Seth F Oliveria1, Ramon L Rodriguez2, Dawn Bowers3, Daniel Kantor4, Justin D Hilliard5, Erin H Monari2, Bonnie M Scott3, Michael S Okun6, Kelly D Foote5. 1. Department of Neurosurgery, Center for Movement Disorders and Neurorestoration, University of Florida, Gainesville, FL, USA. Electronic address: seth.oliveria@neurosurgery.ufl.edu. 2. Department of Neurology, Center for Movement Disorders and Neurorestoration, University of Florida, Gainesville, FL, USA. 3. Department of Clinical and Health Psychology, Center for Movement Disorders and Neurorestoration, University of Florida, Gainesville, FL, USA. 4. Kantor Neurology, Coconut Creek, FL, USA. 5. Department of Neurosurgery, Center for Movement Disorders and Neurorestoration, University of Florida, Gainesville, FL, USA. 6. Department of Neurosurgery, Center for Movement Disorders and Neurorestoration, University of Florida, Gainesville, FL, USA; Department of Neurology, Center for Movement Disorders and Neurorestoration, University of Florida, Gainesville, FL, USA.
Abstract
BACKGROUND: Efficacy in previous studies of surgical treatments of refractory multiple sclerosis tremor using lesioning or deep brain stimulation (DBS) has been variable. The aim of this study was to investigate the safety and efficacy of dual-lead thalamic DBS (one targeting the ventralis intermedius-ventralis oralis posterior nucleus border [the VIM lead] and one targeting the ventralis oralis anterior-ventralis oralis posterior border [the VO lead]) for the treatment of multiple sclerosis tremor. METHODS: We did a single centre, single-blind, prospective, randomised pilot trial at the University of Florida Center for Movement Disorders and Neurorestoration clinic (Gainesville, FL, USA). We recruited adult patients with a clinical diagnosis of multiple sclerosis tremor refractory to previous medical therapy. Before surgery to implant both leads, we randomly assigned patients (1:1) to receive 3 months of optimised single-lead DBS-either VIM or VO. We did the randomisation with a computer-generated sequence, using three blocks of four patients, and independent members of the Center did the assignment. Patients and all clinicians other than the DBS programming nurse were masked to the choice of lead. Patients underwent surgery 1 month after their baseline visit for implantation of the dual lead DBS system. A pulse generator and two extension cables were implanted in a second surgery 3-4 weeks later. Patients then received an initial 3-month period of continuous stimulation of either the VIM or VO lead followed by blinded safety assessment of their tremor with the Tolosa-Fahn-Marin Tremor Rating Scale (TRS) during optimised VIM or VO lead stimulation at the end of the 3 months. After this visit, both leads were activated in all patients for an additional 3 months, and optimally programmed during serial visits as dictated by a prespecified programming algorithm. At the 6-month follow-up visit, TRS score was measured, and mood and psychological batteries were administered under four stimulation conditions: VIM on, VO on, both on, and both off (the order of testing was chosen by a computer-generated random sequence, assigned by independent members of the centre, and enacted by an unmasked DBS programming nurse). Each of four stimulation settings were tested over 4 consecutive days, with stimulation settings held constant for at least 12 h before testing. The primary outcome was change in mean total TRS score at the 6-month postoperative assessment with both leads activated, compared with the preoperative baseline mean TRS score. Analysis was by intention to treat. Safety was analysed in all patients who received the surgical implantation except in one patient who discontinued before the safety assessment. This trial is registered with ClinicalTrials.gov, number NCT00954421. FINDINGS:Between Jan 16, 2007, and Dec 17, 2013, we enrolled 12 patients who were randomly assigned either to 3 initial months of VIM-only or VO-only stimulation. One patient from the VO-only group developed an infection necessitating DBS explantation, and was excluded from the assessment of the primary outcome. Compared with the mean baseline TRS score of 57·0 (SD 10·2), the mean score at 6 months decreased to 40·1 (17·6), -29·6% reduction; t=-0·28, p=0·03. Three of 11 patients did not respond to surgical intervention. One patient died suddenly 2 years after surgery, but this was judged to be unrelated to DBS implantation. Serious adverse events included a superficial wound infection in one patient that resolved with antibiotic therapy, and transient altered mental status and late multiple sclerosis exacerbation in another patient. The most common non-serious adverse events were headache and fatigue. INTERPRETATION: Dual lead thalamic DBS might be a safe and effective option for improving severe, refractory multiple sclerosis tremor. Larger studies are necessary to show whether this technique is widely applicable, safe in the long-term, and effective in treating multiple sclerosis tremor or other severe tremor disorders. FUNDING: US National Institutes of Health, the Cathy Donnellan, Albert E Einstein, and Birdie W Einstein Fund, and the William Merz Professorship.
RCT Entities:
BACKGROUND: Efficacy in previous studies of surgical treatments of refractory multiple sclerosis tremor using lesioning or deep brain stimulation (DBS) has been variable. The aim of this study was to investigate the safety and efficacy of dual-lead thalamic DBS (one targeting the ventralis intermedius-ventralis oralis posterior nucleus border [the VIM lead] and one targeting the ventralis oralis anterior-ventralis oralis posterior border [the VO lead]) for the treatment of multiple sclerosis tremor. METHODS: We did a single centre, single-blind, prospective, randomised pilot trial at the University of Florida Center for Movement Disorders and Neurorestoration clinic (Gainesville, FL, USA). We recruited adult patients with a clinical diagnosis of multiple sclerosis tremor refractory to previous medical therapy. Before surgery to implant both leads, we randomly assigned patients (1:1) to receive 3 months of optimised single-lead DBS-either VIM or VO. We did the randomisation with a computer-generated sequence, using three blocks of four patients, and independent members of the Center did the assignment. Patients and all clinicians other than the DBS programming nurse were masked to the choice of lead. Patients underwent surgery 1 month after their baseline visit for implantation of the dual lead DBS system. A pulse generator and two extension cables were implanted in a second surgery 3-4 weeks later. Patients then received an initial 3-month period of continuous stimulation of either the VIM or VO lead followed by blinded safety assessment of their tremor with the Tolosa-Fahn-Marin Tremor Rating Scale (TRS) during optimised VIM or VO lead stimulation at the end of the 3 months. After this visit, both leads were activated in all patients for an additional 3 months, and optimally programmed during serial visits as dictated by a prespecified programming algorithm. At the 6-month follow-up visit, TRS score was measured, and mood and psychological batteries were administered under four stimulation conditions: VIM on, VO on, both on, and both off (the order of testing was chosen by a computer-generated random sequence, assigned by independent members of the centre, and enacted by an unmasked DBS programming nurse). Each of four stimulation settings were tested over 4 consecutive days, with stimulation settings held constant for at least 12 h before testing. The primary outcome was change in mean total TRS score at the 6-month postoperative assessment with both leads activated, compared with the preoperative baseline mean TRS score. Analysis was by intention to treat. Safety was analysed in all patients who received the surgical implantation except in one patient who discontinued before the safety assessment. This trial is registered with ClinicalTrials.gov, number NCT00954421. FINDINGS: Between Jan 16, 2007, and Dec 17, 2013, we enrolled 12 patients who were randomly assigned either to 3 initial months of VIM-only or VO-only stimulation. One patient from the VO-only group developed an infection necessitating DBS explantation, and was excluded from the assessment of the primary outcome. Compared with the mean baseline TRS score of 57·0 (SD 10·2), the mean score at 6 months decreased to 40·1 (17·6), -29·6% reduction; t=-0·28, p=0·03. Three of 11 patients did not respond to surgical intervention. One patient died suddenly 2 years after surgery, but this was judged to be unrelated to DBS implantation. Serious adverse events included a superficial wound infection in one patient that resolved with antibiotic therapy, and transient altered mental status and late multiple sclerosis exacerbation in another patient. The most common non-serious adverse events were headache and fatigue. INTERPRETATION: Dual lead thalamic DBS might be a safe and effective option for improving severe, refractory multiple sclerosis tremor. Larger studies are necessary to show whether this technique is widely applicable, safe in the long-term, and effective in treating multiple sclerosis tremor or other severe tremor disorders. FUNDING: US National Institutes of Health, the Cathy Donnellan, Albert E Einstein, and Birdie W Einstein Fund, and the William Merz Professorship.
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