McCarter, Stuart J.

Abstract Introduction Accurate, early diagnosis of isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is crucial given its injury potential and neurological prognosis. We aimed to analyze visual and automated REM sleep without atonia (RSWA) diagnostic thresholds in a current cohort of iRBD patients using submentalis (SM) and individual four limb electromyography (EMG) recordings, including bilateral flexor digitorum superificialis (FDS) and anterior tibialis (AT) during polysomnography. Methods We analyzed RSWA in 20 iRBD patients and 20 age-sex-AHI matched controls who underwent polysomnography between 2017-2021 for phasic burst durations, phasic, tonic, and "any" muscle activity, and automated REM atonia index (RAI). Group RSWA metrics were analyzed with non-parametric comparisons, logistic regression, and receiver operating characteristic (ROC) curves to determine optimal diagnostic cutoff thresholds for iRBD. Correlation explored associative relationships between RSWA metrics, and principal components analysis (PCA) defined determinants of RSWA metric variance. Results All mean RSWA metrics were higher in iRBD patients than controls (p<0.05), except for left and bilateral AT phasic density and duration. RSWA(phasic%, AUC; "any"%, AUC) cutoffs were: SM (6.5%, AUC=90.2; 6.5%, AUC=92.5); L FDS (7.3%, AUC=95.8; 7.3%, AUC=95.8%); R FDS (5.4%, AUC=93.5; 5.8%, AUC=93.2%); Bilateral FDS (10.7%, AUC=96; 15.3%, AUC=95.8); L AT (6.7%, AUC=74.5; 6.7%, AUC=74.8%); R AT (4.7%, AUC=76.8; 4.7%, AUC=76.8%); Bilateral AT (7.5%, AUC=77.5; 7.5%, AUC=77.5%), combined SM/FDS (15.0%, AUC=95.5; 15.1%; AUC=95.8), combined SM/AT (16.5%, AUC=85.8; 21.0%; AUC=88.8),tonic (0.5%; AUC=85.9), and RAI (0.90; AUC=91.4). Phasic burst duration cutoffs were: SM=0.7s (AUC=90.2), L FDS=0.5 s (AUC=83.2), R FDS=0.6 (AUC=85.2), L AT=0.3 s (AUC=65.0) and R AT=0.4 s (AUC=77.0). PCA demonstrated that FDS and combined SM/FDS and SM/AT RSWA metrics best explained RSWA variance and differentiated controls from RBD, while SM and AT alone were less explanatory. Conclusion This study provides evidence for quantitative RSWA diagnostic thresholds applicable in current iRBD populations, and confirms the key importance of FDS to assure accurate iRBD diagnosis. Interestingly, these RSWA diagnostic thresholds are lower than previously determined thresholds, suggesting secular trends toward earlier iRBD detection and heterogeneous disease duration relative to polysomnography acquisition, underscoring the necessity of future large scale prospective, multicenter polysomnographic analyses to determine definitive iRBD diagnostic RSWA thresholds. Support (If Any)

Abstract Introduction Discontinuation of opioid medications may be associated with emergence of restless legs syndrome (RLS), which may complicate opioid withdrawal. However, this has not been systematically studied. We aimed to prospectively determine the frequency of the occurrence and severity of RLS symptoms in patients undergoing physician supervised opioid tapering during a 3-week interdisciplinary pain rehabilitation program. Methods Adult patients undergoing prescription opioid taper were prospectively recruited during their participation in the Mayo Pain Rehabilitation Center from 2016 to 2021. Subjects completed the Cambridge-Hopkins RLS Questionnaire 13 and International Restless Legs Syndrome Study Group Rating Scale (IRLS) at baseline, midpoint, and dismissal from the program as well as 2 weeks, 1 and 3 months after dismissal from the program. Results 101 patients participated with 61% being female taking a mean morphine equivalent dose of 46.6 ± 49.0 mg. Baseline prevalence of RLS symptoms was 29% (29/101), increasing to 32% (32/101) at midpoint of treatment and further to 35% (34/97) at dismissal from the program. Frequency of RLS symptoms peaked 2 weeks after dismissal at 38% (30/78) and steadily declined to 35% (28/80) and 31% (21/68) at 1 month and 3 months after dismissal, respectively. Thirty-five percent of patients without baseline RLS symptoms reported de novo RLS symptoms at some point during their opioid taper. RLS severity score followed a similar trend as the presence of symptoms with a baseline of 16.6 ± 10.0. RLS severity score was maximum at 19.1 ± 7.3 one month following dismissal and decreased but remained elevated above baseline at 3 months following dismissal. Conclusion Symptoms of RLS occurred in over a third of patients on chronic opioids and increased during opioid withdrawal, appearing to peak in frequency and severity 2-4 weeks after discontinuation and gradually improved 3 months after discontinuation. Over one-third of patients in our cohort developed de novo symptoms of RLS at some point during their opioid withdrawal. Physicians supervising individuals undergoing opioid withdrawal should be aware of the potential development of RLS symptoms which may hinder successful opioid withdrawal. Support (If Any)

Abstract Introduction REM sleep without atonia (RSWA) is the neurophysiological substrate of REM sleep behavior disorder (RBD), a form of prodromal parkinsonism in most older adults. Isolated RSWA (without clinical RBD) elevation was demonstrated recently in older adults following SARS-CoV2 (COVID-19) infection, but comparison to controls was not reported. We aimed to comparatively analyze RSWA between patients with previous COVID-19 infection and COVID-19 negative controls. Methods 25 patients with previous COVID-19 infection were compared to 25 age-sex matched controls who tested negative for COVID-19 prior to polysomnography. Patients receiving medications known to increase RSWA were excluded. We reviewed medical records to determine clinical features and quantitatively analyzed RSWA in the submentalis (SM) and anterior tibialis (AT) muscles for phasic, tonic, and “any” muscle activity, phasic burst duration, and the automated REM atonia index. Non-parametric analyses compared clinical and polysomnographic features between groups, with combined SM and AT RSWA as the defined primary outcome. The comparative frequency of COVID-19 positive cases and COVID-19 negative controls who met or exceeded proposed isolated RSWA thresholds was also determined. Results COVID-19 patients had significantly greater RSWA than COVID-19 negative controls in the combined SM and AT muscles (p = 0.00076). Most other RSWA metrics were also higher in COVID-19 patients than controls (p<0.03), except tonic muscle activity, phasic burst durations, and RAI. Isolated RSWA occurred more frequently in COVID-19 (9 patients, 36%) than controls (3, 12%; p>0.05). No patients had a clinical history or polysomnographic evidence for parasomnia behavior or a primary neurological condition. Conclusion Quantitative RSWA amounts were comparatively greater in COVID-19 patients than in COVID-19 tested-negative controls, suggesting association of previous COVID-19 infection with central nervous system brainstem dysfunction in the region of the dorsal pons and/or ventromedial medulla. Further prospective studies are needed to determine whether RSWA is a predisposing influence to, or consequence of, COVID-19 infection in these patients, and whether COVID-19 survivors might harbor neurodegenerative risk or disease markers. Support (If Any)

Background: Cerebral microbleeds (CMBs) are a common vascular pathology associated with future intracerebral hemorrhage. Plasma biomarkers of amyloid, tau, and neurodegeneration may provide a screening avenue to identify those with CMBs, but evidence is conflicting. Objective: To determine the association between plasma biomarkers (Aβ40, Aβ42, t-tau, p-tau181, p-tau217, neurofilament light chain (NfL)) and CMBs in a population-based study of aging and whether these biomarkers predict higher signal on Aβ-PET imaging in patients with multiple CMBs. Methods: 712 participants from the Mayo Clinic Study of Aging with T2* GRE MRI and plasma biomarkers were included. Biomarkers were analyzed utilizing Simoa (Aβ40, Aβ42, t-tau, NfL) or Meso Scale Discovery (p-tau181, p-tau217) platforms. Cross-sectional associations between CMBs, plasma biomarkers and Aβ-PET were evaluated using hurdle models and multivariable regression models. Results: Among the 188 (26%) individuals with≥1 CMB, a lower plasma Aβ42/Aβ40 ratio was associated with more CMBs after adjusting for covariables (IRR 568.5 95% CI 2.8–116,127). No other biomarkers were associated with risk or number CMBs. In 81 individuals with≥2 CMBs, higher plasma t-tau, p-tau181, and p-tau217 all were associated with higher Aβ-PET signal, with plasma p-tau217 having the strongest predictive value (r2 0.603, AIC –53.0). Conclusion: Lower plasma Aβ42/Aβ40 ratio and higher plasma p-tau217 were associated with brain amyloidosis in individuals with CMBs from the general population. Our results suggest that in individuals with multiple CMBs and/or lobar intracranial hemorrhage that a lower plasma Aβ42/Aβ40 ratio or elevated p-tau217 may indicate underlying cerebral amyloid angiopathy.

AbstractBackgroundTo examine patient preferences regarding prognostic counseling for idiopathic/isolated REM sleep behavior disorder (iRBD). Idiopathic/isolated REM sleep behavior disorder (iRBD) carries an approximate 73‐91% long term risk for phenoconversion to dementia with Lewy bodies (DLB) and Parkinson disease (PD). Previous research has shown that most providers counsel their patients concerning this risk, yet patients’ values and preferences regarding counseling are unknown.Methods122 participants with iRBD in the Mayo Clinic iRBD Patient Registry enrolled. Participants were sent a survey concerning prognostic counseling and their experience in being diagnosed with iRBD.ResultsOf 81 respondents (67.2% response rate), 74% were men with an average age of 65.7 ± 9.7 years. Responses indicated a strong preference toward receiving prognostic information; 92.5% felt knowledge concerning neurodegenerative disease risk was important, while 87.6% felt prognostic discussion was important to maintain trust in their physician. Additionally, 95.7% indicated they desired more information, while only 4.3% would have desired less information regarding prognostic risk following iRBD diagnosis. Most respondents agreed strongly that prognostic information was important for discussions with their family and friends and future life planning, and expressed interest in learning more about future neuroprotective therapies and symptomatic treatments for parkinsonism and dementia.ConclusionsiRBD patients indicated a strong preference for disclosure of neurodegenerative prognostic risk information, preferred more rather than less information, and felt prognostic information was important for family discussions and life planning. This data informs prognostic counseling practices regarding iRBD and other neurodegenerative diseases.

Abstract Study Objectives Post-traumatic stress disorder (PTSD) and rapid eye movement (REM) sleep behavior disorder (RBD) share some common features including prominent nightmares and sleep disturbances. We aimed to comparatively analyze REM sleep without atonia (RSWA) between patients with chronic PTSD with and without dream enactment behavior (DEB), isolated RBD (iRBD), and controls. Methods In this retrospective study, we comparatively analyzed 18 PTSD with DEB (PTSD+DEB), 18 PTSD without DEB, 15 iRBD, and 51 controls matched for age and sex. We reviewed medical records to determine PTSD clinical features and quantitatively analyzed RSWA. We used nonparametric analyses to compare clinical and polysomnographic features. Results PTSD patients, both with and without DEB, had significantly higher RSWA than controls (all p < .025, excepting submentalis phasic duration in PTSD+DEB). Most RSWA measures were also higher in PTSD+DEB than in PTSD without DEB patients (all p < .025). Conclusions PTSD patients have higher RSWA than controls, whether DEB is present or not, indicating that REM sleep atonia control is abnormal in chronic PTSD. Further prospective studies are needed to determine whether neurodegenerative risk and disease markers similar to RBD might occur in PTSD patients.

Abstract Study Objectives To analyze cognitive deficits leading to unsafe driving in patients with REM Sleep Behavior Disorder (RBD), strongly associated with cognitive impairment and synucleinopathy-related neurodegeneration. Methods Twenty isolated RBD (iRBD), 10 symptomatic RBD (sRBD), and 20 age- and education-matched controls participated in a prospective case-control driving simulation study. Group mean differences were compared with correlations between cognitive and driving safety measures. Results iRBD and sRBD patients were more cognitively impaired than controls in global neurocognitive functioning, processing speeds, visuospatial attention, and distractibility (p < .05). sRBD patients drove slower with more collisions than iRBD patients and controls (p < .05), required more warnings, and had greater difficulty following and matching speed of a lead car during simulated car-following tasks (p < .05). Driving safety measures were similar between iRBD patients and controls. Slower psychomotor speed correlated with more off-road accidents (r = 0.65) while processing speed (−0.88), executive function (−0.90), and visuospatial impairment (0.74) correlated with safety warnings in sRBD patients. Slower stimulus recognition was associated with more signal-light (0.64) and stop-sign (0.56) infractions in iRBD patients. Conclusions iRBD and sRBD patients have greater selective cognitive impairments than controls, particularly visuospatial abilities and processing speed. sRBD patients exhibited unsafe driving behaviors, associated with processing speed, visuospatial awareness, and attentional impairments. Our results suggest that iRBD patients have similar driving-simulator performance as healthy controls but that driving capabilities regress as RBD progresses to symptomatic RBD with overt signs of cognitive, autonomic, and motor impairment. Longitudinal studies with serial driving simulator evaluations and objective on-road driving performance are needed.

AbstractStudy ObjectivesRapid eye movement (REM) sleep behavior disorder (RBD) and other sleep disturbances are frequent in leucine-rich, glioma inactivated protein 1-IgG (LGI1) and contactin-associated protein 2-IgG (CASPR2) autoimmunity, yet polysomnographic analyses of these disorders remain limited. We aimed to characterize clinical presentations and analyze polysomnographic manifestations, especially quantitative REM sleep without atonia (RSWA) in LGI1/CASPR2-IgG seropositive (LGI/CASPR2+) patients.MethodsWe retrospectively analyzed clinical and polysomnographic features and quantitative RSWA between LGI1+/CASPR2+ patients and age-sex matched controls. Groups were compared with Wilcoxon rank-sum and chi-square tests. Combined submentalis and anterior tibialis (SM + AT) RSWA was the primary outcome.ResultsAmong 11 (LGI1+, n = 9; CASPR2+, n = 2) patients, Morvan syndrome sleep features were present in seven (63.6%) LGI1+/CASPR2+ patients, with simultaneous insomnia and dream enactment behavior (DEB) in three (27.3%), and the most common presenting sleep disturbances were DEB (n = 5), insomnia (n = 5), and sleep apnea (n = 8; median apnea-hypopnea index = 15/hour). Median Epworth Sleepiness Scale was nine (range 3–24; n = 10), with hypersomnia in four (36.4%). LGI1+/CASPR2+ patients had increased N1 sleep (p = .02), decreased REM sleep (p = .001), and higher levels of SM + AT any RSWA (p < .001). Eight of nine (89%) LGI1+ exceeded RBD RSWA thresholds (DEB, n = 5; isolated RSWA, n = 3). RSWA was greater in AT than SM. All 10 LGI1+/CASPR2+ patients treated with immunotherapy benefitted, and 5/10 had improved sleep disturbances.ConclusionsLGI1/CASPR2-IgG autoimmunity is associated with prominent dream enactment, insomnia, RSWA, sleep apnea, and shallower sleep. Polysomnography provides objective disease markers in LGI1+/CASPR2+ autoimmunity and immunotherapy may benefit associated sleep disturbances.

Abstract Video-polysomnography (v-PSG) is essential for diagnosing rapid eye movement (REM) sleep behavior disorder (RBD). Although there are current American Academy of Sleep Medicine standards to diagnose RBD, several aspects need to be addressed to achieve harmonization across sleep centers. Prodromal RBD is a stage in which symptoms and signs of evolving RBD are present, but do not yet meet established diagnostic criteria for RBD. However, the boundary between prodromal and definite RBD is still unclear. As a common effort of the Neurophysiology Working Group of the International RBD Study Group, this manuscript addresses the need for comprehensive and unambiguous v-PSG recommendations to diagnose RBD and identify prodromal RBD. These include: (1) standardized v-PSG technical settings; (2) specific considerations for REM sleep scoring; (3) harmonized methods for scoring REM sleep without atonia; (4) consistent methods to analyze video and audio recorded during v-PSGs and to classify movements and vocalizations; (5) clear v-PSG guidelines to diagnose RBD and identify prodromal RBD. Each section follows a common template: The current recommendations and methods are presented, their limitations are outlined, and new recommendations are described. Finally, future directions are presented. These v-PSG recommendations are intended for both practicing clinicians and researchers. Classification and quantification of motor events, RBD episodes, and vocalizations are however intended for research purposes only. These v-PSG guidelines will allow collection of homogeneous data, providing objective v-PSG measures and making future harmonized multicentric studies and clinical trials possible.