“ET Plus”: Instability of the Diagnosis During Prospective Longitudinal Follow-up of Essential Tremor Cases

Abstract

Background: A recent consensus statement introduced the term “ET plus”. Although investigators have quantified the prevalence of ET plus in cross-sectional studies, patients with ET plus have not been tracked longitudinally; hence, there is no understanding of its stability over time.Methods: We present prospective, longitudinal phenotypic data on an ET cohort that was followed regularly at 18-month intervals (T1, T2, T3, T4) for up to 64 months. We assigned an ET or ET plus diagnosis to each case at each time interval.Results: There were 201 participants at baseline. The proportion with ET plus increased from 58.7% at baseline to 72.1% at T4 (p = 0.046). Of 172 (85.6%) who received a diagnosis of ET plus at one or more time intervals, the diagnosis was unstable (e.g., with reversion) in 62 (36.0%). We also assessed the stability of the clinical features of ET plus. Rest tremor was the most unstable clinical feature of ET plus; it was present in 59 participants, among whom it reverted from present to absent in 23 (39.0%). By contrast, for “memory impairment” (i.e., either mild cognitive impairment or dementia), the proportion who reverted from present to absent was only 21.3%.Conclusion: These data support our two a priori hypotheses: (1) the prevalence of ET plus would increase progressively, as it likely represents a more advanced stage of ET, and (2) the ET plus diagnosis would not be stable over time, as cases would fluctuate with respect to their phenotypic features and their assigned diagnoses.

Milestones in Tremor Research: 10 Years Later

“… 15 It should be noted, however, that the transition between syndromic allocations (ie, from ET to ET‐plus) can occur in the other direction (ie, from ET‐plus to ET because of the resolution of the soft signs). 16 This example highlights one of the novelties of the current classification, that is, the possibility that one syndrome might “evolve” over time into another. Tracking transitions across different tremor syndromes will eventually clarify the controversial relationship between them, for example between ET and ET‐plus or between ET and PD, 17 which is the reason why the idea of diseases with “antecedent ET” are described in the new classification.…”

“…Nonetheless, the construct of ET‐plus has generated an enlightened debate about its validity, 12,14 with some researchers proposing that it could represent a later stage of ET based on the evidence that its defining characteristics vary as a function of disease duration 15 . It should be noted, however, that the transition between syndromic allocations (ie, from ET to ET‐plus) can occur in the other direction (ie, from ET‐plus to ET because of the resolution of the soft signs) 16 . This example highlights one of the novelties of the current classification, that is, the possibility that one syndrome might “evolve” over time into another.…”

Essential tremor plus rest tremor: current concepts and controversies

“…Interestingly, the available longitudinal studies showed that no patients with ET + RT developed PD during a follow-up of 24–64 months (Gilmour et al 2021 ; Martinelli et al 1987 ; Bugalho et al 2021 ), but also that RT was an unstable feature, reverting from present to absent in more than one-third of cases (Iglesias-Hernandez et al 2021 ).…”

“…In this regard, a few methodological considerations should be done. First, it seems in truth paradoxical that RT was found to fluctuate in a longitudinal study where it reverted from present to absent in more than one-third of cases (Iglesias-Hernandez et al 2021 ). This admittedly curious finding, in addition to selection biases (Louis et al 2015 ), might explain the discrepancies in prevalence of RT across the reviewed studies and might be partly due to the fact that RT in ET-plus can be observed in some conditions (while seated) but not in others (while standing) (Louis et al 2021 ).…”

Essential tremor patients experience significant burden beyond tremor: A systematic literature review

“…First, it is worth noting that a diagnostic classification of "ET plus" has been proposed for cases in which the clinical manifestation of ET includes other mild neurologic signs of unknown clinical significance and some of the features reviewed herein (i.e., cognitive decline and motor symptoms, such as impaired gait and questionable dystonia) (5). However, there is controversy surrounding the use of ET plus as a diagnostic label (68)(69)(70). Much work remains to be done in terms of defining how various neurologic features arise at different points throughout the ET disease course and whether the emergence of such symptoms, in fact, represents an entity that is distinguishable from ET.…”