Objective: To define and characterize clinically fluctuating transition phases from isolated RBD (iRBD) to overt alpha-synucleinopathy.

Background: Patients with iRBD often develop motor and non-motor signs and symptoms before phenoconversion to overt alpha-synucleinopathy. These may fluctuate (wobble) over time, making the clinical diagnosis of phenoconversion difficult. Although such patients may be called prodromal PD, prodromal DLB or prodromal MSA, they do not yet fulfil diagnostic criteria for any overt synucleinopathy or other neurodegenerative disorder.

Method: IRBDSG centres included patients over a 3-year followup period who underwent ≥3 assessments at intervals ≥6 months apart. A wobble event was defined as an improvement at least once in at least one of the following: MDS-UPDRS III (≥4 points); MoCA (≥4 points) or MMSE (≥3 points) or MCI reverting to normal; orthostatic hypotension reverting to normal. PD, DLB or MSA criteria could not be fulfilled at any timepoint.

Results: 87 iRBD wobblers (17.2% female) from 15 centres (Europe, Canada, USA, Australia, Hong Kong, South Korea) were included. Mean age at iRBD diagnosis was 65.3±7.2 y, with time from diagnosis to first wobble event of 4.9±4.3 y. Baseline MDS-UPDRS-III was 3.7±3.6 and MoCA 23.7±3.2. At baseline, 26.1% had MCI, 13.0% OH, 55.6% a cardiovascular disease, 29.6% a psychiatric disorder, and 12.0% diabetes mellitus. 50.0% of patients were taking symptomatic treatment for RBD. 41 patients (48%) were classified as pure cognitive (C) wobblers, 22 as pure motor (M) wobblers, 19 as both cognitive and motor (C+M) wobblers. Age at RBD diagnosis, sex, time from diagnosis to first wobble event, presence of MCI, OH, comorbidities, and use of RBD symptomatic treatment did not differ among groups. Baseline MDS-UPDRS-III scores were higher in the M wobblers and in the C+M wobblers compared to C wobblers. MoCA scores were lower in the C wobblers and in the C+M wobblers compared to the M wobblers [table1].

Conclusion: In iRBD, cognitive and motor symptoms can wobble over time, making the clinical diagnosis of phenoconversion difficult. Wobbling is a yet unreported phenomenon in iRBD and presents important clinical and research implications: if these measures are selected as outcomes in neuroprotective trials, wobbling could be misinterpreted as treatment efficacy. Further observations of wobblers are necessary to determine their final outcomes.

Table 1

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cognitive-and-motor-wobbling-in-isolated-rbd-a-multicentric-study-by-the-international-rbd-study-group-irbdsg/