal forebrain (acetylcholine), median raphe (serotonin), and lateral hypothalamus (hypocretin/orexin) [31]. OH frequently develops in PD due to neurogenic dysfunction, reflecting cardiac and extracardiac sympathetic noradrenergic denervation and baroreflex failure [32]. A significant orthostatic blood pressure drop can trigger decreased firing of the arterial baroreceptors [33]. Together with orthostatic hypotension, decreased cardiovagal function can disturb maintenance of neurovascular autoregulation. In line with the Braak schema for the pathogenetic sequence in synucleinopathies [29], PD may feature early involvement of the locus ceruleus, PPN, raphe nucleus, and hypothalamus along with early deposition of alpha-synuclein in the sympathetic noradrenergic nerves of the heart [34,35]. Several clusters of noradrenergic, cholinergic, serotonergic, and orexinergic neurons outflow extensively to each brain area [31]. Impairments of these systems can provoke RBD and orthostatic hypotension. Such dysfunctions could directly lead to cardiac sympathetic denervation (decreasing MIBG uptake). In this study of PD patients, the RBD group was older and shorter disease duration than non RBD group. They had a tendency to have severer motor symptoms. The aging effect on occurrence of RBD in PD has not been widely studied yet. Recent study showed that the older-onset PD had a higher frequency of RBD than young-onset PD
Table 2 Autonomic abnormalities of patients and controls.
Orthostatic hypotension, n (%) Supine hypertension, n (%) Non-dipper, n (%) Nocturnal hypertension, n (%) Low MIBG, n (%)a
PD (n = 94)
Controls (n = 25)
p
No RBD (n = 41)
RBD (n = 53)
p
25 (26.6%) 17 (18.1%) 82 (87.2%) 20 (21.3%) 69 (73.4%)
1 (4.0%) 3 (12.0%) 19 (76.0%) 2 (8.0%) 0 (0%)
0.015 0.470 0.164 0.129 b0.001
3 (7.3%) 5 (12.2%) 38 (92.7%) 8 (19.5%) 24 (58.5%
22 (41.5%) 12 (22.6%) 44 (83.0%) 12 (22.6%) 45 (84.9%)
b0.001 0.192 0.164 0.713 0.004
Abbreviations: PD = Parkinson's disease, RBD = REM sleep behavioral disorders. Analyses were performed by χ2 test. a Low MIBG is defined as the value below mean − (2 × standard deviation) of healthy controls (cutoff value = 1.80046).
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Fig. 1. Mean values (±standard error of the mean [SEM]) for neurocirculatory measures in patients with Parkinson's disease with/without REM sleep behavioral disorder (RBD). (A) Mean systolic blood pressure (SBP) during supine rest before head-up tilting; (B) systolic BP change (ΔSBP) during tilt testing; (C) nighttime systolic BP by ambulatory blood pressure monitoring; (D) nocturnal percent fall in BP; (E) early heartto-mediastinum (H/M) ratio; and (F) late H/M ratio. (**) Group differences are significant at p b 0.01. The RBD group had a higher orthostatic BP change (ΔSBP) and lower H/M ratio than the group without RBD and controls.
[36]. The presence of RBD was associated with the non-tremorpredominant motor subtype of PD and more rapid decline in motor and cognitive dysfunctions [37]. While our study had strengths, it also had some limitations. A major strength was that it enrolled patients with relatively early and mild PD who had never taken dopaminergic medications. Because most anti-Parkinsonian drugs have hemodynamic effects and affect sleep and arousal, our results were less likely to be affected by confounders. Therefore, we can suggest that the association occurred independently of such treatment. However, several limitations should also be considered. First, simple questionnaires were used to detect RBD and polysomnography was not performed. Although the gold standard of RBD diagnosis is polysomnography, a recent report suggested that questionnaire-based diagnosis could herald a sensitivity of 100% and a specificity of 82.4% [13]. Second, the sex distribution between controls and patient group was different. Because the male predominance of RBD was observed in general population and neurodegenerative disorders [38], this difference may be a confounder. This is attributed to several factors, including hormonal and anatomical factors and lifestyle factors such as physical activity, dietary intake, and smoking behavior. Third, the proportion of hypertension was higher in PD patients than controls, and most subjects with hypertension were on anti-hypertensive medications. Care should be taken to interpret the result that RBD patients
Fig. 2. Mean values (±standard error of the mean [SEM]) for neurocirculatory measures in patients with Parkinson's disease (PD) with/without orthostatic hypotension (OH). (A) Mean systolic blood pressure (SBP) during supine rest before head-up tilting; (B) systolic BP change (ΔSBP) during tilt testing; (C) nighttime systolic BP by ambulatory blood pressure monitoring; (D) nocturnal percent fall in BP; (E) early heart-tomediastinum (H/M) ratio; and (F) late H/M ratio. (**) Group differences are significant at p b 0.01. The PD + OH group had a higher orthostatic BP change (ΔSBP) than those with PD–no OH and controls, and the PD group had lower nocturnal BP dip than those with controls. The OH group had lower H/M ratio than the group without OH and controls.
had a higher ΔSBP during tilt than non-RBD patients and controls because the use of anti-hypertensive medication can contribute to orthostatic hypotension. Fourth, other mechanisms that might play Table 3 Binary logistic regression models for clinical, autonomic variables for contributors of REM sleep behavioral disorder in patients with Parkinson's disease. Characteristics
Model 1 Constant Age Disease duration Orthostatic hypotension Non-dipper Model 2 Constant Age Disease duration Orthostatic ΔSBP
B
SE
Wald
−2.271 0.065 −0.521 2.463
1.856 1.479 0.028 5.215 0.201 6.723 0.770 10.230
df p
1 1 1 1
Exp (B)
95% confidence interval
0.221 0.103 0.022 1.067 1.009, 1.128 0.010 0.594 0.400, 0.881 0.001 11.736 2.595, 53.076
−1.546 0.797
3.758 1
0.053
0.213 0.045, 1.017
−3.689 0.064 −0.512 0.061
4.522 5.815 7.231 9.273
0.033 0.016 0.007 0.002
0.025 1.066 1.012, 1.123 0.599 0.412, 0.870 1.063 1.022, 1.106
1.735 0.026 0.191 0.020
1 1 1 1
Abbreviations: SBP = systolic blood pressure. Analysis was performed by forward binary logistic regression tests.
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a pathophysiologic role in OH and cardiac sympathetic denervation were not assessed. Patients with DM can have cardiac autonomic neuropathy and reduced heart uptake of MIBG is a useful marker of cardiac autonomic neuropathy [39]. Although the PD without diabetes group and the PD with diabetes showed similar MIBG uptake (PD–no DM vs. PD + DM, 1.6 ± 0.5 vs. 1.6 ± 0.4, p = 0.815), this could be a potential confounding factor. Finally, the study was performed in a confined geographical region with a relatively homogeneous ethnic background. Further studies are needed in patients of different ethnic origins to generalize to the overall population of PD patients worldwide. In conclusion, our results showed that RBD was closely associated with OH and cardiac sympathetic denervation in patients with early and mild PD. The result also suggests that impaired cardiac sympathetic innervation could be the mechanism behind OH in PD. OH may cause cerebral hypoperfusion, which can disturb normal neurotransmitter and hormone functions associated with sleep and arousal. It is also possible that lesions responsible for RBD may be located or clustered closely to the lesions responsible for the cardiovascular autonomic dysfunctions and cardiac sympathetic denervation. This study suggests that some nonmotor symptoms are related to each other, although further comprehensive works are needed to confirm this association. Conflict of interest The authors have no conflicts of interest or financial support to report. Acknowledgments This study was supported by the Research Fund of Seoul St. Mary's Hospital, The Catholic University of Korea. The authors thank Byung Min Yoo for his excellent statistical assistance on this project. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.jns.2016.01.020. References [1] V.C. De Cock, M. Vidailhet, I. Arnulf, Sleep disturbances in patients with parkinsonism, Nat. Clin. Pract. Neurol. 4 (2008) 254–266. [2] I. Arnulf, REM sleep behavior disorder: motor manifestations and pathophysiology, Mov. Disord. 27 (2012) 677–689. [3] H.M. Lee, S.B. Koh, Many faces of Parkinson's disease: non-motor symptoms of Parkinson's disease, J. Mov. Disord. 8 (2015) 92–97. [4] J.S. Kim, Y.S. Oh, K.S. Lee, Y.I. Kim, D.W. Yang, D.S. Goldstein, Association of cognitive dysfunction with neurocirculatory abnormalities in early Parkinson disease, Neurology 79 (2012) 1323–1331. [5] D.S. Goldstein, B.A. Eldadah, C. Holmes, S. Pechnik, J. Moak, A. Saleem, et al., Neurocirculatory abnormalities in Parkinson disease with orthostatic hypotension: independence from levodopa treatment, Hypertension 46 (2005) 1333–1339. [6] D.S. Goldstein, Orthostatic hypotension as an early finding in Parkinson disease, Clin. Auton. Res. 16 (2006) 46–64. [7] J.M. Senard, S. Rai, M. Lapeyre-Mestre, C. Brefel, O. Rascol, A. Rascol, et al., Prevalence of orthostatic hypotension in Parkinson's disease, J. Neurol. Neurosurg. Psychiatry 63 (1997) 584–589. [8] E.J. Chung, S.J. Kim, 123I-metaiodobenzylguanidine myocardial scintigraphy in Lewy body-related disorders; literature review, J. Mov. Disord. 8 (2015) 55–66. [9] R. Sakakibara, F. Tateno, M. Kishi, Y. Tsuyusaki, H. Terada, T. Inaoka, MIBG myocardial scintigraphy in pre-motor Parkinson's disease: a review, Parkinsonism Relat. Disord. 20 (2014) 267–273. [10] T. Nomura, Y. Inoue, B. Högl, Y. Uemura, M. Kitayama, T. Abe, et al., Relationship between (123)I-MIBG scintigrams and REM sleep behavior disorder in Parkinson's disease, Parkinsonism Relat. Disord. 16 (2010) 683–685. [11] W.R. Gibb, A.J. Lees, The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease, J. Neurol. Neurosurg. Psychiatry 51 (1988) 745–752.
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