Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease

Abstract

Gait disturbances are frequent and disabling in advanced Parkinson's disease. These symptoms respond poorly to usual medical and surgical treatments but were reported to be improved by stimulation of the pedunculopontine nucleus. We studied the effects of stimulating the pedunculopontine nucleus area in six patients with severe freezing of gait, unresponsive to levodopa and subthalamic nucleus stimulation. Electrodes were implanted bilaterally in the pedunculopontine nucleus area. Electrode placement was checked by postoperative magnetic resonance imaging. The primary outcome measures were a composite gait score, freezing of gait questionnaire score and duration of freezing episodes occurring during a walking protocol at baseline and one-year follow-up. A double-blind cross-over study was carried out from months 4 to 6 after surgery with or without pedunculopontine nucleus area stimulation. At one-year follow-up, the duration of freezing episodes under off-drug condition improved, as well as falls related to freezing. The other primary outcome measures did not significantly change, nor did the results during the double-blind evaluation. Individual results showed major improvement of all gait measures in one patient, moderate improvement of some tests in four patients and global worsening in one patient. Stimulation frequency ranged between 15 and 25 Hz. Oscillopsia and limb myoclonus could hinder voltage increase. No serious adverse events occurred. Although freezing of gait can be improved by low-frequency electrical stimulation of the pedunculopontine nucleus area in some patients with Parkinson's disease our overall results are disappointing compared to the high levels of expectation raised by previous open label studies. Further controlled studies are needed to determine whether optimization of patient selection, targeting and setting of stimulation parameters might improve the outcome to a point that could transform this experimental approach to a treatment with a reasonable risk-benefit ratio.

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

“…Vim receives strong inputs from the cerebellum, and the effectiveness of tremor control with DBS at this location is a strong argument in favor of cerebellar involvement in the pathophysiology of tremor. PPN DBS [226][227][228][229][230][231][232][233][234][235][236][237][238][239], alone or in combination with STN or GPi DBS, is currently under study for patients with advanced PD who develop levodopaunresponsive freezing of gait, balance impairments, and falls. DBS of the PPN has been shown to be most effective at low stimulation frequencies [240].…”

“…DBS of the PPN has been shown to be most effective at low stimulation frequencies [240]. However, the location of effective PPN stimulation sites remains debated [e.g., 231,241]. Other groups have targeted the zona incerta and CM in patients with PD [7,59], particularly for tremor or dyskinesias.…”

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

“…These studies have lead to variable results (Plaha and Gill, 2005;Stefani et al, 2007Stefani et al, , 2010Mazzone et al, 2007Mazzone et al, , 2008Pereira et al, 2008;Pierantozzi et al, 2008;Alessandro et al, 2010;Peppe et al, 2010;Rauch et al, 2010). In some patients, PPN DBS reduces gait and freezing problems unresponsive to drug and conventional stimulation approaches directed at subthalamic and pallidal targets, reduces falls and occasionally improves patients' state of vigilance and quality of sleep (Pereira et al, 2008;Ferraye et al, 2010). The magnitude of the effects, the exact location of the stimulation electrode and best technique of implantation of DBS leads into this nucleus are still being debated (Aravamuthan et al, 2007(Aravamuthan et al, , 2008(Aravamuthan et al, , 2009Weinberger et al, 2008;Fu et al, 2009;Shimamoto et al, 2010).…”

Advances in Therapeutic Options for Gait and Balance in Parkinson’s Disease

“…Ferraye et al reported an open-label study of bilateral PPN stimulation in six PD patients who had previously undergone STN DBS, but with gait and postural problems unresponsive to STN DBS. 125 There was significant improvement in freezing of gait and falls at one year compared to baseline, but blinded on and off stimulation comparisons at one year failed to demonstrate any difference in gait or posture.…”

“…123,124 Subsequent reports, unfortunately, are not as impressive. [125][126][127] Moro et al reported six patients with PD who underwent low frequency unilateral PPN stimulation and demonstrated improvements in falls and freezing of gait at 3 months compared to the baseline "off medication" state. 126 There were, however, no improvements in the UPDRS total motor or in gait/posture scores.…”