Analysis of sleep, daytime sleepiness, and autonomic function in multiple system atrophy and Parkinson disease: a prospective study

Abstract

Study Objectives:

Sleep disorders, daytime sleepiness, and autonomic dysfunction are commonly reported among patients with multiple system atrophy and Parkinson disease (PD). We aimed to assess sleep and autonomic function in these patients to evaluate the relationships between sleep disorders, excessive daytime sleepiness, and autonomic function.

Methods:

Twenty patients with multiple system atrophy (n = 7) and PD (n = 13) underwent clinical assessment including questionnaires for autonomic function and sleep. Cardiovascular autonomic function tests and 2-night video-polysomnography were followed by administration of the Multiple Sleep Latency Test. Rapid eye movement sleep without atonia was quantified in the chin, flexor digitorum superficialis, tibial anterior, and sternocleidomastoid muscles.

Results:

Rapid eye movement sleep behavior disorder was associated with orthostatic hypotension (P = .017) and constipation (P = .019) in PD. Patients with orthostatic hypotension had higher rapid eye movement sleep without atonia indices than those without orthostatic hypotension (P < .001). The Sleep Innsbruck Barcelona rapid eye movement sleep without atonia index (“any” chin and/or flexor digitorum superficialis) correlated with systolic/diastolic blood pressure fall upon tilt-table examination in patients with multiple system atrophy (P < .05) and with gastrointestinal (P = .010), urinary (P = .022), and total Scales for Outcomes in Parkinson’s Disease-Autonomic Dysfunction scores (P = .006) in all patients. Patients with a pathological deep breathing ratio showed higher Sleep Innsbruck Barcelona indices (P = .031). Objective daytime sleepiness was exclusively present in PD (P = .034) and correlated with levodopa-equivalent dosage (P = .031).

Conclusions:

The relationship of autonomic dysfunction with rapid eye movement sleep without atonia in PD and multiple system atrophy is accounted for by shared brainstem neuropathology and likely identifies patients in a more advanced stage of disease. Excessive daytime sleepiness is found exclusively in PD and may be secondary to levodopa treatment and not related to α-synuclein disease.

Citation:

Eckhardt C, Fanciulli A, Högl B, et al. Analysis of sleep, daytime sleepiness, and autonomic function and multiple system atrophy and Parkinson disease: a prospective study. J Clin Sleep Med. 2023;19(1):63–71.

BRIEF SUMMARY

Current Knowledge/Study Rationale: Sleep disorders and autonomic dysfunction are commonly reported among people with multiple system atrophy and Parkinson disease. This study assessed sleep (including objective daytime sleepiness) and autonomic function in these patients to evaluate their relationships.

Study Impact: This study highlights the relationships of autonomic dysfunction with rapid eye movement sleep behavior disorder and rapid eye movement sleep without atonia and reports no objective daytime sleepiness in people with MSA. Understanding the link between autonomic dysfunction and rapid eye movement sleep behavior disorder or rapid eye movement sleep without atonia will help identify patients who need combined diagnostics and therapy and likely recognize patients in a more advanced state of neurodegeneration or with a more severe disease phenotype.

INTRODUCTION

Multiple system atrophy (MSA) and Parkinson disease (PD) are alpha-synuclein–related neurodegenerative disorders with distinct neuropathology and progression. MSA presents with autonomic failure, parkinsonism, and a cerebellar syndrome in various combinations and pathologically with glial cytoplasmatic inclusions and neuronal loss predominantly in the striatonigral and olivopontocerebellar systems.¹ PD is a clinical syndrome defined by the presence of bradykinesia combined with either rest tremor, rigidity, or both. However, a wide range of nonmotor symptoms, including autonomic dysfunction, is present.² PD’s main pathological hallmarks are neural inclusions called Lewy bodies in the substantia nigra and in other brain areas like the brainstem.

People with MSA and PD report a wide range of sleep disturbances, including rapid eye movement (REM) sleep behavior disorder (RBD), insomnia, excessive daytime sleepiness (EDS), sleep apnea, and restless legs syndrome (RLS).^3,4 Among them, RBD has a specific relevance in MSA and PD. Almost 90% of people with MSA⁴ and approximately 50% of those with PD show RBD.³ RBD has been associated with autonomic failure, rapid disease progression, and a more severe motor phenotype in both PD and MSA.^5–10 The neuronal loss in mesencephalic and pontine centers controlling muscle activity during REM sleep and in the brainstem autonomic regions (rostral ventrolateral medulla, dorsal motor nucleus of vagus) in MSA point toward a close relationship between RBD and autonomic dysfunction.^11,12

EDS has been reported in up to one-third of patients with MSA and half of patients with PD, with multifactorial causes.^13,14 However, the interrelation of self-reported and objective EDS with disease severity, clinical phenotype (eg, presence and severity of autonomic dysfunction), medication, and sleep-related breathing disorder is heterogeneous. Previous studies with objective assessment of daytime sleepiness using the Multiple Sleep Latency Test (MSLT) in PD are scarce^15–17 and limited to only one in MSA.¹⁸ Based on these considerations, we aimed to assess sleep and autonomic function in IPD and MSA to (1) assess the relationships between sleep disorders and autonomic function and (2) evaluate self-reported and objective daytime sleepiness and its relationship with autonomic dysfunction.

METHODS

Study design and participants

In this prospective study, we consecutively recruited 20 patients with PD or MSA with a history of sleep disturbances (including sleep fragmentation, insomnia, daytime sleepiness, and RBD) among patients routinely presenting at the Sleep Laboratory or the Movement Disorders Clinic of the Medical University of Innsbruck, Austria. MSA was diagnosed according to the 2008 consensus criteria,¹⁹ and PD was diagnosed following the 2015 International Parkinson Disease and Movement Disorder Society Criteria.²⁰ Patients were matched for age, sex, and Hoehn & Yahr (H&Y) stage. Nocturnal breathing support of either continuous positive airway pressure or biphasic positive airway pressure treatment, pre-existing treatment with benzodiazepine or melatonin, and conditions known to result in secondary autonomic failure (eg, diabetes mellitus) represented exclusion criteria. Only patients with an H&Y ≤ 3 were included. The study was approved by the ethics committee of the Medical University of Innsbruck, and all participants signed the informed consent before inclusion in the study.

Clinical examination and questionnaires/scales

Each patient underwent a structured interview including assessment of medical history, disease onset and duration, and disease-specific features and medication schedule. Disease severity and motor symptoms were evaluated using H&Y, the Unified Multiple System Atrophy Rating Scale (UMSARS) for patients with MSA,²¹ and the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale for patients with PD.²² Patients were assessed under current treatment (including dopamine replacement therapy). The levodopa-equivalent dosage (LED) was calculated according to the current recommendations.²³ Sleep-related complaints were investigated using the Parkinson’s Disease Sleep Scale 2.²⁴ The presence of probable RBD was assessed using the Innsbruck RBD inventory,²⁵ and daytime sleepiness was evaluated with the Epworth Sleepiness Scale (ESS).²⁶ Sleep disorders were diagnosed according to the International Classification of Sleep Disorders, third edition (ICSD-3) criteria,²⁷ with the exception of RLS, which was diagnosed according to the current diagnostic criteria defined by the International Restless Legs Syndrome Study group.²⁸

Video-polysomnography and MSLT

All patients underwent 2 nights of video-polysomnography (v-PSG; referred to as night 1 and night 2 throughout the article) according to standard criteria,²⁷ followed by the MSLT.

Eight-hour v-PSG was recorded at the sleep laboratory in the Department of Neurology of the Medical University of Innsbruck and included electroencephalogram according to the 10-20-system (F3-A2/F4-A1/C3-A2/C4-A1/O1-A2/O2-A1), electro-oculogram monitoring horizontal and vertical eye movements, and surface electromyography (EMG) of the following muscles: the chin, bilateral tibialis anterior, bilateral flexor digitorum superficialis, and bilateral sternocleidomastoid muscles (SCM). The low-frequency filter was set at 50 Hz, and the high-frequency filter was set at 300 Hz. Single-channel electrocardiogram, oronasal respiratory flow, transcutaneous oxygen saturation, thoracic and abdominal respiratory movements, assessment of body position, and sound recording via microphone were performed. Time-synchronized digital videography was performed using an infrared high-resolution camera. To account for internight variability, general sleep parameters are provided as means of both evaluation nights. On the day following the second v-PSG, the MSLT was conducted according to standard criteria.²⁹

Analysis of v-PSGs

Sleep stages were scored according to the American Academy of Sleep Medicine criteria (The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications, Version 2.5),³⁰ with the allowance to score REM sleep despite excessive chin EMG activity. Diagnosis of RBD was made according to ICSD-3 criteria²⁷ and the International RBD Study Group recommendations.³¹ For each night of v-PSG, REM sleep without atonia (RWA) in 3-second mini-epochs was quantified according to the Sleep Innsbruck Barcelona (SINBAR) criteria,³² using validated software integrated in the v-PSG system.³³ Manual artifact correction was performed after running the automated RWA detection analyses and consisted of the exclusion of muscle activity related to snoring/breathing, artifacts, or periodic limb movements in sleep (PLMS).

PLMS were scored according to the American Academy of Sleep Medicine criteria using a validated software algorithm.³⁴ PLMS indices (PLMS/h) for total sleep time and REM sleep are provided as means of both evaluation nights.

Apneas and hypopneas were scored and classified according to the current AASM Scoring Manual,³⁰ and the average number of apneas/hypopneas per hour of sleep (apnea-hypopnea index) was calculated. Sleep-related breathing disorder was defined according to the ICSD-3.²⁷ Provided apnea-hypopnea index data refer to the first night of v-PSG because patients with sleep apnea were treated with positive airway pressure therapy during the second night.

Autonomic symptoms

The Scales for Outcomes in Parkinson’s Disease-Autonomic Dysfunction (SCOPA-AUT Questionnaire) was used to evaluate the presence of autonomic symptoms.³⁵

Cardiovascular autonomic function

Cardiovascular autonomic function was investigated using a standard tilt-table examination, Valsalva maneuver (blowing into a mouthpiece for 15 seconds at an expiratory pressure of 40 mm Hg––3 trials with 60-second intervals in between), and deep breathing. Patients were asked to avoid coffee, tea, or taurine-containing beverages on the day of the tilt-table examination and to have their last meal 2 hours before the scheduled test. The tilt-table battery was performed in a quiet setting, with a mean 22°C room temperature, following standardized protocols as described elsewhere.³⁶ Briefly, heart rate and blood pressure were continuously monitored with noninvasive beat-to-beat blood pressure recording and impedance cardiography (Task Force Monitor, CNSystems 2007 Graz, Austria). After lying for 10 minutes in the supine position, patients were passively tilted up to 60° for 10 minutes. Oscillometric blood pressure measurements were performed at the tenth minute of the supine phase and repeated 3 minutes after head-up tilting.

Orthostatic hypotension (OH) was diagnosed in patients with a systolic blood pressure fall of at least 20 mm Hg and/or at least 10 mm Hg diastolic at the third minute upon head-up tilt. Metronomic breathing at 6 cycles/minute for 2 minutes and the Valsalva maneuver were performed. The Valsalva maneuver and deep breathing ratios were calculated by a trained examiner (A.F.) and adjusted for age according to normative values.³⁷

Statistical analyses

Statistical analyses were performed using SPSS Statistics version 25 (SPSS, Inc., Chicago, IL). The Shapiro–Wilk test was applied to assess the distribution of data. Frequencies and group differences of qualitative data were computed using cross tabs and the chi square test. The Fisher exact test was applied for small sample sizes. We performed the following 2 group comparisons using the Student t test or Mann–Whitney U test as appropriate: PD vs MSA, patients with vs patients without RBD, patients with vs patients without OH. Comparisons between more than 2 groups were performed using a univariate analysis of variance or the Kruskal–Wallis test. Night-to-night variability of RWA variables was investigated using repeated-measures analysis of variance. Linear regression was calculated to predict (1) RWA indices based on diagnosis, disease duration, disease severity, LED, antidepressant medication, OH, RLS, and PLMS; and (2) daytime sleep latency during the MSLT based on diagnosis, disease duration, disease severity, LED, antidepressant medication, RBD, OH, ESS, RLS, PLMS, sleep-related breathing disorder, and apnea-hypopnea index. Further, relationships between clinical, autonomic, and polysomnographic variables were evaluated using Pearson or Spearman correlation as appropriate, and Bonferroni correction for multiple comparisons was performed. Data are presented as mean ± standard deviation in case of normal distribution or median (interquartile range) when data were not normally distributed and as frequencies throughout the text and tables. The level of significance was set at P < .05.

RESULTS

Demographic and clinical characteristics of the study population

Of the 20 patients included, 13 were diagnosed with PD and 7 with MSA (5 with MSA-predominant parkinsonism, MSA-P, 2 with MSA-predominant cerebellar ataxia, MSA-C). Thirteen patients (6 patients with MSA and 7 with PD) had a history suggestive of RBD, 4 patients with PD had a history of insomnia, 2 patients with PD were referred to the sleep laboratory because of self-reported daytime sleepiness, and 1 patient with MSA had a history of sleep fragmentation.

RBD was diagnosed in 7 out of 13 (53.8%) patients with PD (referred to as PDwRBD; 6 patients with PD did not have RBD, referred to as PDwoRBD), and in all patients with MSA.

Patient groups were comparable in terms of disease duration, sex, age at examination, LED (all patients, except the 2 patients with MSA-C, received dopamine replacement therapy) (P > .05; Table 1). In the MSA group, all patients were categorized as H&Y stage 3, in the PD group 5 patients were categorized as H&Y stage 2, and 8 patients were categorized as H&Y stage 3. The Movement Disorders Society-Unified Parkinson’s Disease Rating Scale total and subscores were similar in PDwoRBD and PDwRBD (P > .05; see Table S1 ^{(309KB, pdf)} in the supplemental material). The mean total UMSARS score was 43.29 ± 10.06 (UMSARS section I, 21.14 ± 05.40; UMSARS section II, 22.14 ± 05.05). Within the PD group there was a strong correlation of disease duration with LED (r = .774; P = .002). Moreover, LED correlated with Movement Disorders Society-Unified Parkinson’s Disease Rating Scale part IV in the PD group (r = .784; P = .003) and to UMSARS II (motor score) in the MSA group (r = .823; P = .023). Demographics and clinical characteristics are reported in Table 1.

Table 1.

Demographic and clinical characteristics of the study population.

	PDwoRBD (n = 6)	PDwRBD (n = 7)	MSA (n = 7)	P
	PD		MSA
Age (y)	63.67 ± 11.50	68.40 ± 5.44	60.86 ± 08.05	.270
	66.23 ± 08.72			.194
Female, n (%)	3/6 (50)	3/7 (43)	3/7 (43)	.958
	6/13 (46)			.630
Disease duration (mo)	66 (36–96)	89 (48–144)	46 (24–60)	.331
	60 (36–96)			.157
Dopamine replacement therapy, n (%)	6/6 (100)	7/7 (100)	5/7 (71)	.127
	13/13 (100)			.111
LED (mg/100 mg l-dopa)	916 ± 605	782 ± 573	581 ± 311	.225
	844 ± 567			.091
Antidepressant medication, n (%)	2/6 (33)	2/7 (29)	2/7 (29)	.978
	4/13 (31)			.664

Data for patients with PD (PDwoRBD, PDwRBD) and patients with MSA are reported as mean ± SD, median (interquartile range), and frequencies. LED = levodopa-equivalent dosage, MSA = multiple system atrophy, PD = Parkinson disease, PDwoRBD = Parkinson disease without rapid eye movement sleep behavior disorder, PDwRBD = Parkinson disease with rapid eye movement sleep behavior disorder, SD = standard deviation.

SCOPA-AUT questionnaire and cardiovascular autonomic function tests

The results of the SCOPA-AUT questionnaire are summarized in Table 2. OH was diagnosed in 8/20 patients (40%), 3 patients with PD and 5 patients with MSA (P = .067). Cardiovascular autonomic function parameters are summarized in Table S2 ^{(309KB, pdf)} .

Table 2.

SCOPA-AUT questionnaire.

	PDwoRBD	PDwRBD	MSA	P
	woRBD	RBD
Gastrointestinal domain	3 (0.5–3)	3.57 ± 1.72	6.67 ± 3.5	.029	PDwoRBD vs MSA: .027
		5 (2.5–6)		.040
Urinary domain	3.40 ± 1.67	5.86 ± 2.61	6.83 ± 5.98	.361
		6.31 ± 4.31		.084
Cardiovascular domain	0 (0–2.5)	1 (0–2)	2 (0–3.25)	.311
		2 (0–2.5)		.303
Thermoregulatory domain	2 (1–6)	3 (2–6)	3.5 (0–5.25)	.856
		3 (0–5.5)		.842
Pupillomotor domain	0 (0–1)	1 (0–2)	0.5 (0–2)	.535
		1 (0–2)		.275
Sexual domain	0 (0–0.5)	2 (0–2)	3 ± 2.1	.036	PDwoRBD vs MSA: > .05
		2.08 ± 1.85		.046
Total SCOPA-AUT score	10.2 ± 3.63	16.71 ± 7.23	22.5 ± 9.81	.051	PDwoRBD vs MSA: .049
		19.38 ± 8.68		.014

Data are presented as mean ± SD and as median (interquartile range). MSA = multiple system atrophy, PDwoRBD = Parkinson disease without rapid eye movement sleep behavior disorder, PDwRBD = Parkinson disease with rapid eye movement sleep behavior disorder, SCOPA-AUT = Scales for Outcomes in Parkinson’s Disease-Autonomic Dysfunction, SD = standard deviation.

Sleep architecture

Sleep parameters are shown in Table S3 ^{(309KB, pdf)} . Sleep efficiency was reduced and REM sleep latency was increased in all groups. Sleep efficiency and total sleep time were significantly reduced in patients with MSA compared to patients with PD (P = .005 and P = .012, respectively), and correspondingly wake after sleep onset was significantly increased in patients with MSA compared to patients with PD (P = .013). No correlations between disease duration and sleep macrostructure were identified.

Sleep disorders in the study population

Results of administered sleep questionnaires are presented in Table S4 ^{(309KB, pdf)} . RLS was diagnosed in 1 patient with PDwRBD and in 1 patient with MSA. The presence of RLS did not differ among the groups of patients. Insomnia was present in 4/6 (67%) of patients with PDwoRBD and in none of the patients with RBD (P = .003).

RBD was diagnosed in 14 patients. The Innsbruck RBD inventory (cutoff, 0.25) identified 11 of the 14 v-PSG confirmed patients with RBD (P = .018; sensitivity, 79%; specificity, 83%; accuracy, 80%). Among 13 patients with a history of dream enactment behavior, the diagnosis was confirmed by v-PSG in 12. One patient with PD with a clinical history suggestive of RBD did not show RWA (none of the cutoff values proposed by the SINBAR study group were reached in this patient), and the v-PSG did not show any dream enactment behavior in REM sleep. Two patients without a history of RBD (1 with MSA and 1 with PD, neither with a bed partner) showed dream enactment behavior during REM sleep and RWA on v-PSG, meeting the diagnostic criteria for RBD. Therefore, a total of 14 patients were diagnosed with RBD: 7/7 (100%) patients with MSA and 7/13 (54%) patients with PD. In our cohort, the PD phenotype (tremor-dominant or akinetic-rigid) did not differ between patients with or without RBD (P > .05).

Data on sleep apnea are reported in Table S5 ^{(309KB, pdf)} . Four patients with MSA showed obstructive sleep apnea (2 with mild sleep apnea and 2 with severe sleep apnea), and 1 patient with MSA had moderate central sleep apnea. Among patients with PD, 3 patients had severe central sleep apnea and 2 patients had mild obstructive sleep apnea. There was no significant association between the diagnosis of PD or MSA and sleep apnea or between RBD and sleep apnea. Inspiratory stridor was present in 2 out of 7 (29%) patients with MSA, both with severe sleep apnea.

PLMS indices are reported in Table S6 ^{(309KB, pdf)} . Patients with RBD (PDwRBD and MSA) showed higher PLMS indices during total sleep time compared to patients with PDwoRBD. This difference was no longer significant after excluding the 2 patients with RLS. However, there was still an association between RBD and a PLMS index > 15 events/h (P = .024).

RWA

All patients, except 1 patient with PDwoRBD and 1 patient with PDwRBD, showed REM sleep in the first night of PSG. Both patients had REM sleep in the second evaluation night, so the quantification of RWA was possible in all patients. There was no significant night-to-night variability in RWA indices (P > .05). RWA indices on nights 1 and 2 are reported in Table S7 ^{(309KB, pdf)} and Table S8 ^{(309KB, pdf)} . Comparison of RWA indices among the different groups is reported in Table 3.

Table 3.

RWA.

	PDwoRBD n = 6	PDwRBD n = 7	MSA n = 7	P	P values for two-groups comparisons
	woRBD n = 6	RBD n = 14			PDwoRBD vs PDwRBD	PDwoRBD vs MSA	PDwRBD vs MSA
Tonic, chin (%)	0.0 (0.0–0.84)	40.90 ± 31.85	51.04 ± 31.30	.045	>.99	.027	>.99
		45.97 ± 30.79		< .001
Phasic, chin (%)	21.63 ± 8.93	36.40 ± 14.25	30.38 ± 16.43	1	n.a.	n.a.	n.a.
		33.39 ± 15.10		1
Phasic, FDS (%)	12.49 ± 5.46	44.13 (42.85–45.24)	49.23 ± 12.05	.018	.027	.027	>.99
		48.15 ± 5.46		< .001
Phasic, SCM (%)	1.79 ± 0.87	22.49 ± 7.77	27.73 ± 12.77	< .001	.002	<.001	>.99
		25.11 ± 10.52		< .001
Phasic, TA (%)	38.31 ± 30.27	36.56 ± 13.96	44.37 ± 17.70	1	n.a.	n.a.	n.a.
		31.96 (26.44-64.17)		1
“Any”, chin (%)	16.56 ± 7.94	58.10 ± 24.29	61.70 ± 21.68	.009	<.001	<.001	>.99
		59.90 ± 22.19		< .001
SINBAR index (%)	25.24 ± 10.55	74.97 ± 16.23	79.34 ± 7.47	< .001	<.001	<.001	>.99
		77.16 ± 12.35		< .001
“Any” chin or phasic SCM (%)	16.80 ± 8.82	64.64 ± 22.64	70.89 ± 14.78	< .001	<.001	<.001	>.99
		67.76 ± 18.65		< .001
“Any” chin or phasic TA (%)	47.11 ± 26.17	69.37 ± 20.86	79.32 ± 8.10	.234	>.99	.225	>.99
		74.35 ± 16.05		.090

Data are reported as mean ± SD and as median (interquartile range). “Any” refers to tonic or phasic electromyogram activity. FDS = flexor digitorum superficialis, MSA = multiple system atrophy, PDwoRBD = Parkinson disease without rapid eye movement sleep disorder, PDwRBD = Parkinson disease with rapid eye movement sleep disorder, RWA, rapid eye movement sleep without atonia, SCM = sternocleidomastoid, SD = standard deviation, SINBAR = Sleep Innsbruck Barcelona, TA = tibialis anterior.

Tonic and “any” EMG activity in the chin, as well as phasic EMG activity in the flexor digitorum superficialis and SCM differentiated patients with RBD from patients with PDwoRBD (P < .001). The highest phasic EMG activity was detected in the flexor digitorum superficialis muscles, which was significantly higher compared to phasic EMG activity in the SCM (P < .001) and phasic EMG activity in the chin (P < .009) in patients with RBD. Phasic EMG activity in the chin and in the tibialis anterior muscles did not differentiate between patients with and without RBD. All patients with a diagnosis of RBD exceeded the SINBAR index cutoff of 32% (P < .001). Two more patients without a history of RBD and without dream enactment behaviors on v-PSG also presented with RWA above this cutoff.

Daytime sleepiness

Mean total ESS scores are reported in Table S4 ^{(309KB, pdf)} ; mean sleep latencies during the MSLT are reported in Table S3 ^{(309KB, pdf)} . The ESS total scores were comparable between the groups (PD vs MSA) and when comparing patients with and without RBD and comparing patients with and without OH (P > .05).

Objective daytime sleepiness (mean sleep latency less than 8 minutes during the MSLT) was associated with a diagnosis of PD (P = .034), because it was present in 50% of patients with PD and in none of the patients with MSA. Five of the 6 patients with PD (83%) with objective daytime sleepiness presented with the akinetic-rigid phenotype.

No correlation was found between mean sleep latency during the MSLT and disease duration, disease severity (as evaluated by the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale and UMSARS, or H&Y), antidepressant medication, diagnosis of RBD, presence of OH, ESS score, diagnosis of RLS, presence of PLMS, severity of sleep-related breathing disorder, or apnea-hypopnea index. There was a moderate correlation of mean sleep latency and LED in patients with PD (r = −.621; P = .031), but not in patients with MSA. No significant correlations between RWA (SINBAR index) and mean sleep latency were found. Mean sleep latency correlated with systolic and diastolic blood pressure fall upon head-up tilt in patients with PD (r = .729; P = .022 and r = .717; P = .026, respectively).

Autonomic function in relation to RBD and RWA

The SCOPA-AUT total score (P = .014) and the gastrointestinal (P = .040) and sexual domains (P = .046) were more affected in patients with RBD compared to patients without RBD (Table 2). This was also true for the sexual domain and total SCOPA-AUT score comparisons between patients with PD with and without RBD (P = .034 and P = .048, respectively). Constipation was associated with a diagnosis of RBD in patients with PD (P = .038). The SINBAR index correlated with the gastrointestinal (r = .588; P = .010), the urinary domain (r = .536; P = .022), and the total SCOPA-AUT score (r = .619; P = .006). In patients with PD, there was a significant correlation between the SINBAR index and the urinary domain (r = .668; P = .018) and the total SCOPA-AUT score (r = .699; P = .011).

RBD was associated with a diagnosis of OH (P = .017): We found that 57% (8/14) of patients with RBD (3 with PDwRBD and 5 with MSA) were diagnosed with OH; none of the 6 patients with PD without RBD had OH. In patients with a diagnosis of OH, the systolic and diastolic blood pressure fall during tilt-table examination correlated with the SINBAR index (r = −.865; P = .048 and r = −.929; P = .0012). In addition, in patients with a diagnosis of RBD, the fall in systolic and diastolic blood pressure during tilt-table examination correlated with the SINBAR index (r = −.725; P = .032 and r = −.793; P = .008).

Multiple linear regression showed that among disease duration, disease severity, medication, diagnosis, and OH, only a diagnosis of OH was a significant predictor of RWA indices (tonic chin: β = 0.505, P = .009; phasic FDS: β = 0.466, P = .049; SINBAR: β = 0.606, P = .013; “any” chin or phasic SCM: β = 0.580, P = .021). The following RWA indices were significantly higher in patients with a diagnosis of OH compared to those without OH: tonic chin (P = .018), “any” chin (P < .001), SINBAR index (P < .001), and “any” chin or phasic SCM (P < .001). Significant correlations were identified between the SINBAR index and the fall in systolic and diastolic blood pressure during tilt-table examination (r = −.657; P = .006 and r = −.645; P = .008). Subgroup analyses showed that these correlations were driven by the MSA group (r = −.829; P = .042 and r = −.841; P = .036). Patients with a pathologic deep breathing ratio showed higher SINBAR indices compared to patients with a normal deep breathing ratio (P = .031).

DISCUSSION

This study assessed sleep, daytime sleepiness, and autonomic function in people with PD and MSA, providing new insights into the relationship of autonomic function with RBD and RWA. We found an association between RBD and the total scores of the SCOPA-AUT questionnaire and subscores addressing gastrointestinal and sexual domains, along with a diagnosis of OH. Moreover, RWA indices correlated with the gastrointestinal, urinary, and total SCOPA-AUT scores, with the presence of OH, and with a pathologic deep breathing ratio. Further, in people with MSA, RWA correlated with blood pressure reductions upon tilt-table examination. In addition, this study shows that objective daytime sleepiness as evaluated using the MSLT is not present in people with MSA.

RBD and RWA

This study supports evidence from previous observations regarding the prevalence of RBD in the investigated cohort: all patients with MSA and half of the patients with PD were diagnosed with RBD.^3,4 Among RWA indices, the SINBAR index best differentiated patients with RBD from patients without RBD, supporting evidence from the literature on the usefulness of EMG of the upper extremities to identify patients with RBD,^31,38 also in the context of PD and MSA. High rates of phasic chin EMG activity were observed in patients with PDwoRBD, and 2 patients with PD without a history of RBD and without dream enactment behaviors in REM sleep during v-PSG exceeded the SINBAR index cutoff. When we also considered recent findings of increased frequency of RWA and RBD in patients with advanced PD compared to patients in early stages of disease and data on RBD evolution over time in de novo patients with PD, we found that the presence of RWA likely indicates the involvement of brainstem circuits controlling motor activity during REM sleep as a consequence of the underlying synucleinopathy, which may lead to the development of RBD in these patients over time.³⁹

In line with previous reports, phasic EMG activity in the tibialis anterior muscles was not specific to RBD, likely because of confounding EMG activities such as excessive fragmentary myoclonus.^38,40 Studies evaluating differences in RWA activities between PD and MSA are limited, and inconsistent results have been reported.^41,42 In the current study, RWA indices did not differ between patients with PDwRBD and patients with MSA.

In our cohort, motor phenotype or disease severity were comparable in patients with PD with or without RBD, in contrast to previous reports.^8,9,43 These differences may result from the small sample size of the present study. In contrast to recent investigations, we could not identify any correlation between disease duration³⁹ or motor symptom severity⁴⁴ and EMG activity, also potentially because of the small sample size of our cohort.

Autonomic function in relation to RBD and RWA

The relationships between RWA and autonomic dysregulation in parkinsonism are complex, and available data from the literature are heterogeneous.^8,41,45 As shown previously, RBD was associated with constipation and greater autonomic symptom severity was present in patients with PDwRBD (total SCOPA-AUT score, gastrointestinal and sexual domains) compared to patients with PDwoRBD.^45,46 Relationships between orthostatic symptoms (as evaluated by the SCOPA-AUT questionnaire) and a diagnosis of OH (tilt-table examination) were absent, confirming a limited screening performance of the questionnaire to identify patients with orthostatic dysregulation.⁴⁷ We here confirm the previously reported association of RBD with OH.⁸ Further, we show for the first time that a laboratory-confirmed diagnosis of OH is a predictor of RWA, potentially indicating a more severe phenotype in PD. Therefore, we suggest a thorough assessment of autonomic function in patients with PD and RBD or RWA, because this could allow the timely diagnosis and treatment of autonomic dysfunction, improving patients’ quality of life.

Correlations between the SINBAR index and systolic and diastolic blood pressure fall during tilt-table examination in patients with MSA reflect a predominant central origin of orthostatic intolerance (including neuronal loss in the rostral ventrolateral medulla), close to the brainstem REM sleep atonia control regions.⁴⁸ In PD, the correlations between blood pressure fall and SINBAR were not significant, potentially because of the different origin of OH in PD, caused by postganglionic noradrenergic denervation.¹² The correlations between gastrointestinal complaints and RWA in patients with PD and patients with MSA point toward the centrally mediated dysfunction controlled by the dorsal motor nerve of the vagal nucleus, located close to control brainstem regions for REM sleep without atonia.⁴⁸ The combined brainstem pathology of the nucleus ambiguus and REM sleep atonia control structures in PD and MSA may also account for the higher SINBAR indices in patients with a pathologic deep breathing ratio compared to patients with unremarkable deep breathing. Finally, the correlation of the SINBAR index and the urinary complaints was driven by the patients with PD, which may be explained by the REM sleep–regulating nuclei and the pontine micturition center regulating the micturition reflex affected in patients with PD,⁴⁹ whereas in MSA the main site of the lesion responsible for neurogenic bladder disturbances is in the sacral spinal cord.⁵⁰

Daytime sleepiness

The literature concerning the potential intrinsic nature of EDS in PD and MSA is inconsistent.^18,51,52 Our data shed some light on this topic, which can impact patients’ quality of life.

Similar to the results of the SLEEMSA study, no differences in total ESS scores were detected between patients with PD and patients with MSA,¹⁴ with an EDS present in 23% of patients with PD and 14% of patients with MSA. Objective daytime sleepiness did not relate to the ESS score. Accordingly, results derived from the self-reported ESS questionnaires need to be interpreted with caution because patients may not be aware of EDS, or they may report EDS that is not reflected in objective tests.

Despite the significant reduction of total sleep time and sleep efficacy and the increased amount of wakefulness during the night in patients with MSA compared to patients with PD (Table S2 ^{(309KB, pdf)} ), likely reflecting a more advanced neurodegeneration, no objective daytime sleepiness was observed in the MSA group. In contrast, pathologic mean sleep latencies were present in 50% of patients with PD. In accordance with the present results, it has been previously reported that the majority of patients with PD with daytime sleepiness presented with the akinetic-rigid phenotype, and there was a link to autonomic dysfunction in these patients.⁵²

In the past, several studies have pointed out the impact of dopamine replacement therapy on daytime sleepiness in PD,³ which can be confirmed here by a moderate correlation between LED and MSLT mean sleep latency in people with PD (but not in patients with MSA). This finding, together with the lack of correlation between blood pressure upon tilt-table examination and dopamine replacement therapy and with the finding of a correlation between blood pressure reductions and daytime sleep latency in PD but not in MSA, indicates that dopaminergic medication possibly exerts its effects acting on different intrinsic networks in PD and MSA.

Reports evaluating the relationship between EDS and RBD are conflicting. In the current study, a diagnosis of RBD and the presence of RWA were not related to self-reported or objective EDS, in contrast to the report by Amara and colleagues.⁵²

Our work clearly has some limitations. The cross-sectional design of the current study lacks information about the evolution over time of RWA, RBD, autonomic function, and EDS in PD and MSA. The sample size was modest, and there was no postmortem confirmation of clinical diagnosis of PD or MSA. The main strength of the study is the thorough and objective assessment of sleep, daytime sleepiness, and autonomic function in a neurology tertiary referral center with expertise on sleep disorders, movement disorders, and dysautonomia.

CONCLUSIONS

This study highlights the relationships of autonomic dysfunction with RBD and RWA and characterizes daytime sleepiness in PD and MSA. In people with MSA, the link between blood pressure reductions during tilt-table examination and RWA can be explained by the predominant central origin of orthostatic intolerance and the neighboring brainstem pathology accounting for RWA. In both entities, gastrointestinal disturbances result from neurodegeneration in the brainstem, which likely causes the correlation to RWA in PD and MSA. Understanding the link between autonomic dysfunction and RBD or RWA will help identify patients who need combined diagnostics and therapy in the future, and it likely identifies patients in a more advanced state of neurodegeneration or with a more severe phenotype of disease. Further, objective daytime sleepiness is not present in MSA, suggesting that dopaminergic medication exerts its effects acting on different intrinsic networks in PD and MSA.

DISCLOSURE STATEMENT

The manuscript has been read and approved by all named authors. Work for this study was performed at the Medical University of Innsbruck, Department of Neurology. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. Conflict of interest/financial disclosures outside of the submitted work: Alessandra Fanciulli reports royalties from Springer Nature Publishing Group and Thieme Verlag; speaker fees and honoraria from the Austrian Neurology Society, International Parkinson Disease and Movement Disorders Society, Impact Medicom, AbbVie, and Theravance Biopharma; and research grants from the Stichting ParkinsonFond, MSA Coalition, Dr. Johannes Tuba Stiftung, and the Österreichischer Austausch Dienst, outside of the submitted work. Birgit Högl is supported by Speaker Jazz; has conducted consulting for Lubdback, and has worked as a speaker for AbbVie. Anna Heidbreder reports receiving honoraria for lectures from and advisory board work for UCB, Desitin, and Jazz Pharmaceuticals. Florian Krismer reports receiving personal fees from Institut de Recherches Internationales Servier, Takeda Pharmaceuticals, and the Austrian Society of Neurology and grant support from the MSA Coalition outside of the submitted work. Fabian Leys is supported by the U.S. MSA Coalition and the Dr. Johannes & Hertha Tuba Foundation. Gerhard Ransmayr received research support from the Jubilee Funds of the Austrian National Bank and the Austrian Research Promotion Funds and received honoraria as a speaker and for consulting work from AbbVie GmbH, Alpine Market Research, Grünenthal, MedAhead, Novartis Pharma GmbH, Ratiopharm, Roche Austria GmbH, Sanofi Aventis GmbH, Stada Arzneimittel-Gesellschaft, and UCB Pharma GmbH. Birgit Frauscher is supported by a salary award (Chercheur-boursier clinicien Senior) of the Fonds de Recherche du Québec–Santé for 2021–2025. Outside of the submitted work, Dr. Frauscher has received fees for speaker’s engagements and participation in advisory board committees related to epilepsy from Eisai and UCB. Her laboratory is supported by research funding for an investigator-initiated trial with the indication of epilepsy by Eisai. Klaus Seppi reports honoraria from the International Parkinson and Movement Disorders Society and grants from the FWF Austrian Science Fund, the Michael J. Fox Foundation, and the International Parkinson and Movement Disorder Society, as well as personal fees from Teva, UCB, Lundbeck, AOP Orphan Pharmaceuticals AG, AbbVie, Roche, and Grünenthal outside the submitted work. Ambra Stefani reports receiving travel support from AOP Orphan, UCB, and Habel Medizintechnik, as well as royalties from Elsevier and support from research from Axovant. The remaining authors report no conflicts of interest.

ABBREVIATIONS

EDS

excessive daytime sleepiness

EMG

electromyography

ESS

Epworth Sleepiness Scale

H&Y

Hoehn and Yahr

LED

levodopa-equivalent dosage

MSLT

Multiple Sleep Latency Test

MSA

multiple system atrophy

OH

orthostatic hypotension

PD

Parkinson disease

PDwoRBD

Parkinson disease without REM sleep behavior disorder

PDwRBD

Parkinson disease with REM sleep behavior disorder

PLMS

periodic limb movements in sleep

RBD

REM sleep behavior disorder

REM

rapid eye movement

RLS

restless legs syndrome

RWA

REM sleep without atonia

SCM

sternocleidomastoid

SCOPA-AUT

Scales for Outcomes in Parkinson’s Disease-Autonomic Dysfunction

SINBAR

Sleep Innsbruck Barcelona

UMSARS

Unified MSA Rating Scale

v-PSG

video-polysomnography