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Cardiac sympathetic index identifies patients with Parkinson's disease and REM behavior disorder
Parkinsonism and Related Disorders xxx (2016) 1e5
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Cardiac sympathetic index identifies patients with Parkinson's disease and REM behavior disorder Maria Salsone a, Basilio Vescio a, Alessandra Fratto b, Miriam Sturniolo b, Gennarina Arabia b, Antonio Gambardella b, Aldo Quattrone a, b, * a b
Neuroimaging Research Unit, Institute of Bioimaging and Molecular Physiology, National Research Council, Germaneto, Catanzaro, Italy Institute of Neurology, Department of Medical Sciences, University Magna Graecia, Catanzaro, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 August 2015 Received in revised form 2 March 2016 Accepted 7 March 2016
Objective: To compare circadian autonomic fluctuations in patients with Parkinson's Disease (PD) with or without REM sleep behavior disorder (RBD) by using heart rate variability (HRV) analysis. Methods: This is a case-control study including 20 PD patients with RBD (PD-RBD) and 20 PD patients without RBD (PD). In all patients, we measured the components of HRV in the frequency domain during 24-h with daytime and night time recordings. Selected variables considered were low-frequency (LF) influenced by the sympathetic system and high-frequency (HF) influenced by the parasympathetic system. Moreover, we calculated night-to-day ratio for both LF (cardiac sympathetic index) and HF (cardiac parasympathetic index) spectral components. Video-polysomnography was performed in all patients to diagnose RBD. Results: Both nocturnal LF and HF spectral power values were significantly higher in PD-RBD patients than in PD patients (P < 0.001 and P ¼ 0.004 respectively). Moreover, in PD-RBD patients LF and HF values were higher at night than during the day while no difference between night time and daytime values was observed in patients with PD. Cardiac sympathetic index value was significantly higher in PDRBD patients (median 1.83, range 1.65e3.66) than in PD patients (median 0.93, range 0.44e1.3) without overlap of individual values between groups (accuracy 100%). By contrast, cardiac parasympathetic index had sensitivity of 45% and specificity of 100% for differentiating between PD groups. Conclusions: Cardiac sympathetic index distinguishes PD-RBD patients from those with PD on an individual basis, thus representing a valid help in everyday clinical practice for screening of RBD in PD patients. © 2016 Published by Elsevier Ltd.
Keywords: Parkinson's disease REM sleep behavior disorder Heart rate variability
1. Introduction Numerous evidences [1] suggest that cardiac autonomic dysfunction is frequently found in patients with Parkinson's disease (PD) even at the early stage of the disease and in the absence of dopaminergic treatment. Cardiovascular dysautonomia has been recently evaluated by heart rate variability (HRV) analysis, a simple and non-invasive measure of the cardiac impulses representing one of the most promising quantitative markers of the cardiac autonomic balance [2]. Studies investigating cardiac autonomic function in PD patients
* Corresponding author. Institute of Neurology, Department of Medical Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy. E-mail address: [email protected] (A. Quattrone).
have demonstrated that the spectral components of HRV were lower during wakefulness and that there was an inverse correlation between the autonomic impairment and disease-related aspects such as disease severity [3]. Similar changes in HRV have also been observed during nocturnal sleep in PD patients [1]. Moreover, circadian autonomic fluctuation of HRV has been evaluated in untreated PD patients indicating that spectral components of HRV were significantly suppressed especially during the night-time [4]. To our knowledge, there are no previous reports investigating the circadian autonomic fluctuation of HRV in patients with PD associated with REM sleep behavior disorder (RBD) (PD-RBD). Owing to this lack of investigation, the primary aim of the current study was to evaluate the spectral components of HRV in PD-RBD patients compared to those with PD without RBD (PD) during 24h, daytime and night time recordings. The secondary aim of this
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Please cite this article in press as: M. Salsone, et al., Cardiac sympathetic index identifies patients with Parkinson's disease and REM behavior disorder, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.03.004
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M. Salsone et al. / Parkinsonism and Related Disorders xxx (2016) 1e5
study was to assess the sensitivity and specificity of an index that we termed cardiac autonomic index (sympathetic or parasympathetic) for differentiating PD-RBD patients from those with PD.
exponent, multiscale entropy analysis and multifractal analysis were performed by means of the PhysioNet open source libraries for the nonlinear analysis of time series. 2.3. Heart rate variability study design
2. Methods 2.1. Patients A total of 24 patients with PD associated with RBD (PD-RBD) and 20 patients with PD without RBD (PD) were consecutive enrolled in the current study from the Neurology Unit of the University “Magna Graecia” of Catanzaro. All subjects met the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria [5] for PD. All patients underwent a video-polysomnography (PSG) to diagnose RBD. On PSG, a prominent muscle activity in REM sleep associated with abnormal behaviours was required to confirm clinical or subclinical diagnosis of RBD [6] according to the International Classification of Sleep Disorders-third edition (ICSD-3). The current treatment with medications known to modify REM sleep architecture and muscle tone as serotonin reuptake inhibitors was considered as exclusion criteria. Moreover, the presence of periodic leg movements (PLMs) on PSG was considered as exclusion criterion. Four (17%) of the 24 PD-RBD patients showed PLMs on PSG and thus they were excluded from the current study. No PD patient had PLMs on PSG. The remaining 20 PD-RBD patients and all 20 PD patients underwent a careful clinical assessment including Hohen-Yahr (H-Y) [7] and Unified Parkinson's Disease Rating scale (UPDRS) [8] and Mini Mental State Examination (MMSE) [9]. In all patients, the levodopa response was considered positive when the clinical improvement was 20% or greater according to results of the acute single-dose levodopa test. DAT-SPECT imaging and cardiac MIBG scintigraphy were performed in all patients to support the clinical diagnosis of PD [10]. Magnetic resonance imaging (MRI) was assessed in all our patients to exclude cerebrovascular disease, intracranial lesions in brain or other degenerative neurologic disease. Before inclusion in the study, written informed consent was obtained from all patients, and the study was approved by the Ethical Committee of the University ‘Magna Graecia’ of Catanzaro according to the Helsinki Declaration. 2.2. Heart rate variability analysis Autonomic control of heart rate (HR) was obtained in all our patients by heart rate variability (HRV) analysis [11]. R-R intervals were taken from 24-h ambulatory ECG recording (ECG/HRV device: Mega Electronics Emotion Faros 180 , 2-leads wearable ECG- HRV monitor). Sampling rate for ECG was set at 500 Hz. The electrodes were placed approximately along the electrical axis of the heart. The optimal placement of the electrodes followed the locations of electrodes RA and V5 in the Mason-Likar modification of the standard 12 lead ECG: the negative electrode was placed in the right infraclavicular fossa (just below the right clavicle), and the positive electrode on the left side of the chest, below the pectoral muscle in the left anterior axillary line. The RR signal (tachogram) was processed using PhysioNet HRV Toolkit base functions, integrated in the Matlab® computing environment. Time series acquisition was then divided into 10-min epochs, with an overlapping of 5 min, for frequency analysis. In particular, each epoch was processed with means of the Lomb-Scargle algorithm, which computes the power spectrum of unevenly sampled data. LF (low frequency, sympathetic system) power was taken in the 0.04e0.15 Hz frequency band, while HF (high frequency, parasympathetic system) power is taken in the 0.15e0.4 Hz band. Detrended fluctuation analysis, information-based similarity, estimate of largest Lyapunov
A circadian (24-h) HRV recording was performed in all patients. During the registration the patients were independent in their activities. The mean values of the spectral components of HRV were calculated for the circadian 24-h period. The mean values of the different measures of the night time (from 10 p.m. to 6 a.m.) and daytime (from 09 a.m. to 10 p.m. and from 06 a.m. to 09 a.m. of the next day) HR variability were calculated. In all patients, we calculated night-to-day ratio for both LF (cardiac sympathetic index) and HF (cardiac parasympathetic index) spectral components. The presence of comorbidities known to affect the autonomic nervous system and interfering with autonomic evaluation was considered as exclusion criteria. Finally, all subjects stopped taking any anticholinergic, antidepressant, sympathomimetic, or parasympathomimetic medications 72 h before testing and stopped taking levodopa 12 h before testing. 2.4. Statistical analysis The sex and familiarity distributions in all patients were compared using Fisher's exact test. Shapiro-Wilk's test was used to check for normality before comparing clinical and demographic variables. Differences in age at examination, age at disease onset, DAT-SPECT right, DAT-SPECT left and cardiac parasympathetic index were assessed using the t-test. The Mann-Whitney U test was used to assess differences in disease duration, UPDRS, UPDRS-ME and H-Y scores, MMSE, cardiac MIBG scintigraphy (H/M early and delayed), 24 h LF, and HF, night-time and daytime LF and HF and cardiac sympathetic index. Statistical analysis was performed with R Statistical Software (R for Unix/Linux, version 2.15.1, The R Foundation for Statistical Computing, 2012). Sensitivity, specificity, positive predictive value and accuracy evaluations were carried out using the ROCR package for R. 3. Results There were no significant differences in demographic, clinical and neuroimaging data between PD groups as shown in Table 1. All PD patients (with and without RBD) had a positive response to levodopa. Moreover, levodopa dosage treatment was not significantly different between the two groups (Table 1). No patient had cognitive impairment or brain MRI abnormalities. All PD patients showed a marked decrease of the tracer uptake in both DAT and MIBG scintigraphies (Table 1). Both LF and HF spectral component of HRV were significantly higher during night time registrations in the PD-RBD group than in the PD group (Table 2, Fig. 1) whereas daytime LF and HF values were not significantly different between groups (Table 2, Fig. 1). Moreover, during 24 h registration, LF values were significantly different between groups while no statistical difference was detected for HF values (Table 2). Of note, in PD-RBD patients both LF and HF values were higher at night than during the day while no difference between night time and daytime values was observed in patients with PD (PD-RBD: night vs day, LF p ¼ 0.000002, HF ¼ 0.0001; PD: night vs day, LF ¼ 0.85, HF ¼ 0.33) (Fig. 1A, B). Patients with PD-RBD showed higher cardiac autonomic indexes values than patients with PD (Table 2). There was no overlap of individual values for cardiac sympathetic index between patients with PD-RBD (median 1.83; range 1.65e3.66) and patients with PD (median 0.93; range 0.44e1.3). At the cut off level of 1.65, the
Please cite this article in press as: M. Salsone, et al., Cardiac sympathetic index identifies patients with Parkinson's disease and REM behavior disorder, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.03.004
M. Salsone et al. / Parkinsonism and Related Disorders xxx (2016) 1e5 Table 1 Demographic, clinical characteristics and neuroimaging features. Variables
PD-RBD
PD
p-value
Age (y) Gender (M/F) Age at onset (y) Disease duration (y) Hoen and Yahr (HY) stage UPDRS UPDRS-ME Rigid-Akinetic form (n) Levodopa Dosage (mg/die) MMSE DAT-SPECT* Put/Cau Right Put/Cau Left Cardiac MIBG scintigraphy** H/M ratio of early images H/M ratio of delayed images
66.4 ± 8.8 16/4 61.6 ± 9.3 4.18 ± 3.62 1.75 ± 0.58 30.3 ± 15.9 21.4 ± 11.3 10 300 ± 297 25.6 ± 3.77
66.3 ± 10.7 13/7 61 ± 10.6 5.3 ± 4.85 2.03 ± 0.91 35.1 ± 23.5 21.7 ± 14.1 8 314 ± 345 26.6 ± 2.82
0.975a 0.48b 0.844a 0.663c 0.52c 0.75c 0.807c 0.76c 1c 0.5b
2.03 ± 0.61 2.15 ± 0.63
2.27 ± 0.68 2.23 ± 0.74
0.244a 0.689a
1.37 ± 0.29 1.28 ± 0.30
1.32 ± 0.24 1.29 ± 0.30
0.607a 0.925c
Data are given as mean values± standard deviations or median range when appropriate. Abbreviations: PD-RBD, Parkinson's disease with REM sleep behavior disorder; PD, Parkinson's disease without REM sleep behavior disorder. at-test; b c2 test; cMann-Whitney U test. * Put/Cau right (n.v: mean ± SD, 4.29 ± 0.34) and Put/ Cau left (n.v: mean ± SD, 4.19 ± 0.39); **H/M ratio: mean ± SD, 1.94 ± 0.18 early; 2.02 ± 0.19 delayed. n.v (normal values).
Table 2 Heart rate variability parameters in the frequency domain. Variables 24 hour LF, ms2 HF, ms2 Day LF, ms2 HF, ms2 Night LF, ms2 HF, ms2 Cardiac Autonomic Index Cardiac Sympathetic Index Cardiac Parasympathetic Index
PD-RBD
PD
p-value
657 ± 524 632 ± 475
266 ± 197 336 ± 200
0.005a 0.076a
446 ± 359 391 ± 349
267 ± 187 334 ± 273
0.063a 0.947a
995 ± 791 896 ± 694
264 ± 221 343 ± 190
<0.001a 0.004a
1.83 (1.65e3.66) 1.93 (0.72e4.4)
0.93 (0.44e1.3) 1.15 (0.3e2)
<0.001a 0.002b
Data are given as mean values± standard deviations except for cardiac autonomic index given as median (range). Abbreviations: LF, low-frequency; HF, highfrequency; PD-RBD, Parkinson's disease with REM sleep behavior disorder; PD, Parkinson's disease without REM sleep behavior disorder; aMann-Whitney U test; b t-test; In PD-RBD patients, LF night vs day p ¼ 0.000002 (Wilcoxon rank sum test) and HF night vs day p ¼ 0.0001 (Wilcoxon rank sum test); in PD patients LF night vs day p ¼ 0.85 (paired t-test) and HF night vs day p ¼ 0.33 (Wilcoxon rank sum test).
cardiac sympathetic index correctly identified patients with PDRBD with sensitivity, specificity, PPV and accuracy of 100% (Fig. 2A). Moreover, in the PD-RBD group, no statistical correlation was found between cardiac sympathetic index and clinical features such as disease duration and severity (P ¼ 0.538 and P ¼ 0.8 respectively). The cardiac parasympathetic index was significantly higher in PD-RBD patients than in PD patients (PD-RBD vs PD, P ¼ 0.002) (Table 2). At the cut off level of 2.1 the sensitivity, sensibility, PPV and accuracy of cardiac parasympathetic index were 45%, 100%, 100% and 72,5% respectively with overlap of individual values between PD groups shown in Fig. 2B. 4. Discussion This is the first study exploring the circadian autonomic changes of HRV spectral components in patients with PD associated with RBD (PD-RBD) compared to those with PD without RBD (PD) during long-term conditions (24 h recording). Our study demonstrates that night-to-day ratio of LF values (cardiac sympathetic index)
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accurately distinguished PD-RBD patients from those with PD on an individual basis. RBD is a REM sleep parasomnia characterized by loss of the muscle atonia with prominent motor activity accompanying dreaming. RBD is frequently related to synucleinopathies, including PD, dementia with Lewy Bodies and multiple system atrophy. In PD, RBD affects 30e60% of patients [12]. Studies estimated that approximately half of patients with RBD will eventually develop PD so RBD may be an indicator of presymptomatic PD. Impairment in color discrimination, olfactory function, and autonomic symptoms were the nonmotor symptoms more common in RBD patients, suggesting that many potential early markers of PD are significantly abnormal in idiopathic REM sleep behavior disorder [13]. Only two studies [4,14] have previously investigated HRV parameters in PD patients during long-term conditions. Both studies evaluated the circadian autonomic fluctuation of HRV in the time and frequency domains in treated [14] and untreated [4] PD patients respectively in comparison to age-and sex-matched control subjects. The two studies [4,14] concordantly demonstrated that in PD patients LF and HF spectral components were suppressed particularly at night respect to control subjects. Other studies investigated HRV in PD patients in comparison to control subjects in short-term conditions. Some authors [3] demonstrated that in untreated PD patients LF and HF values were lower during the day in respect to controls while others [1] reported that treated PD patients showed a reduced sympathetically driven HRV in both REM and non-REM stages in comparison to controls. Taken together these findings demonstrate that patients with PD showed reduced HRV parameters (LF and HF) during both night time and daytime recordings. Our report differs considerably from the cited studies because we evaluated the circadian autonomic fluctuation in patients with PD-RBD in comparison with those with PD to elucidate whether the presence of RBD might influence cardiac autonomic activity. Indeed, in our study HRV analysis revealed a significant increase of nocturnal sympathetic and parasympathetic activities in PD-RBD patients in respect to patients with PD. It is noteworthy, that in PD-RBD group, both nocturnal LF and HF values were significantly higher than daytime values while no difference between daytime and night time recordings were observed in PD. In the current study we did not evaluate the nocturnal autonomic fluctuations across the different sleep stages, and we cannot exclude a possible influence of REM or non-REM sleep stages on HRV. However, some authors [1] in a polysomnography-based study in patients with PD demonstrated that LF values were reduced in both REM and non-REM stages, and others [15] in a small sample of idiopathic RBD patients showed that sympathetic activity was not different between different sleep stages. In our PDRBD patients, LF and HF values during nocturnal sleep were continuously elevated, suggesting that the nocturnal increase of sympathetic and parasympathetic activity might not be related to sleep stages. In our study, both patient groups showed decreased MIBG uptake, a finding strongly indicative of cardiac sympathetic denervation, but only PD-RBD patients had increased nocturnal LF and HF values, suggesting that RBD itself may influence nocturnal cardiac autonomic activity. Some authors [16e18] showed that cardiac MIBG accumulation was lower in patients with idiopathic RBD and in those with PD-RBD than in patients with PD or PD with subclinical RBD, suggesting that lesions responsible for RBD may be located or linked more closely to the lesion responsible for reduced MIBG uptake than are lesions in patients with PD [16]. The mechanism by which RBD may increase nocturnal sympathetic function in patients with damage to cardiac noradrenergic fibers is still unknown. Some authors found in patients with PD that cardiac sympathetic denervation detected by MIBG scanning was
Please cite this article in press as: M. Salsone, et al., Cardiac sympathetic index identifies patients with Parkinson's disease and REM behavior disorder, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.03.004
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M. Salsone et al. / Parkinsonism and Related Disorders xxx (2016) 1e5
A PD PD−RBD
2
LF (medians, [ms ])
800 600 400 200 0
9
11
13
15
17
19 21 23 time (hour of the day)
1
3
5
7
9
B
700 PD PD−RBD
2
HF (medians, [ms ])
600 500 400 300 200 100 0
9
11
13
15
17
19 21 23 time (hour of the day)
1
3
5
7
9
Fig. 1. Circadian autonomic fluctuation. The 24-h circadian fluctuation of the low frequency (LF) (A) and high frequency (HF) (B) components of HRV (medians) in patients with PD-RBD (triangles) and in patients with PD (squares). PD-RBD. (Parkinson's Disease with REM sleep behavior disorder); PD (Parkinson's disease without REM sleep behavior disorder).
Fig. 2. Cardiac autonomic index. Upper limits of cardiac sympathetic index (1.65, light gray area) and parasympathetic index (2.1, light gray area) in patients with PD without RBD (A and B). The optimal cutoff levels were obtained as the points with the highest sum of sensitivity and specificity on ROC curves. PD-RBD. (Parkinson's Disease with REM sleep behavior disorder); PD (Parkinson's disease without REM sleep behavior disorder).
unrelated to the LF:HF ratio, a putative index of sympathovagal balance [19], and others [20] have shown that drugs increasing release of norepinephrine from cardiac sympathetic nerves increased LF power in patients with neuroimaging evidence of cardiac sympathetic denervation. In addition, recent studies have demonstrated that LF may reflect baroreflex function independently of cardiac sympathetic innervation [21]. In accordance with a previous study [22], these findings indicate that the assumption
that complex sympathetic influences can be summarized as variations in the LF band and that parasympathetic influences can be summarized as variations in HF band is too simplistic, and needs further investigations. We believe that the differences in HRV parameters observed between PD patients with and without RBD cannot be attributed to presence of artifactual conditions during HRV analysis or demographic/clinical variables for some reasons. First, all patients
Please cite this article in press as: M. Salsone, et al., Cardiac sympathetic index identifies patients with Parkinson's disease and REM behavior disorder, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.03.004
M. Salsone et al. / Parkinsonism and Related Disorders xxx (2016) 1e5
from both groups having respiratory disturbances during sleep, particularly obstructive sleep apnea syndrome and sleep disorders as restless legs syndrome or period limb movements known to cause HRV abnormalities were excluded from the study. Second, in our sample there was not a predominantly female gender. This is a crucial point as it is known that women have a higher parasympathetic tone during sleep stages than men regardless of their hormonal status [23]. Third, PD-RBD patients were matched for all remaining variables including age, disease duration, severity and levodopa dose. Thus, we can speculate that the increase of cardiac autonomic activity reported in PD-RBD patients at night may result from RBD itself rather than to be a consequence of some clinical variables or artifacts. Whether such an increase of nocturnal cardiac autonomic activity might be related to a vigorous and emotionally intense “acting out dreams” typical of RBD or to an effect of microawakenings or to vigorous movements more frequent in such patients is not yet known. However, because sleep movements observed in patients with PD-RBD typically occur in REM stage, the possibility that these movements may influence HRV parameters during the night time seems unlikely. In the current study we calculated night-to-day ratio for both LF (cardiac sympathetic index) and HF (cardiac parasympathetic index) spectral components. In PD-RBD patients, the values obtained by using this calculation for both sympathetic and parasympathetic systems were significantly higher than those obtained in PD group. Moreover, the cardiac sympathetic index values in patients with PD-RBD showed no overlap with values obtained in patients with PD demonstrating that this index accurately differentiated patients between the two groups on an individual basis. Indeed, no patients with PD with or without RBD symptoms were misdiagnosed when the cardiac sympathetic index was used. In addition, the cardiac sympathetic index was not statistically related to either to the duration or to the severity of the disease thus suggesting that it may be used in both early and late stages of PD. There were some limitations to this study. First, our patients with PD (with and without RBD) were chronically treated with dopaminergic drugs at the time of the HRV and PSG recordings. The possibility that levodopa may affect HRV parameters exists but a clear effect has not been shown yet. Some authors [24] have recently reported that in PD patients changes in LF components were inversely correlated with UPDRS-III scores but not with age or levodopa dose. In our study, levodopa dosage was not significantly different between the two groups. Second, in all our patients we did not evaluate the cardiac autonomic fluctuations across the different sleep stages. In our study, however, the increase of the nocturnal LF and HF values was observed continuously the night, thus suggesting this cardiac autonomic excitatory response might not be linked to different sleep stages. Further studies are needed to better elucidate the relationship between RBD-increased cardiac autonomic activity and sleep stages. Our study, has several strengths. First, the cardiac sympathetic index allowed a correct identification of PD patients with RBD, and no patient received a misdiagnosis when this index was used (sensitivity and specificity, 100%). Second, cardiac sympathetic index is based on a simple and non-invasive measure that makes this index of particular practical value because it may be a valid help for screening of PD patients suspected of having RBD in large populations. In conclusion, our findings indicate that the cardiac sympathetic index may help distinguish PD-RBD patients from PD patients
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without RBD. Additional studies in larger cohort are needed to validate the utility of cardiac sympathetic index in clinical practice.
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Please cite this article in press as: M. Salsone, et al., Cardiac sympathetic index identifies patients with Parkinson's disease and REM behavior disorder, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.03.004
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Cardiac sympathetic index identifies patients with Parkinson's disease and REM behavior disorder Maria Salsone a, Basilio Vescio a, Alessandra Fratto b, Miriam Sturniolo b, Gennarina Arabia b, Antonio Gambardella b, Aldo Quattrone a, b, * a b
Neuroimaging Research Unit, Institute of Bioimaging and Molecular Physiology, National Research Council, Germaneto, Catanzaro, Italy Institute of Neurology, Department of Medical Sciences, University Magna Graecia, Catanzaro, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 August 2015 Received in revised form 2 March 2016 Accepted 7 March 2016
Objective: To compare circadian autonomic fluctuations in patients with Parkinson's Disease (PD) with or without REM sleep behavior disorder (RBD) by using heart rate variability (HRV) analysis. Methods: This is a case-control study including 20 PD patients with RBD (PD-RBD) and 20 PD patients without RBD (PD). In all patients, we measured the components of HRV in the frequency domain during 24-h with daytime and night time recordings. Selected variables considered were low-frequency (LF) influenced by the sympathetic system and high-frequency (HF) influenced by the parasympathetic system. Moreover, we calculated night-to-day ratio for both LF (cardiac sympathetic index) and HF (cardiac parasympathetic index) spectral components. Video-polysomnography was performed in all patients to diagnose RBD. Results: Both nocturnal LF and HF spectral power values were significantly higher in PD-RBD patients than in PD patients (P < 0.001 and P ¼ 0.004 respectively). Moreover, in PD-RBD patients LF and HF values were higher at night than during the day while no difference between night time and daytime values was observed in patients with PD. Cardiac sympathetic index value was significantly higher in PDRBD patients (median 1.83, range 1.65e3.66) than in PD patients (median 0.93, range 0.44e1.3) without overlap of individual values between groups (accuracy 100%). By contrast, cardiac parasympathetic index had sensitivity of 45% and specificity of 100% for differentiating between PD groups. Conclusions: Cardiac sympathetic index distinguishes PD-RBD patients from those with PD on an individual basis, thus representing a valid help in everyday clinical practice for screening of RBD in PD patients. © 2016 Published by Elsevier Ltd.
Keywords: Parkinson's disease REM sleep behavior disorder Heart rate variability
1. Introduction Numerous evidences [1] suggest that cardiac autonomic dysfunction is frequently found in patients with Parkinson's disease (PD) even at the early stage of the disease and in the absence of dopaminergic treatment. Cardiovascular dysautonomia has been recently evaluated by heart rate variability (HRV) analysis, a simple and non-invasive measure of the cardiac impulses representing one of the most promising quantitative markers of the cardiac autonomic balance [2]. Studies investigating cardiac autonomic function in PD patients
* Corresponding author. Institute of Neurology, Department of Medical Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy. E-mail address: [email protected] (A. Quattrone).
have demonstrated that the spectral components of HRV were lower during wakefulness and that there was an inverse correlation between the autonomic impairment and disease-related aspects such as disease severity [3]. Similar changes in HRV have also been observed during nocturnal sleep in PD patients [1]. Moreover, circadian autonomic fluctuation of HRV has been evaluated in untreated PD patients indicating that spectral components of HRV were significantly suppressed especially during the night-time [4]. To our knowledge, there are no previous reports investigating the circadian autonomic fluctuation of HRV in patients with PD associated with REM sleep behavior disorder (RBD) (PD-RBD). Owing to this lack of investigation, the primary aim of the current study was to evaluate the spectral components of HRV in PD-RBD patients compared to those with PD without RBD (PD) during 24h, daytime and night time recordings. The secondary aim of this
http://dx.doi.org/10.1016/j.parkreldis.2016.03.004 1353-8020/© 2016 Published by Elsevier Ltd.
Please cite this article in press as: M. Salsone, et al., Cardiac sympathetic index identifies patients with Parkinson's disease and REM behavior disorder, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.03.004
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M. Salsone et al. / Parkinsonism and Related Disorders xxx (2016) 1e5
study was to assess the sensitivity and specificity of an index that we termed cardiac autonomic index (sympathetic or parasympathetic) for differentiating PD-RBD patients from those with PD.
exponent, multiscale entropy analysis and multifractal analysis were performed by means of the PhysioNet open source libraries for the nonlinear analysis of time series. 2.3. Heart rate variability study design
2. Methods 2.1. Patients A total of 24 patients with PD associated with RBD (PD-RBD) and 20 patients with PD without RBD (PD) were consecutive enrolled in the current study from the Neurology Unit of the University “Magna Graecia” of Catanzaro. All subjects met the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria [5] for PD. All patients underwent a video-polysomnography (PSG) to diagnose RBD. On PSG, a prominent muscle activity in REM sleep associated with abnormal behaviours was required to confirm clinical or subclinical diagnosis of RBD [6] according to the International Classification of Sleep Disorders-third edition (ICSD-3). The current treatment with medications known to modify REM sleep architecture and muscle tone as serotonin reuptake inhibitors was considered as exclusion criteria. Moreover, the presence of periodic leg movements (PLMs) on PSG was considered as exclusion criterion. Four (17%) of the 24 PD-RBD patients showed PLMs on PSG and thus they were excluded from the current study. No PD patient had PLMs on PSG. The remaining 20 PD-RBD patients and all 20 PD patients underwent a careful clinical assessment including Hohen-Yahr (H-Y) [7] and Unified Parkinson's Disease Rating scale (UPDRS) [8] and Mini Mental State Examination (MMSE) [9]. In all patients, the levodopa response was considered positive when the clinical improvement was 20% or greater according to results of the acute single-dose levodopa test. DAT-SPECT imaging and cardiac MIBG scintigraphy were performed in all patients to support the clinical diagnosis of PD [10]. Magnetic resonance imaging (MRI) was assessed in all our patients to exclude cerebrovascular disease, intracranial lesions in brain or other degenerative neurologic disease. Before inclusion in the study, written informed consent was obtained from all patients, and the study was approved by the Ethical Committee of the University ‘Magna Graecia’ of Catanzaro according to the Helsinki Declaration. 2.2. Heart rate variability analysis Autonomic control of heart rate (HR) was obtained in all our patients by heart rate variability (HRV) analysis [11]. R-R intervals were taken from 24-h ambulatory ECG recording (ECG/HRV device: Mega Electronics Emotion Faros 180 , 2-leads wearable ECG- HRV monitor). Sampling rate for ECG was set at 500 Hz. The electrodes were placed approximately along the electrical axis of the heart. The optimal placement of the electrodes followed the locations of electrodes RA and V5 in the Mason-Likar modification of the standard 12 lead ECG: the negative electrode was placed in the right infraclavicular fossa (just below the right clavicle), and the positive electrode on the left side of the chest, below the pectoral muscle in the left anterior axillary line. The RR signal (tachogram) was processed using PhysioNet HRV Toolkit base functions, integrated in the Matlab® computing environment. Time series acquisition was then divided into 10-min epochs, with an overlapping of 5 min, for frequency analysis. In particular, each epoch was processed with means of the Lomb-Scargle algorithm, which computes the power spectrum of unevenly sampled data. LF (low frequency, sympathetic system) power was taken in the 0.04e0.15 Hz frequency band, while HF (high frequency, parasympathetic system) power is taken in the 0.15e0.4 Hz band. Detrended fluctuation analysis, information-based similarity, estimate of largest Lyapunov
A circadian (24-h) HRV recording was performed in all patients. During the registration the patients were independent in their activities. The mean values of the spectral components of HRV were calculated for the circadian 24-h period. The mean values of the different measures of the night time (from 10 p.m. to 6 a.m.) and daytime (from 09 a.m. to 10 p.m. and from 06 a.m. to 09 a.m. of the next day) HR variability were calculated. In all patients, we calculated night-to-day ratio for both LF (cardiac sympathetic index) and HF (cardiac parasympathetic index) spectral components. The presence of comorbidities known to affect the autonomic nervous system and interfering with autonomic evaluation was considered as exclusion criteria. Finally, all subjects stopped taking any anticholinergic, antidepressant, sympathomimetic, or parasympathomimetic medications 72 h before testing and stopped taking levodopa 12 h before testing. 2.4. Statistical analysis The sex and familiarity distributions in all patients were compared using Fisher's exact test. Shapiro-Wilk's test was used to check for normality before comparing clinical and demographic variables. Differences in age at examination, age at disease onset, DAT-SPECT right, DAT-SPECT left and cardiac parasympathetic index were assessed using the t-test. The Mann-Whitney U test was used to assess differences in disease duration, UPDRS, UPDRS-ME and H-Y scores, MMSE, cardiac MIBG scintigraphy (H/M early and delayed), 24 h LF, and HF, night-time and daytime LF and HF and cardiac sympathetic index. Statistical analysis was performed with R Statistical Software (R for Unix/Linux, version 2.15.1, The R Foundation for Statistical Computing, 2012). Sensitivity, specificity, positive predictive value and accuracy evaluations were carried out using the ROCR package for R. 3. Results There were no significant differences in demographic, clinical and neuroimaging data between PD groups as shown in Table 1. All PD patients (with and without RBD) had a positive response to levodopa. Moreover, levodopa dosage treatment was not significantly different between the two groups (Table 1). No patient had cognitive impairment or brain MRI abnormalities. All PD patients showed a marked decrease of the tracer uptake in both DAT and MIBG scintigraphies (Table 1). Both LF and HF spectral component of HRV were significantly higher during night time registrations in the PD-RBD group than in the PD group (Table 2, Fig. 1) whereas daytime LF and HF values were not significantly different between groups (Table 2, Fig. 1). Moreover, during 24 h registration, LF values were significantly different between groups while no statistical difference was detected for HF values (Table 2). Of note, in PD-RBD patients both LF and HF values were higher at night than during the day while no difference between night time and daytime values was observed in patients with PD (PD-RBD: night vs day, LF p ¼ 0.000002, HF ¼ 0.0001; PD: night vs day, LF ¼ 0.85, HF ¼ 0.33) (Fig. 1A, B). Patients with PD-RBD showed higher cardiac autonomic indexes values than patients with PD (Table 2). There was no overlap of individual values for cardiac sympathetic index between patients with PD-RBD (median 1.83; range 1.65e3.66) and patients with PD (median 0.93; range 0.44e1.3). At the cut off level of 1.65, the
Please cite this article in press as: M. Salsone, et al., Cardiac sympathetic index identifies patients with Parkinson's disease and REM behavior disorder, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.03.004
M. Salsone et al. / Parkinsonism and Related Disorders xxx (2016) 1e5 Table 1 Demographic, clinical characteristics and neuroimaging features. Variables
PD-RBD
PD
p-value
Age (y) Gender (M/F) Age at onset (y) Disease duration (y) Hoen and Yahr (HY) stage UPDRS UPDRS-ME Rigid-Akinetic form (n) Levodopa Dosage (mg/die) MMSE DAT-SPECT* Put/Cau Right Put/Cau Left Cardiac MIBG scintigraphy** H/M ratio of early images H/M ratio of delayed images
66.4 ± 8.8 16/4 61.6 ± 9.3 4.18 ± 3.62 1.75 ± 0.58 30.3 ± 15.9 21.4 ± 11.3 10 300 ± 297 25.6 ± 3.77
66.3 ± 10.7 13/7 61 ± 10.6 5.3 ± 4.85 2.03 ± 0.91 35.1 ± 23.5 21.7 ± 14.1 8 314 ± 345 26.6 ± 2.82
0.975a 0.48b 0.844a 0.663c 0.52c 0.75c 0.807c 0.76c 1c 0.5b
2.03 ± 0.61 2.15 ± 0.63
2.27 ± 0.68 2.23 ± 0.74
0.244a 0.689a
1.37 ± 0.29 1.28 ± 0.30
1.32 ± 0.24 1.29 ± 0.30
0.607a 0.925c
Data are given as mean values± standard deviations or median range when appropriate. Abbreviations: PD-RBD, Parkinson's disease with REM sleep behavior disorder; PD, Parkinson's disease without REM sleep behavior disorder. at-test; b c2 test; cMann-Whitney U test. * Put/Cau right (n.v: mean ± SD, 4.29 ± 0.34) and Put/ Cau left (n.v: mean ± SD, 4.19 ± 0.39); **H/M ratio: mean ± SD, 1.94 ± 0.18 early; 2.02 ± 0.19 delayed. n.v (normal values).
Table 2 Heart rate variability parameters in the frequency domain. Variables 24 hour LF, ms2 HF, ms2 Day LF, ms2 HF, ms2 Night LF, ms2 HF, ms2 Cardiac Autonomic Index Cardiac Sympathetic Index Cardiac Parasympathetic Index
PD-RBD
PD
p-value
657 ± 524 632 ± 475
266 ± 197 336 ± 200
0.005a 0.076a
446 ± 359 391 ± 349
267 ± 187 334 ± 273
0.063a 0.947a
995 ± 791 896 ± 694
264 ± 221 343 ± 190
<0.001a 0.004a
1.83 (1.65e3.66) 1.93 (0.72e4.4)
0.93 (0.44e1.3) 1.15 (0.3e2)
<0.001a 0.002b
Data are given as mean values± standard deviations except for cardiac autonomic index given as median (range). Abbreviations: LF, low-frequency; HF, highfrequency; PD-RBD, Parkinson's disease with REM sleep behavior disorder; PD, Parkinson's disease without REM sleep behavior disorder; aMann-Whitney U test; b t-test; In PD-RBD patients, LF night vs day p ¼ 0.000002 (Wilcoxon rank sum test) and HF night vs day p ¼ 0.0001 (Wilcoxon rank sum test); in PD patients LF night vs day p ¼ 0.85 (paired t-test) and HF night vs day p ¼ 0.33 (Wilcoxon rank sum test).
cardiac sympathetic index correctly identified patients with PDRBD with sensitivity, specificity, PPV and accuracy of 100% (Fig. 2A). Moreover, in the PD-RBD group, no statistical correlation was found between cardiac sympathetic index and clinical features such as disease duration and severity (P ¼ 0.538 and P ¼ 0.8 respectively). The cardiac parasympathetic index was significantly higher in PD-RBD patients than in PD patients (PD-RBD vs PD, P ¼ 0.002) (Table 2). At the cut off level of 2.1 the sensitivity, sensibility, PPV and accuracy of cardiac parasympathetic index were 45%, 100%, 100% and 72,5% respectively with overlap of individual values between PD groups shown in Fig. 2B. 4. Discussion This is the first study exploring the circadian autonomic changes of HRV spectral components in patients with PD associated with RBD (PD-RBD) compared to those with PD without RBD (PD) during long-term conditions (24 h recording). Our study demonstrates that night-to-day ratio of LF values (cardiac sympathetic index)
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accurately distinguished PD-RBD patients from those with PD on an individual basis. RBD is a REM sleep parasomnia characterized by loss of the muscle atonia with prominent motor activity accompanying dreaming. RBD is frequently related to synucleinopathies, including PD, dementia with Lewy Bodies and multiple system atrophy. In PD, RBD affects 30e60% of patients [12]. Studies estimated that approximately half of patients with RBD will eventually develop PD so RBD may be an indicator of presymptomatic PD. Impairment in color discrimination, olfactory function, and autonomic symptoms were the nonmotor symptoms more common in RBD patients, suggesting that many potential early markers of PD are significantly abnormal in idiopathic REM sleep behavior disorder [13]. Only two studies [4,14] have previously investigated HRV parameters in PD patients during long-term conditions. Both studies evaluated the circadian autonomic fluctuation of HRV in the time and frequency domains in treated [14] and untreated [4] PD patients respectively in comparison to age-and sex-matched control subjects. The two studies [4,14] concordantly demonstrated that in PD patients LF and HF spectral components were suppressed particularly at night respect to control subjects. Other studies investigated HRV in PD patients in comparison to control subjects in short-term conditions. Some authors [3] demonstrated that in untreated PD patients LF and HF values were lower during the day in respect to controls while others [1] reported that treated PD patients showed a reduced sympathetically driven HRV in both REM and non-REM stages in comparison to controls. Taken together these findings demonstrate that patients with PD showed reduced HRV parameters (LF and HF) during both night time and daytime recordings. Our report differs considerably from the cited studies because we evaluated the circadian autonomic fluctuation in patients with PD-RBD in comparison with those with PD to elucidate whether the presence of RBD might influence cardiac autonomic activity. Indeed, in our study HRV analysis revealed a significant increase of nocturnal sympathetic and parasympathetic activities in PD-RBD patients in respect to patients with PD. It is noteworthy, that in PD-RBD group, both nocturnal LF and HF values were significantly higher than daytime values while no difference between daytime and night time recordings were observed in PD. In the current study we did not evaluate the nocturnal autonomic fluctuations across the different sleep stages, and we cannot exclude a possible influence of REM or non-REM sleep stages on HRV. However, some authors [1] in a polysomnography-based study in patients with PD demonstrated that LF values were reduced in both REM and non-REM stages, and others [15] in a small sample of idiopathic RBD patients showed that sympathetic activity was not different between different sleep stages. In our PDRBD patients, LF and HF values during nocturnal sleep were continuously elevated, suggesting that the nocturnal increase of sympathetic and parasympathetic activity might not be related to sleep stages. In our study, both patient groups showed decreased MIBG uptake, a finding strongly indicative of cardiac sympathetic denervation, but only PD-RBD patients had increased nocturnal LF and HF values, suggesting that RBD itself may influence nocturnal cardiac autonomic activity. Some authors [16e18] showed that cardiac MIBG accumulation was lower in patients with idiopathic RBD and in those with PD-RBD than in patients with PD or PD with subclinical RBD, suggesting that lesions responsible for RBD may be located or linked more closely to the lesion responsible for reduced MIBG uptake than are lesions in patients with PD [16]. The mechanism by which RBD may increase nocturnal sympathetic function in patients with damage to cardiac noradrenergic fibers is still unknown. Some authors found in patients with PD that cardiac sympathetic denervation detected by MIBG scanning was
Please cite this article in press as: M. Salsone, et al., Cardiac sympathetic index identifies patients with Parkinson's disease and REM behavior disorder, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.03.004
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M. Salsone et al. / Parkinsonism and Related Disorders xxx (2016) 1e5
A PD PD−RBD
2
LF (medians, [ms ])
800 600 400 200 0
9
11
13
15
17
19 21 23 time (hour of the day)
1
3
5
7
9
B
700 PD PD−RBD
2
HF (medians, [ms ])
600 500 400 300 200 100 0
9
11
13
15
17
19 21 23 time (hour of the day)
1
3
5
7
9
Fig. 1. Circadian autonomic fluctuation. The 24-h circadian fluctuation of the low frequency (LF) (A) and high frequency (HF) (B) components of HRV (medians) in patients with PD-RBD (triangles) and in patients with PD (squares). PD-RBD. (Parkinson's Disease with REM sleep behavior disorder); PD (Parkinson's disease without REM sleep behavior disorder).
Fig. 2. Cardiac autonomic index. Upper limits of cardiac sympathetic index (1.65, light gray area) and parasympathetic index (2.1, light gray area) in patients with PD without RBD (A and B). The optimal cutoff levels were obtained as the points with the highest sum of sensitivity and specificity on ROC curves. PD-RBD. (Parkinson's Disease with REM sleep behavior disorder); PD (Parkinson's disease without REM sleep behavior disorder).
unrelated to the LF:HF ratio, a putative index of sympathovagal balance [19], and others [20] have shown that drugs increasing release of norepinephrine from cardiac sympathetic nerves increased LF power in patients with neuroimaging evidence of cardiac sympathetic denervation. In addition, recent studies have demonstrated that LF may reflect baroreflex function independently of cardiac sympathetic innervation [21]. In accordance with a previous study [22], these findings indicate that the assumption
that complex sympathetic influences can be summarized as variations in the LF band and that parasympathetic influences can be summarized as variations in HF band is too simplistic, and needs further investigations. We believe that the differences in HRV parameters observed between PD patients with and without RBD cannot be attributed to presence of artifactual conditions during HRV analysis or demographic/clinical variables for some reasons. First, all patients
Please cite this article in press as: M. Salsone, et al., Cardiac sympathetic index identifies patients with Parkinson's disease and REM behavior disorder, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.03.004
M. Salsone et al. / Parkinsonism and Related Disorders xxx (2016) 1e5
from both groups having respiratory disturbances during sleep, particularly obstructive sleep apnea syndrome and sleep disorders as restless legs syndrome or period limb movements known to cause HRV abnormalities were excluded from the study. Second, in our sample there was not a predominantly female gender. This is a crucial point as it is known that women have a higher parasympathetic tone during sleep stages than men regardless of their hormonal status [23]. Third, PD-RBD patients were matched for all remaining variables including age, disease duration, severity and levodopa dose. Thus, we can speculate that the increase of cardiac autonomic activity reported in PD-RBD patients at night may result from RBD itself rather than to be a consequence of some clinical variables or artifacts. Whether such an increase of nocturnal cardiac autonomic activity might be related to a vigorous and emotionally intense “acting out dreams” typical of RBD or to an effect of microawakenings or to vigorous movements more frequent in such patients is not yet known. However, because sleep movements observed in patients with PD-RBD typically occur in REM stage, the possibility that these movements may influence HRV parameters during the night time seems unlikely. In the current study we calculated night-to-day ratio for both LF (cardiac sympathetic index) and HF (cardiac parasympathetic index) spectral components. In PD-RBD patients, the values obtained by using this calculation for both sympathetic and parasympathetic systems were significantly higher than those obtained in PD group. Moreover, the cardiac sympathetic index values in patients with PD-RBD showed no overlap with values obtained in patients with PD demonstrating that this index accurately differentiated patients between the two groups on an individual basis. Indeed, no patients with PD with or without RBD symptoms were misdiagnosed when the cardiac sympathetic index was used. In addition, the cardiac sympathetic index was not statistically related to either to the duration or to the severity of the disease thus suggesting that it may be used in both early and late stages of PD. There were some limitations to this study. First, our patients with PD (with and without RBD) were chronically treated with dopaminergic drugs at the time of the HRV and PSG recordings. The possibility that levodopa may affect HRV parameters exists but a clear effect has not been shown yet. Some authors [24] have recently reported that in PD patients changes in LF components were inversely correlated with UPDRS-III scores but not with age or levodopa dose. In our study, levodopa dosage was not significantly different between the two groups. Second, in all our patients we did not evaluate the cardiac autonomic fluctuations across the different sleep stages. In our study, however, the increase of the nocturnal LF and HF values was observed continuously the night, thus suggesting this cardiac autonomic excitatory response might not be linked to different sleep stages. Further studies are needed to better elucidate the relationship between RBD-increased cardiac autonomic activity and sleep stages. Our study, has several strengths. First, the cardiac sympathetic index allowed a correct identification of PD patients with RBD, and no patient received a misdiagnosis when this index was used (sensitivity and specificity, 100%). Second, cardiac sympathetic index is based on a simple and non-invasive measure that makes this index of particular practical value because it may be a valid help for screening of PD patients suspected of having RBD in large populations. In conclusion, our findings indicate that the cardiac sympathetic index may help distinguish PD-RBD patients from PD patients
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without RBD. Additional studies in larger cohort are needed to validate the utility of cardiac sympathetic index in clinical practice.
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Please cite this article in press as: M. Salsone, et al., Cardiac sympathetic index identifies patients with Parkinson's disease and REM behavior disorder, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.03.004