REM SLEEP BEHAVIORAL EVENTS: A NEW MARKER FOR EARLY PARKINSON DISEASE http://dx.doi.org/10.5665/sleep.3468
Rapid Eye Movement Sleep Behavioral Events: A New Marker for Neurodegeneration in Early Parkinson Disease? Friederike Sixel-Döring, MD1,2; Ellen Trautmann, PhD1,3; Brit Mollenhauer, MD1,4,5; Claudia Trenkwalder, MD1,4
1 Paracelsus-Elena-Klinik, Kassel, Germany; 2Department of Neurology, Philipps-University Marburg, Germany; 3Department of Psychology, University Kassel, Germany; 4Department of Neurosurgery, Georg-August University Goettingen, Germany; 5Department of Neuropathology, Georg-August University, Goettingen, Germany
Objective: To analyze potential markers in sleep for early recognition of neurodegenerative disease in newly diagnosed, unmedicated patients with Parkinson disease (PD) compared to controls. Methods: Videopolysomnography (vPSG) was available in 158 newly diagnosed, unmedicated patients with PD and 110 age-, sex-, and educationmatched healthy controls (HC). Rapid eye movement (REM) sleep was analyzed for REM without atonia (RWA) and studied by review of timesynchronized video. Motor behaviors and/or vocalizations in REM sleep with a purposeful component other than comfort moves were identified as REM sleep behavioral events (RBE). Two or more events had to be present to be classified as “RBE positive.” RBE subjects included rapid eye movement sleep behavior disorder (RBD) and non-RBD subjects based on the presence or absence of RWA > 18.2%. Results: RBE were detected in 81 of 158 patients with de novo PD (51%) and 17 of 110 HC (15%) (P < 0.001). RBD was identified in 40/81 RBEpositive patients with PD (25% of all PD patients) and 2 of 17 RBE-positive HC (2% of all controls). RBE-positive patients showed no specific motor or neuropsychological features compared to RBE-negative patients. Patients with PD and HC with RBE had more REM sleep (P = 0.002) and a higher periodic leg movements in sleep index (P = 0.022) compared to subjects without RBE. Conclusion: This first description of REM sleep behavioral events (RBE) shows it occurs more frequently in patients with de novo Parkinson disease (PD) than in healthy controls and may be an early sign of neurodegeneration and precede rapid eye movement sleep behavior disorder (RBD). There is no specific phenotype of PD associated with newly defined RBE or RBD at this early stage. Keywords: Parkinson disease, REM sleep behavior disorder, REM sleep behavioral events, somnological marker Citation: Sixel-Döring F; Trautmann E; Mollenhauer B; Trenkwalder C. Rapid eye movement sleep behavioral events: a new marker for neurodegeneration in early Parkinson disease? SLEEP 2014;37(3):431-438.
INTRODUCTION A loss of slow wave sleep, sleep fragmentation, periodic limb movements in sleep (PLMS), and rapid eye movement (REM) sleep behavior disorder (RBD) have been labeled as somnological hallmarks of neurodegenerative diseases.1-4 Several studies5-7 have identified patients with idiopathic RBD at risk for parkinsonism and/or dementia, 81% of whom develop neurodegeneration after a mean interval of 14 years.7 Therefore, idiopathic RBD as defined by the International Classification of Sleep Disorders in its current 2005 version (ICSD-2)8 is considered a possible marker for premotor manifestations of PD. However, large-scale polysomnographic studies on sleep alterations in newly diagnosed, untreated PD are lacking. Moreover, the hypothesis of RBD as a hallmark of neurodegeneration originates from long-term observations of spectacular, violent RBD cases in sleep centers, not in PD cohorts. We analyzed potentially new and earlier somnological markers for neurodegeneration in a large cohort of newly diagnosed, unmedicated PD patients in comparison with matched neurologically healthy controls (HC) and correlated our findings to clinical disease phenotypes.
Submitted for publication April, 2013 Submitted in final revised form July, 2013 Accepted for publication July, 2013 Address correspondence to: Friederike Sixel-Döring, Paracelsus-Elena-Klinik, Center of Parkinsonism and Movement Disorders, Klinikstr. 16, 34128 Kassel, Germany; Tel: ++49-0561-60090; Fax: ++49-05616009126 E-mail: [email protected] SLEEP, Vol. 37, No. 3, 2014 431 Downloaded from https://academic.oup.com/sleep/article-abstract/37/3/431/2595936 by guest on 27 March 2018
METHODS The data presented here are part of the baseline evaluation of a prospective longitudinal single-center observational cohort study of patients with de novo PD and matched neurologically HC, which prospectively investigates nonmotor features and potential biomarkers in PD (“DeNoPa cohort”).9 Inclusion Criteria For patients: Men and women age 40-85 y with a clinical diagnosis of PD according to UK Brain Bank Criteria. Patients had to be drug-naïve for PD medication.9 For controls: Men and women age 40-85 y, no dementia or specific sleep complaints, recruited by public advertisement and participation requests to family and spouses. Controls were matched using frequency matching by age, sex, and educational level: the proportions of controls with these characteristics were identical to the proportions of cases with the same characteristics. Age was a continuous variable. The selection was possible through a 5-mo recruitment delay for controls. Exclusion Criteria For patients: (1) known severe vascular encephalopathy or normal pressure hydrocephalus on magnetic resonance imaging (MRI); (2) signs or symptoms suggestive of multiple system atrophy or progressive supranuclear palsy or medication-induced PD; or (3) current or past treatment with antipsychotic drugs. For controls: (1) active known/treated condition of the central nervous system; (2) history of PD in a parent, sibling, or child; (3) evident cognitive decline (MMSE < 26); and (4) exclusion of those reporting sleep disorders during the first interview REM Behavioral Events in Parkinson Disease—Sixel-Döring et al
with the investigator to avoid a bias toward sleep-disturbed controls as the polysomnographic recording was mentioned in the advertisement. Standard Protocol Approvals, Registrations, and Participants’ Consent All participants gave consent for their data to be scientifically evaluated, and signed additional consent forms agreeing for their nighttime video to be used for scientific and medical educational purposes. The local Ethical Committee approved the project (Approval No. FF89/2008). The DeNoPa study is registered with the German Register for Clinical Trials (DRKS00000540) according to the World Health Organization Trial Registration Dataset. Polysomnography Patients and controls were studied in the sleep laboratory for 2 nights. The second night was used for analysis. If the patient refused the second nighttime recording, or one of the two videopolysomnographies (vPSG) was invalid due to technical artifacts, the valid recording was used. Standard cardiorespiratory PSG (Xltec: Excel Tech Ltd; Oakville, Ontario; Canada) was applied according to American Academy of Sleep Medicine (AASM) criteria. All patients were documented with an infrared video recording synchronized to the PSG. Each recording was monitored. Sleep, sleep stages, PLMS, and respiratory events were scored according to standard criteria. All sleep evaluations were reviewed and supervised by board-certified sleep specialists (FSD and CT). Sleep efficiency was defined as total sleep time (TST)/time in bed (TIB). Quantitative analysis of sleep stages was calculated as a percentage of TST. REM Sleep Assessments The videos of all REM sleep phases were reviewed in real time with registration of all visible movements and noises as best as possible despite using blankets. Comfort moves, neck myoclonus, respiratory noises, and events related to arousals were omitted from further analysis. All motor behaviors and/or vocalizations with a purposeful component, seemingly expressive of a subject’s mentation, were classified as REM sleep behavioral events (RBE). This included minor movements as well as violent behaviors. Subjects were not awakened to check for dream recall. For comparative analyses, RBE episodes were characterized with the RBD severity scale.10 This scale has been validated for RBD in patients with PD and grades motor behaviors and the presence of vocalizations. We defined a cutoff of at least two separate behavioral events and/or vocalizations during REM sleep to classify a patient or control as “RBE positive.” For measurement of REM without atonia (RWA) surface electromyography (EMG) activity of the mentalis muscle was quantified during REM sleep according to the method recently published by the SINBAR Group11: each REM sleep 30-sec epoch was divided into 10 3-sec miniepochs. All miniepochs showing any muscle activity on chin EMG exceeding 0.1 sec with an amplitude exceeding twice the background EMG activity were counted as positive for RWA. The number of RWA-positive miniepochs was calculated as a percentage of all REM sleep miniepochs. Increases in muscle tone associated with snoring and arousals from respiratory events were SLEEP, Vol. 37, No. 3, 2014 432 Downloaded from https://academic.oup.com/sleep/article-abstract/37/3/431/2595936 by guest on 27 March 2018
excluded. For RWA measurement, the scorer (FSD) was blinded to the video evaluation. The cutoff value for 100% specificity for RBD was set at a mentalis EMG activity rate of 18.2% in accordance with the results of the SINBAR Group.11 RBD was defined according to ICSD-28 only with RWA above this cutoff. History of possible RBD was assessed by evaluation of questions 6.1 to 6.4 of the RBD screening questionnaire (RBD-SQ),12 asking for previous nocturnal occurrence of vocalizations (question 6.1), motor behaviors (questions 6.2 and 6.3) or any indication of nocturnal disturbances around the bed (question 6.4). Clinical Data The following data were assessed: 1. Sex and age at the time of vPSG. 2. In patients: Hoehn and Yahr stage, motor impairment measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score (UPDRS-3), subscores for tremor, calculated as the average of all tremor items on UPDRS-3 and postural instability/gait disorder (PIGD), calculated as the average of postural instability and gait disorder items on UPDRS-3. Motor subtypes were defined according to Jankovic et al.13 3. Olfactory function: “odor discrimination and identification” test using Sniffin’ Sticks developed by Kobal and Hummel (Burghart Medizintechnik GmbH, Wedel, Germany). 4. Cognitive screening with the MMSE and the clock drawing test. 5. Neuropsychological assessments of executive functions, attention, and speech (Similarities Wechsler Intelligenztest für Erwachsene [WIE], verbal fluency Regensburger Wortflüssigkeitstest [RWT], Stroop test FWIT [Farbe-Wort Interferenz Test], Wisconsin Card Sorting Test [WCST 64 card], Trail Making test [TMT]), memory (verbal learning test [VLMT], Wechsler Memory Scale [WMS-R]), and visuospatial function (cube analysis, fragmented letters Visual Object and Spatial Perception [VOSP]). 6. Use of selective serotonin/noradrenaline reuptake inhibitors (SSRI/SNRI), tricyclic antidepressants, benzodiazepines, and opioids at the time of vPSG. Statistical Analysis Patients with PD were compared with healthy controls. Subgroups were formed according to RBE-positive or -negative status: PD + RBE (A), PDnonRBE (B), HCnonRBE (C), and HC + RBE (D). The mean, standard deviation, and range were computed for descriptive characteristics. For qualitative and ordinal data, absolute and relative frequencies were used. Statistical analyses for dichotomous variables were tested with the χ2 test. Group differences (PD versus HC) were tested using (multivariate) analyses of variance for continuous variables. Nonparametric testing (Kruskal-Wallis test and for post hoc analysis Mann-Whitney U test) was used to compare the four groups (PD + RBE, PDnonRBE, HCnonRBE, HC + RBE). Data analysis was carried out with SPSS 20.0 (IBM). The alpha level was set at 5%. Preliminary subgroup analysis was performed for those PD+RBE patients who also fulfilled ICDS-2 criteria for RBD. REM Behavioral Events in Parkinson Disease—Sixel-Döring et al
RESULTS A total of 159 patients with de novo PD and 110 neurologically HC were investigated. Four controls receiving antidepressants for years from their general practitioner for “burnout” (n = 1) and “mild affective disorder” (n = 3) as well as three controls on long-standing stable nocturnal ventilation therapy were kept in the study. Altogether 268 data sets were available for analysis, one data set of a patients with PD was excluded because of invalid PSG. None of the patients or controls had a prediagnosis of RBD or had previously sought medical advice because of abnormal behaviors in sleep. Forty of 158 patients with PD (25%) and 2 of 110 controls (2%) showed clinical RBD with motor behaviors and/or vocalizations during REM sleep together with mentalis EMG activity at and above the cutoff value for 100% RBD specificity11 and thus fulfilled ICSD-28 criteria for RBD. Three of the 77 patients with PD and 2 of 93 controls without any behaviors during REM showed RWA rates in the mentalis muscle above the cutoff value, with 1 of 3 patients with PD and 1 of 2 controls with a positive history for possible RBD. In addition, 41 of 158 patients with PD (26%) and 15 of 110 controls (14%) were identified in vPSG with two or more behavioral motor events and/or vocalizations during REM sleep on time-synchronized video recordings and were classified as “RBE-positive”. In 6 of 81 patients and 1 of 17 controls with RBE, completed RWA measurement failed due to technical artifacts on chin EMG. In the other 35 of 81 patients and 14 of 17 controls with RBE, RWA was measured below the proposed cutoff.11 The videos included in the supplemental material show examples of RBE in patients and controls when RWA measures were below cutoff values11 and RBD criteria were not met. Preliminary statistical calculation of subgroup analyses for “definite RBD” positive study subjects failed to reach significance. Altogether, RBE occurred in 51% of this de novo PD cohort and 15% of controls (P < 0.001). Historical information on potential RBD showed poor sensitivity (0.68) and specificity (0.29). PD + RBE patients with RWA below RBD cutoff revealed more RWA than PDnonRBE patients (P = 0.032). This was not reproduced in controls, probably due to the small number of HC + RBE. Twenty-three of 89 HC (26%) with normal REM sleep reported an RBD suggestive history. Sleep starts, myoclonic jerks, leg movements, and sleep disordered breathing were found in these study participants. Figure 1 shows a study tree. Phenomenology of REM Sleep Behavioral Events We saw mostly mild, nonviolent behaviors that will easily escape self-perception as well as bedpartners’ notice. RBE with axial movements and changes of body position with or without vocalizations (RBDSS 3.0 and 3.1) affected 14 of 81 PD + RBE patients (17%) and 2 of 17 HC + RBE subjects (12%). Movements generated in the proximal extremities with or without vocalizations (RBDSS 2.0 and 2.1) were identified in 34 of 81 PD+RBE patients (42%) and 8 of 17 HC + RBE subjects (47%). Small movements in the distal extremities and facial movements with or without vocalizations (RBDSS 1.0 and 1.1) were present in 29 of 81 PD+RBE patients (36%) and 7 of 17 HC+RBE subjects (42%). Four PD+RBE patients (5%) showed only vocalizations. Patterns were similar in PD patients and controls (P = 0.325). SLEEP, Vol. 37, No. 3, 2014 433 Downloaded from https://academic.oup.com/sleep/article-abstract/37/3/431/2595936 by guest on 27 March 2018
Clinical Phenotypes Demographic, clinical, and medication data are presented in Table 1. RBE was not associated with age, sex, Hoehn and Yahr stage, UPDRS 3 score, subscores for tremor and PIGD, cognitive screening, and medication data. All patients with PD performed worse on olfactory tests (A, B < C, D; P < 0.001), MMSE (A, B < C, D; P = 0.020) and clock-drawing test (A, B < C, D; P < 0.001). One of 17 HC+RBE was on SSRI/SNRI; otherwise there was no intake of antidepressants in this subgroup. PSG Parameters PSG parameters are shown in Table 2. Patients with PD had longer REM latency (P = 0.003), more RWA (P < 0.001) and less awakenings (P = 0.003) compared with controls. All other sleep parameters were similar in both groups. The presence of RBE correlated to more REM sleep stage (A, D > B, C; P = 0.002), more RWA (A > B, C; P < 0.001; A > D; P = 0.019; D > B; P = 0.016; D > C; P = 0.043) and a higher PLMS index (A > B, C; P = 0.022; D > B; P = 0.043; D > C; P = 0.024). Neuropsychological Assessments Results are presented in Table 3. Worse performance of patients with PD in verbal fluency semantic (P = 0.003) and lexical (P = 0.001); Stroop test (P = 0.001), and trail making test (P = 0.006); delayed recall of verbal learning test VLMT (P = 0.006); WMS-R (P = 0.017); and fragmented letters VSOP (P = 0.036) showed no correlation to RBE. DISCUSSION To our knowledge, this study describes the largest cohort of patients with de novo PD and controls examined with vPSG, and for the first time analyzes systematically motor phenomena in REM sleep, matching these results to independent measurements of RWA and subjects’ history of potential RBD. RBE, defined as movements and/or vocalizations with a seemingly expressive, purposeful component detected on vPSG, were found in 51% of all patients with PD and 15% of all HC investigated. Presuming that the SINBAR Group’s proposal for RWA values on chin EMG with 100% specificity for RBD11 does indeed define the “substantial” amount of RWA required by the ICSD-28 for the diagnosis of RBD, 40 of 158 patients with de novo PD (25%) and 2 of 110 HC (2%) in this cohort also fulfill diagnostic criteria for RBD. If RBD as a potential marker for premotor manifestations of PD is detected in only a quarter of all newly afflicted PD patients, it appears less suitable than RBE as part of a set of nonmotor criteria for de novo PD in the future. The finding of RBE in 15% of HC was quite surprising. This cannot be explained by differences in medication, i.e., the use of antidepressants, as this affected only one RBE positive control. Follow-up vPSG will clarify these findings. We did not label behavioral events as subclinical RBD for several reasons: in contrast with previously described patients with idiopathic RBD5-7 none of the RBE-positive study participants was aware of a disorder and had previously sought medical advice because of abnormal nocturnal behaviors. Many of the movements observed did not seem bothersome. We did not awaken subjects after a REM-associated movement or vocalization to ask for dream recall as an indicator for dream-enacting behaviors. The term subclinical RBD has been proposed to REM Behavioral Events in Parkinson Disease—Sixel-Döring et al
A
159 PD patients
1 PD patient excluded due to invalid vPSG
40 PD patients with definite RBD
35 PD patients with RBE RWA < 18.2%
27 cases with a positive history for potential RBD
15 cases with a positive history for potential RBD
6 PD patients with RBE: no RWA measurement
77 PD patients without RBE
No RWA measurement: n = 4
3 PD patients without RBE RWA ≥ 18.2%
74 PD patients without RBE RWA < 18.2%
1 case with a positive history for potential RBD
B
17 cases with a positive history for potential RBD
110 HC
2 HC with definite RBD
14 HC with RBE RWA < 18.2%
0 case with a positive history for potential RBD
4 cases with a positive history for potential RBD
1 HC with RBE: no RWA measurement
93 HC without RBE
No RWA measurement: n = 2
2 HC without RBE RWA ≥ 18.2%
89 HC without RBE RWA < 18.2%
1 case with a positive history for potential RBD
23 cases with a positive history for potential RBD
Figure 1—(A) Study tree of the DeNoPa sleep cohort with 159 patients with de novo Parkinson disease (PD). (B) Study tree of the DeNoPa sleep cohort with 110 healthy controls (HC) matched for age, gender and education. RBD, rapid eye movement sleep behavioral disorder; RBE, rapid eye movement sleep behavioral event; RWA, rapid eye movement sleep without atonia. SLEEP, Vol. 37, No. 3, 2014 434 Downloaded from https://academic.oup.com/sleep/article-abstract/37/3/431/2595936 by guest on 27 March 2018
REM Behavioral Events in Parkinson Disease—Sixel-Döring et al
Table 1—Clinical and medication data in patients with Parkinson disease and healthy controls with and without rapid eye movement sleep behavioral events PD n = 158 65 ± 10 (40-85)
HC n = 110 65 ± 7 (44-84)
Significance P n.s.
PD + RBE n = 81, A 66 ± 9 (42-82)
PDnonRBE n = 77, B 65 ± 10 (40-85)
HCnonRBE n = 93, C 65 ± 7 (49-84)
HC + RBE n = 17, D 64 ± 7 (44-71)
Significance P n.s.
Sex, M / F, %
66 / 34
60 / 40
n.s.
72 / 28
60 / 40
58 / 42
76 / 24
n.s.
Hoehn and Yahr stage
1.8 ± 0.7 (1-3)
–
–
1.9 ± 0.7 (1-3)
1.7 ± 0.6 (1-3)
–
–
n.s.
UPDRS motor scorea
19 ± 10 (3-53)
–
–
19 ± 10 (3-41)
19 ± 11 (3-53)
–
–
n.s.
Tremor scoreb
0.3 ± 0.3 (0-1.7)
–
–
0.3 ± 0.2 (0-0.9)
0.3 ± 0.3 (0-1.7)
–
–
n.s.
PIGD scorec
0.7 ± 0.6 (0-2.5)
–
–
0.7 ± 0.6 (0-2.5)
0.7 ± 0.6 (0-2)
–
–
n.s.
28.3 ± 1.6 (21-30)
28.9 ± 1.1 (26-30)
0.001
28.1 ± 1.9 (21-30)
28.5 ± 1.3 (23-30)
28.9 ± 1.1 (26-30)
28.8 ± 1.3 (26-30)
0.020 A, B < C, D
Clock drawing test
1.8 ± 1 (1-5)
1.3 ± 0.6 (1-4)
0.001
1.7 ± 1.0 (1-5)
1.9 ± 1.0 (1-5)
1.2 ± 0.6 (1-4)
1.4 ± 0.8 (1-3)
< 0.001 A, B > C, D
Odor identification
7±4 (0-15)
12 ± 3 (0-16)
< 0.001
7.1 ± 3.4 (0-15)
7.4 ± 3.7 (0-15)
12 ± 2.7 (0-16)
12.2 ± 2.5 (7-16)
< 0.001 A, B < C, D
SSRI/SNRI, n (%)
16 (10)
2 (2)
0.008
10 (12)
6 (8)
1 (1)
1 (6)
0.03 A, B > C; D n.s.
Tricylcic antidepressants, n (%)
5 (3)
2 (2)
n.s.
1 (1)
4 (5)
2 (2)
0
n.s.
Benzodiazepines, n (%)
2 (1)
0
n.s.
2 (2)
0
0
0
n.s.
Opioids, n (%)
8 (5)
1 (1)
n.s.
4 (5)
4 (5)
1 (1)
0
n.s.
Age, years
MMSE
Values are mean ± standard deviation (range) unless otherwise indicated. aUnified Parkinson’s Disease Rating Scale subscale 3. bCalculated as the average of all tremor scorings on UPDRS motor score. cCalculated as the average of postural instability and gait disorder scorings on UPDRS motor score. Cutoff for significance was defined at P < 0.05. HC, healthy controls; M/F, male/female; MMSE, Mini-Mental State Examination; n.s., not significant; PD, Parkinson disease; PIGD, postural instability/gait disorder; RBE, rapid eye movement sleep behavioral events; SNRI, selective noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; UPDRS, Unified Parkinson’s Disease Rating Scale.
describe patients with an increased EMG activity in REM sleep with a cut-off value set at 15-20%, without clinical RBD behaviors or with nonclinical behaviors such as limb twitching, jerking, or other “simple behaviors” usually as an incidental finding during a PSG.14-16 This term is not applicable to our findings of RBE as all our study subjects with EMG activity below this threshold would be excluded. No definition of subclinical RBD related to the video assessments is known. Moreover, “subclinical” implies a transition to “clinical” RBD. Currently, however, it is unclear whether there is a natural continuum from individual variations of REM sleep regulation to the pathological state of RBD. Current pathophysiological concepts for RBD propose a specific degeneration of glutamatergic brain stem neurons,17 whereas recent animal experiments point to a specific lesion of glycine and gamma-aminobutyric acid A (GABA A) receptors,18 resulting in a malfunctioning of the proposed “flipflop switch” for REM-on and REM-off neurons.19 Assuming that the regulation of REM atonia and REM is a dynamic process, it is conceivable that normal aging may lead to a fragility with increased excitability of these neuronal networks, resulting in behavioral events in REM sleep before the full picture of RBD evolves. Follow-up investigations scheduled every 2 y will eventually clarify the significance of these findings. SLEEP, Vol. 37, No. 3, 2014 435 Downloaded from https://academic.oup.com/sleep/article-abstract/37/3/431/2595936 by guest on 27 March 2018
Sleep habits limit this video method: as all study participants slept with a blanket and sometimes with their face turned away from the camera we may have missed some minor movements. However, the difference in occurrence rates in the two groups is highly significant and may indicate RBE as a somnological marker for early PD. Another limitation is the restriction to chin EMG analysis. The use of additional muscle channels may have yielded a higher rate of RWA, but was not available for this study in a standard clinical sleep laboratory setting. Our data on an RBD suggestive history in patients and controls with poor sensitivity and specificity furthermore underline the necessity of an RBD expert personal interview to improve accuracy of historical information. RBD in clinically manifest PD has been associated with a nontremor-predominant phenotype of the disease,20,21 a specific neuropsychological profile,6 a higher rate of motor complications22 and falls,21 as well as cognitive decline,23-27 and psychotic symptoms.25,28,29 We failed to demonstrate a specific motor subtype of PD associated with RBE as well as with ICSD-2 criteria for RBD in this de novo cohort. This is in accordance with a prospective study comparing treadmill performance in patients with mild to moderate PD with and without RBD and controls30 as well as our previous analysis of REM Behavioral Events in Parkinson Disease—Sixel-Döring et al
Table 2—Sleep parameters in patients with Parkinson disease and healthy controls with and without rapid eye movement sleep behavioral events (RBE) PD n = 158 24 ± 19 (0-115)
HC n = 110 20 ± 14 (1-85)
Significance P n.s.
PD + RBE n = 81, A 25 ± 20 (1-104)
PDnonRBE n = 77, B 25 ± 21 (0-115)
HCnonRBE n = 93, C 22 ± 17 (1-85)
HC + RBE n = 17, D 26 ± 18 (9-69)
Significance P n.s.
Sleep efficiency, %TIB
74 ± 11 (46-96)
74 ± 11 (38-92)
n.s.
73 ± 10 (46-92)
71 ± 15 (6-96)
74 ± 11 (38-92)
73 ± 11 (48-92)
n.s.
Sleep stages 1 & 2, %TST
74 ± 10 (44-95)
75 ± 9 (43-91)
n.s.
73 ± 10 (45-91)
74 ± 10 (44-100)
76 ± 8 (58-91)
72 ± 12 (43-87)
n.s.
Sleep stages 3 & 4, %TST
8±8 (0-42)
7±7 0-24)
n.s.
7±8 (0-35)
9±8 (0-42)
8±7 (0-24)
6±8 (0-24)
n.s.
Sleep stage REM, %TST
19 ± 7 (1-43)
18 ± 6 (3-38)
n.s.
20 ± 6 (7-43)
17 ± 7 (0-32)
17 ± 5 (3-29)
22 ± 8 (9-38)
0.002 A, D > B, C
REM latency in min
107 ± 73 (16-444)
84 ± 47 (31-328)
0.003
100 ± 66 (16-319)
105 ± 66 (28-346)
86 ± 45 (32-328)
75 ± 48 (31-212)
0.014 A, B > C, D
RWA % REMa
15 ± 19 (0-99)
6±7 (0-59)
< 0.001
23 ± 22 (1-99)
6±8 (0-51)
5±5 (0-30)
11 ± 14 (2-59)
< 0.001 A > B, C 0.019 A > D 0.016 D > B 0.043 D > C
Awakenings total
25 ± 12 (7-69)
33 ± 14 (7-68)
0.003
23 ± 11 (7-56)
28 ± 18 (7-69)
32 ± 14 (7-68)
32 ± 17 (13-65)
0.001 C, D > A, B
PLM index all
37 ± 39 (0-192)
36 ± 35 (0-175)
n.s.
42 ± 43 (0-192)
29 ± 29 (0-114)
30 ± 29 (0-115)
50 ± 48 (0-175)
n.s.
PLMS index
37 ± 46 (0-223)
28 ± 34 (0-168)
n.s.
44 ± 51 (0-223)
28 ± 34 (0-153)
24 ± 30 (0-130)
46 ± 45 (0-168)
PLMW index
31 ± 30 (0-133)
40 ± 39 (0-179)
n.s.
32 ± 34 (0-133)
27 ± 27 (0-109)
37 ± 34 (0-151)
50 ± 56 (0-179)
n.s.
SDB, n (%)
42 (27)
22 (20)
n.s.
17 (21)
26 (34)
21 (23)
1 (6)
n.s.
Sleep latency in min
0.022 A > B, C 0.043 D > B 0.024 D > C
Values are mean ± standard deviation (range) unless otherwise indicated. aRapid eye movement sleep without atonia (RWA) was measured as any activity on mentalis muscle EMG per 3 sec miniepoch calculated as percent of total REM (11). Cutoff for significance was defined at P < 0.05. HC, healthy controls; n.s., not significant; PD, Parkinson disease; PLMS, periodic limb movements in sleep; PLMW, periodic limb movements in wake; RBE, rapid eye movement (REM) sleep behavioral event; RWA, REM without atonia; SDB, sleep disordered breathing (defined as having apnea-hypopnea index > 5); TIB, time in bed; TST, total sleep time; sleep efficiency was calculated as % of sleep during TIB; sleep stages were calculated as % of TST; index of periodic leg movements (PLM) was calculated per hour of TIB (PLM index all), per hour of sleep (PLMS index), and per hour of wakefulness (PLMW index).
a large cohort of medicated patients with PD in various stages of the disease.31 Also, we cannot deduce a specific neuropsychological profile or signs of impending cognitive decline associated with RBE or RBD, as described in previous studies on patients with PD in various, sometimes more advanced, stages of the disease.6,23-26 In contrast to medicated patients with PD of all stages who show a reduction of sleep efficiency, increased PLMS indices, sleep fragmentation, and RBD as typical alterations of sleep macrostructure, with a negative influence of dopamine agonists on sleep maintenance,32,33 sleep in patients with de novo PD in this study did not differ substantially from that in HC, except for more RBE, more RWA, and longer REM latency. PSGbased data on sleep in patients with de novo PD compared to controls are rare, mostly describing small cohorts and finding contradictory results: although one study34 found lower sleep efficiency, less REM sleep, and longer REM latency in patients with de novo PD, another previous PSG-based study35 showed no difference in conventional sleep parameters. In summary, we propose RBE as a somnological marker for PD affecting 51% of this de novo PD cohort. It may predict a specific phenotype of PD with a more severe course of SLEEP, Vol. 37, No. 3, 2014 436 Downloaded from https://academic.oup.com/sleep/article-abstract/37/3/431/2595936 by guest on 27 March 2018
the disease. Follow-up studies will reveal if RBE heralds neurodegenerative disease in healthy controls and if it is a precursor to RBD. ACKNOWLEDGMENTS Drs Mollenhauer and Trenkwalder contributed equally to the manuscript. The authors thank Arthur Walters, Department of Neurology, Division of Sleep Medicine, Vanderbilt University, Nashville, TN, USA, for his most helpful comments on the manuscript. The authors thank Anne-Marie Williams for her editorial assistance. DISCLOSURE STATEMENT The study was supported by unrestricted grants from the Paracelsus-Elena Klinik, Kassel, Germany and TEVA Pharma/ Lundbeck, as well as funding from GE Healthcare. Dr. SixelDöring has participated in speaking engagements for Abbott, Bayer Health Care, Boehringer Ingelheim, GSK, Meda Pharma, Orion Pharma and UCB. Congress participation was sponsored by Cephalon and Medtronic. She serves on an Advisory Board for Orion Pharma, Medtronic, and UCB. Dr. Mollenhauer has received research support from TEVA-Pharma, Desitin, REM Behavioral Events in Parkinson Disease—Sixel-Döring et al
Table 3—Neuropsychological assessments in patients with Parkinson disease and healthy controls with and without rapid eye movement sleep behavioral events (RBE)
Similarities
PD n = 158 21.9 ± 6.6 (0-33) n = 154
HC n = 110 25 ± 5.7 (5-33) n = 109
Significance P n.s.
PD + RBE n = 81, A 21.4 ± 7.4 (0-32) n = 79
PDnonRBE n = 77, B 22.4 ± 5.7 (7-33) n = 75
HCnonRBE n = 93, C 25.2 ± 5.3 (5-32) n = 92
HC + RBE n = 17, D 23.5 ± 7.6 (8-33) n = 17
Significance P < 0.001 A, B < C; D n.s.
Verbal fluency semantic
12.1 ± 6.1 (1-31) n = 153
15.6 ± 6.6 (1-32) n = 110
0.003
11.7 ± 6.1 (2-31) n = 78
12.5 ± 6.1 (1-26) n = 75
15.4 ± 6.5 (1-32) n = 93
16.4 ± 7.2 (4-26) n = 17
< 0.001 A, B < D 0.006 A,B < C
Verbal fluency lexical
29.2 ± 9 (5-57) n = 154
34.6 ± 7.4 (21-55) n = 110
0.001
28.2 ± 9.2 (5-57) n = 78
30.1 ± 8.8 (8-49) n = 76
35.4 ± 7.2 (21-55) n = 93
35.9 ± 8.2 (24-51) n = 17
< 0.001 A < C 0.003 A < D 0.006 B < C 0.018 B < D
Stroop test interference time in sec
98.7 ± 26.9 (53-200) n = 143
80.1 ± 17.8 (43-170) n = 107
0.001
103.5 ± 34.4 (58-280) n = 71
97.4 ± 26.5 (53-200) n = 72
79.9 ± 17.1 (43-170) n = 91
80.9 ± 21.8 (51-140) n = 16
< 0.001 A,B < C 0.007 A < D 0.014 B < D
WCST categories achieved
2.2 ± 1.5 (0-5) n = 107
2.6 ± 1.4 (0-5) n = 97
n.s.
2.2 ± 1.5 (0-5) n = 53
2.2 ± 1.5 (0-5) n = 54
43.3 ± 9 (16-56) n = 84
38.2 ± 14.3 (12-56) n = 13
n.s.
WCST total errors
24.8 ± 10.9 (8-51) n = 107
21.4 ± 9.9 (8-52) n = 97
n.s.
24.9 ± 10.7 (8-48) n = 53
24.7 ± 11.3 (8-51) n = 54
20.7 ± 9 (8-48) n = 84
25.9 ± 14.3 (8-52) n = 13
n.s.
Trail making test
136.9 ± 99.9 (40-999) n = 143
101.8 ± 51.3 (43-320) n = 110
0.006
139.6 ± 68.3 (47-322) n = 73
134.6 ± 125.5 (40-999) n = 70
101.3 ± 49.6 (43-312) n = 93
104.1 ± 61.7 (55-320) n = 17
< 0.001 A > C 0.03 B > C, D 0.02 A > D
VLMT recall
9.6 ± 10.3 (0-12) n = 143
9.9 ± 4.5 (0-15) n = 106
n.s.
12.5 ± 2.4 (0-18) n = 71
12.9 ± 1.8 (7-15) n = 72
13.1 ± 1.6 (9-15) n = 90
9.4 ± 5.1 (0-15) n = 16
n.s.
VLMT delayed recall
6.9 ± 3.6 (0-15) n = 144
8.1 ± 3.5 (1-15) n = 108
0.006
6.6 ± 3.8 (0-15) n = 71
7.2 ± 3.3 (1-15) n = 73
8.2 ± 3.4 (1-15) n = 91
8.1 ± 3.7 (3-15) n = 17
0.001 A < C, D 0.047 B < C, D
12.5 ± 3.3 (5-20) n = 156
13.8 ± 3.5 (5-21) n = 110
0.017
12.6 ± 3.6 (5-20) n = 79
12.4 ± 3.1 (6-19) n = 74
13.6 ± 3.2 (7-21) n = 93
14.9 ± 4.3 (5-21) n = 17
0.024 A, B < D 0.011 A, B < C
Cube analysis VOSP
9.3 ± 1.4 (0-10) n = 152
9.5 ± 1 (4-10) n = 110
n.s.
9.1 ± 1.7 (0-10) n = 78
9.5 ± 0.8 (7-10) n = 74
9.6 ± 0.8 (6-10) n = 93
8.9 ± 1.5 (4-10) n = 17
n.s.
Fragmented letters VOSP
19 ± 1.7 (8-20) n = 152
19.4 ± 0.8 (17-20) n = 110
0.036
18.9 ± 1.8 (10-20) n = 78
19.1 ± 1.7 (8-20) n = 74
19.4 ± 0.8 (17-20) n = 93
19.2 ± 0.8 (18-20) n = 17
n.s.
WMS
Values are mean ± standard deviation (range) unless otherwise indicated. HC, healthy controls; n.s., not significant; PD, Parkinson disease; RBE, rapid eye movement sleep behavioral event; VOSP, Visual Object and Spatial Perception; WCST, Wisconsin Card Sorting Test; WMS, Wechsler Memory Scale.
Boehringer Ingelheim and GE Healthcare. She has consulted for Bayer, Schering Pharma, AG and made presentations for GlaxoSmithKline and Orion Pharma. She has received travel and meeting expenses from Boehringer Ingelheim and Novartis. Dr. Trenkwalder has consulted for Boehringer Ingelheim, UCB, Novartis, TEVA, Mundipharma,and Britannia. She has participated in speaking engagements for Boehringer Ingelheim, Glaxo-SmithKline, UCB, and Pfizer. Dr. Trautmann has indicated no financial conflicts of interest. REFERENCES
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REM Behavioral Events in Parkinson Disease—Sixel-Döring et al
9. Mollenhauer B, Trautmann E, Sixel-Doring F, et al. Nonmotor and diagnostic findings in subjects with de novo Parkinson disease of the DeNoPa cohort. Neurology 2013;81:1226-34. 10. Sixel-Doring F, Schweitzer M, Mollenhauer B, Trenkwalder C. Intraindividual variability of REM sleep behavior disorder in Parkinson’s disease: a comparative assessment using a new REM sleep behavior disorder severity scale (RBDSS) for clinical routine. J Clin Sleep Med 2011;7:75-80. 11. Frauscher B, Iranzo A, Gaig C, et al. Normative EMG values during REM sleep for the diagnosis of REM sleep behavior disorder. Sleep 2012;35:835-47. 12. Stiasny-Kolster K, Mayer G, Schafer S, Moller JC, Heinzel-Gutenbrunner M, Oertel WH. The REM sleep behavior disorder screening questionnaire-a new diagnostic instrument. Mov Disord 2007;22:2386-93. 13. Jankovic J, McDermott M, Carter J, et al. Variable expression of Parkinson’s disease: a base-line analysis of the DATATOP cohort. The Parkinson Study Group. Neurology 1990;40:1529-34. 14. Schenck CH, Mahowald MW. Subclinical REM sleep behavior disorder and its clinical and research implications. Sleep 2008;31:1627. 15. Eisensehr I, Linke R, Tatsch K, et al. Increased muscle activity during rapid eye movement sleep correlates with decrease of striatal presynaptic dopamine transporters. IPT and IBZM SPECT imaging in subclinical and clinically manifest idiopathic REM sleep behavior disorder, Parkinson’s disease, and controls. Sleep 2003;26:507-12. 16. Gagnon JF, Bedard MA, Fantini ML, et al. REM sleep behavior disorder and REM sleep without atonia in Parkinson’s disease. Neurology 2002;59:585-9. 17. Luppi PH, Clement O, Sapin E, et al. The neuronal network responsible for paradoxical sleep and its dysfunctions causing narcolepsy and rapid eye movement (REM) behavior disorder. Sleep Med Rev 2011;15:153-63. 18. Brooks PL, Peever JH. Impaired GABA and glycine transmission triggers cardinal features of rapid eye movement sleep behavior disorder in mice. J Neurosci 2011;31:7111-21. 19. Lu J, Sherman D, Devor M, Saper CB. A putative flip-flop switch for control of REM sleep. Nature 2006;441:589-94. 20. Kumru H, Santamaria J, Tolosa E, Iranzo A. Relation between subtype of Parkinson’s disease and REM sleep behavior disorder. Sleep Med 2007;8:779-83. 21. Postuma RB, Gagnon JF, Vendette M, Charland K, Montplaisir J. REM sleep behaviour disorder in Parkinson’s disease is associated with specific motor features. J Neurol Neurosurg Psychiatry 2008;79:1117-21. 22. Ozekmekci S, Apaydin H, Kilic E. Clinical features of 35 patients with Parkinson’s disease displaying REM behavior disorder. Clin Neurol Neurosurg 2005;107:306-9.
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23. Boeve BF, Silber MH, Parisi JE, et al. Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism. Neurology 2003;61:40-5. 24. Gagnon JF, Postuma RB, Mazza S, Doyon J, Montplaisir J. Rapid-eyemovement sleep behaviour disorder and neurodegenerative diseases. Lancet Neurol 2006;5:424-32. 25. Sinforiani E, Pacchetti C, Zangaglia R, Pasotti C, Manni R, Nappi G. REM behavior disorder, hallucinations and cognitive impairment in Parkinson’s disease: a two-year follow up. Mov Disord 2008;23:1441-5. 26. Vendette M, Gagnon JF, Decary A, et al. REM sleep behavior disorder predicts cognitive impairment in Parkinson disease without dementia. Neurology 2007;69:1843-9. 27. Marion MH, Qurashi M, Marshall G, Foster O. Is REM sleep behaviour disorder (RBD) a risk factor of dementia in idiopathic Parkinson’s disease? J Neurol 2008;255:192-6. 28. Onofrj M, Thomas A, D’Andreamatteo G, et al. Incidence of RBD and hallucination in patients affected by Parkinson’s disease: 8-year followup. Neurol Sci 2002;23 Suppl 2:S91-4. 29. Pacchetti C, Manni R, Zangaglia R, et al. Relationship between hallucinations, delusions, and rapid eye movement sleep behavior disorder in Parkinson’s disease. Mov Disord 2005;20:1439-48. 30. Benninger DH, Michel J, Waldvogel D, et al. REM sleep behavior disorder is not linked to postural instability and gait dysfunction in Parkinson. Mov Disord 2010;25:1597-604. 31. Sixel-Doring F, Trautmann E, Mollenhauer B, Trenkwalder C. Associated factors for REM sleep behavior disorder in Parkinson disease. Neurology 2011;77:1048-54. 32. Sixel-Doring F, Trautmann E, Mollenhauer B, Trenkwalder C. Age, drugs or disease - what alters the macrostructure of sleep in Parkinson’s disease? Sleep Med 2012;13:1178-83. 33. Chahine LM, Daley J, Horn S, et al. Association between dopaminergic medications and nocturnal sleep in early-stage Parkinson’s disease. Parkinsonism Relat Disord 2013;19:859-63. 34. Placidi F, Izzi F, Romigi A, et al. Sleep-wake cycle and effects of cabergoline monotherapy in de novo Parkinson’s disease patients. An ambulatory polysomnographic study. J Neurol 2008;255:1032-7. 35. Brunner H, Wetter TC, Hogl B, Yassouridis A, Trenkwalder C, Friess E. Microstructure of the non-rapid eye movement sleep electroencephalogram in patients with newly diagnosed Parkinson’s disease: effects of dopaminergic treatment. Mov Disord 2002;17:928-33.
REM Behavioral Events in Parkinson Disease—Sixel-Döring et al
SUPPLEMENTAL MATERIAL Video Captions Video 1 shows a control with repetitive short movement of the right hand and left shoulder, short vocalization at 02:24 during third REM phase; RWA on chin EMG measured at 11.2%. Video 2 shows a control with elevation of right arm at 02:12 during the third REM phase; RWA measured on chin EMG at 3.3%. Video 3 shows the same control as in Video 2 with elevation of both arms at 02:16 during the third REM phase; RWA measured on chin EMG at 3.3%. Video 4 shows a control with short episode of body rocking then extension and repetitive movements of the left arm with
knocking against the nightstand at 02:17 during the second REM phase; RWA on chin EMG measured at 3.9%. Video 5 shows a patient with PD with slight jerking in left shoulder and alternating in both legs visible under the blanket, short vocalization at 11:14 during the first REM phase; RWA on chin EMG measured at 3.5% Video 6 shows a patient with PD with short, jerky movements alternating in both hands, left shoulder, short flexion in the left hip, then repetitive extension of the right arm at 03:53 during the second REM phase; RWA on chin EMG measured at 9.1%.
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REM Behavioral Events in Parkinson Disease—Sixel-Döring et al
Rapid Eye Movement Sleep Behavioral Events: A New Marker for Neurodegeneration in Early Parkinson Disease? Friederike Sixel-Döring, MD1,2; Ellen Trautmann, PhD1,3; Brit Mollenhauer, MD1,4,5; Claudia Trenkwalder, MD1,4
1 Paracelsus-Elena-Klinik, Kassel, Germany; 2Department of Neurology, Philipps-University Marburg, Germany; 3Department of Psychology, University Kassel, Germany; 4Department of Neurosurgery, Georg-August University Goettingen, Germany; 5Department of Neuropathology, Georg-August University, Goettingen, Germany
Objective: To analyze potential markers in sleep for early recognition of neurodegenerative disease in newly diagnosed, unmedicated patients with Parkinson disease (PD) compared to controls. Methods: Videopolysomnography (vPSG) was available in 158 newly diagnosed, unmedicated patients with PD and 110 age-, sex-, and educationmatched healthy controls (HC). Rapid eye movement (REM) sleep was analyzed for REM without atonia (RWA) and studied by review of timesynchronized video. Motor behaviors and/or vocalizations in REM sleep with a purposeful component other than comfort moves were identified as REM sleep behavioral events (RBE). Two or more events had to be present to be classified as “RBE positive.” RBE subjects included rapid eye movement sleep behavior disorder (RBD) and non-RBD subjects based on the presence or absence of RWA > 18.2%. Results: RBE were detected in 81 of 158 patients with de novo PD (51%) and 17 of 110 HC (15%) (P < 0.001). RBD was identified in 40/81 RBEpositive patients with PD (25% of all PD patients) and 2 of 17 RBE-positive HC (2% of all controls). RBE-positive patients showed no specific motor or neuropsychological features compared to RBE-negative patients. Patients with PD and HC with RBE had more REM sleep (P = 0.002) and a higher periodic leg movements in sleep index (P = 0.022) compared to subjects without RBE. Conclusion: This first description of REM sleep behavioral events (RBE) shows it occurs more frequently in patients with de novo Parkinson disease (PD) than in healthy controls and may be an early sign of neurodegeneration and precede rapid eye movement sleep behavior disorder (RBD). There is no specific phenotype of PD associated with newly defined RBE or RBD at this early stage. Keywords: Parkinson disease, REM sleep behavior disorder, REM sleep behavioral events, somnological marker Citation: Sixel-Döring F; Trautmann E; Mollenhauer B; Trenkwalder C. Rapid eye movement sleep behavioral events: a new marker for neurodegeneration in early Parkinson disease? SLEEP 2014;37(3):431-438.
INTRODUCTION A loss of slow wave sleep, sleep fragmentation, periodic limb movements in sleep (PLMS), and rapid eye movement (REM) sleep behavior disorder (RBD) have been labeled as somnological hallmarks of neurodegenerative diseases.1-4 Several studies5-7 have identified patients with idiopathic RBD at risk for parkinsonism and/or dementia, 81% of whom develop neurodegeneration after a mean interval of 14 years.7 Therefore, idiopathic RBD as defined by the International Classification of Sleep Disorders in its current 2005 version (ICSD-2)8 is considered a possible marker for premotor manifestations of PD. However, large-scale polysomnographic studies on sleep alterations in newly diagnosed, untreated PD are lacking. Moreover, the hypothesis of RBD as a hallmark of neurodegeneration originates from long-term observations of spectacular, violent RBD cases in sleep centers, not in PD cohorts. We analyzed potentially new and earlier somnological markers for neurodegeneration in a large cohort of newly diagnosed, unmedicated PD patients in comparison with matched neurologically healthy controls (HC) and correlated our findings to clinical disease phenotypes.
Submitted for publication April, 2013 Submitted in final revised form July, 2013 Accepted for publication July, 2013 Address correspondence to: Friederike Sixel-Döring, Paracelsus-Elena-Klinik, Center of Parkinsonism and Movement Disorders, Klinikstr. 16, 34128 Kassel, Germany; Tel: ++49-0561-60090; Fax: ++49-05616009126 E-mail: [email protected] SLEEP, Vol. 37, No. 3, 2014 431 Downloaded from https://academic.oup.com/sleep/article-abstract/37/3/431/2595936 by guest on 27 March 2018
METHODS The data presented here are part of the baseline evaluation of a prospective longitudinal single-center observational cohort study of patients with de novo PD and matched neurologically HC, which prospectively investigates nonmotor features and potential biomarkers in PD (“DeNoPa cohort”).9 Inclusion Criteria For patients: Men and women age 40-85 y with a clinical diagnosis of PD according to UK Brain Bank Criteria. Patients had to be drug-naïve for PD medication.9 For controls: Men and women age 40-85 y, no dementia or specific sleep complaints, recruited by public advertisement and participation requests to family and spouses. Controls were matched using frequency matching by age, sex, and educational level: the proportions of controls with these characteristics were identical to the proportions of cases with the same characteristics. Age was a continuous variable. The selection was possible through a 5-mo recruitment delay for controls. Exclusion Criteria For patients: (1) known severe vascular encephalopathy or normal pressure hydrocephalus on magnetic resonance imaging (MRI); (2) signs or symptoms suggestive of multiple system atrophy or progressive supranuclear palsy or medication-induced PD; or (3) current or past treatment with antipsychotic drugs. For controls: (1) active known/treated condition of the central nervous system; (2) history of PD in a parent, sibling, or child; (3) evident cognitive decline (MMSE < 26); and (4) exclusion of those reporting sleep disorders during the first interview REM Behavioral Events in Parkinson Disease—Sixel-Döring et al
with the investigator to avoid a bias toward sleep-disturbed controls as the polysomnographic recording was mentioned in the advertisement. Standard Protocol Approvals, Registrations, and Participants’ Consent All participants gave consent for their data to be scientifically evaluated, and signed additional consent forms agreeing for their nighttime video to be used for scientific and medical educational purposes. The local Ethical Committee approved the project (Approval No. FF89/2008). The DeNoPa study is registered with the German Register for Clinical Trials (DRKS00000540) according to the World Health Organization Trial Registration Dataset. Polysomnography Patients and controls were studied in the sleep laboratory for 2 nights. The second night was used for analysis. If the patient refused the second nighttime recording, or one of the two videopolysomnographies (vPSG) was invalid due to technical artifacts, the valid recording was used. Standard cardiorespiratory PSG (Xltec: Excel Tech Ltd; Oakville, Ontario; Canada) was applied according to American Academy of Sleep Medicine (AASM) criteria. All patients were documented with an infrared video recording synchronized to the PSG. Each recording was monitored. Sleep, sleep stages, PLMS, and respiratory events were scored according to standard criteria. All sleep evaluations were reviewed and supervised by board-certified sleep specialists (FSD and CT). Sleep efficiency was defined as total sleep time (TST)/time in bed (TIB). Quantitative analysis of sleep stages was calculated as a percentage of TST. REM Sleep Assessments The videos of all REM sleep phases were reviewed in real time with registration of all visible movements and noises as best as possible despite using blankets. Comfort moves, neck myoclonus, respiratory noises, and events related to arousals were omitted from further analysis. All motor behaviors and/or vocalizations with a purposeful component, seemingly expressive of a subject’s mentation, were classified as REM sleep behavioral events (RBE). This included minor movements as well as violent behaviors. Subjects were not awakened to check for dream recall. For comparative analyses, RBE episodes were characterized with the RBD severity scale.10 This scale has been validated for RBD in patients with PD and grades motor behaviors and the presence of vocalizations. We defined a cutoff of at least two separate behavioral events and/or vocalizations during REM sleep to classify a patient or control as “RBE positive.” For measurement of REM without atonia (RWA) surface electromyography (EMG) activity of the mentalis muscle was quantified during REM sleep according to the method recently published by the SINBAR Group11: each REM sleep 30-sec epoch was divided into 10 3-sec miniepochs. All miniepochs showing any muscle activity on chin EMG exceeding 0.1 sec with an amplitude exceeding twice the background EMG activity were counted as positive for RWA. The number of RWA-positive miniepochs was calculated as a percentage of all REM sleep miniepochs. Increases in muscle tone associated with snoring and arousals from respiratory events were SLEEP, Vol. 37, No. 3, 2014 432 Downloaded from https://academic.oup.com/sleep/article-abstract/37/3/431/2595936 by guest on 27 March 2018
excluded. For RWA measurement, the scorer (FSD) was blinded to the video evaluation. The cutoff value for 100% specificity for RBD was set at a mentalis EMG activity rate of 18.2% in accordance with the results of the SINBAR Group.11 RBD was defined according to ICSD-28 only with RWA above this cutoff. History of possible RBD was assessed by evaluation of questions 6.1 to 6.4 of the RBD screening questionnaire (RBD-SQ),12 asking for previous nocturnal occurrence of vocalizations (question 6.1), motor behaviors (questions 6.2 and 6.3) or any indication of nocturnal disturbances around the bed (question 6.4). Clinical Data The following data were assessed: 1. Sex and age at the time of vPSG. 2. In patients: Hoehn and Yahr stage, motor impairment measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score (UPDRS-3), subscores for tremor, calculated as the average of all tremor items on UPDRS-3 and postural instability/gait disorder (PIGD), calculated as the average of postural instability and gait disorder items on UPDRS-3. Motor subtypes were defined according to Jankovic et al.13 3. Olfactory function: “odor discrimination and identification” test using Sniffin’ Sticks developed by Kobal and Hummel (Burghart Medizintechnik GmbH, Wedel, Germany). 4. Cognitive screening with the MMSE and the clock drawing test. 5. Neuropsychological assessments of executive functions, attention, and speech (Similarities Wechsler Intelligenztest für Erwachsene [WIE], verbal fluency Regensburger Wortflüssigkeitstest [RWT], Stroop test FWIT [Farbe-Wort Interferenz Test], Wisconsin Card Sorting Test [WCST 64 card], Trail Making test [TMT]), memory (verbal learning test [VLMT], Wechsler Memory Scale [WMS-R]), and visuospatial function (cube analysis, fragmented letters Visual Object and Spatial Perception [VOSP]). 6. Use of selective serotonin/noradrenaline reuptake inhibitors (SSRI/SNRI), tricyclic antidepressants, benzodiazepines, and opioids at the time of vPSG. Statistical Analysis Patients with PD were compared with healthy controls. Subgroups were formed according to RBE-positive or -negative status: PD + RBE (A), PDnonRBE (B), HCnonRBE (C), and HC + RBE (D). The mean, standard deviation, and range were computed for descriptive characteristics. For qualitative and ordinal data, absolute and relative frequencies were used. Statistical analyses for dichotomous variables were tested with the χ2 test. Group differences (PD versus HC) were tested using (multivariate) analyses of variance for continuous variables. Nonparametric testing (Kruskal-Wallis test and for post hoc analysis Mann-Whitney U test) was used to compare the four groups (PD + RBE, PDnonRBE, HCnonRBE, HC + RBE). Data analysis was carried out with SPSS 20.0 (IBM). The alpha level was set at 5%. Preliminary subgroup analysis was performed for those PD+RBE patients who also fulfilled ICDS-2 criteria for RBD. REM Behavioral Events in Parkinson Disease—Sixel-Döring et al
RESULTS A total of 159 patients with de novo PD and 110 neurologically HC were investigated. Four controls receiving antidepressants for years from their general practitioner for “burnout” (n = 1) and “mild affective disorder” (n = 3) as well as three controls on long-standing stable nocturnal ventilation therapy were kept in the study. Altogether 268 data sets were available for analysis, one data set of a patients with PD was excluded because of invalid PSG. None of the patients or controls had a prediagnosis of RBD or had previously sought medical advice because of abnormal behaviors in sleep. Forty of 158 patients with PD (25%) and 2 of 110 controls (2%) showed clinical RBD with motor behaviors and/or vocalizations during REM sleep together with mentalis EMG activity at and above the cutoff value for 100% RBD specificity11 and thus fulfilled ICSD-28 criteria for RBD. Three of the 77 patients with PD and 2 of 93 controls without any behaviors during REM showed RWA rates in the mentalis muscle above the cutoff value, with 1 of 3 patients with PD and 1 of 2 controls with a positive history for possible RBD. In addition, 41 of 158 patients with PD (26%) and 15 of 110 controls (14%) were identified in vPSG with two or more behavioral motor events and/or vocalizations during REM sleep on time-synchronized video recordings and were classified as “RBE-positive”. In 6 of 81 patients and 1 of 17 controls with RBE, completed RWA measurement failed due to technical artifacts on chin EMG. In the other 35 of 81 patients and 14 of 17 controls with RBE, RWA was measured below the proposed cutoff.11 The videos included in the supplemental material show examples of RBE in patients and controls when RWA measures were below cutoff values11 and RBD criteria were not met. Preliminary statistical calculation of subgroup analyses for “definite RBD” positive study subjects failed to reach significance. Altogether, RBE occurred in 51% of this de novo PD cohort and 15% of controls (P < 0.001). Historical information on potential RBD showed poor sensitivity (0.68) and specificity (0.29). PD + RBE patients with RWA below RBD cutoff revealed more RWA than PDnonRBE patients (P = 0.032). This was not reproduced in controls, probably due to the small number of HC + RBE. Twenty-three of 89 HC (26%) with normal REM sleep reported an RBD suggestive history. Sleep starts, myoclonic jerks, leg movements, and sleep disordered breathing were found in these study participants. Figure 1 shows a study tree. Phenomenology of REM Sleep Behavioral Events We saw mostly mild, nonviolent behaviors that will easily escape self-perception as well as bedpartners’ notice. RBE with axial movements and changes of body position with or without vocalizations (RBDSS 3.0 and 3.1) affected 14 of 81 PD + RBE patients (17%) and 2 of 17 HC + RBE subjects (12%). Movements generated in the proximal extremities with or without vocalizations (RBDSS 2.0 and 2.1) were identified in 34 of 81 PD+RBE patients (42%) and 8 of 17 HC + RBE subjects (47%). Small movements in the distal extremities and facial movements with or without vocalizations (RBDSS 1.0 and 1.1) were present in 29 of 81 PD+RBE patients (36%) and 7 of 17 HC+RBE subjects (42%). Four PD+RBE patients (5%) showed only vocalizations. Patterns were similar in PD patients and controls (P = 0.325). SLEEP, Vol. 37, No. 3, 2014 433 Downloaded from https://academic.oup.com/sleep/article-abstract/37/3/431/2595936 by guest on 27 March 2018
Clinical Phenotypes Demographic, clinical, and medication data are presented in Table 1. RBE was not associated with age, sex, Hoehn and Yahr stage, UPDRS 3 score, subscores for tremor and PIGD, cognitive screening, and medication data. All patients with PD performed worse on olfactory tests (A, B < C, D; P < 0.001), MMSE (A, B < C, D; P = 0.020) and clock-drawing test (A, B < C, D; P < 0.001). One of 17 HC+RBE was on SSRI/SNRI; otherwise there was no intake of antidepressants in this subgroup. PSG Parameters PSG parameters are shown in Table 2. Patients with PD had longer REM latency (P = 0.003), more RWA (P < 0.001) and less awakenings (P = 0.003) compared with controls. All other sleep parameters were similar in both groups. The presence of RBE correlated to more REM sleep stage (A, D > B, C; P = 0.002), more RWA (A > B, C; P < 0.001; A > D; P = 0.019; D > B; P = 0.016; D > C; P = 0.043) and a higher PLMS index (A > B, C; P = 0.022; D > B; P = 0.043; D > C; P = 0.024). Neuropsychological Assessments Results are presented in Table 3. Worse performance of patients with PD in verbal fluency semantic (P = 0.003) and lexical (P = 0.001); Stroop test (P = 0.001), and trail making test (P = 0.006); delayed recall of verbal learning test VLMT (P = 0.006); WMS-R (P = 0.017); and fragmented letters VSOP (P = 0.036) showed no correlation to RBE. DISCUSSION To our knowledge, this study describes the largest cohort of patients with de novo PD and controls examined with vPSG, and for the first time analyzes systematically motor phenomena in REM sleep, matching these results to independent measurements of RWA and subjects’ history of potential RBD. RBE, defined as movements and/or vocalizations with a seemingly expressive, purposeful component detected on vPSG, were found in 51% of all patients with PD and 15% of all HC investigated. Presuming that the SINBAR Group’s proposal for RWA values on chin EMG with 100% specificity for RBD11 does indeed define the “substantial” amount of RWA required by the ICSD-28 for the diagnosis of RBD, 40 of 158 patients with de novo PD (25%) and 2 of 110 HC (2%) in this cohort also fulfill diagnostic criteria for RBD. If RBD as a potential marker for premotor manifestations of PD is detected in only a quarter of all newly afflicted PD patients, it appears less suitable than RBE as part of a set of nonmotor criteria for de novo PD in the future. The finding of RBE in 15% of HC was quite surprising. This cannot be explained by differences in medication, i.e., the use of antidepressants, as this affected only one RBE positive control. Follow-up vPSG will clarify these findings. We did not label behavioral events as subclinical RBD for several reasons: in contrast with previously described patients with idiopathic RBD5-7 none of the RBE-positive study participants was aware of a disorder and had previously sought medical advice because of abnormal nocturnal behaviors. Many of the movements observed did not seem bothersome. We did not awaken subjects after a REM-associated movement or vocalization to ask for dream recall as an indicator for dream-enacting behaviors. The term subclinical RBD has been proposed to REM Behavioral Events in Parkinson Disease—Sixel-Döring et al
A
159 PD patients
1 PD patient excluded due to invalid vPSG
40 PD patients with definite RBD
35 PD patients with RBE RWA < 18.2%
27 cases with a positive history for potential RBD
15 cases with a positive history for potential RBD
6 PD patients with RBE: no RWA measurement
77 PD patients without RBE
No RWA measurement: n = 4
3 PD patients without RBE RWA ≥ 18.2%
74 PD patients without RBE RWA < 18.2%
1 case with a positive history for potential RBD
B
17 cases with a positive history for potential RBD
110 HC
2 HC with definite RBD
14 HC with RBE RWA < 18.2%
0 case with a positive history for potential RBD
4 cases with a positive history for potential RBD
1 HC with RBE: no RWA measurement
93 HC without RBE
No RWA measurement: n = 2
2 HC without RBE RWA ≥ 18.2%
89 HC without RBE RWA < 18.2%
1 case with a positive history for potential RBD
23 cases with a positive history for potential RBD
Figure 1—(A) Study tree of the DeNoPa sleep cohort with 159 patients with de novo Parkinson disease (PD). (B) Study tree of the DeNoPa sleep cohort with 110 healthy controls (HC) matched for age, gender and education. RBD, rapid eye movement sleep behavioral disorder; RBE, rapid eye movement sleep behavioral event; RWA, rapid eye movement sleep without atonia. SLEEP, Vol. 37, No. 3, 2014 434 Downloaded from https://academic.oup.com/sleep/article-abstract/37/3/431/2595936 by guest on 27 March 2018
REM Behavioral Events in Parkinson Disease—Sixel-Döring et al
Table 1—Clinical and medication data in patients with Parkinson disease and healthy controls with and without rapid eye movement sleep behavioral events PD n = 158 65 ± 10 (40-85)
HC n = 110 65 ± 7 (44-84)
Significance P n.s.
PD + RBE n = 81, A 66 ± 9 (42-82)
PDnonRBE n = 77, B 65 ± 10 (40-85)
HCnonRBE n = 93, C 65 ± 7 (49-84)
HC + RBE n = 17, D 64 ± 7 (44-71)
Significance P n.s.
Sex, M / F, %
66 / 34
60 / 40
n.s.
72 / 28
60 / 40
58 / 42
76 / 24
n.s.
Hoehn and Yahr stage
1.8 ± 0.7 (1-3)
–
–
1.9 ± 0.7 (1-3)
1.7 ± 0.6 (1-3)
–
–
n.s.
UPDRS motor scorea
19 ± 10 (3-53)
–
–
19 ± 10 (3-41)
19 ± 11 (3-53)
–
–
n.s.
Tremor scoreb
0.3 ± 0.3 (0-1.7)
–
–
0.3 ± 0.2 (0-0.9)
0.3 ± 0.3 (0-1.7)
–
–
n.s.
PIGD scorec
0.7 ± 0.6 (0-2.5)
–
–
0.7 ± 0.6 (0-2.5)
0.7 ± 0.6 (0-2)
–
–
n.s.
28.3 ± 1.6 (21-30)
28.9 ± 1.1 (26-30)
0.001
28.1 ± 1.9 (21-30)
28.5 ± 1.3 (23-30)
28.9 ± 1.1 (26-30)
28.8 ± 1.3 (26-30)
0.020 A, B < C, D
Clock drawing test
1.8 ± 1 (1-5)
1.3 ± 0.6 (1-4)
0.001
1.7 ± 1.0 (1-5)
1.9 ± 1.0 (1-5)
1.2 ± 0.6 (1-4)
1.4 ± 0.8 (1-3)
< 0.001 A, B > C, D
Odor identification
7±4 (0-15)
12 ± 3 (0-16)
< 0.001
7.1 ± 3.4 (0-15)
7.4 ± 3.7 (0-15)
12 ± 2.7 (0-16)
12.2 ± 2.5 (7-16)
< 0.001 A, B < C, D
SSRI/SNRI, n (%)
16 (10)
2 (2)
0.008
10 (12)
6 (8)
1 (1)
1 (6)
0.03 A, B > C; D n.s.
Tricylcic antidepressants, n (%)
5 (3)
2 (2)
n.s.
1 (1)
4 (5)
2 (2)
0
n.s.
Benzodiazepines, n (%)
2 (1)
0
n.s.
2 (2)
0
0
0
n.s.
Opioids, n (%)
8 (5)
1 (1)
n.s.
4 (5)
4 (5)
1 (1)
0
n.s.
Age, years
MMSE
Values are mean ± standard deviation (range) unless otherwise indicated. aUnified Parkinson’s Disease Rating Scale subscale 3. bCalculated as the average of all tremor scorings on UPDRS motor score. cCalculated as the average of postural instability and gait disorder scorings on UPDRS motor score. Cutoff for significance was defined at P < 0.05. HC, healthy controls; M/F, male/female; MMSE, Mini-Mental State Examination; n.s., not significant; PD, Parkinson disease; PIGD, postural instability/gait disorder; RBE, rapid eye movement sleep behavioral events; SNRI, selective noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; UPDRS, Unified Parkinson’s Disease Rating Scale.
describe patients with an increased EMG activity in REM sleep with a cut-off value set at 15-20%, without clinical RBD behaviors or with nonclinical behaviors such as limb twitching, jerking, or other “simple behaviors” usually as an incidental finding during a PSG.14-16 This term is not applicable to our findings of RBE as all our study subjects with EMG activity below this threshold would be excluded. No definition of subclinical RBD related to the video assessments is known. Moreover, “subclinical” implies a transition to “clinical” RBD. Currently, however, it is unclear whether there is a natural continuum from individual variations of REM sleep regulation to the pathological state of RBD. Current pathophysiological concepts for RBD propose a specific degeneration of glutamatergic brain stem neurons,17 whereas recent animal experiments point to a specific lesion of glycine and gamma-aminobutyric acid A (GABA A) receptors,18 resulting in a malfunctioning of the proposed “flipflop switch” for REM-on and REM-off neurons.19 Assuming that the regulation of REM atonia and REM is a dynamic process, it is conceivable that normal aging may lead to a fragility with increased excitability of these neuronal networks, resulting in behavioral events in REM sleep before the full picture of RBD evolves. Follow-up investigations scheduled every 2 y will eventually clarify the significance of these findings. SLEEP, Vol. 37, No. 3, 2014 435 Downloaded from https://academic.oup.com/sleep/article-abstract/37/3/431/2595936 by guest on 27 March 2018
Sleep habits limit this video method: as all study participants slept with a blanket and sometimes with their face turned away from the camera we may have missed some minor movements. However, the difference in occurrence rates in the two groups is highly significant and may indicate RBE as a somnological marker for early PD. Another limitation is the restriction to chin EMG analysis. The use of additional muscle channels may have yielded a higher rate of RWA, but was not available for this study in a standard clinical sleep laboratory setting. Our data on an RBD suggestive history in patients and controls with poor sensitivity and specificity furthermore underline the necessity of an RBD expert personal interview to improve accuracy of historical information. RBD in clinically manifest PD has been associated with a nontremor-predominant phenotype of the disease,20,21 a specific neuropsychological profile,6 a higher rate of motor complications22 and falls,21 as well as cognitive decline,23-27 and psychotic symptoms.25,28,29 We failed to demonstrate a specific motor subtype of PD associated with RBE as well as with ICSD-2 criteria for RBD in this de novo cohort. This is in accordance with a prospective study comparing treadmill performance in patients with mild to moderate PD with and without RBD and controls30 as well as our previous analysis of REM Behavioral Events in Parkinson Disease—Sixel-Döring et al
Table 2—Sleep parameters in patients with Parkinson disease and healthy controls with and without rapid eye movement sleep behavioral events (RBE) PD n = 158 24 ± 19 (0-115)
HC n = 110 20 ± 14 (1-85)
Significance P n.s.
PD + RBE n = 81, A 25 ± 20 (1-104)
PDnonRBE n = 77, B 25 ± 21 (0-115)
HCnonRBE n = 93, C 22 ± 17 (1-85)
HC + RBE n = 17, D 26 ± 18 (9-69)
Significance P n.s.
Sleep efficiency, %TIB
74 ± 11 (46-96)
74 ± 11 (38-92)
n.s.
73 ± 10 (46-92)
71 ± 15 (6-96)
74 ± 11 (38-92)
73 ± 11 (48-92)
n.s.
Sleep stages 1 & 2, %TST
74 ± 10 (44-95)
75 ± 9 (43-91)
n.s.
73 ± 10 (45-91)
74 ± 10 (44-100)
76 ± 8 (58-91)
72 ± 12 (43-87)
n.s.
Sleep stages 3 & 4, %TST
8±8 (0-42)
7±7 0-24)
n.s.
7±8 (0-35)
9±8 (0-42)
8±7 (0-24)
6±8 (0-24)
n.s.
Sleep stage REM, %TST
19 ± 7 (1-43)
18 ± 6 (3-38)
n.s.
20 ± 6 (7-43)
17 ± 7 (0-32)
17 ± 5 (3-29)
22 ± 8 (9-38)
0.002 A, D > B, C
REM latency in min
107 ± 73 (16-444)
84 ± 47 (31-328)
0.003
100 ± 66 (16-319)
105 ± 66 (28-346)
86 ± 45 (32-328)
75 ± 48 (31-212)
0.014 A, B > C, D
RWA % REMa
15 ± 19 (0-99)
6±7 (0-59)
< 0.001
23 ± 22 (1-99)
6±8 (0-51)
5±5 (0-30)
11 ± 14 (2-59)
< 0.001 A > B, C 0.019 A > D 0.016 D > B 0.043 D > C
Awakenings total
25 ± 12 (7-69)
33 ± 14 (7-68)
0.003
23 ± 11 (7-56)
28 ± 18 (7-69)
32 ± 14 (7-68)
32 ± 17 (13-65)
0.001 C, D > A, B
PLM index all
37 ± 39 (0-192)
36 ± 35 (0-175)
n.s.
42 ± 43 (0-192)
29 ± 29 (0-114)
30 ± 29 (0-115)
50 ± 48 (0-175)
n.s.
PLMS index
37 ± 46 (0-223)
28 ± 34 (0-168)
n.s.
44 ± 51 (0-223)
28 ± 34 (0-153)
24 ± 30 (0-130)
46 ± 45 (0-168)
PLMW index
31 ± 30 (0-133)
40 ± 39 (0-179)
n.s.
32 ± 34 (0-133)
27 ± 27 (0-109)
37 ± 34 (0-151)
50 ± 56 (0-179)
n.s.
SDB, n (%)
42 (27)
22 (20)
n.s.
17 (21)
26 (34)
21 (23)
1 (6)
n.s.
Sleep latency in min
0.022 A > B, C 0.043 D > B 0.024 D > C
Values are mean ± standard deviation (range) unless otherwise indicated. aRapid eye movement sleep without atonia (RWA) was measured as any activity on mentalis muscle EMG per 3 sec miniepoch calculated as percent of total REM (11). Cutoff for significance was defined at P < 0.05. HC, healthy controls; n.s., not significant; PD, Parkinson disease; PLMS, periodic limb movements in sleep; PLMW, periodic limb movements in wake; RBE, rapid eye movement (REM) sleep behavioral event; RWA, REM without atonia; SDB, sleep disordered breathing (defined as having apnea-hypopnea index > 5); TIB, time in bed; TST, total sleep time; sleep efficiency was calculated as % of sleep during TIB; sleep stages were calculated as % of TST; index of periodic leg movements (PLM) was calculated per hour of TIB (PLM index all), per hour of sleep (PLMS index), and per hour of wakefulness (PLMW index).
a large cohort of medicated patients with PD in various stages of the disease.31 Also, we cannot deduce a specific neuropsychological profile or signs of impending cognitive decline associated with RBE or RBD, as described in previous studies on patients with PD in various, sometimes more advanced, stages of the disease.6,23-26 In contrast to medicated patients with PD of all stages who show a reduction of sleep efficiency, increased PLMS indices, sleep fragmentation, and RBD as typical alterations of sleep macrostructure, with a negative influence of dopamine agonists on sleep maintenance,32,33 sleep in patients with de novo PD in this study did not differ substantially from that in HC, except for more RBE, more RWA, and longer REM latency. PSGbased data on sleep in patients with de novo PD compared to controls are rare, mostly describing small cohorts and finding contradictory results: although one study34 found lower sleep efficiency, less REM sleep, and longer REM latency in patients with de novo PD, another previous PSG-based study35 showed no difference in conventional sleep parameters. In summary, we propose RBE as a somnological marker for PD affecting 51% of this de novo PD cohort. It may predict a specific phenotype of PD with a more severe course of SLEEP, Vol. 37, No. 3, 2014 436 Downloaded from https://academic.oup.com/sleep/article-abstract/37/3/431/2595936 by guest on 27 March 2018
the disease. Follow-up studies will reveal if RBE heralds neurodegenerative disease in healthy controls and if it is a precursor to RBD. ACKNOWLEDGMENTS Drs Mollenhauer and Trenkwalder contributed equally to the manuscript. The authors thank Arthur Walters, Department of Neurology, Division of Sleep Medicine, Vanderbilt University, Nashville, TN, USA, for his most helpful comments on the manuscript. The authors thank Anne-Marie Williams for her editorial assistance. DISCLOSURE STATEMENT The study was supported by unrestricted grants from the Paracelsus-Elena Klinik, Kassel, Germany and TEVA Pharma/ Lundbeck, as well as funding from GE Healthcare. Dr. SixelDöring has participated in speaking engagements for Abbott, Bayer Health Care, Boehringer Ingelheim, GSK, Meda Pharma, Orion Pharma and UCB. Congress participation was sponsored by Cephalon and Medtronic. She serves on an Advisory Board for Orion Pharma, Medtronic, and UCB. Dr. Mollenhauer has received research support from TEVA-Pharma, Desitin, REM Behavioral Events in Parkinson Disease—Sixel-Döring et al
Table 3—Neuropsychological assessments in patients with Parkinson disease and healthy controls with and without rapid eye movement sleep behavioral events (RBE)
Similarities
PD n = 158 21.9 ± 6.6 (0-33) n = 154
HC n = 110 25 ± 5.7 (5-33) n = 109
Significance P n.s.
PD + RBE n = 81, A 21.4 ± 7.4 (0-32) n = 79
PDnonRBE n = 77, B 22.4 ± 5.7 (7-33) n = 75
HCnonRBE n = 93, C 25.2 ± 5.3 (5-32) n = 92
HC + RBE n = 17, D 23.5 ± 7.6 (8-33) n = 17
Significance P < 0.001 A, B < C; D n.s.
Verbal fluency semantic
12.1 ± 6.1 (1-31) n = 153
15.6 ± 6.6 (1-32) n = 110
0.003
11.7 ± 6.1 (2-31) n = 78
12.5 ± 6.1 (1-26) n = 75
15.4 ± 6.5 (1-32) n = 93
16.4 ± 7.2 (4-26) n = 17
< 0.001 A, B < D 0.006 A,B < C
Verbal fluency lexical
29.2 ± 9 (5-57) n = 154
34.6 ± 7.4 (21-55) n = 110
0.001
28.2 ± 9.2 (5-57) n = 78
30.1 ± 8.8 (8-49) n = 76
35.4 ± 7.2 (21-55) n = 93
35.9 ± 8.2 (24-51) n = 17
< 0.001 A < C 0.003 A < D 0.006 B < C 0.018 B < D
Stroop test interference time in sec
98.7 ± 26.9 (53-200) n = 143
80.1 ± 17.8 (43-170) n = 107
0.001
103.5 ± 34.4 (58-280) n = 71
97.4 ± 26.5 (53-200) n = 72
79.9 ± 17.1 (43-170) n = 91
80.9 ± 21.8 (51-140) n = 16
< 0.001 A,B < C 0.007 A < D 0.014 B < D
WCST categories achieved
2.2 ± 1.5 (0-5) n = 107
2.6 ± 1.4 (0-5) n = 97
n.s.
2.2 ± 1.5 (0-5) n = 53
2.2 ± 1.5 (0-5) n = 54
43.3 ± 9 (16-56) n = 84
38.2 ± 14.3 (12-56) n = 13
n.s.
WCST total errors
24.8 ± 10.9 (8-51) n = 107
21.4 ± 9.9 (8-52) n = 97
n.s.
24.9 ± 10.7 (8-48) n = 53
24.7 ± 11.3 (8-51) n = 54
20.7 ± 9 (8-48) n = 84
25.9 ± 14.3 (8-52) n = 13
n.s.
Trail making test
136.9 ± 99.9 (40-999) n = 143
101.8 ± 51.3 (43-320) n = 110
0.006
139.6 ± 68.3 (47-322) n = 73
134.6 ± 125.5 (40-999) n = 70
101.3 ± 49.6 (43-312) n = 93
104.1 ± 61.7 (55-320) n = 17
< 0.001 A > C 0.03 B > C, D 0.02 A > D
VLMT recall
9.6 ± 10.3 (0-12) n = 143
9.9 ± 4.5 (0-15) n = 106
n.s.
12.5 ± 2.4 (0-18) n = 71
12.9 ± 1.8 (7-15) n = 72
13.1 ± 1.6 (9-15) n = 90
9.4 ± 5.1 (0-15) n = 16
n.s.
VLMT delayed recall
6.9 ± 3.6 (0-15) n = 144
8.1 ± 3.5 (1-15) n = 108
0.006
6.6 ± 3.8 (0-15) n = 71
7.2 ± 3.3 (1-15) n = 73
8.2 ± 3.4 (1-15) n = 91
8.1 ± 3.7 (3-15) n = 17
0.001 A < C, D 0.047 B < C, D
12.5 ± 3.3 (5-20) n = 156
13.8 ± 3.5 (5-21) n = 110
0.017
12.6 ± 3.6 (5-20) n = 79
12.4 ± 3.1 (6-19) n = 74
13.6 ± 3.2 (7-21) n = 93
14.9 ± 4.3 (5-21) n = 17
0.024 A, B < D 0.011 A, B < C
Cube analysis VOSP
9.3 ± 1.4 (0-10) n = 152
9.5 ± 1 (4-10) n = 110
n.s.
9.1 ± 1.7 (0-10) n = 78
9.5 ± 0.8 (7-10) n = 74
9.6 ± 0.8 (6-10) n = 93
8.9 ± 1.5 (4-10) n = 17
n.s.
Fragmented letters VOSP
19 ± 1.7 (8-20) n = 152
19.4 ± 0.8 (17-20) n = 110
0.036
18.9 ± 1.8 (10-20) n = 78
19.1 ± 1.7 (8-20) n = 74
19.4 ± 0.8 (17-20) n = 93
19.2 ± 0.8 (18-20) n = 17
n.s.
WMS
Values are mean ± standard deviation (range) unless otherwise indicated. HC, healthy controls; n.s., not significant; PD, Parkinson disease; RBE, rapid eye movement sleep behavioral event; VOSP, Visual Object and Spatial Perception; WCST, Wisconsin Card Sorting Test; WMS, Wechsler Memory Scale.
Boehringer Ingelheim and GE Healthcare. She has consulted for Bayer, Schering Pharma, AG and made presentations for GlaxoSmithKline and Orion Pharma. She has received travel and meeting expenses from Boehringer Ingelheim and Novartis. Dr. Trenkwalder has consulted for Boehringer Ingelheim, UCB, Novartis, TEVA, Mundipharma,and Britannia. She has participated in speaking engagements for Boehringer Ingelheim, Glaxo-SmithKline, UCB, and Pfizer. Dr. Trautmann has indicated no financial conflicts of interest. REFERENCES
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REM Behavioral Events in Parkinson Disease—Sixel-Döring et al
SUPPLEMENTAL MATERIAL Video Captions Video 1 shows a control with repetitive short movement of the right hand and left shoulder, short vocalization at 02:24 during third REM phase; RWA on chin EMG measured at 11.2%. Video 2 shows a control with elevation of right arm at 02:12 during the third REM phase; RWA measured on chin EMG at 3.3%. Video 3 shows the same control as in Video 2 with elevation of both arms at 02:16 during the third REM phase; RWA measured on chin EMG at 3.3%. Video 4 shows a control with short episode of body rocking then extension and repetitive movements of the left arm with
knocking against the nightstand at 02:17 during the second REM phase; RWA on chin EMG measured at 3.9%. Video 5 shows a patient with PD with slight jerking in left shoulder and alternating in both legs visible under the blanket, short vocalization at 11:14 during the first REM phase; RWA on chin EMG measured at 3.5% Video 6 shows a patient with PD with short, jerky movements alternating in both hands, left shoulder, short flexion in the left hip, then repetitive extension of the right arm at 03:53 during the second REM phase; RWA on chin EMG measured at 9.1%.
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REM Behavioral Events in Parkinson Disease—Sixel-Döring et al
