pii: sp- 00577-15

http://dx.doi.org/10.5665/sleep.5300

COMMENTARY

Expanded Insights into Idiopathic REM Sleep Behavior Disorder Commentary on Fernández-Arcos et al. The clinical phenotype of idiopathic rapid eye movement sleep behavior disorder at presentation: a study in 203 consecutive patients. SLEEP 2016;39(1):121–132. Carlos H. Schenck, MD Minnesota Regional Sleep Disorders Center, Hennepin County Medical Center and University of Minnesota Medical School, Minneapolis, MN

bona fide RBD, with dual therapy of the comorbid conditions being required for complete parasomnia symptom control. Since 44% of the patients were not aware of their dreamenactment behaviors, in most cases the spouses (whose observations indicated that their husbands were acting-out dreams) were essential to convince patients to seek medical attention. This is particularly true since 70% of patients felt that they generally slept well. Also, in 11% of cases, RBD was elicited only after specific questioning when patients consulted for other reasons (suspected sleep apnea, hypersomnia). This finding was also identified by the Innsbruck group in a study that found a 4.8% rate of RBD in a consecutive series of 703 sleep-disordered patients presenting to their sleep center.5 Most patients (28/34) were diagnosed with RBD either upon specific questioning for RBD by the evaluating sleep physician (20/34) or during vPSG monitoring showing typical RBD episodes (8/34). Only 6/34 patients were referred specifically for RBD evaluation. Furthermore, only 1 of 11 patients with iRBD was referred because of a parasomnia complaint. This study emphasized the importance of eliciting a comprehensive sleep history with specific questions related to RBD, regardless of the presenting complaint in patients being evaluated at a sleep clinic. The highest-yield screening question for RBD involves dream-enactment. A multicenter study of 242 iRBD patients and 242 controls that utilized a single RBD screening question on dream enactment with a simple yes/no response, followed by the “gold standard” vPSG study of all 484 participants, found that there was a sensitivity of 93.8% and a specificity of 87.2% for detecting RBD.6 This single-question screen for RBD compared favorably to longer RBD screening questionnaires. The Mayo Sleep Questionnaire (MSQ) contains one primary question on RBD in regards to the presence of dream enacting behavior.7 If there is a yes answer (provided by the patient and/or spouse), then five additional questions on RBD are asked, including duration of symptoms, any history of sleeprelated injury to self or bed partner, dreams of being chased or attacked, and the extent of congruence of recalled dream content and observed behaviors. vPSG confirmation of RBD provided validation of the primary RBD screening question of the MSQ with high sensitivity and specificity, although the sample size was small and involved an aging and dementia cohort (n = 48). Some other useful screening questions (directed at the patient and the spouse) for RBD involve the presence of sleepdisruptive behaviors, falling out of bed during sleep, and vivid dreaming. The literature on RBD screening questionnaires has recently been comprehensively and critically reviewed.8 In the Fernández-Arcos study, the authors identified “previously unnoticed or not sufficiently emphasized clinical features.” 1 One of these features involved the onset of RBD being

In this issue, Fernández-Arcos et al. from the Barcelona group present findings on the largest series of idiopathic RBD (iRBD) patients reported to date.1 Data from their consecutive series of 203 patients strongly reinforce the typical RBD clinical profile in regard to the predominance of middle- and older-aged males presenting with injurious dream-enacting behaviors who carry a greatly increased risk for eventual parkinsonism. The authors recognize how a gender referral bias could be linked with the presenting complaint, i.e., males having more aggressive and violent RBD than females in their series, and raise the distinct possibility that a much higher percent of women than currently recognized have RBD, but since it is a less aggressive and injurious form of RBD, medical attention is not sought. Notably, in this iRBD series with longitudinal follow-up, the increased risk of future parkinsonism is present in patients having mild and uncommon presentations of RBD in addition to those patients with more typical and severe RBD. Therefore, when an effective neuroprotective therapy (hopefully) becomes available to retard or halt the progression of iRBD to overt neurodegeneration,2 a proactive approach will be necessary to find patients with mild RBD, especially females, who might benefit from such neuroprotective therapy, but who would not have gone to a sleep clinic and been diagnosed with RBD. This proactive effort would include educating primary care physicians, along with sleep and geriatric specialists, including nurses. There are a number of other findings in this study that have important clinical implications. A single video-PSG (vPSG) study was sufficient to confirm the diagnosis of RBD in 84% of patients, with a second vPSG study being necessary in 16% of patients for one of four reasons: First, there was insufficient or no REM sleep recorded on the first vPSG study in 17 patients, including 6 taking antidepressants. Second, there was a lack of vPSG confirmation of RBD in the first vPSG study despite a compelling history of RBD in 6 patients. A second vPSG study confirmed the diagnosis of RBD in 5 of these 6 patients. Third, there were excessive EMG artifacts from apneic events during REM sleep in 7 patients. Fourth, there were technical problems during REM sleep in the first vPSG study in 3 patients. Similar findings on the sensitivity of a single vPSG study in RBD were reported by Zhang et al.,3 in which a single vPSG study was sufficient to diagnose RBD in > 80% of RBD cases. Therefore, findings from these two studies indicate that a second vPSG study is required to diagnose RBD in up to at least 20% of cases in which there is a strong clinical suspicion of RBD that was not confirmed during an initial vPSG study. Also, comorbid obstructive sleep apnea (OSA) with CPAP improved, but did not eliminate, RBD symptomatology in the Fernández-Arcos study, indicating that OSA “pseudo-RBD”4 can coexist with SLEEP, Vol. 39, No. 1, 2016

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Commentary—Schenck

associated with a life event, which occurred in 3% (n = 6) of patients in their series. The life event was either a major psychological stress (“a robbery, a fraud”), or a medical-surgical event (cancer diagnosis; cardiac pacemaker implantation; cardiac by-pass surgery [n = 2]) that likely also carried major psychological stress. At least 4 other cases of RBD triggered by major life stress have been published, involving a divorce, a frightening automobile accident without physical injury, a sea disaster, and public humiliation, as reviewed.9 A critical question in these 10 cases was whether there was preexisting REM-without-atonia that predisposed these patients to develop rapid-onset RBD, since most people subjected to these stressful circumstances and medical procedures do not develop RBD. These findings should encourage clinicians evaluating new cases of RBD to question their patients and the spouses about any known trigger for the onset of RBD. Furthermore, a novel parasomnia encompassing features of RBD (viz. REMwithout-atonia) with nightmares and disruptive sleep behaviors has been proposed: “Trauma Associated Sleep Disorder (TSD).” 10 Four young male soldiers, 22–39 years old, without any prior parasomnia history, developed TSD from their active duty traumatic experiences. Their TSD consisted of screaming (with cursing), combative (punching, kicking) and thrashing movements, and one episode of choking the spouse. Therapy with prazosin that was directed at the combat-related nightmares was fully effective in controlling the TSD in two patients and partially effective in two patients. Three patients in the Fernández-Arcos study had longstanding histories of epilepsy with strictly daytime seizures that had fully responded to carbamazepine therapy.1 Their vPSG studies confirmed RBD and did not detect any epileptiform activity or seizures. Manni and colleagues conducted a study on the frequency and clinical features of RBD in a group of 80 elderly subjects (n = 47 male) with epilepsy.11 They were screened for RBD by clinical interview and vPSG. Previously undiagnosed or misdiagnosed idiopathic RBD was detected in 12.5% (10/80) of patients, all males. In 6/10 patients RBD preceded epilepsy onset (by a mean 4.5 years), and in 4/10 patients the RBD followed epilepsy onset (by a mean 9.7 years). Therefore, undiagnosed or misdiagnosed RBD can coexist with epilepsy in the elderly. Increased awareness of this potential comorbidity may help to prevent misdiagnosis and improper therapy of these RBD patients. Seventy percent of patients in the Fernández-Arcos study of 203 iRBD patients reported good sleep quality despite their RBD activity that included limb twitching and jerking, besides complex and aggressive behaviors. Similar findings were reported in a series of 96 mixed iRBD and symptomatic RBD patients, in which there was a complaint of sleep disruption in only 21% of patients.12 In the latter series, 80% of RBD patients > 58 years old had increased slow wave sleep for age, i.e., 15% to 46% of total sleep time (mean 26%). It is possible that the energy conservation present in the increased amounts of slow wave sleep compensated for the increased energy expenditure from the RBD, and thus contributed to the sense of restorative sleep in most of the RBD patients in that study.12 However, the Fernández-Arcos study did not report sleep architecture data. Another striking finding was that 46% of SLEEP, Vol. 39, No. 1, 2016

iRBD patients in their series were completely amnestic for their RBD behaviors that were often aggressive and injurious, which is difficult to explain. However, since most of these patients were in the process of developing a neurodegenerative disorder, including Dementia with Lewy Bodies and Parkinson Disease with Dementia, then one of the earliest manifestations of cognitive dysfunction might have been compromised recall of dreams and dream-enacting behaviors with injuries. These considerations address the paradox of how patients with iRBD often consider themselves to be clinically asymptomatic, despite strong evidence to the contrary provided by the spouses and by the findings from their vPSG studies. Nevertheless, this paradox underscores the critical role that the bed partners (viz. the spouses) play in having RBD patients seek medical attention. Therefore, spouses of patients being evaluated for suspected RBD (or in cases where RBD is found during a vPSG study for another sleep complaint) should be strongly encouraged to attend all appointments, since their input is often an invaluable source of clinical information. Lack of therapy with clonazepam in the Fernández-Arcos study resulted in an increased risk of sleep-related injuries, even in mild cases of RBD.1 The important point of treating RBD was emphasized in a recent retrospective study from the Mayo clinic on the factors associated with injury in RBD: “The frequency of DEB [dream-enacting behaviors] did not predict RBD-related injuries, highlighting the importance of timely initiation of treatment for RBD in patients having even rare DEB episodes.” 13 In both these reports1,13 severe and potentially life-threatening injuries resulted from untreated RBD (even in low-frequency and mild cases), which has also been found in a review of the world literature.14 Furthermore, a host of medical vulnerability factors (e.g., osteoporosis, anticoagulant therapy) affecting an RBD patient and the spouse can greatly lower the threshold for sustaining severe injury from RBD.14 These factors could explain, at least for some of the reported cases in the Fernández-Arcos study,1 the discordance between the level of severity and frequency of RBD and the increased risk for injury. In the Fernández-Arcos series on iRBD, leaving the bed during reported RBD episodes occurred occasionally in 24% (49/203) of patients, including 7 patients who walked out of the bedroom and 3 who walked out of the house. Moreover, 40.8% (20/49) of those patients leaving the bed were eventually diagnosed with a defined neurodegenerative syndrome, and were significantly more likely to develop Dementia with Lewy Bodies (DLB) (n = 14) and Mild Cognitive Impairment (MCI) (n = 3) than Parkinson Disease (n = 3) (P = 0.043). Therefore, leaving the bed and ambulating during sleep in patients with iRBD appears to be a prodromal symptom of DLB and MCI, i.e., neurodegenerative disorders with cognitive impairment, which is an important novel finding from this study. The authors state that “it is impossible to know if these episodes of ambulation in our IRBD subjects represented confirmed RBD episodes or confusional awakenings in pre-demented subjects.” 1 The topic of ambulation in RBD remains enigmatic and merits further study. To conclude, sleep clinicians should maintain an index of suspicion for RBD regardless of the presenting sleep complaint 8

Commentary—Schenck

in patients greater than 50 years of age, or in those at any age with narcolepsy and other neurological disorders. Sleep clinicians should also be aware of the heterogeneous profile of iRBD that can facilitate correctly diagnosing this parasomnia and enhance patient management and counseling. The systematic and meticulous gathering of clinical and vPSG data in the largest series of iRBD patients reported to date by the Fernández-Arcos study1 has broadened the phenotypic spectrum of iRBD, and deepened our knowledge of RBD and its associated features and comorbidities.

7. Boeve BF, Molano JR, Ferman TJ, et al. Validation of the Mayo Sleep Questionnaire to screen for REM sleep behaviour disorder in an aging and dementia cohort. Sleep Med 2011;12:445–53. 8. Lam SP, Li SX, Zhang J, Wing YK. Development of scales for assessment of rapid eye movement sleep behavior disorder (RBD). Sleep Med 2013;14:734–8. 9. Schenk CH, Mahowald MW. REM sleep behavior disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in SLEEP. Sleep 2002;25:120–38. 10. Mysliwiec V, O’Reilly B, Polchinski J, Kwon HP, Germain A, Roth BJ. Trauma associated sleep disorder: a proposed parasomnia encompassing disruptive nocturnal behaviors, nightmares, and REM without atonia in trauma survivors. J Clin Sleep Med 2014;10:1143–8. 11. Manni R, Terzaghi M, Zambrelli E. REM sleep behaviour disorder in elderly subjects with epilepsy: frequency and clinical aspects of the comorbidity. Sleep 2006;29:934–7. 12. Schenck CH, Hurwitz TD, Mahowald MW. REM sleep behaviour disorder: an update on a series of 96 patients and a review of the world literature. J Sleep Res 1993;2:224–31. 13. McCarter SJ, St Louis EK, Boswell CL, et al. Factors associated with injury in REM sleep behavior disorder. Sleep Med 2014;15:1332–8. 14. Schenck CH, Lee SA, Cramer Bornemann MA, Mahowald MW. Potentially lethal behaviors associated with rapid eye movement sleep behavior disorder (RBD): review of the literature and forensic implications. J Forensic Sci 2009;54:1475–84.

CITATION

Schenck CH. Expanded insights into idiopathic REM sleep behavior disorder. SLEEP 2016;39(1):7–9.

REFERENCES 1. Fernández-Arcos A, Iranzo A, Serradell M, Gaig C, Santamaria J. The clinical phenotype of idiopathic rapid eye movement sleep behavior disorder at presentation: a study in 203 consecutive patients. Sleep 2016;39:121–32. 2. Schenck CH, Montplasir, JY, Frauscher B, et al. Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy—a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group. Sleep Med 2013;14:795–806. 3. Zhang J, Lam SP, Ho CKW, et al. Diagnosis of REM sleep behavior disorder by video-polysomnographic study: is one night enough? Sleep 2008;31:1179–85. 4. Iranzo A, Santamaria J. Severe obstructive sleep apnea/hypopnea syndrome mimicking REM sleep behavior disorder. Sleep 2005;28:203–6. 5. Frauscher B, Gschliesser V, Brandauer E, et al. REM sleep behavior disorder in 703 sleep-disorder patients: the importance of eliciting a comprehensive sleep history. Sleep Med 2010;11:167–71. 6. Postuma RB, Arnulf I, Hogl B, et al. A single-question screen for rapid eye movement sleep behavior disorder: a multicenter validation study. Mov Disord 2012;27:913–6.

SLEEP, Vol. 39, No. 1, 2016

SUBMISSION & CORRESPONDENCE INFORMATION Submitted for publication October, 2015 Accepted for publication October, 2015 Address correspondence to: Carlos H. Schenck, MD, Minnesota Regional Sleep Disorders Center, Departments of Psychiatry, Hennepin County Medical Center and University of Minnesota Medical School, 701 Park Ave., Minneapolis, MN 55415; Tel: (612) 873-6288; Fax: (612) 904-4207; Email: [email protected]

DISCLOSURE STATEMENT Dr. Schenck consults for Sunovion Pharmaceuticals, Inc.

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Expanded Insights into Idiopathic REM Sleep Behavior Disorder.

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