REM sleep behavior disorder: Updated review of the core features, the REM sleep behavior disorder-neurodegenerative disease association, evolving concepts, controversies, and future directions

Abstract

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia manifested by vivid, often frightening dreams associated with simple or complex motor behavior during REM sleep. The polysomnographic features of RBD include increased electromyographic tone +/- dream enactment behavior during REM sleep. Management with counseling and pharmacologic measures is usually straightforward and effective. In this review, the terminology, clinical and polysomnographic features, demographic and epidemiologic features, diagnostic criteria, differential diagnosis, and management strategies are discussed. Recent data on the suspected pathophysiologic mechanisms of RBD are also reviewed. The literature and our institutional experience on RBD are next discussed, with an emphasis on the RBD-neurodegenerative disease association and particularly the RBD-synucleinopathy association. Several issues relating to evolving concepts, controversies, and future directions are then reviewed, with an emphasis on idiopathic RBD representing an early feature of a neurodegenerative disease and particularly an evolving synucleinopathy. Planning for future therapies that impact patients with idiopathic RBD is reviewed in detail.

Figure 1

Thirty-second epoch polysomnograms showing normal REM sleep (A) and REM sleep without atonia—the electrophysiologic substrate for RBD (B). In A, note the absence of electromyographic (EMG) activity in the submental (Chin 1-Chin 2), and limb (Leg EMG) derivations, whereas increased EMG tone is present in the submental (Chin 1-Chin 3), upper limb (Left Arm-Right Arm), and lower limb (Left Leg-Right Leg) derivations in B (denoted by red arrows).

Figure 2. Proposed nuclei involved in REM sleep control as shown on human brainstem templates

Letters represent cross-sectional views through the brainstem, with A corresponding to the pontomesencephalic junction, B to the upper/mid pons, C to lower/mid pons, and D just rostral to the pontomedullary junction. The REM-off region is represented by the vlPAG and LPT in red, and the REM-on region is represented by the PC and SLD in green. eVLPO= extended part of the ventrolateral preoptic nucleus, LC=locus coeruleus, LDTN=laterodorsal tegmental nucleus, LPT=lateral pontine tegmentum, PC=pre-coeruleus, PPN=pedunculopontine nucleus, REM=rapid eye movement, RN=raphe nucleus, SLD=sublaterodorsal nucleus, vlPAG=ventrolateral part of the periaqueductal grey matter. See text for details. From Boeve et al, Brain 2007;130:2770-2788. Reprinted with permission from Oxford University Press.

Figure 3. Proposed pathophysiology of REM sleep behavior disorder in humans

Excitatory projections represented by ⊕, inhibitory projections represented by ⊖, with the size of these symbols representing the relative effect of each projection on the synapsing nuclei. Nuclei are represented by circles or ovals, with solid colored circles and ovals reflecting those with normal populations of neurons, and speckled circles and ovals reflecting those with significantly reduced populations of neurons. An X reflects ablation of a nucleus. The relative tonic influences of each projection are represented by line thickness, with thicker lines depicting stronger influences, thinner lines depicting weaker influences, and dashed and dotted lines depicting weak influences due to damage to neurons in the respective nuclei. The REM-off region is represented by the vlPAG and LPT in red, and the REM-on region is represented by the PC and SLD in green. The SLD (or analogous nucleus in humans) projects to spinal interneurons (“direct route,” denoted by the dotted line from SLD to spinal interneurons) and likely represents the final common pathway that causes active inhibition of skeletal muscle activity in REM sleep. The “indirect route,” denoted by the dashed line from SLD to the MCRF to the spinal interneurons, may also contribute to EMG atonia. However, in humans, it is not yet known whether lesions in structures which project to and from the MCRF, and lesioning the MCRF itself, are critical in affecting EMG atonia during REM sleep. EMG=electromyographic, eVLPO= extended part of the ventrolateral preoptic nucleus, LC=locus coeruleus, LDTN=laterodorsal tegmental nucleus, LPT=lateral pontine tegmentum, MCRF=magnocellular reticular formation, PC=pre-coeruleus, PPN=pedunculopontine nucleus, REM=rapid eye movement, RN=raphe nucleus, SLD=sublaterodorsal nucleus, vlPAG=ventrolateral part of the periaqueductal grey matter. See text for details. From Boeve et al, Brain 2007;130:2770-2788. Reprinted with permission from Oxford University Press.

Figure 4

The clinical syndromes and histopathologic disorders associated with each proteinopathy in the major neurodegenerative disorders which cause dementia and/or parkinsonism. Those syndromes and disorders which are commonly associated with REM sleep behavior disorder (RBD) are shown in red, and those which have been rarely associated with RBD are shown in blue. Those syndromes and disorders associated with RBD in which at least 1 pathologically-verified case has been identified are in italics. Those in black print have not been reported in association with RBD.

Figure 5

Schematic of brainstem nuclei and connections pertinent to REM sleep, movement, and cognition. As per the Braak staging scheme, the temporal sequence of α-synuclein pathology begins mainly in the medulla and then ascends to the cortex (6 stages). In stage 1 (not shown), the dorsal IX/X motor nucleus, intermediate reticular zone, and olfactory bulb is affected, with presumably coexisting degenerative changes in these structures. In stage 2, there is progression in the structures involved in stage 1, plus the caudal raphe nuclei, MCRF, Peri-LC structures, and possibly SLD. RBD may evolve when sufficient degenerative changes have occurred in the SLD, peri-LC structures, and MCRF (denoted by red Xs within nuclei). In stage 3, there is progression in the structures involved in stage 2, plus the PPN, SN, and NBM (denoted by red Xs within nuclei). When sufficient degeneration occurs in the SN, then parkinsonism becomes manifest. When sufficient degeneration occurs in the NBM, then cognitive changes may become manifest. Additional α-synuclein pathology and neurodegeneration evolves in limbic and neocortical structures over stages 4-6 (not shown). This temporal sequence of pathology could explain why RBD precedes parkinsonism and dementia in many patients with Lewy body pathology. Abbreviations: AHC=anterior horn cell, LC=locus coeruleus, LDTN=laterodorsal tegmental nucleus, LPT=lateral pontine tegmentum, MCRF=magnocellular reticular formation, NBM=nucleus basalis of Meynert, PC=pre-coeruleus, PPN=pedunculopontine nucleus, SLD=sublaterodorsal nucleus, SN=substantia nigra, vlPAG=ventrolateral part of the periaqueductal grey matter

Figure 6

Schematic representation of the brain, spinal cord, and key peripheral and autonomic structures which can be affected by Lewy body disease pathology, and the clinical features associated with dysfunction of each structure. The structures (abbreviations) and likely associated clinical features are as follows: olfactory bulb (OB)=anosmia, tuberomamillary nucleus (TMN)=altered arousal/sleep, lateral hypothalamus (LHT)=hypersomnia, nucleus basalis of Meynert (NBM)=cognitive impairment, hippocampal formation (HF)=cognitive impairment, neocortex (N)=cognitive impairment, substantia nigra (SN)=parkinsonism, pedunculopontine nucleus (PPN)=altered arousal/attention, raphe nucleus (RN)=depression, locus ceruleus (LC)=depression, sublaterodorsal nucleus (SLD)=? RBD, magnocellular reticular formation (MCRF)=? RBD, intermediolateral cell column (ILDN)=orthostatism, sympathetic innervation of the heart (H)=cardiac dysfunction, enteric innervation of the intenstines (I)=constipation, and autonomic innervation of the sex organs (SO)=impotence

Figure 7

Schematic representation of the hypothesized progression in motor functioning with increasing age and disease severity in evolving Lewy body disease in the Parkinson's disease-predominant phenotype. The onset of RBD typically begins years or decades prior to the onset of subtle motor signs (mild parkinsonian signs or MPS); such motor signs may be asymptomatic and only detectable on clinical examination. Typical features of Parkinson's disease (PD) evolves months or years later. Over time, PD with mild cognitive impairment (PD+MCI) evolves, followed some time thereafter by parkinsonism which is less levodopa-responsive, and a full dementia syndrome (PD with dementia or PDD) becomes manifest.

Figure 8

Schematic representation of the hypothesized progression in cognitive functioning with increasing age and disease severity in evolving Lewy body disease in the dementia with Lewy bodies (DLB)-predominant phenotype. The onset of RBD typically begins years or decades prior to the onset of cognitive decline and a diagnosis of mild cognitive impairment (MCI), with subtle and often asymptomatic motor signs (mild parkinsonian signs or MPS – represented by the area shaded in light yellow) evolving concurrently or after the onset of cognitive decline. More obvious features of parkinsonism (represented by the area shaded in dark yellow) evolves no earlier than 1 year prior to the onset of dementia to warrant the DLB diagnosis. Over time, dementia, parkinsonism, and problematic neuropsychiatric features such as visual hallucinations and delusions tend to progress.

Figure 9

Schematic representation of the hypothesized progression in functioning with increasing age and disease severity in evolving Lewy body disease (LBD) in the Parkinson's disease (PD)- and dementia with Lewy bodies (DLB)-predominant phenotypes, and the potential effect of therapy. The onset of REM sleep behavior disorder (RBD) typically begins many years prior to the onset of cognitive decline and a diagnosis of mild cognitive impairment (MCI), and/or many years prior to the onset of motor decline and detectable mild parkinsonian signs (MPS). Progression typically continues over subsequent years to either PD or DLB, and ultimately on to death. This evolution of progression in the current era of primarily symptomatic treatments, with no agent convincingly showing altered progression in the underlying disease process of LBD, is depicted by the red line marked “a”. One could envision at least four potential effects of a synucleinopathy-active therapy (labeled “Tx” and instituted along the time course as shown by the orange arrow) in patients with appropriately identified “idiopathic” RBD. The agent could slow down the rate of progression (as shown by the green line marked “b”), or delay the onset of cognitive and/or motor decline (as shown by the green line marked “c”), or prevent progression to cognitive and motor decline altogether (as shown by the green line marked “d”). Or, perhaps a synucleinopathy-active therapy could delay the onset of symptoms and slow down the rate of progression (as shown by the green line marked “e”).

Figure 10

Proposed decision tree for assessing patients with “idiopathic” RBD for research and ultimately treatment purposes. Presuming that one of the ultimate goals of identifying patients with apparently “idiopathic” RBD is to commence one or more therapies which could delay the onset of cognitive impairment and/or parkinsonism, slow down the course, or halt progression of an underlying neurodegenerative disorder altogether, one would first seek to determine in individual patients who is manifesting features of an early neurodegenerative disorder and who is not (step 1). Perhaps many of the clinical features and ancillary test findings covered in this review, and hopefully many others yet to be developed, will function as accurate biomarkers. Next, if the biomarkers are sufficiently specific to pinpoint the underlying proteinopathy (ie, synucleinopathy vs non-synucleinopathy), then such biomarkers will function in steps 1 and 2; if not, new biomarkers with adequate sensitivity and specificity for proteinopathies and particularly synucleinopathies will need to be developed. Finally, it remains to be seen if agents that ultimately affect synucleinopathy pathophysiology will be safe and efficacious in all of the synucleinopathies regardless of whether the pathologic process is LBD or MSA, or the phenotype is PD-predominant, DLB-predominant, MSA-predominant, or PAF-predominant. Incidental LBD (iLBD) will be impossible to predict without pathology. The challenge for investigators at present is to study adequate numbers of patients with “idiopathic” RBD with a spectrum of clinical tests and potential biomarkers longitudinally to assess the natural history and prepare for future clinical trials. Abbreviations: DLB=dementia with Lewy bodies, MSA=multiple system atrophy PAF=pure autonomic failure, PD=Parkinson's disease, RBD=REM sleep behavior disorder

Figure 11

List of potential biomarkers to study in patients with idiopathic RBD.

Figure 12

Hypothesized profile of abnormalities on various biomarkers in patients with iRBD resulting from an underlying synucleinopathy. The phenotypes/diseases include incidental Lewy body disease (iLBD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF). One would predict a different pattern of normal (Nl) and abnormal (Abnl) findings based on the biomarkers being performed, with some results more difficult to predict (represented by “+/-”). Some abnormal findings may be particularly suggestive of specific phenotypes/disorders (represented by an asterisk). Abbreviations: Cog=cognitive/neuropsychological testing, Aut=autonomic studies, MRI=magnetic resonance imaging, MRS=magnetic resonance spectroscopy, DaT=DaTSCAN, PET=positron emission tomography of the brain using various ligands, MIBG=Cardiac (123)I-metaiodobenzylguanidine imaging.

Figure 13

Hypothesized profile of abnormalities on various biomarkers in patients with iRBD resulting from an underlying non-synucleinopathy neurodegenerative disorder. The phenotypes/diseases include Alzheimer's disease (AD), one of the tauopathies (Pick's disease, corticobasal degeneration, progressive supranuclear palsy, multisystem tauopathy, or frontotemporal dementa with parkinsonism associated with a mutation in the microtubule associated protein tau), or one of the TDP-43-associated pathologies (frontotemporal lobar degeneration [FTLD] with TDP-43 positive inclusions, FTLD with motor neuron disease, or FTLD with a mutation in progranulin). One would predict a different pattern of normal (Nl) and abnormal (Abnl) findings based on the biomarkers being performed, with some results more difficult to predict (represented by “+/-”). Some abnormal findings may be particularly suggestive of specific phenotypes/disorders (represented by an asterisk). Abbreviations: Cog=cognitive/neuropsychological testing, Aut=autonomic studies, MRI=magnetic resonance imaging, MRS=magnetic resonance spectroscopy, DaT=DaTSCAN, PET=positron emission tomography of the brain using various ligands, MIBG=Cardiac (123)I-metaiodobenzylguanidine imaging