Elsevier

Sleep Medicine

Volume 14, Issue 8, August 2013, Pages 754-762
Sleep Medicine

Original Article
Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder

https://doi.org/10.1016/j.sleep.2012.10.015Get rights and content

Abstract

Objective

To determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder.

Methods

The clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria.

Results

172 cases were identified, of whom 143 (83%) were men. The mean ± SD age of onset in years for the core features were as follows – RBD, 62 ± 14 (range, 20–93), cognitive impairment (n = 147); 69 ± 10 (range, 22–90), parkinsonism (n = 151); 68 ± 9 (range, 20–92), and autonomic dysfunction (n = 42); 62 ± 12 (range, 23–81). Death age was 75 ± 9 years (range, 24–96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10 ± 12 (range, 1–61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n = 97), Parkinson’s disease with or without mild cognitive impairment or dementia (n = 32), multiple system atrophy (MSA) (n = 19), Alzheimer’s disease (AD)(n = 9) and other various disorders including secondary narcolepsy (n = 2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n = 1). The neuropathologic diagnoses were Lewy body disease (LBD)(n = 77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n = 59), MSA (n = 19), AD (n = 6), progressive supranulear palsy (PSP) (n = 2), other mixed neurodegenerative pathologies (n = 6), NBIA-1/LBD/tauopathy (n = 1), and hypothalamic structural lesions (n = 2). Among the neurodegenerative disorders associated with RBD (n = 170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features.

Conclusions

In this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.

Introduction

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by loss of normal skeletal muscle atonia during REM sleep with prominent motor activity and dreaming [1], [2], [3], [4], [5]. The parasomnia occurs more frequently in males, and usually begins manifesting after the age of 50 years [3], [4], [5]. RBD can occur without any coexisting neurologic disorders or findings (so-called idiopathic RBD or iRBD) and can be precipitated or aggravated by certain classes of medications, particularly selective serotonin or norepinephrine reuptake inhibitors [6], [7]. RBD often is a manifestation of the state dissociation characteristic of narcolepsy [8]. Some cases of autoimmune and paraneoplastic encephalopathies, particularly in association with high titers of antibodies against proteins that form part of the voltage-gated potassium channel complex were identified over recent years [9]. RBD also can be triggered by structural brain lesions such as brainstem infarcts, tumors, vascular malformations, and demyelinating plaques associated with multiple sclerosis [10], [11]; these accidents of nature have provided insights into the location of the networks implicated in human RBD. All structural lesions identified to date have been localized in the dorsal midbrain, pons, or medulla. Neuroimaging studies in the voltage-gated potassium channel complex–associated RBD cases show abnormalities in the mesial temporal lobe structures and usually not in the brainstem [12]. These unique cases underscore that the precise networks and neurotransmitter systems involved in human RBD remain unclear but most consistently relate to brainstem networks and their efferent or afferent connections.

RBD associated with neurodegenerative disease was first appreciated over 15 years ago [13], and because RBD often precedes the onset of a slowly evolving neurodegenerative syndrome by years or decades [3], [5], [10], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], international attention has turned to view iRBD as a potential early clinical manifestation and biomarker of sorts of neurodegeneration rather than a curious parasomnia. Other features on PSG also can suggest an evolving neurodegenerative disorder such as laryngeal stridor and slowing of electroencephalogram activity [29], [30], [31]. If iRBD is a harbinger of parkinsonism, cognitive impairment, autonomic dysfunction, or some combination of these, at least in some individuals, one would hope that an intervention could be commenced and potentially delay the onset of these disabling features or prevent them from occurring altogether. Therefore, attention is focused on iRBD representing a “window of opportunity” with a glimpse of the future like few other neurologic or medical disorders can offer [26], [27], [32], [33], [34]. However, many questions remain.

Most studies based on clinically diagnosed cases have found that some neurodegenerative disorders are commonly associated with RBD and thus the rule, while others infrequently are associated with RBD, and hence the exceptions. Those commonly associated with RBD include multiple system atrophy (MSA) [1], [2], [5], [14], [15], [23], [25], [29], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], Parkinson’s disease (PD) with or without dementia [1], [5], [6], [10], [17], [18], [23], [25], [26], [40], [43], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], dementia with Lewy bodies (DLB) [10], [21], [22], [23], [24], [25], [26], [27], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], and less commonly pure autonomic failure [40], [86]. These disorders are collectively termed the synucleinopathies due to the presence of α-synuclein-positive inclusions in neurons or glia [87], [88], [89], [90]. Yet several nonsynucleinopathy disorders also have been reported in association with RBD, namely spinocerebellar atrophy type 3 (Machado–Joseph disease) [91], [92], [93], [94], progressive supranuclear palsy (PSP) [5], [40], [95], [96], Guadalupian parkinsonism [97], Huntington disease [98], and Alzheimer’s disease (AD) [26], [99], [100]. A single case of suspected corticobasal degeneration [101] was found to have REM sleep without atonia – the electrophysiologic substrate for RBD – but no history of dream enactment behavior. This case was considered representative of subclinical RBD. The clinically diagnosed cases therefore suggest that RBD often is (but not always associated with one proteinopathy – the synucleinopathies and less commonly associated with other proteinopathies; this is a phenomenon known in neurodegenerative disease circles as selective vulnerability. As disease-modifying therapies are being refined in the transgenic mouse models of neurodegenerative diseases to target proteinopathy pathophysiology, it will be critical for clinicians to accurately predict during life which proteinopathy is likely underlying any patient’s features. Although clinicians make syndromic diagnoses in the clinic every day and infer which disease (and hence which proteinopathy) is underlying each patient’s syndrome, this is an imperfect science and numerous examples abound in the literature on clinicopathologic inaccuracies. Assumptions often are made when the gold standard of neuropathologic examination rarely is or is never performed. Herein we describe the value of clinicopathologic correlations and the purpose of this large collaborative clinicopathologic analysis.

Section snippets

Case ascertainment

The International RBD Study Group initially convened in 2007 led by Professors Moller, Oertel and Stiasny-Kolster from the University of Marburg and includes investigators from many sites in North American and Europe who are devoted to clinical practice and research issues pertaining to RBD. Investigators at each site were contacted in March of 2012 and asked to query their local databases or recall specific cases they had followed with RBD from January 1990 to March 2012 through to autopsy.

Results

One hundred and seventy two cases were identified. Eight centers had one or more cases with adequate antemortem and pathologic data. The breakdown of contributed cases was as follows, Mayo Clinic Rochester (n = 85), Mayo Clinic Jacksonville (n = 44), Mayo Clinic Arizona/Banner Sun Health (n = 27), University of Miami (n = 6), Hospital Clinic of Barcelona (n = 5), Pitié-Salpêtrière Hospital (n = 2), University of Minnesota (n = 2), and University Hospital of Montpellier (n = 1). Seventy-six of the 172 cases

Overview

Our study is the largest series to date of PSG-verified and probable RBD who have undergone neuropathologic examination. The strong association of RBD with the synucleinopathies was further substantiated, and a wider spectrum of disorders that can underlie RBD now is more apparent.

Demographic and clinical considerations

The high frequency of RBD among males (83%) was present in this series, like in all other series. However, the frequency of RBD among men was lower in MSA (63%). These findings further support that the male

Disclosures

Dr. Boeve has no relevant disclosures for this paper. He has served as an investigator for clinical trials sponsored by Cephalon, Inc., Allon Pharmaceuticals, and GE Healthcare. He receives royalties from the publication of a book entitled Behavioral Neurology Of Dementia (Cambridge Medicine, 2009). He has received honoraria from the American Academy of Neurology.

Dr. Silber has no relevant disclosures for this paper. He receives royalties from the publication of 2 books [Sleep Medicine in

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: http://dx.doi.org/10.1016/j.sleep.2012.10.015.

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

Acknowledgments

We are grateful to the many sources of funding and clinicopathologic case material. These sources the include the National Institute on Aging grant AG015866 – Neuropsychology of Dementia with Lewy Bodies, the National Institute on Aging grant AG006786 – Mayo Clinic Study of Aging, the National Institute on Aging grant AG016574 - Mayo Alzheimer’s Disease Research Center, the Mayo Clinic Morris K. Udall Center grants P50NS072187 and P50 NS072187-01S2, the Banner Sun Health Research Institute

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