Curr Neurol Neurosci Rep (2012) 12:182–192 DOI 10.1007/s11910-012-0253-z

SLEEP (M THORPY AND M BILLIARD, SECTION EDITORS)

REM Sleep Behavior Disorder and REM Sleep Without Atonia as an Early Manifestation of Degenerative Neurological Disease Stuart J. McCarter & Erik K. St. Louis & Bradley F. Boeve

Published online: 12 February 2012 # Springer Science+Business Media, LLC 2012

Abstract Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by repeated episodes of dream enactment behavior and REM sleep without atonia (RSWA) during polysomnography recording. RSWA is characterized by increased phasic or tonic muscle activity seen on polysomnographic electromyogram channels. RSWA is a requisite diagnostic feature of RBD, but may also be seen in patients without clinical symptoms or signs of dream enactment as an incidental finding in neurologically normal individuals, especially in patients receiving antidepressant therapy. RBD may be idiopathic or symptomatic. Patients with idiopathic RBD often later develop other neurological features including parkinsonism, orthostatic hypotension, anosmia, or cognitive impairment. RSWA without clinical symptoms as well as clinically overt RBD also often occurs concomitantly with the αsynucleinopathy family of neurodegenerative disorders, which includes idiopathic Parkinson disease, Lewy body dementia, and multiple system atrophy. This review article considers the epidemiology of RBD, clinical and polysomnographic diagnostic standards for both RBD and RSWA, previously reported associations of RSWA and RBD with neurodegenerative disorders and other potential causes, the pathophysiology of which brain structures and networks mediate dysregulation of REM sleep muscle atonia, and S. J. McCarter : E. K. St. Louis : B. F. Boeve (*) Mayo Center for Sleep Medicine and Department of Neurology, Mayo Clinic and Foundation, 200 First Street Southwest, Rochester, MN 55905, USA e-mail: [email protected] S. J. McCarter e-mail: [email protected] E. K. St. Louis e-mail: [email protected]

considerations for the effective and safe management of RBD. Keywords REM sleep behavior disorder . REM sleep without atonia . Parasomnia . α-synucleinopathy . Parkinsonism . Neurodegeneration . Braak staging . Melatonin . Clonazepam . Treatment . Neuropsychological testing . Neurological disease

Introduction Rapid eye movement (REM) sleep behavior disorder (RBD) results from loss of normal skeletal muscle atonia during REM sleep, leading to dream enactment behavior characterized by excessive motor activity ranging from simple limb twitches to violent, complex movements that may result in injury to the patient and/or sleeping partner [1, 2••, 3–7, 8••, 9, 10]. RBD may be either idiopathic or symptomatic, caused by neurodegenerative disorders [2••, 3–6, 11, 12•, 13, 14••, 15–17], or seen in association with antidepressant treatments or by the use or withdrawal of drugs or alcohol [18–20]. Recent evidence has demonstrated convincingly that both idiopathic and symptomatic forms of RBD are strongly associated with neurodegenerative diseases, particularly the α-synucleinopathies, often preceding other characteristic neurological manifestations of such disorders by several years to decades [2••, 10, 11, 12•, 13, 14••, 15, 17, 21]. REM sleep without atonia (RSWA) is characterized by increased phasic or tonic muscle activity seen on electromyography channels during polysomnography (PSG) [5, 22, 23•, 24–28]. RSWA is a requisite diagnostic feature of RBD [2••, 28], but may also be seen in patients without clinical symptoms or signs of dream enactment as an incidental finding in neurologically normal individuals, especially in

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patients receiving antidepressant therapy [19, 20, 29]. RSWA, with or without clinically overt RBD symptoms, may also precede or occur concomitantly with the αsynucleinopathies [2••, 8••, 15, 21]. This review considers the epidemiology of RBD, clinical and polysomnographic diagnostic standards for both RBD and RSWA, previously reported associations of RSWA and RBD with neurodegenerative disorders and other potential causes, the pathophysiology of RSWA and RBD, and considerations for the effective and safe management of RBD.

Illustrative Case This patient was a normal control participant in a longitudinal study of aging, and examination at the age of 88 years showed no abnormal findings on neurological examination or on neuropsychological testing. At age 89 years, she started to have cognitive changes, and family expressed concerns about snoring and hypersomnia. PSG showed mild obstructive sleep apnea plus REM sleep without atonia, but there was no history of dream enactment behavior during sleep. By age 90 years she was experiencing vivid and fully formed visual hallucinations that proved challenging to treat, yet she remained independent in her complex activities of daily living. Shortly thereafter occasional dream enactment behavior evolved. A comprehensive neurobehavioral examination revealed a Mini-Mental State Examination (MMSE) score of 27/30 and no evidence of parkinsonism. Neuropsychological examination showed impairment in the attention-executive function and visuospatial function domains, with above average memory skills and preserved language function. She was diagnosed with RBD and mild cognitive impairment (MCI) and was treated with donepezil. By age 92 years, she was observed to repeatedly vocalize and flail her limbs while asleep. Vivid visual hallucinations re-emerged with associated delusions and confabulations. Cognition declined such that residence in a 24-h skilled care facility was needed. Her MMSE dropped to 12/30, and mild parkinsonism was now apparent. She was diagnosed with Lewy body dementia (LBD), and despite multiple medication manipulations and physical and occupational therapy over the subsequent 2 years, she died at age 94 years. Neuropathologic examination revealed Lewy body disease. Thus, this case illustrates 1) RSWA may be one of the early findings of evolving LBD on ancillary testing, even in otherwise normally functioning individuals; 2) dream enactment behavior may evolve some time after the appreciation of RSWA, thereby indicating RBD; 3) the features of MCI, parkinsonism, and then full LBD may evolve after the onset of RSWA and RBD; and 4) the substrate for the syndromic evolution of RSWA, then RBD, then cognitive impairment

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and parkinsonism, is almost always underlying Lewy body disease.

Epidemiology The prevalence of RBD has been estimated between 0.38% and 0.5% in large population-based studies [3, 6], but RBD patients represent up to 4.8% of patients presenting to sleep disorders clinics [4]. Probable RBD based on a screening questionnaire (the Mayo Sleep Questionnaire) in a population-based study was found in over 6% of community-dwelling subjects aged 70 to 89 years [30], suggesting RBD among the aged population may be more common than currently appreciated. RBD predominantly affects males in the later decades of life with a large case series reporting that 82% of RBD cases occurred in men [10]. However, some have argued that RBD actually occurs at least as commonly in women as men, but is often under diagnosed due to less violent dream enactment behaviors. When RBD is comorbid with narcolepsy, the gender gap decreases further, and prevalence is essentially equal between the sexes [1]. In RBD diagnosed earlier in life (prior to the age of 50 years), the ratio of affected men to women is approximately 1.25:1 to 1.4:1 [1, 18]. In younger patients with RBD, the most frequent causes are antidepressant use and underlying narcolepsy, and evidence for co-existent autoimmunity is found in 20% of women with RBD [18, 19]. Secondary RBD in the late-onset group is most frequently associated with an α-synucleinopathy disorder, which is found in up to 50% of patients with RBD [8••]. Antidepressant use increases the likelihood of RBD fivefold, while a psychiatric diagnosis increases the likelihood of RBD nine- to 10-fold [20]. The mean age of onset of RBD is in the 5th to 6th decade. RBD is most common in elderly men, except in the setting of multiple system atrophy (MSA) [15], narcolepsy [8••], or in early-onset cases [18].

Diagnosis of RBD The minimal diagnostic criteria according to the International Classification of Sleep Disorders include: 1) presence of RSWA on polysomnogram; 2) sleep-related injurious or potentially injurious disruptive behaviors by history, and/or abnormal REM sleep behaviors during PSG; 3) absence of epileptiform activity during REM sleep unless RBD can be clearly distinguished from any concurrent REM sleeprelated seizure disorder; and 4) sleep disturbance is not better explained by another disorder [28]. The core clinical feature of RBD is a history of witnessed dream enactment by the patient’s bed partner, with or without recall of dream mentation by the patient his or herself

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[2••, 6, 9, 10, 31]. Patients are often but not invariably able to vividly recall their dreams in preceding days and weeks, and when enacted dreams are recalled, patients typically report that their dream mentation contains a theme of being chased or protecting themselves or a loved one from an attack [6]. The dream content of RBD often includes attack by insects, snakes, bears, and other large animals, but very rarely is the dreamer an aggressor in their dreams. Collateral history obtained from the patient’s bed partners is crucial in diagnosing RBD [2, 31, 32]. RBD signs reported by bed partner witnesses include coherent vocalizations such as shouting, screaming, laughing, crying, and swearing that most often matches any recalled dream content described by the patient [2••, 3, 4, 6]. In addition, excessive, repetitive phasic muscle bursts develop into complex motor behaviors such as punching, kicking, and running [2••, 6]. Behaviors can lead the patient to leave the bed, which can result in lurching out of bed and associated injuries [2••]. Due to the violent nature of dreams, injury often results in the form of bruises, head contusions, hair pulling, or fractures [2••, 6, 9], and recently a single fatality caused by strangling of a patient’s bed partner has been reported as resulting from RBD [1]. Several validated screening measures for RBD are available [31–33]. The RBD-HK is a 13-item measure with high internal consistency and test-retest reliability that indicates severity of RBD symptoms, with a cutoff score of 18 out of 100, yielding positive and negative predictive values of over 80% [32]. The REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), which is a 10-item patient selfrating questionnaire, (maximum total score of 13 points) covers the clinical features of RBD with RBD patients scoring an average of 9.5 compared to 4.6 in the control group [33]. The Mayo Sleep Questionnaire (MSQ) is another validated diagnostic tool for RBD screening in older patients with cognitive impairment and/or parkinsonism [31]; this measure is completed by bed partners and may be more reliable in those who are cognitively impaired and who have little recall of their dreams. Several other mimicking disorders must be distinguished from RBD, including nightmares, sleep walking, sleep terrors, nocturnal seizures, obstructive sleep apnea with atypical arousals from REM sleep, posttraumatic stress disorder, nocturnal panic disorder, psychogenic dissociative states, and delirium [2••, 4, 34]. PSG is necessary to differentiate RBD from other sleep disorders and parasomnias, and to confirm the necessary diagnostic feature of RSWA [2••, 9, 28].

Diagnosis of RSWA Polysomnographic diagnosis of RSWA requires the presence of abnormally elevated muscle tone during REM sleep,

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especially in the mentalis and tibialis muscles, but also seen in arm electromyogram (EMG) leads [5, 26, 28, 35]. While often not sampled commonly in most laboratories, a recent report by the SINBAR group suggested that best yield for identifying RSWA may be provided by an expanded EMG montage including the biceps brachii, flexor digitorum superficialis, and abductor pollicis brevis muscles [26, 35]. Muscle activity is classified as short phasic bursts, with muscle tone reaching at least two to four times larger than the amplitude of the lowest background EMG during REM or non-REM sleep, or as longer abnormal tonic segments with twice the background amplitude usually lasting longer than 10 to 15 s in duration [26, 27]. RSWA may also be found incidentally on polysomnographic recording without dream enactment behavior [2••]. Since normal individuals may also have short bursts of abnormal phasic or tonic muscle activity during REM sleep [29], the American Academy of Sleep Medicine (AASM) has established formal suggested diagnostic standards for the scoring of RSWA during PSG [28]. The AASM standard requires that at least five mini-epochs of 3-s duration contain abnormally excessive phasic muscle activity within a single 30-s epoch of REM sleep, and that abnormally excessive tonic muscle activity in the chin EMG channel last over 15 s in duration [28]. A typical example of RSWA from an 84year-old patient with RBD is shown in the Fig. 1.

The Association of RSWA and RBD with Neurodegenerative α-Synucleinopathy Disorders: How Can We Identify At-Risk Patients? Several symptomatic pathologies may cause RSWA and RBD (Table 1). Both idiopathic and symptomatic RBD have been shown to be especially strongly associated with the αsynucleinopathies, a group of neurodegenerative disorders of unknown etiology related to intracellular accumulation of the protein α-synuclein, including Parkinson disease (PD), LBD, MSA, and pure autonomic failure (PAF) [7, 11, 13, 15, 17, 21, 28, 36]. MCI associated with underlying Lewy body disease also is commonly associated with RBD [2••]. RBD is strongly associated with parkinsonism, which affects as many as 38% of RBD patients [37]. iRBD patients have an approximate 20% to 45% risk of developing parkinsonism or dementia within 5 years of RBD symptom onset, which rises to 45% to 55% within 12 years [8••, 13, 15]. Recently, evidence is emerging that the presence of “soft,” subtle neurological and neuropsychologic abnormalities may portend a heightened risk for evolving future αsynucleinopathy [2••, 38, 39•, 40]. Clinical tests found predictive of future neurodegeneration in iRBD patients include assessments of color vision and olfaction [38, 39•, 40, 41]. Two useful batteries for assessment of vision and olfactory

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Fig. 1 Muscle tone during rapid eye movement (REM) sleep in a normal subject and in a patient with REM sleep behavior disorder. The figure shows two representative examples of 30-s polysomnogram epochs recorded during REM sleep. Muscle tone in the chin, leg, and arm are shown in the sixth, seventh, and eighth channels of each example epoch, respectively. The top portion demonstrates a normal level of REM sleep muscle atonia, while the bottom portion demonstrates clear excessive phasic and tonic muscle tone in the chin, leg, and arm muscle channels, consistent with REM sleep without atonia, the neurophysiologic substrate of REM sleep behavior disorder

function include the Farnsworth-Munsell-100-Hue test (FM 100) for color vision, and the University of Pennsylvania Table 1 Symptomatic causes of RBD α-Synucleinopathy neurodegenerative disorders Parkinson disease Lewy body dementia Multiple system atrophy Pure autonomic failure Tauopathies (rare) Progressive supranuclear palsy Alzheimer dementia Narcolepsy RBD associated with antidepressant medication Paraneoplastic disorders Brain stem lesional pathology RBD—rapid eye movement sleep behavior disorder

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Smell Identification test (UPSIT) and Brief University of Pennsylvania Smell Identification test (B-SIT) test olfaction [38, 40]. Studies analyzing olfaction and vision have helped clarify which RBD patients are most likely to develop parkinsonism, and poor performance on the FM-100 and UPSIT tests appear to be good predictors for development of probable neurodegenerative disease in patients with iRBD [38, 39•, 41]. RBD patients with impaired olfaction have a 35.4% of remaining disease free for 5 years, compared with an 86% chance of disease-free survival in RBD patients having normal olfaction [17]. Abnormal olfaction in RBD appears similar to olfactory deficits in previously diagnosed PD patients, indicating that progressive neurodegeneration in RBD leads to PD [38, 40]. Patients with idiopathic RBD (iRBD) and PD with RBD had difficulties with object identification compared to controls and patients with PD lacking RBD [39•]. In addition to declining olfaction, RBD patients who also had vision problems had a 5year disease-free survival for evolution of neurodegeneration of only 18% [17]. Neuropsychological performance is also a useful indicator of emerging neurodegeneration in RBD patients [36, 42]. On neuropsychological assessment, RBD patients often demonstrate verbal memory and executive functions indicating that neuropsychological tests may be a useful diagnostic tool for assessing risk of future neurodegeneration [43]. Similarly, quantitative electroencephalography (EEG) has been shown to demonstrate slowing in patients with iRBD, with higher theta power similar to patients with αsynucleinopathies [43, 44]. The degree of waking EEG slowing appears to predict MCI associated with RBD [45]. Several studies have also found increased cardiac denervation in patients with iRBD, as well as in patients with PD. However, the amount of cardiac denervation does not appear to predict the development of neurodegenerative disease [41, 46, 47]. Imaging with cardiac 123I-MIBG scintigraphy has been found to be different between iRBD and PD; iRBD patients have reduced uptake of MIBG when compared to PD patients without RBD and neurologically normal controls. In addition, reduced 123I-MIBG uptake appears to begin as early as Braak stage 1, indicating that cardiac scintography may be useful in the early identification of RBD and PD. However, the degree of MIBG uptake reduction does not seem to predict development of a neurodegenerative disease [47]. Similarly, objective neuroimaging tests have shown similar value in identifying patients at risk for evolving a neurodegenerative disorder [2••], including dopamine transporter uptake 123I-FP-CIT single photon emission computed tomography (SPECT) and transcranial sonography (TCS), which have been shown to be effective in detecting subclinical changes in the substantia nigra that may reflect an evolving α-synucleinopathy disorder; this could be useful to target patients who could become participants in future

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clinical trials of neuroprotective therapies designed to slow progression or arrest neurodegeneration in patients with iRBD [14••]. Iranzo et al. [14••] demonstrated the utility of dopamine transporter uptake imaging (DaTscan) for the identification of iRBD patients who are likely to evolve neurodegenerative disorders. ¹²³I-FP-CIT binding deficiencies in the striatum and substantia nigra hyperechogenicity have been shown by TCS or ¹²³I-FP-CIT SPECT scans (DaTscan) in all iRBD patients that developed αsynucleinopathies. All patients with normal neuroimaging remained disease free during follow-up [14••]. The sensitivity of combined TCS and I-FP-CIT SPECT scans was 100% for predicting development of neurodegenerative disease within 2.5 years, indicating that DaTscan and TCS may be useful in diagnosing neurodegenerative disease before clinical symptoms of parkinsonism, cognitive decline, or dysautonomia appear [14••].

RBD and RSWA Association with Specific α-Synucleinopathy Disorders: PD, Lewy Body Dementia, and MSA RBD and PD RBD is strongly associated with PD [11, 37]. In a cohort of 457 PD patients with sleep disturbances, 46% were found to have RBD [17]. The appearance of RBD symptoms can occur before PD diagnosis or during any of the six stages of PD [7]. PD patients with RBD are more likely to have a comorbid psychiatric disorder compared to PD patients without RBD [37]. Curiously, patients with motor impairments during wakefulness related to PD appear to have improvement in motor control and speech during dream enactment behavior when compared to their waking functioning [48], probably due to normal sleep-related motor pathway transmission through corticofugal and corticospinal neural circuitry that bypass the basal ganglia, where functioning is impaired by α-synucleinopathies [49]. The amount of REM muscle atonia loss appears to predict the development of PD, with one study finding that iRBD patients who developed PD had baseline abnormal tonic chin muscle activity of 73%, compared to 41% of those who remained disease free; patients who developed LBD also had increased chin tone (54%) [21]. RBD and Lewy Body Dementia RBD patients frequently have cognitive impairment, with many later developing dementia [7, 41, 50–52]. Visuospatial impairment is a hallmark in LBD, but may also be present in PD. In addition, executive functioning is also affected in patients with LBD [41, 50, 51]. Two studies found that

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patients with iRBD show visuospatial, visuoconstructive, and cognitive dysfunction that were similar to patients with LBD, indicating that RBD may be a predictor of the development of dementia [39•, 41]. Virtually all RBD patients with MCI who subsequently develop dementia have clinical±pathologic features of Lewy body dementia/disease [13, 36, 51–53]. RSWA has also been shown in patients with MCI without RBD [31, 53, 54]. Further insights clarifying the association between MCI, dementia, RBD, and RSWA—in particular which patients are at highest risk for deteriorating cognitive functioning—are needed. RBD and MSA Abnormal autonomic symptoms in iRBD patients have been implicated as markers of neurodegenerative disease, including orthostatic blood pressure drop, erectile dysfunction, constipation, and decrease in urinary function, findings that could imply the presence of emerging MSA, PAF, or PD/LBD [11, 39•]. Of the α-synucleinopathies, MSA appears to be the most strongly associated with RBD, with one study finding 100% of MSA patients had RBD [42] and other recent studies confirming that 68% to 88% of patients with MSA have RBD [48, 49]. Why MSA is more strongly associated with RBD than PD or LBD remains unclear. The diagnosis of RBD may be able to differentiate MSA with autonomic failure from PAF; in one case series, four patients with MSA had dream enactment behaviors, while all six patients diagnosed with PAF had no sleep disturbances [49]. However, a more recent case study found that all three patients with PAF had RBD, indicating that further research is required on the association of PAF with RBD [55].

A Remaining Controversy: Is RBD Also Associated with Tauopathies? While RBD has been reported in some cases of clinically diagnosed Alzheimer’s disease, most experts suspect that these cases are likely to involve concomitant Lewy body deposits, which are better explanatory of the presence of RBD in these patients [56]. RSWA and RBD have also been found in patients with progressive supranuclear palsy (PSP), to a similar degree as symptomatic RBD in PD, yet RBD rarely presents years in advance of PSP features and rather tends to occur concurrently with the motor dysfunction [2••, 57, 58]. RBD has not been found in other primary tauopathies [59]. Yet, rare examples of autopsy-proven Alzheimer’s disease and PSP with RBD have been documented [2••]. The most parsimonious perspective on RBD associated with neurodegenerative disease is that RBD can occur in a variety of the neurodegenerative proteinopathies, but the frequency of RBD associated with

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the α-synucleinopathies is far greater than that associated with the non-synucleinopathy disorders [2••].

Other Causes of RBD and RSWA Narcolepsy is clearly associated with RSWA and RBD [60]. As a dissociative disorder bridging the wakefulness/REM sleep boundary, this makes good intuitive sense that narcolepsy and RSWA/RBD tend to co-occur [60]. Increased REM sleep muscle tone has been found in patients with narcolepsy and cataplexy compared to controls; however, dream enactment behavior is not always present. The relationship between RSWA and narcolepsy may provide a better understanding of the pathophysiology of RBD [23•, 61]. In a recent PSG study of narcolepsy, 50% of patients were also found to have RBD [62], while 36% of narcoleptic patients in a questionnaire study showed possible RBD symptoms [16]. The onset of RBD associated with narcolepsy tends to be much earlier (eg, second to fourth decade of life) than in iRBD or RBD associated with neurodegenerative disease. Also, RBD associated with narcolepsy tends to be less violent than when RBD is associated with structural lesions or neurodegenerative disease [61, 63]. The link between narcolepsy and RBD is important to remember when treating narcoleptic patients with antidepressants or stimulants as they may induce clinical RBD symptoms. Rarely, paraneoplastic and autoimmune neurologic disorders such as Morvan syndrome (anti-voltage-gated potassium channel antibody syndrome) and brainstem lesions caused by tumors or multiple sclerosis may cause RBD [61, 64–69]. However, further research on the association of RBD with these entities is necessary, as the localization of causative brainstem pathologic lesions associated with RSWA and RBD development may help provide further insights into the pathophysiology of these conditions. Additionally, concurrent use of selective serotonin reuptake inhibitors and tricyclic antidepressants has been shown to cause or exacerbate RBD symptoms, although it is unclear whether the neurochemical effects mediated by antidepressants cause a reversible state of RSWA and RBD or whether instead antidepressants are simply unveiling RSWA and RBD in predisposed individuals [4, 19, 20]. Autoimmune disorders, most commonly narcolepsy, have also been found to be a possible cause with one study finding 20% of RBD cases in women were due to autoimmunity [19].

Pathophysiology of RBD The mechanisms for RSWA and RBD remain poorly understood. Much of our understanding of REM sleep control comes from animal studies involving the rat and cat. Study

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of sleep in the cat brain has shown complex regulation of REM sleep, especially involving pontine nuclei including the noradrenergic locus coeruleus (LC), cholinergic pedunculopontine nucleus (PPN), and laterodorsal tegmental nucleus (LDTN). The medullary magnocellular reticular formation (MCRF) plays a role in motor neuron inhibition and the hypothalamus, thalamus, substantia nigra, basal forebrain, and frontal cortex also participate in REM sleep regulation [70, 71]. The most commonly implicated brainstem regions in the pathophysiology of RSWA and RBD are the MCRF, locus coeruleus/subcoeruleus (LC/SC) complex, PPN, LDTN, and the substantia nigra. Jouvet [70, 72] first described the pontine lesions in the vicinity of the LC causing RSWA, predicting the eventual clinical expression of RSWA as RBD in humans. Lesions in the LC/SC cause RSWA, and the site and severity of the lesion determines whether simple or complex behaviors result [12•]. In rats, the sublaterodorsal nucleus (SLD), an analogous structure to the cat SC, is responsible for control of REM sleep. In addition, rats possess a “REM-on” and “REM-off” region [73••]. The REM-on region is inhibited by GABAergic and galaninergic projections from the forebrain ventrolateral preoptic nucleus (VLPO), in addition to cholinergic projections from the PPN/LDTN. The REM-off nuclei are activated by projections from the noradrenergic LC, serotonergic raphe nucleus, and by hypocretinergic pathways from the lateral hypothalamus [12•]. The REM-on nuclei in the SLD and the precoeruleus also interact with REM-off nuclei and are mutually inhibitory. The SLD additionally contains glutamatergic neurons that connect with inhibitory interneurons in the spinal cord, thereby hyperpolarizing anterior horn motor neurons and resulting in RSWA [73••]. Lesions in the SLD result in RSWA in rats. REM sleep control in humans is more poorly understood than in animals, and as such, there may be interspecies differences. The pathophysiology of RBD in humans proposes that analogous human pontine structures to the SLD and MCRF play similar roles to those in animal models. Lesions in the ventral SLD-analogous structure lead to decreased motor inhibition, as well as decreased excitation of the MCRF, which also contributes to a decreased amount of motor inhibition, thereby potentially causing RBD symptoms. Whether lesions to the MCRF alone, or also involving the REM-off regions of the brain, are necessary to cause RBD in humans remains unclear [73••]. The relationship between narcolepsy and RBD has inspired interest in the relationship between hypocretin-1 and RBD. Decreased levels of cerebrospinal fluid hypocretin-1 from damage to the lateral hypothalamus have been shown to correlate with a greater amount of muscle activation during REM and nonREM sleep in patients with narcolepsy with and without cataplexy. Hypocretin may be responsible for stabilizing the REM-on and REM-off regions of the brain, and could also

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play a role in motor neuron inhibition, so diminished hypocretin levels would lead to unstable REM regulation of muscle atonia, possibly causing RSWA [74]. However, in a small case study of patients with iRBD, hypocretin levels were normal, so further research on the role of hypocretin in mediating RSWA and RBD is warranted [75]. Because of the strong association of RBD with PD and other α-synuclein disorders, the Braak staging hypothesis of PD may be applicable to the timing of RSWA occurrence and RBD symptom expression in these disorders [2••, 12•]. The Braak staging postulates that, at least as this applies to the clinical phenotype of PD, Lewy body deposition and Lewy neurite accumulation initially occur in the dorsal motor nucleus of the medulla (stage 1), with subsequent progression up through the magnocellularis reticular nucleus, subcoeruleuscoeruleus complex, and olfactory bulb and anterior olfactory nucleus (stage 2). Stages 1 and 2 comprise the presymptomatic phase of parkinsonism, preceding the evolution of motor or cognitive symptoms. Patients with RBD symptoms are considered to be in stage 2 based on the reports of impairment in olfaction and increased cardiac denervation that has been observed in previous studies [46, 47]. In stage 3, Lewy deposits progress to also involve the substantia nigra, the PPN, and the amygdala. Stage 4 results from progression of Lewy deposits into the temporal mesocortex. Stages 3 and 4 are considered the parkinsonian stage. In stages 5 and 6, Lewy deposits affect the neocortex, and patients may develop cognitive impairment [76••]. Further evidence for the relationship between RBD and Braak staging stems from reported impaired olfaction and dysautonomia in patients with iRBD, indicating that RBD may be a precursor of PD [37, 38, 39•, 40, 47]. There is also an increasing hypocretin cell loss as PD disease progresses from stage 1 to stage 6, supporting the hypothesis that hypocretin deficiency plays a role in RBD pathology [77]. However, Braak staging does not well explain why some RBD patients never develop PD, or why some with PD and other Lewy body spectrum disorders do not ever exhibit RBD.

Treatment of RBD Safety of the patient and bed partner is the primary concern when treating RBD. All dangerous objects, such as guns and ammunition, should be removed from the bedroom. Corners of bedside tables and other furniture in the room also should be padded to prevent injury should the patient leave the bed. If bed partner injury has occurred or may be likely, advising separate beds or bedrooms may be necessary. Patients who routinely leave their beds during RBD episodes may benefit from a mattress placed next to the bed to prevent injuries that may occur from falling out of bed, or moving the mattress and box spring to the floor. Bed rails or barriers

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between the patient and bed partner may also be utilized, and bed alarms may be useful if the bed partner has had to move to another room. A novel treatment for RBD patients also has been recently devised to provide a calming instruction to the patient to return to sleep [78]. The Posey Sitter Select bed alarm system (Posey Company, Arcadia, CA) dramatically decreased the amount of sleep-related injuries in four medication-resistant RBD patients. The alarm system includes a pressure-sensitive pad underneath the shoulders of the patient, as well as a clothing tether that is attached magnetically to the alarm system. When the patient becomes active, the tether detaches from the alarm system, activating the alarm and waking the patient from sleep averting the RBD episode [78]. If comorbid obstructive sleep apnea is present, treatment of apnea may result in improvement in the frequency and severity of RBD episodes. The two most commonly used pharmacologic treatments for treatment of RBD are clonazepam and melatonin (Table 2) [79–82]. Clonazepam has been found to be successful in treating both iRBD and secondary RBD symptoms, with the recommended dose of 0.25 to 2.0 mg given approximately 30 min before bedtime [1, 7, 10, 27, 65, 82–84]. However, clonazepam has no effect to restore REM sleep muscle atonia [82, 84, 85], since clonazepam is thought to act on the phasic locomotor regions of the brain and not on those responsible for REM sleep atonia [84]. Clonazepam has been shown to be efficacious in treating RBD symptoms, but may exacerbate comorbid obstructive sleep apnea and dementia. Adverse effects seen on occasion with clonazepam include morning sedation, sexual dysfunction, and memory dysfunction [79, 84], although most patients with RBD associated with parkinsonism and/or dementia tolerate clonazepam well and benefit from its use. Patients with dementia and sleep apnea must be monitored carefully when treated with clonazepam. Zopiclone is similar to clonazepam, but with a much shorter half-life, and may be effective in treating RBD symptoms. Adverse effects may be less severe since zopiclone selectively binds α1 and α5 receptors, whereas clonazepam equally binds all α receptors [86]. Melatonin also has been shown to be effective for RBD treatment, with fewer side effects than clonazepam

Table 2 Treatments for RBD Drug

Mechanism

Dose, mg Adverse effects

Clonazepam GABA receptor 0.25–2.0 agonist Melatonin Unknown Pramipexole Dopamine agonist

Sedation, sexual and cognitive dysfunction, respiratory depression 3–12 Sedation 0.125–0.5 Sedation, nausea, impulse control disorders

RBD—rapid eye movement sleep behavior disorder

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[79–81]. Adverse effects are dose related and include morning headache, daytime sleepiness, and hallucinations [79, 87]. Melatonin is effective in treating secondary RBD and can be used preferentially in patients with comorbid sleep apnea or memory problems (that might be worsened by clonazepam), with a recommended dose of 3 to 12 mg at bedtime. Melatonin appears to alter the pathology of RBD, by increasing REM sleep atonia during treatment [80, 81, 86]. Other treatments for RBD have been limited and little literature exists. Because of the strong association of RBD with PD, patients being treated with levodopa should be carefully monitored. Originally thought to treat the symptoms of RBD by decreasing the amount of REM sleep time, high doses of levodopa have actually been shown to increase phasic and tonic muscle tone [88•, 89]. In addition, levodopa may also increase hallucinations, which may be mistaken for RBD [88•]. Pramipexole has shown mixed results (Table 2), varying from little to no effect to reduced RBD episodes [90–92]. Donepezil, which enhances cholinergic neurotransmission, was effective at reducing symptoms in three cases with its main effects being increased sleep quality and decreased motor events [93, 94], although clinical experience with more than 100 RBD patients with comorbid cognitive impairment has revealed that patients experience no significant change, or RBD has worsened, with donepezil (Boeve, Unpublished observations). Yi-Gan San, which contains seven different herbal ingredients, has been shown to fully suppress RBD symptoms in three patients, possibly by acting on serotonergic and GABAergic systems [95]. Larger prospective treatment trials are necessary to better inform effective and tolerable treatment options for RBD patients (Table 2).

course at a time point before clinically significant motor or cognitive sequelae unfold, or at least delaying the onset of these features. Symptomatic treatment of RBD is focused on injury prevention by advising environmental measures to assure bedroom safety, and reduction of the frequency and severity of RBD episodes through administration of pharmacotherapy with clonazepam or melatonin. Future research of RSWA and RBD is necessary to determine its specificity as a biomarker for α-synucleinopathies, to more effectively manage its manifestations to prevent injury, and to better understand the time course and causes of progressive neurodegeneration so as to design future neuroprotective treatment trials.

Conclusions

References

RBD is a unique parasomnia characterized by dream enactment behavior and RSWA. Both RBD and RSWA have a very strong association with the α-synucleinopathy neurodegenerative disorders including PD, LBD, and MSA. RSWA and clinically overt RBD are potential “biomarkers” for the future development of α-synucleinopathies. The Braak staging hypothesis of PD holds that a caudal to rostral course of progression is most typically followed, suggesting that RSWA and RBD occur due to involvement of brainstem structures by Lewy body deposition and/or neurodegeneration prior to the progression of degeneration of basal ganglia and cerebral cortex causing motor and cognitive impairments. Early identification of patients with RBD could enable entry of individuals vulnerable to developing future αsynucleinopathy neurodegenerative disorders into clinical trials of neuroprotective therapies [96], with the goal of preventing further neurodegeneration and arresting its

Acknowledgments This publication was made possible by the following grants: 1 UL1 RR024150 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research; P50 AG016574, UO1 AG006786, RO1 AG015866, the Mangurian Foundation, and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program of the Mayo Foundation. Its contents are solely the responsibility of the author and do not necessarily represent the official view of NCRR or NIH. Information on NCRR is available at http://www.ncrr.nih.gov/. Information on Reengineering the Clinical Research Enterprise can be obtained from http:// nihroadmap.nih.gov. Disclosure Conflicts of interest: S.J. McCarter: none; E.K. St. Louis: has received grant support from NCRR/NIH and Mayo CTSA; and has received consultant’s fees for service on clinical trial adverse events committee for an investigational treatment for obstructive sleep apnea from Inspire, Inc.; B.F. Boeve: has received grant support from NIH, Cephalon, Inc., Allon Pharmaceuticals, Mangurian Foundation, Alzheimer’s Association, and GE Healthcare; he is the Co-editor of “Behavioral Neurology of Dementia” text; and he has received payment for development of educational presentations from the American Academy of Neurology.

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