Parkinsonian signs in patients with cervical dystonia treated with pallidal deep brain stimulation

Abstract

Pallidal deep brain stimulation is an established treatment in patients with dystonia. However, evidence from case series or uncontrolled studies suggests that it may lead in some patients to specific parkinsonian symptoms such as freezing of gait, micrographia, and bradykinesia. We investigated parkinsonian signs using the Movement Disorder Society Unified Parkinson's Disease Rating Scale motor score by means of observer-blinded video ratings in a group of 29 patients treated with pallidal stimulation and a non-surgical control group of 22 patients, both with predominant cervical dystonia. Additional assessments included MRI-based models of volume of neural tissue activated to investigate areas of stimulation related to dystonic symptom control and those likely to induce parkinsonian signs as well as an EMG analysis to investigate functional vicinity of stimulation fields to the pyramidal tract. Compared with controls, stimulated patients had significantly higher motor scores (median, 25th-75th percentile: 14.0, 8.0-19.5 versus 3.0, 2.0-8.0; P < 0.0001), as well as bradykinesia (8.0, 6.0-14.0 versus 2.0, 0.0-3.0; P < 0.0001) and axial motor subscores (2.0, 1.0-4.0 versus 0.0, 0.0-1.0; P = 0.0002), while rigidity and tremor subscores were not different between groups. Parkinsonian signs were partially reversible upon switching stimulation off for a median of 90 min in a subset of 19 patients tolerating this condition. Furthermore, the stimulation group reported more features of freezing of gait on a questionnaire basis. Quality of life was better in stimulated patients compared with control patients, but parkinsonian signs were negatively associated with quality of life. In the descriptive imaging analysis maximum efficacy for dystonia improvement projected to the posteroventrolateral internal pallidum with overlapping clusters driving severity of bradykinesia and axial motor symptoms. The severities of parkinsonian signs were not correlated with functional vicinity to the pyramidal tract as assessed by EMG. In conclusion, parkinsonian signs, particularly bradykinesia and axial motor signs, due to pallidal stimulation in dystonic patients are frequent and negatively impact on motor functioning and quality of life. Therefore, patients with pallidal stimulation should be monitored closely for such signs both in clinical routine and future clinical trials. Spread of current outside the internal pallidum is an unlikely explanation for this phenomenon, which seems to be caused by stimulation of neural elements within the stimulation target volume.

Pallidal Connectivity Profiling of Stimulation‐Induced Dyskinesia in Parkinson's Disease

“…The pallidothalamic fibers, which are the primary efferent fibers of the GPi, likely play an important role in dyskinesia suppression after DBS 22‐24 . Because ventral GPi stimulation can worsen parkinsonism, 4,5,33‐35 it is important to examine whether parkinsonism becomes exacerbated after the change in stimulation settings. Angeli and colleagues reported that, compared with GPi or GPe DBS alone, combined GPi/GPe DBS was superior to improve both parkinsonism and dyskinesia in an acute setting in 13 PD patients 3 .…”

Effective subthalamic and pallidal deep brain stimulation – are we modulating the same network?

“…Finally, previous studies have reported for GPi-DBS in dystonia to in fact induce bradykinetic symptoms. 27,28 In direct comparison with the two cohorts shown here, we noted that bradykinetic symptoms became worse in a larger fraction of patients from the GPi-DBS cohort. When contrasting DBS connectivity profiles in the six patients in which bradykinetic symptoms worsened most with the ones in which it improved most, connectivity to cerebellar, occipital and parieto-occipital regions was associated with symptom worsening.…”

“…The induction of bradykinetic symptoms by GPi-DBS has been reported even in cohorts without Parkinson’s disease (such as dystonia), before. 27,28 Hence, as an opportunity to study this relationship further, we contrasted functional connectivity profiles calculated from the six GPi patients in which bradykinesia improved most strongly (by 67.9 ±11.6 percent) with the six ones in which bradykinesia worsened most strongly (by −58.4 ±19.7 percent). This revealed significant differences in connectivity profiles.…”

Neurophysiological insights in dystonia and its response to deep brain stimulation treatment

“…DBS is not a cure for dystonia and symptoms return after switching DBS off but benefits persist longer in those with more robust plasticity. While GPi DBS has proved a successful and beneficial intervention for dystonia, it has some potential side effects including stimulation-induced Parkinsonian features (Tisch et al 2007c ; Mahlknecht et al 2018 ; Kosutzka et al 2020 ). Further refinements of DBS including adaptive stimulation may allow improvement in DBS efficacy and side effect profile.…”