Natural disease progression vs. DBS-related worsening in essential tremor

Essential tremor is a disabling and highly prevalent movement disorder. Deep brain stimulation of the ventral intermediate nucleus provides substantial symptom relief; however, many patients experience diminishing benefit over time. The underlying causes range from natural disease progression and worsening ataxia to, less commonly, habituation or tolerance. We performed a retrospective longitudinal analysis of 86 individuals with essential tremor who underwent unilateral ventral intermediate nucleus deep brain stimulation and had three or more follow-up visits (mean follow-up duration 5.2 years; maximum 15.4 years; >470 total visits). This approach provided a unique opportunity to assess contralateral limbs in addition to long term effects of stimulation. Tremor severity was quantified using the Fahn-Tolosa-Marin Tremor Rating Scale total score and subscores, with particular focus on contralateral and ipsilateral upper-extremity tremor. Longitudinal trajectories were assessed across limbs and stimulation states at both the population and individual levels. Comparison of tremor between the non-stimulated side and the stimulated side were conducted in the stimulation off condition and served as an intrinsic control to disentangle natural disease progression from tolerance to deep brain stimulation. Contralateral and ipsilateral upper-extremity tremor assessed with stimulation off showed slow, bilateral progression over time. Tremor in the ipsilateral limb followed the same trajectory as the unstimulated contralateral limb, consistent with natural disease progression. Stimulation exerted no measurable cross-hemispheric influence, as ipsilateral tremor progressed similarly with stimulation on and off. During chronic stimulation, tremor progression in the stimulated limb closely tracked that of the ipsilateral limb, with most patients showing no meaningful difference between sides. Progression in the stimulated limb was also similar during stimulation on and off conditions, suggesting that habituation, stimulation-induced maladaptation, or deep brain stimulation-accelerated decline was not observed in this cohort. Long-term symptoms of worsening tremor in essential tremor patients with unilateral ventral intermediate nucleus deep brain stimulation were primarily driven by natural disease progression, not by deep brain stimulation-related causes. While tolerance may rarely emerge, the dominant effect of worsening is disease progression. In this cohort, the stimulation programming parameters were individually optimised over time, likely minimizing the influence of suboptimal programming or stimulation-related decline. These findings underscore the importance of extended comprehensive outcome assessment in essential tremor, incorporating objective measures to distinguish disease progression from treatment-related effects. Follow-up studies are needed to better characterise the relative contributions of tremor and ataxia to long-term disability.