Thalamic deep brain stimulation for acquired dystonia in children and young adults: a phase 1 clinical trial

Abstract

Objective: The aim of this study was to evaluate the feasibility and preliminary efficacy and safety of combined bilateral ventralis oralis posterior/ventralis intermedius (Vop/Vim) deep brain stimulation (DBS) for the treatment of acquired dystonia in children and young adults. Pallidal DBS is efficacious for severe, medication-refractory isolated dystonia, providing 50%-60% long-term improvement. Unfortunately, pallidal stimulation response rates in acquired dystonia are modest and unpredictable, with frequent nonresponders. Acquired dystonia, most commonly caused by cerebral palsy, is more common than isolated dystonia in pediatric populations and is more recalcitrant to standard treatments. Given the limitations of pallidal DBS in acquired dystonia, there is a need to explore alternative brain targets. Preliminary evidence has suggested that thalamic stimulation may be efficacious for acquired dystonia.

Methods: Four participants, 3 with perinatal brain injuries and 1 with postencephalitic symptomatic dystonia, underwent bilateral Vop/Vim DBS and bimonthly evaluations for 12 months. The primary efficacy outcome was the change in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Barry-Albright Dystonia Scale (BADS) scores between the baseline and 12-month assessments. Video documentation was used for blinded ratings. Secondary outcomes included evaluation of spasticity (Modified Ashworth Scale score), quality of life (Pediatric Quality of Life Inventory [PedsQL] and modified Unified Parkinson's Disease Rating Scale Part II [UPDRS-II] scores), and neuropsychological assessments. Adverse events were monitored for safety.

Results: All participants tolerated the procedure well, and there were no safety concerns or serious adverse events. There was an average improvement of 21.5% in the BFMDRS motor subscale score, but the improvement was only 1.6% according to the BADS score. Following blinded video review, dystonia severity ratings were even more modest. Secondary outcomes, however, were more encouraging, with the BFMDRS disability subscale score improving by 15.7%, the PedsQL total score by 27%, and the modified UPDRS-II score by 19.3%. Neuropsychological assessment findings were unchanged 1 year after surgery.

Conclusions: Bilateral thalamic neuromodulation by DBS for severe, medication-refractory acquired dystonia was well tolerated. Primary and secondary outcomes showed highly variable treatment effect sizes comparable to those of pallidal stimulation in this population. As previously described, improvements in quality of life and disability were not reflected in dystonia severity scales, suggesting a need for the development of scales specifically for acquired dystonia.Clinical trial registration no.: NCT03078816 (clinicaltrials.gov).

Keywords: DBS; deep brain stimulation; dystonia; functional neurosurgery; pediatric; thalamic.

Figures

Figure 1.

Participant Flow Chart

Figure 2.

DBS lead tip location. Axial 3T T1 MRI images showing DBS lead tip artifact for each participant (A. Participant 1, B. Participant 2, C. Participant 3, and D. Participant 4.

Figure 3.

Axial T2 preoperative MRI images from all participants A) Participant 1: preoperative MRI showed vermis and pontine atrophy, abnormal cerebellar signal and diffusely diminished supratentorial white matter with thinning of corpus callosum. B) Participant 2: His preoperative imaging at age 19 showed posterior predominant cerebral as well as bilateral thalamic volume loss and posterior corpus callosum atrophy. C) Participant 3: Brain MRI prior to surgery showed global cerebral, bilateral thalamic and left more than right putaminal volume loss, as well as Wallerian degeneration of bilateral internal capsules and cerebral peduncles. D) Participant 4: MRI brain showed very mild T2 hyperintensities in bilateral pallidum, posterior putamen, ventrolateral thalami and perirolandic regions, representing sequelae of prior injury.