Features of “ET plus” correlate with age and tremor duration: “ET plus” may be a disease stage rather than a subtype of essential tremor

Background: Essential tremor (ET) is characterized by considerable clinical heterogeneity. In 2018, the term “ET plus” was introduced to mark a potential stratification point for dividing ET into subtypes – ET vs ET plus (i.e., ET cases with neurological features other than action tremor). However, as ET progresses, patients often develop increasingly severe tremor, spread of tremor, tremor under different activation conditions, and other features. Given this situation, ET plus may represent a disease stage rather than a disease classification or subtype. In theory, if the defining characteristics of a disease subtype fluctuate with age or disease duration, it raises the distinct possibility the “subtype” is a disease stage. Methods: A cohort of 241 prospectively enrolled ET cases underwent a detailed motor and cognitive assessment in which the features of ET plus including cerebellar signs (intention tremor, tandem gait difficulty), rest tremor, dystonia, and cognitive performance were evaluated. We determined whether these features of ET plus correlated with action tremor duration and age. Results: We demonstrated that numerous ET plus features were significantly correlated with both age and action tremor duration (numerous p values < 0.05). The same relationships were observed in a series of sensitivity analyses. Conclusion: We observed that the component parts of ET plus are highly age- and stage-dependent. These features are yearly-changing features conditional on a demographic and disease stage variable. These data support the notion that ET plus may represent a disease stage rather than a distinct disease subtype or disease classification.