Letter to the Editor in Reply to: “Advanced ET” Is a More Appropriate Term Than “ET‐Plus”

Dear Editor,

We sincerely thank the author for his thoughtful comments [1] and for his generous appraisal of our longitudinal study. We are particularly encouraged that our work [2] is viewed as contributing to the ongoing discussion on the natural history, heterogeneity, and classification of essential tremor (ET). We fully agree that prospective longitudinal studies are essential to better understand disease evolution and ultimately develop a biologically meaningful staging system.

Indeed, we believe that one of the main messages of our study is that ET is a dynamic disorder, in which both motor and non‐motor manifestations evolve over time [2, 3]. Our findings support the concept that, in many patients, additional neurological features progressively emerge due to the combined effects of disease evolution and aging phenomena per se. In this respect, we agree that some manifestations currently included within the ET‐plus construct may represent later stages of ET rather than a separate disease entity.

At the same time, we believe that the currently available evidence does not yet allow ET‐plus to be considered synonymous with “advanced ET.” While this remains an attractive and plausible hypothesis, it has not yet been validated longitudinally. A staging framework requires that stage‐defining features show relatively consistent longitudinal trajectories. However, the ET‐plus construct encompasses a heterogeneous spectrum of soft signs that may differ in their biological significance and temporal evolution.

Importantly, the diagnosis of ET‐plus is longitudinally unstable, with patients moving between ET and ET‐plus during prospective follow‐up [4]. This suggests that at least some soft signs may not behave as stable stage‐defining features and reinforces the need to better understand their natural history before incorporating them into a staging model. Rather than viewing these observations as arguments against disease staging, we believe they highlight an important intermediate step. Staging and phenotyping may represent complementary rather than competing approaches.

Future studies may instead characterize individual soft‐sign phenotypes, as previously proposed [5], since parkinsonian, dystonic, cerebellar, gait‐related, and cognitive features may differ in longitudinal stability, biological substrate, and prognostic significance. Some of these phenotypes may reflect disease progression, whereas others may identify distinct or overlapping biological trajectories.

We therefore share the author's view that longitudinal studies are fundamental for refining the classification of ET and for developing a clinically meaningful staging system. However, we believe that an important prerequisite is to determine the longitudinal significance of individual soft signs, that is, which consistently reflect disease progression and which instead identify distinct biological trajectories. Only then can we determine whether the concept of “advanced ET” should replace, complement, or refine the current ET‐plus construct.

We once again thank the author for this stimulating perspective, which we believe further emphasizes the value of longitudinal studies in advancing our understanding of ET.

Author Contributions

Luca Angelini: writing – original draft. Matteo Bologna: conceptualization, supervision, writing – original draft, writing – review and editing.

Funding

This work was supported by Ministero della Salute, Ricerca corrente 2026.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.