Clinical significance of REM sleep behavior disorder in Parkinson’s disease

doi:10.1016/j.sleep.2012.10.011

Sleep Medicine

Volume 14, Issue 2, February 2013, Pages 131-135

https://doi.org/10.1016/j.sleep.2012.10.011 Get rights and content

Abstract

Objective

Rapid eye movement (REM) sleep behavior disorder (RBD) may be a risk factor for dementia development in patients with Parkinson’s disease (PD); however, the role of subclinical RBD remains unknown. Patients with PD and clinical RBD, subclinical RBD, or with normal REM sleep were examined in a cross sectional study and a longitudinal follow-up.

Methods

Interviews regarding RBD symptoms and polysomnographies were performed on 82 PD patients divided into RBD subcategories based on the presence/absence of REM sleep without atonia (RWA) and/or RBD symptoms. Descriptive variables were compared and patients were followed-up longitudinally for 21.4 ± 10.8 months.

Results

The existence of RBD, but not subclinical RBD, was associated with orthostatic hypotension and levodopa dose equivalents (LDEs) in patients with PD. Kaplan–Myer curves indicated that the occurrence of dementia in the PD group with clinical RBD was significantly faster than in the PD group with normal REM sleep (p = 0.013). A Cox hazard regression analysis revealed that development to PD with dementia was only significantly associated with the presence of clinical RBD (hazard ratio: 14.1, p = 0.017).

Conclusion

Clinical RBD symptoms, but not subclinical RBD, were associated with the development of dementia in PD.

Introduction

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by vigorous, injurious behaviors related to vivid, action-filled, violent dreams during nocturnal REM sleep [1]. REM sleep without atonia (RWA) on polysomnogram (PSG), a physiological correlate of the occurrence of RBD symptoms, may be linked to dysfunction of brain stem regions [2]. RBD has been implicated as a preclinical symptom of α-synucleinopathies including dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) [3], [4], [5].

RBD may be a risk factor for deterioration of autonomic and cognitive functions in PD patients [6], [7], [8], [9], [10]. Approximately two thirds of PD patients show RWA on PSG with one third presenting with clinical RBD symptoms [11], [12] and the other third presenting without the symptoms [13]. Meta-iodobenzylguanidine (MIBG) uptake in PD patients with clinical RBD and PD patients with dementia (PDD) [14] is comparable, and PDD patients display lower MIBG uptake compared to PD patients without either RBD or dementia [15]. PD patients with clinical RBD also have more severe parkinsonian symptoms than those without the symptoms [16]. Additionally, the presence of RBD in PD patients may be significantly higher in those with PDD as compared to those without dementia [10]. Therefore, the presence of clinical RBD may be related to aggravated motor symptoms, cardiac autonomic dysfunction, and development of dementia in PD patients. However, whether subclinical RBD similarly impacts PD related dysfunctions is unknown. Therefore, a cross sectional comparison of descriptive variables among PD patients with clinical RBD, subclinical RBD, and normal REM sleep was conducted. Subsequently, a longitudinal follow-up survey was conducted to assess possible prognostic differences regarding development of dementia.

Section snippets

Methods

The ethics committees of Tottori University approved the current study. PD patients (N = 133) hospitalized at the University Hospital of Tottori University, Division of Neurology, from October, 2004 to January, 2011 gave, informed consent to participate in the study. PD patients were diagnosed according to the standard criteria for the diagnosis of PD [17]. In the current study, patients who could not be followed-up for more than six months were excluded from the analysis, resulting in an

Results

For all patients, baseline mean age was 74.3 ± 7.2 years, 36 were male and 46 were female, the mean length of PD morbidity was 7.1 ± 7.0 years, and the mean Hohen & Yahr grade was 2.6 ± 0.8. According to the above indicated criteria at baseline, PD patients were divided into those with clinical RBD (n = 27, 32.9% of all patients, 14 males, 13 females, mean age: 76.5 ± 5.9 years), patients with subclinical RBD (n = 23, 28.1% of all patients, eight males, 15 females, mean age: 72.4 ± 7.8 years), and patients with

Discussion

Consistent with the results reported by Sixel-Doring et al. [16], PD patients with clinical RBD had more severe parkinsonian symptoms than those with normal REM sleep in the current study. As for autonomic function, larger numbers of PD patients with clinical RBD have been reported to display severe OH than those without it [6]. Commensurate with the aforementioned finding, PD patients with clinical RBD in the current study showed larger decreases in sBP and dBP on the tilt table test,

Limitations

The current study had several limitations. First, the presence/absence of RWA in each patient was examined with only a single night PSG study. Frauscher et al. [33] reported that most motor events were minor and that violent episodes represented only a small fraction on PSG in PD patients. For this reason, it is possible that mild RBD cases were overlooked among the study participants. Second, follow-up PSGs examinations could only be performed on a limited number of patients. During the

Conclusion

In conclusion, the results of the current study suggested that PD patients with clinical RBD symptoms, but not those with subclinical RBD, may develop dementia over a shorter period compared to those with normal REM sleep. Additionally, some PD patients with subclinical RBD may develop dementia after displaying clinical RBD symptoms. These phenomena strongly emphasize that clinical RBD symptoms may be a preclinical symptom of developing dementia; however, the mere existence of RWA itself may

Conflict of interest

The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: doi:10.1016/j.sleep.2012.10.010.

. ICMJE Form for Disclosure of Potential Conflicts of Interest form.

References (33)

A. Iranzo et al.
Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study
Lancet Neurol
(2006)
T. Nomura et al.
Relationship between ¹²³I-MIBG scintigrams and REM sleep behavior disorder in Parkinson’s disease
Parkinsonism Relat Disord
(2010)
T. Nomura et al.
Comparison of REM sleep behavior disorder variables between patients with progressive supranculear palsy and those with Parkinson’s disease
Parkinsonism Relat Disorder
(2012)
T. Nomura et al.
Authors’ reply to the comments of Miyamoto et al. regarding “Cardiac 123I-MIBG accumulation in Parkinson’s disease differ in association with REM sleep behavior disorder”
Parkinsonism Relat Disord
(2011)
M. Zucconi et al.
The official World Association of Sleep Medicine (WASM) standards for recording and scoring periodic leg movements in sleep (PLMS) and wakefulness (PLMW) developed in collaboration with a task force from the International Restless Legs Syndrome Study Group (IRLSSG)
Sleep Med
(2006)
Y. Uemura et al.
Validation of the Parkinson’s disease sleep scale in Japanese patients: a comparison study using the Pittsburgh Sleep Quality Index, the Epworth sleepiness scale and polysomnography
J Neurol Sci
(2009)
J.E. Lee et al.
Factors related to clinically probable REM sleep behavior disorder in Parkinson disease
Parkinsonism Relat Disord
(2010)
P. McNamara et al.
REM and NREM sleep mentation
Int Rev Neurobiol
(2010)
B. Frauscher et al.
REM sleep behavior disorder in 703 sleep-disorder patient: the importance of eliciting a comprehensive sleep history
Sleep Med
(2010)
International classification of sleep disorders. Diagnostic and coding manual
(2005)

B.F. Boeve et al.

Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease

Brain

(2007)

C.H. Schenck et al.

Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder

Neurology

(1996)

R.B. Postuma et al.

Qualifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder

Neurology

(2009)

R.B. Postuma et al.

Cardiac autonomic denervation in Parkinson’s disease is linked to REM sleep behavior disorder

Mov Disord

(2011)

R.B. Postuma et al.

Markers of neurodegeneration in idiopathic REM sleep behavior disorder and Parkinson disease

Brain

(2009)

J.F. Gagnon et al.

Mild cognitive impairment in rapid eye movement sleep behavior disorder and Parkinson’s disease

Ann Neurol

(2009)

Cited by (102)

Slow-wave sleep and REM sleep without atonia predict motor progression in Parkinson's disease
2024, Sleep Medicine
Growing evidence supports the potential role of sleep in the motor progression of Parkinson's disease (PD). Slow-wave sleep (SWS) and rapid eye movement (REM) sleep without atonia (RWA) are important sleep parameters. The association between SWS and RWA with PD motor progression and their predictive value have not yet been elucidated.
We retro-prospectively analyzed clinical and polysomnographic data of 136 patients with PD. The motor symptoms were assessed using Unified Parkinson's Disease Rating Scale Part III (UPDRS III) at baseline and follow-up to determine its progression. Partial correlation analysis was used to explore the cross-sectional associations between slow-wave energy (SWE), RWA and clinical symptoms. Longitudinal analyses were performed using Cox regression and linear mixed-effects models.
Among 136 PD participants, cross-sectional partial correlation analysis showed SWE decreased with the prolongation of the disease course (P = 0.046), RWA density was positively correlated with Hoehn & Yahr (H-Y) stage (tonic RWA, P < 0.001; phasic RWA, P = 0.002). Cox regression analysis confirmed that low SWE (HR = 1.739, 95% CI = 1.038–2.914; P = 0.036; FDR-P = 0.036) and high tonic RWA (HR = 0.575, 95% CI = 0.343–0.963; P = 0.032; FDR-P = 0.036) were predictors of motor symptom progression. Furthermore, we found that lower SWE predicted faster rate of axial motor progression (P < 0.001; FDR-P < 0.001) while higher tonic RWA density was associated with faster rate of rigidity progression (P = 0.006; FDR-P = 0.024) using linear mixed-effects models.
These findings suggest that SWS and RWA might represent markers of different motor subtypes progression in PD.
Comparison of quantitative REM without atonia parameters in isolated REM sleep behavior disorder and early untreated Parkinson's disease
2024, Sleep Medicine
To analyze REM sleep without atonia (RWA) metrics in patients with isolated REM sleep behavior disorder (iRBD), Parkinson's disease (PD) and healthy subjects and compare them in terms of degree of presumed brainstem damage.
Forty-nine iRBD patients, 62 PD patients and 38 healthy controls were included into the analysis. Detailed polysomnographic and clinical data including motor, olfactory, autonomic, and cognitive assessment were obtained in all participants and subsequently compared within groups without RBD (i.e., healthy controls, PD-RBD-) and with RBD (i.e., iRBD, PD-RBD+). SINBAR criteria were used to score RWA.
Twenty-one PD patients (33.8 %) had RBD. When comparing PD-RBD-patients and controls, RWA tonic (p = 0.001) and RWA mixed (p = 0.03) were higher in PD-RBD-group. PD-RBD-patients had worse olfactory function than controls (p < 0.001); no significant difference in autonomic or cognitive function was registered. There were no significant differences in RWA parameters when comparing iRBD and PD-RBD + groups. iRBD patients had better olfactory function than PD-RBD+ (p = 0.006); no significant difference in autonomic or cognitive function was registered. PD-RBD + had worse autonomic (p = 0.006) and olfactory (p = 0.001) but not motor and cognitive function compared to PD-RBD-.
Untreated de-novo PD patients without RBD have increased RWA metrics compared to healthy subjects indicating subclinical degeneration of brainstem nuclei responsible for RWA. iRBD patients do not differ in RWA metrics from untreated de-novo PD patients with premotor RBD suggesting a similar level of brainstem degeneration caudal to substantia nigra in both groups. Groups with RBD are associated with autonomic dysfunction.
Comparison of sleep characteristics between Parkinson's disease with and without freezing of gait: A systematic review
2024, Sleep Medicine
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a range of motor and non-motor symptoms. Among the motor complaints, freezing of gait (FOG) is a common and disabling phenomenon that episodically hinders patients' ability to produce efficient steps. Concurrently, sleep disorders are prevalent in PD and significantly impact the quality of life of affected individuals. Numerous studies have suggested a bidirectional relationship between FOG and sleep disorders. Therefore, our objective was to systematically review the literature and compare sleep outcomes in PD patients with FOG (PD + FOG) and those without FOG (PD-FOG). By conducting a comprehensive search of the PubMed and Web of Science databases, we identified 20 eligible studies for inclusion in our analysis. Our review revealed that compared to PD-FOG, PD + FOG patients exhibited more severe symptoms of rapid eye movement sleep behavior disorder in nine studies, increased daytime sleepiness in eight studies, decreased sleep quality in four studies, and more frequent and severe sleep disturbances in four studies. These findings indicate that PD + FOG patients generally experience worse sleep quality, higher levels of daytime sleepiness, and more disruptive sleep disturbances compared to those without FOG (PD-FOG). The association between sleep disturbances and FOG highlights the importance of evaluating and monitoring these symptoms in PD patients and open the possibility for future studies to assess the impact of managing sleep disturbances on the severity and occurrence of FOG, and vice versa.
Quantification of REM sleep without atonia: A review of study methods and meta-analysis of their performance for the diagnosis of RBD
2023, Sleep Medicine Reviews
The present review focuses on REM sleep without atonia (RSWA) scoring methods. In consideration of the numerous papers published in the last decade, that used different methods for the quantification of RSWA, their systematic revision is an emerging need. We made a search using the PubMed, Embase, Scopus and Web of Science Databases, from 2010 until December 2021, combining the search term “RSWA” with “scoring methods”, “IRBD”, “alfasyn disease”, and “neurodegenerative disease”, and with each of the specific sleep disorders, diagnosed according to current criteria, with the identification of the references of interest for the topic.
Furthermore, a Meta-analysis of the diagnostic performance of RSWA scoring methods, in terms of sensitivity and specificity, was carried out. The comparison of the hierarchical summary receiver-operating characteristic curves obtained for visual methods and that obtained for the automated REM sleep atonia index (RAI), shows substantially similar prediction areas indicating a comparable performance.
This systematic review and meta-analysis support the validity of a series of visual methods and of the automated RAI in the quantification of RSWA with the purpose to guide clinicians in the interpretation of their results and their correct and efficient use within the diagnostic work-up for REM sleep behavior disorder.
White matter changes in drug-naïve Parkinson's disease patients with impulse control & probable REM sleep behavior disorders
2021, Journal of the Neurological Sciences
According to epidemiological studies, Parkinson's disease (PD) patients with probable REM sleep behavior disorder (pRBD) are more prone to develop impulse control disorders (ICDs), which is shown to be present in drug-naïve PD patients, and vice versa.
To investigate white-matter integrity differences, with and without comorbid pRBD and ICDs.
149 de-novo PD patients and 30 age- and gender-matched controls from the Parkinson's Progression Markers Initiative were studied. PD subjects were categorized into four groups with and without these comorbidities. We investigated the white matter integrity differences between these groups.
PDs with only ICDs manifested greater fractional anisotropy (FA) and lower mean diffusivity (MD) in ipsilateral cerebellar connections when compared to controls and to Parkinson's with both comorbid disorders. In contrast, significantly lower FA and higher MD in the ipsilateral fornix-stria-terminalis was observed in PDs with only pRBD compared to controls and to PDs without either comorbid disorder. Also, PDs with only pRBD manifested greater FA in contralateral putamen when compared to controls.
Our results suggest the presence of an underlying neural network in PDs with ICDs, particularly involving cerebellar connections, which makes the subjects susceptible to pRBD. Lower white-matter integrity in the fornix of PDs with only pRBD suggests a neuropathological pathway specific to sleep behavior disorder, independent of impulse control disorders. Greater white-matter integrity observed in PDs without comorbid ICDs, regardless of their comorbid pRBD status, might reflect compensatory mechanisms. Targeted therapies for this particular neuropathology may help prevent these comorbidities.
Objective sleep data as predictors of cognitive decline in dementia with Lewy Bodies and Parkinson's disease
2021, Sleep Medicine
Citation Excerpt :
Longitudinal investigations have been discrepant. While Nomura et al. [5] found that only clinical RBD (ie dream enacting plus RSWA) and not subclinical RBD (RSWA only) predicted conversion to dementia in PD, in Postuma et al. work [3] RSAW was a predictor of dementia irrespective of RBD diagnosis. RSWA is defined by the presence of excessive tonic and/or phasic muscular activity, in various possible combinations.
Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) prognosis depends on cognitive function evolution. Sleep disorders, as objectivated by polysomnography (PSG), are intimately connected with PD and DLB pathophysiology, but have seldomly been used to predict cognitive decline.
20 DLB and 49 PD patients underwent one-night in-lab video-PSG. Sleep variables were defined, including REM sleep motor events, Tonic and phasic REM sleep muscular tone and RBD diagnosis. Cognitive state (assessed with the Global Deterioration Scale (GDS) was collected from case files for 6 months intervals, for a maximum period of 3.5 years or until death/drop-out.). The relation between PSG data at baseline and variation of GDS scores over time was tested with mixed linear regression analysis.
GDS scores were higher in DLB, than in PD. We confirmed significant cognitive decline in both disorders, but no significant differences in progression between them. There were no significant interactions between PSG data and GDS variation for the entire group and DLB separately. In PD patients, there was a significant interaction between RBD diagnosis and tonic excessive muscular tone and GDS increase.
Our data suggests that PSG data can be useful in predicting cognitive decline in PD but not in DLB patients. In PD patients, an RBD diagnosis is predictive of cognitive deterioration, confirming the notion that this non-motor symptom relates to a malignant sub-type. Tonic excessive muscular activity, but not other RBD features, had predictive value in this group, pointing to a specific relation with the disease pathophysiology.

View all citing articles on Scopus

View full text

Original ArticleClinical significance of REM sleep behavior disorder in Parkinson’s disease

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Methods

Results

Discussion

Limitations

Conclusion

Conflict of interest

Lancet Neurol

Parkinsonism Relat Disord

Parkinsonism Relat Disorder

Parkinsonism Relat Disord

Sleep Med

J Neurol Sci

Parkinsonism Relat Disord

Int Rev Neurobiol

Sleep Med

International classification of sleep disorders. Diagnostic and coding manual

Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease

Brain

Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder

Neurology

Qualifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder

Neurology

Cardiac autonomic denervation in Parkinson’s disease is linked to REM sleep behavior disorder

Mov Disord

Markers of neurodegeneration in idiopathic REM sleep behavior disorder and Parkinson disease

Brain

Mild cognitive impairment in rapid eye movement sleep behavior disorder and Parkinson’s disease

Ann Neurol

Original Article
Clinical significance of REM sleep behavior disorder in Parkinson’s disease