title: Progressive gait ataxia following deep brain stimulation for essential tremor: adverse effect or lack of efficacy?
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.
authors.affiliation: Department of Neurology, University Hospital and Julius-Maximilian-University, Wuerzburg, Germany.
authors.forename: Martin M
authors.initials: MM
authors.lastname: Reich
authors.affiliation: Department of Nuclear Medicine, University Hospital and Julius-Maximilian-University, Wuerzburg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Brumberg
authors.affiliation: Department of Neurology, University Hospital and Julius-Maximilian-University, Wuerzburg, Germany.
authors.forename: Nicolò G
authors.initials: NG
authors.lastname: Pozzi
authors.affiliation: Department of Nuclear Medicine, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Marotta
authors.affiliation: Medtronic Neuromodulation, Medtronic Eindhoven Design Center, The Netherlands.
authors.forename: Jonas
authors.initials: J
authors.lastname: Roothans
authors.affiliation: Medtronic Neuromodulation, Medtronic Eindhoven Design Center, The Netherlands.|Department of Biomedical Engineering, Linköping University, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Åström
authors.affiliation: Department of Neurology, University Hospital and Julius-Maximilian-University, Wuerzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Musacchio
authors.affiliation: Neuroscience Department, University of Turin Medical School, Turin, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Lopiano
authors.affiliation: Neuroscience Department, University of Turin Medical School, Turin, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Lanotte
authors.affiliation: Department of Stereotactic Neurosurgery, St. Barbara - Klinik, Hamm, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Lehrke
authors.affiliation: Department of Nuclear Medicine, University Hospital and Julius-Maximilian-University, Wuerzburg, Germany.
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Buck
authors.affiliation: Department of Neurology, University Hospital and Julius-Maximilian-University, Wuerzburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Volkmann
authors.affiliation: Department of Neurology, University Hospital and Julius-Maximilian-University, Wuerzburg, Germany.
authors.forename: Ioannis U
authors.initials: IU
authors.lastname: Isaias
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001703:Biophysics; D046690:Deep Brain Stimulation / Q000009:adverse effects*; D020329:Essential Tremor / Q000000981:diagnostic imaging / Q000628:therapy; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D020234:Gait Ataxia / Q000000981:diagnostic imaging / Q000209:etiology*; D006801:Humans; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging; D008297:Male; D049268:Positron-Emission Tomography; D013788:Thalamus / Q000502:physiology*; D014057:Tomography, X-Ray Computed
chemical_list: D019788:Fluorodeoxyglucose F18
keywords: ataxia gait; cerebellum; deep brain stimulation; essential tremor; positron emission tomography (PET)