Abstract
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.
Highlights
Motor disability in essential tremor results predominantly from the complex interaction of postural, action- and intention-tremor with goal-directed hand movements, but $10–15% of patients present mild cerebellar symptoms, such as saccadic abnormalities (Helmchen et al, 2003), dysmetria or impaired tandem gait (Flament and Hore, 1986; Hallett et al, 1991; Fasano et al, 2010)
It was not addressed in this study, whether the severe cerebellar syndrome could be an adverse effect of prolonged deep brain stimulation (DBS), given the fact that supra-threshold stimulation provokes ataxia and that rescue programming attempts often lead to increasing stimulation intensity
We forward evidence that chronic-progressive gait ataxia in subjects with essential tremor is reversible after a prolonged DBS washout and emerges from a stimulation-induced vestibulocerebellar network dysfunction
Summary
Motor disability in essential tremor results predominantly from the complex interaction of postural-, action- and intention-tremor with goal-directed hand movements, but $10–15% of patients present mild cerebellar symptoms, such as saccadic abnormalities (Helmchen et al, 2003), dysmetria or impaired tandem gait (Flament and Hore, 1986; Hallett et al, 1991; Fasano et al, 2010). A typical clinical scenario is an improvement of tremor after initial programming, but a subsequent decline in efficacy and the need for repeated stimulation adjustments In these cases, progressive motor disability results from a worsening of intention tremor rather than action or postural tremor and the emergence of additional cerebellar symptoms, such as truncal ataxia and unsteady gait. After an extensive work-up, the authors concluded that only one of seven patients with DBS failure fulfilled their criteria for tolerance, whereas the others likely suffered from disease progression (Favilla et al, 2012) It was not addressed in this study, whether the severe cerebellar syndrome could be an adverse effect of prolonged DBS, given the fact that supra-threshold stimulation provokes ataxia and that rescue programming attempts often lead to increasing stimulation intensity. Following the hypothesis of a stimulation-induced (rather than disease-related) aetiology, we compared the clinical outcome of DBS, the disease severity after prolonged stimulation wash-out, the volume of tissue activated (VTA) and the DBS-related cerebral metabolic changes [18F-fluorodeoxyglucose (FDG) PET] in essential tremor patients with and without DBS failure
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