Deep Brain Stimulation in the Pedunculopontine Nucleus Area in Parkinson's Disease
Abstract & Commentary
By Panida Piboolnurak, MD, Assistant Professor, Department of Neurology and Neuroscience, Weill Medical College, Cornell University. Dr. Piboolnurak reports no financial relationship relevant to this field of study.
Synopsis: PPN DBS may be able to improve gait and postural stability in advanced Parkinson's disease. Although double-blind studies with small sample size did not confirm this effect, further studies are required for better understanding of the effects of PPN DBS in Parkinson's disease.
Sources: Ferraye MU, et al. Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease. Brain 2010:133;205-214. Moro E, et al. Unilateral pedunculopontine stimulation improves falls in Parkinson's disease. Brain 2010:133;215-224.
Gait disturbance and postural instability are major causes of disability in Parkinson's disease. Medications and deep brain stimulation (DBS) in the subthalamic nucleus or internal globus pallidus sometimes do not alleviate freezing of gait and usually do not provide a direct benefit on postural stability. Pedunculopontine nucleus (PPN) is a reticular structure belonging to the mesencephalic reticular formation. Studies in non-human primates suggested a role of PPN and related brainstem areas in gait and posture control. Recent open-label studies also suggested that PPN DBS may provide benefit on gait disorders. Ferraye and Moro and their respective groups conducted double-blind studies on the effects of PPN DBS.
Ferraye evaluated the effects of bilateral PPN DBS in six patients with Parkinson's disease with severe gait freezing, unresponsive to levodopa and STN DBS. At one-year follow-up, during the open-label assessment, although freezing of gait improved in the off-medication / on PPN stimulation state, there was no significant change in the on-medication state compared to pre-surgery condition whether or not PPN DBS was on or off. Moreover, during the double-blind evaluation, there was no significant difference in gait freezing and motor scores between off and on stimulation states. The best stimulation contacts located slightly posterior to the PPN, in the cuneiform and subcuneiform nuclei. Bipolar stimulation was used in most patients with stimulation frequency ranging from 15 to 25 Hz, voltage between 1.2 and 3.8 V, and pulse width of 60 and 90 µs. Because they observed a trend for the benefit to wear off, cyclic stimulation with continuous stimulation during the day and off stimulation at night was preferred after the study. Adverse events included ipsilateral oscillopsia and limb myoclonus induced by low frequency-stimulation (5–35 Hz), and contralateral paresthesia induced by stimulation over 60 Hz. Three patients reported improvement in sleep with an increase in daytime vigilance.
Moro evaluated the effects of unilateral PPN DBS in six patients with Parkinson's disease with freezing of gait and postural instability. However, unlike Ferraye's study, the patients in Moro's study did not have STN DBS. The contacts used were located in the anterolateral tegmentum of the pontomesencephalic junction. PPN DBS did not provide an acute benefit, but it induced reversible and intensity- and frequency-dependent adverse effects, including contralateral paresthesia, unilateral oscillopsia, and contralateral warm sensation. Settings with frequency of 50 Hz and 70 Hz, pulse width of 60 µs, and voltage of 1.9 usually produced better motor scores. Bipolar stimulation provided better motor outcomes than monopolar stimulation. There was no significant difference in UPDRS II and III total scores and subscores for falling, freezing, or gait and balance between on and off stimulation in either on and off medication conditions during the double-blind assessment after three months and 12 months of continuous stimulation. But, during the open-label assessment, there was improvement in total UPDRS II scores (particularly subscores for freezing and fall) in the off-medication/on-stimulation state at three months and 12 months. Total motor scores and subscores for gait and postural stability (open-label assessment) also improved, but the improvement did not reach the statistical significance.
Although studies in non-human primates, previous open-label studies on PPN DBS, and the open-label part of these two most recent studies have shown that PPN DBS may improve gait and postural stability in advanced Parkinson's disease, double-blind studies did not show significant improvement in gait freezing and postural instability. Limitation of the studies include small sample size, limitation of current scoring systems for gait and postural stability, unclear onset of action when PPN DBS was turned on and wash-out period once it was turned off, and limited knowledge on the most effective anatomical location for stimulation as well as the best stimulation setting (bilateral vs unilateral stimulation, polarity, frequency, pulse width, and amplitude).