Progressive gait ataxia following deep brain stimulation for essential tremor: adverse effect or lack of efficacy?

Abstract

*These authors contributed equally to this work.Thalamic deep brain stimulation is a mainstay treatment for severe and drug-refractory essential tremor, but postoperative management may be complicated in some patients by a progressive cerebellar syndrome including gait ataxia, dysmetria, worsening of intention tremor and dysarthria. Typically, this syndrome manifests several months after an initially effective therapy and necessitates frequent adjustments in stimulation parameters. There is an ongoing debate as to whether progressive ataxia reflects a delayed therapeutic failure due to disease progression or an adverse effect related to repeated increases of stimulation intensity. In this study we used a multimodal approach comparing clinical stimulation responses, modelling of volume of tissue activated and metabolic brain maps in essential tremor patients with and without progressive ataxia to disentangle a disease-related from a stimulation-induced aetiology. Ten subjects with stable and effective bilateral thalamic stimulation were stratified according to the presence (five subjects) of severe chronic-progressive gait ataxia. We quantified stimulated brain areas and identified the stimulation-induced brain metabolic changes by multiple 18 F-fluorodeoxyglucose positron emission tomography performed with and without active neurostimulation. Three days after deactivating thalamic stimulation and following an initial rebound of symptom severity, gait ataxia had dramatically improved in all affected patients, while tremor had worsened to the presurgical severity, thus indicating a stimulation rather than disease-related phenomenon. Models of the volume of tissue activated revealed a more ventrocaudal stimulation in the (sub)thalamic area of patients with progressive gait ataxia. Metabolic maps of both patient groups differed by an increased glucose uptake in the cerebellar nodule of patients with gait ataxia. Our data suggest that chronic progressive gait ataxia in essential tremor is a reversible cerebellar syndrome caused by a maladaptive response to neurostimulation of the (sub)thalamic area. The metabolic signature of progressive gait ataxia is an activation of the cerebellar nodule, which may be caused by inadvertent current spread and antidromic stimulation of a cerebellar outflow pathway originating in the vermis. An anatomical candidate could be the ascending limb of the uncinate tract in the subthalamic area. Adjustments in programming and precise placement of the electrode may prevent this adverse effect and help fine-tuning deep brain stimulation to ameliorate tremor without negative cerebellar signs.

Adaptive Deep Brain Stimulation for Movement Disorders: The Long Road to Clinical Therapy

“…Here it leads to habituation to the effects of DBS over time and gait ataxia,59,60 and prolonged trials are necessary to determine whether this also occurs with aDBS.…”

“…58 The converse of the above is maladaptive plasticity, and this is perhaps commonest in the treatment of essential tremor by conventional thalamic DBS. Here it leads to habituation to the effects of DBS over time and gait ataxia, 59,60 and prolonged trials are necessary to determine whether this also occurs with aDBS.…”

Neuronal activity and outcomes from thalamic surgery for spinocerebellar ataxia

“…It has been reported that Vim thalamotomy can be accompanied by ataxia, but it is often mild and transient 34. DBS of Vim or the subthalamic area has also been reported to induce ataxia in some cases of ET 35. 18F‐fluorodeoxyglucose positron emission tomography performed with and without active neurostimulation found metabolic changes induced by DBS that were consistent with antidromic activation of cerebello‐thalamic fibers,35 suggesting that disruption in activity in the cerebello‐thalamo‐cortical tract during Vim DBS lead to the development of ataxia.…”

The Effects of a Postural Balance Training Program on Balance, Gait and Health-Related Quality of Life in Patients with Essential Tremor

“…Additionally, deep brain stimulation is a promising option to treat balance and gait impairment in patients with ET. However, the possible positive and adverse effects are required to be studied (12,13).…”