Evolution of Prodromal REM Sleep Behavior Disorder to Neurodegeneration

Background and Objectives Individuals with a history of recurrent dream-enactment behaviors, but with subthreshold REM sleep without atonia levels for REM sleep behavior disorder (RBD) diagnosis, are currently classified to have prodromal RBD (pRBD). However, the REM sleep–elevated EMG diagnostic cutoff, progression trajectory, and long-term neurodegenerative outcome of pRBD are not well understood. This study aimed to delineate the evolution of REM sleep EMG levels, determine the EMG cutoff score for diagnosing pRBD, and examine the risk for neurodegenerative diseases of pRBD.

Methods This retrospective longitudinal case-control study recruited patients with pRBD and age-matched, sex-matched, and follow-up duration–matched controls who were free of neurodegenerative disease at baseline in the Sleep Assessment Unit, the Chinese University of Hong Kong from 1997 to 2018. Patients and controls underwent clinical and video-polysomnography (PSG) assessments at baseline and follow-up(s). REM sleep EMG activity level on mentalis and anterior tibialis (AT) muscles on video-PSG at each visit was scored. The diagnosis of neurodegenerative diseases was confirmed by a neurologist.

Results A total of 44 patients (age 67.4 ± 8.2 years, 6 females) and 44 controls were recruited. The combined REM sleep EMG level on mentalis and AT muscles of patients with pRBD significantly increased during 8.2 ± 3.3 years of follow-up (from 19.3% ± 9.7% to 47.3% ± 27.4% with estimated annual increase of 3.9%), yielding 29 patients with pRBD (66%) meeting the full-blown RBD diagnostic criteria. Baseline REM sleep mentalis and AT muscles EMG activity of patients who developed full-blown RBD could favorably differentiate pRBD from controls (6.3% for mentalis “any” and 9.1% for combination of mentalis any and bilateral AT muscles phasic EMG with an area under the curve of 0.88 [0.78–0.98] and 0.97 [0.92–1.00], respectively). Patients with pRBD had a higher risk for neurodegenerative diseases (9 developed Parkinson disease and 3 developed dementia with Lewy bodies) when compared with controls (5 developed Alzheimer disease, adjusted hazard ratio = 2.95, 95% CI = 1.02–8.54).

Discussion pRBD has a predictive progression in both pathophysiology and neurodegenerative outcome. This finding has significant implications to the nosological status of pRBD, the current REM sleep-related EMG diagnostic criteria, spectrum concept of RBD, and future neuroprotective intervention.

Classification of Evidence This study provides Class III evidence that EMG activity during REM sleep predicts the development of pRBD.