The Relationship between Rest Tremor and Underlying Lewy Pathology in Essential Tremor: A Clinical-Pathological Study of 201 Cases.

Objectives: Prospective studies demonstrated that essential tremor is a risk factor for Parkinson's disease. Identifying clinical markers for conversion from essential tremor to essential tremor-Parkinson's disease would be of considerable value. Rest tremor can be present in advanced essential tremor and may be a harbinger of conversion. We examined (1) the brain distribution and severity of Lewy pathology and (2) whether patients met pathologically based criteria for Lewy body disease in relation to (1) the presence and severity of isolated rest tremor and (2) the diagnosis of essential tremor-Parkinson's disease during life.

Methods: Two hundred one essential tremor brains in the Essential Tremor Centralized Brain Repository underwent deep clinical phenotyping and complete neuropathological assessment, including assessment of Lewy pathology with α-synuclein immunostaining.

Results: Clinical diagnoses were essential tremor (93.5%), essential tremor with possible Parkinson's disease (3.5%), and essential tremor-Parkinson's disease (3.0%). Among 188 with essential tremor, 90 (47.9%) had rest tremor; 75.6% with rest tremor did not have Lewy pathology and 80% were not assigned pathological diagnoses of Lewy body disease. Rest tremor increased the odds of a pathological diagnosis of Lewy body disease (odds ratios = 1.98-2.73), but its positive predictive value was only 20.0 to 25.6%.

Interpretation: In clinical practice, isolated rest tremor should be viewed as a finding that is associated with increased odds of Parkinson's disease but not, in the large majority of cases, indicative of underlying Lewy body disease. Our quantitative data can be conveyed to patients to provide prognostic information in discussions of risk stratification. ANN NEUROL 2025.