Nigral stimulation for resistant axial motor impairment in Parkinson's disease? A randomized controlled trial

Daniel Weiss, Margarete Walach, Christoph Meisner, Melanie Fritz, Marlieke Scholten, Sorin Breit, Christian Plewnia, Benjamin Bender, Alireza Gharabaghi, Tobias Wächter, Rejko Krüger, Daniel Weiss, Margarete Walach, Christoph Meisner, Melanie Fritz, Marlieke Scholten, Sorin Breit, Christian Plewnia, Benjamin Bender, Alireza Gharabaghi, Tobias Wächter, Rejko Krüger

Abstract

Gait and balance disturbances typically emerge in advanced Parkinson's disease with generally limited response to dopaminergic medication and subthalamic nucleus deep brain stimulation. Therefore, advanced programming with interleaved pulses was put forward to introduce concomittant nigral stimulation on caudal contacts of a subthalamic lead. Here, we hypothesized that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata improves axial symptoms compared with standard subthalamic nucleus stimulation. Twelve patients were enrolled in this 2 × 2 cross-over double-blind randomized controlled clinical trial and both the safety and efficacy of combined subthalamic nucleus and substantia nigra pars reticulata stimulation were evaluated compared with standard subthalamic nucleus stimulation. The primary outcome measure was the change of a broad-scaled cumulative axial Unified Parkinson's Disease Rating Scale score (Scale II items 13-15, Scale III items 27-31) at '3-week follow-up'. Secondary outcome measures specifically addressed freezing of gait, balance, quality of life, non-motor symptoms and neuropsychiatric symptoms. For the primary outcome measure no statistically significant improvement was observed for combined subthalamic nucleus and substantia nigra pars reticulata stimulation at the '3-week follow-up'. The secondary endpoints, however, revealed that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata might specifically improve freezing of gait, whereas balance impairment remained unchanged. The combined stimulation of subthalamic nucleus and substantia nigra pars reticulata was safe, and of note, no clinically relevant neuropsychiatric adverse effect was observed. Patients treated with subthalamic nucleus and substantia nigra pars reticulata stimulation revealed no 'global' effect on axial motor domains. However, this study opens the perspective that concomittant stimulation of the substantia nigra pars reticulata possibly improves otherwise resistant freezing of gait and, therefore, highly warrants a subsequent phase III randomized controlled trial.

Keywords: DBS; Parkinson’s disease; freezing; gait; subthalamic nucleus.

Figures

Figure 1
Figure 1
CONSORT chart. [STN+SNr] = combined STN+SNr stimulation.
Figure 2
Figure 2
Localization of active electrode contacts of (A) dorsolateral STN and (B) dorsolateral SNr. Coordinates relative to the midcommisural point (MCP) were: left STN −11.4 ± 0.8, −0.9 ± 2.0, −3.0 ± 1.7; right STN 13.5 ± 1.1, −0.5 ± 1.7, −2.2 ± 1.5; left SNr −10.0 ± 0.9, −3.4 ± 2.1, −6.4 ± 1.8; right SNr 12.1 ± 1.3, −3.3 ± 1.7, −5.8 ± 1.5 (x, y, z; x = medio-lateral, y = anterio-posterior, z = rostro-caudal). Electrode coordinates (mean ± standard deviation in x- and y-direction) are visualized in coronal view on the Atlas of the Human Brain with permission (Mai et al., 2007). (C) An additional illustrative image of electrode localization including a simulation on volume of tissue activated was kindly provided by Medtronic based on work by Yelnik et al. (2007) (atlas) and D’Haese et al. (2012) (atlas and algorithms).
Figure 3
Figure 3
Primary endpoint at ‘3-week follow-up’. Results are given as box plots. x-axis: therapeutic condition; y-axis: axial score. [STN+SNr] = combined STN+SNr stimulation.
Figure 4
Figure 4
Secondary endpoint: results at (A) ‘immediate testing’ and at (B) ‘3-week follow-up’ are given for the Freezing of Gait Assessment Course. Results are given as box plots. x-axis: therapeutic condition; y-axis: score of the Freezing of Gait Assessment Course. [STN+SNr] = combined STN+SNr stimulation.

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