The Surgical Treatment of Parkinson’s Disease Part 6 of 7 Recent advances in the understanding of Parkinson’s disease pathophysiology, improvement in stereotactic surgery techniques, and a better understanding of the limitations of pharmacologic interventions, have all combined to significantly increase the utility of surgical treatments of Parkinson’s disease. Whereas only five years ago surgical intervention was considered experimental, today it is viewed as a highly effective treatment option for advanced Parkinson’s disease.

Surgical Treatments for Parkinson’s Disease Ablative thalamotomy pallidotomy Electrical stimulation VIM thalamus, globus pallidus internus, sub-thalamic nucleus Transplant autologous adrenal, human fetal, xenotransplants, genetically engineered transplants Surgical treatments can be roughly divided into three separate categories. The first is ablative, in which stereotactic lesions are made in very specific anatomical locations within the brain. The second is deep brain stimulation, where an electrode is placed within specific areas of the brain and a high-frequency pulsatile voltage is used to mimic the effects of ablation. The third is cell transplantation where extraneous cells are placed into the striatum of the brain in an attempt to mimic the function of substantia nigra cells which perish in Parkinson’s disease. www.wemove.org

Technical Aspects of Pallidotomy Sterotactic placement using a Leksell frame Macro-electrode placement: patient awake assess for weakness and visual changes Micro-electrode placement: confirmation using characteristic GPi cell firing patterns and comparing to those of visual tracts (photic stimulation) and other adjacent nuclei Lesioning : 1-3 radiofrequency lesions at 75o C In the United States the most common surgical intervention for Parkinson’s disease is pallidotomy. This involves a cauterization lesion within the globus pallidus internus. Physiologic models demonstrate that this area is overactive in idiopathic Parkinson’s disease. GPi is first identified through stereotactic procedures. In most cases, placement is then confirmed by single-cell microelectrode recordings, as well as macroelectrode stimulation to insure avoidance of the internal capsule and visual tracts which border the GPi. The effects of pallidotomy are seen immediately after ablation. www.wemove.org

Improvements with Pallidotomy Specific Features: Dyskinesia 70-90 % Wearing off dystonia 70-90 % Tremor 25-60 % Rigidity 25-50 % Bradykinesia 25-50 % Gait 25-50 % All aspects of Parkinson’s disease do not respond to the same extent after a pallidotomy. The most dramatic improvement is seen in the levodopa-induced dyskinesias, followed by both wearing off and levodopa dystonia. There is also moderate-to-good improvement in tremor and rigidity with mild-to-moderate improvement in bradykinesia and gait. www.wemove.org

Effects of Pallidotomy Mostly contralateral to surgical side Immediate effect Improvements in cardinal features generally mimic those of levodopa: markedly improved dyskinesia moderately improved “off” scores mildly improved “on” scores The majority of improvement is seen contralateral to the lesion site. However, there is some ipsilateral improvements seen in most of the features. Overall there is a significant improvement in the dyskinesias and significant improvement in the “off” motor examination and mild improvement in the “on” motor examination. www.wemove.org

Features Unresponsive to Pallidotomy Dementia Bulbar Pure balance (gait improves) Autonomic Certain features do not respond to pallidotomy. Bulbar symptoms do not improve, and in fact in some cases they worsen. Autonomic features including symptomatic orthostasis, and bowel and bladder difficulties do not improve. Pure balance does not necessarily improve. However, other gait and freezing features do. Cognitive aspects of Parkinson’s do not seem to be greatly affected, but do not worsen. www.wemove.org

Ideal Patient for Pallidotomy Severe dyskinesia with best medical management Fluctuations with best medical management Asymmetric symptoms Levodopa responsive Absence of significant : dementia bulbar symptoms autonomic symptoms Therefore the ideal candidate for a pallidotomy would be a patient who is clearly levodopa-responsive, suffering from pharmacologically unmanageable fluctuations, with significant dyskinesias, and with a relative absence of dementia, autonomic insufficiency, bulbar or gait difficulties. Since the effects are predominantly unilateral, a patient whose most affected side happens to be his dominant side would have a greater subjective improvement from surgery to the contralateral brain area. www.wemove.org

Unilateral vs. Bilateral Pallidotomy The second-side pallidotomy can : significantly improve residual unilateral dyskinesia moderately improve residual cardinal PD features possibly improve axial symptoms However second-side pallidotomy can: worsen bulbar symptoms possibly slow cognition tends not to have as dramatic effect as the first There is some controversy regarding the benefits of bilateral pallidotomy verses unilateral pallidotomy. The second-side pallidotomy clearly can further reduce dyskinesias, but provides only modest improvement for the residual cardinal manifestations of Parkinson’s disease. www.wemove.org

Pallidotomy Complications Hemorrhage (2 - 6 %) Weakness (2 - 8 %) Visual field deficit (0 - 12 %) Confusion (0 - 8 %) Weight gain (50 - 70%) Complications are seen in all stereotactic surgeries, including the possibility of hemorrhage, infection, and injury from the head frame. Potential complications of the lesion site itself include weakness if the internal capsule is involved, or visual fields deficits. The incidence of these is likely reduced with microelectrical recordings. The majority of Parkinson’s patients gain weight after surgery, and this correlates with the actual improvement in cardinal manifestations. www.wemove.org

Thalamotomy Significant improvement in contralateral tremor depends on correct placement Minimal improvement in other PD signs Bilateral procedures poorly tolerated AEs: bulbar, sensory and motor deficits, gait, surgical complications Gradually being replaced by thalamic DBS Stereotactic thalamotomy generally uses the same technology as pallidotomy, however, the lesion site is the ventral interomedial nucleus of the thalamus. Thalamotomy has been used for many years because it significantly improves in contralateral tremor. Other aspects of Parkinson’s disease however, are not generally improved. Adverse events include bulbar, motor and sensory difficulties, as well as gait problems and the usual complications of surgery. Bilateral thalamotomies are poorly tolerated because these adverse events are greatly augmented. www.wemove.org

Deep Brain Stimulation (DBS) High frequency, pulsatile, bipolar electrical stimulation Stereotactically placed into target nucleus Can be activated and deactivated with an external magnet Exact physiology unknown, but higher frequencies mimic cellular ablation, not stimulation Deep brain stimulation is a newer technology. A high frequency pulsatile current is discharged from an electrode which is implanted in certain areas within the brain. Although exclusively internalized, the device is actually activated or deactivated with the use of an external magnet. The electrode reaches the surface of the brain and is connected via wire retroauricularly to the magnetic switch, which is typically placed under the clavicle. The exact physiology of deep brain stimulation on a cellular level is unknown; however, it mimics the effects of lesioning, possibly by “jamming” normal cellular communication. www.wemove.org

Adjustable Features Voltage (1-7 volts) Pulse width (65-450 msec) Frequency (130-180 Hz) Polarity Lead location (4 leads, each 1.5 mm apart) Several parameters can be adjusted on the main stimulator device, which is currently supplied by Medtronic, Inc. in the United States. These include the actual voltage of the device, the width of each current pulse, the frequency of the pulse, whether each lead is positive or negative, and the exact location of four separate leads. www.wemove.org

VIM Thalamic DBS 80% reduction in contralateral arm and leg tremor Possible mild improvement in bradykinesia and rigidity No functional improvement (UPDRS part II), but significant improvement based upon global scores No effect: gait and bulbar symptoms AEs: bulbar, gait, paresthesia, surgical VIM thalamic stimulation significantly reduces contralateral tremor in both the arms and legs of Parkinson’s disease. It may result in a moderate benefit in bradykinesia and rigidity; however, this is less robust. Global impressions in these studies have shown significant improvement. However, UPDRS part 2, which only briefly concerns tremor, did not show improvement. Therefore, the placement into the VIM thalamus should be limited to patients in whom the tremor itself results in major functional disability. Adverse events can be broken down into the typical surgical events seen in any stereotactic surgery, and those adverse effects which may respond to adjustment of lead parameters. Most commonly these include paresthesias, dysarthria, and gait difficulties. Long term complications include device failure, lead breakage, wire erosion through the skin, and infection. www.wemove.org

Bilateral Thalamic VIM DBS Bilateral tremor control very good, but adverse events (gait and bulbar) become more problematic (PD>ET) Often not able to completely inhibit both sides without AEs Subjective ratings do not improve much from those of unilateral scores There is little formal data evaluating bilateral thalamic stimulators verses unilateral. In our experience there is an equally effective tremor improvement on the second side. However, adverse events, especially gait and bulbar symptoms, often increase to teh point where it is more difficult to completely eliminate tremor on both sides. www.wemove.org

Relative Advantages of Thalamotomy vs. Thalamic Stimulation Proven long term efficacy Lower cost Less risk of infection Less post-operative management Thalamic Stimulation Adjustable Less morbidity Easier to use bilaterally Greater efficacy? Advantages of thalamic stimulation over traditional thalamotomy includes the fact that it is adjustable in both functional lesion size and placement, thus probably resulting in greater efficacy in many cases. It is also better tolerated bilaterally and has less surgical morbidity. Disadvantages of the thalamic stimulator include its higher cost, the possible risk of infection or erosion, and the fact that more postoperative management is required. www.wemove.org

Subthalamic DBS All cardinal features of PD noted to improve in open label trials “Off” UPDRS improved 60% “On” UPDRS improved 10% Dyskinesia tends to improve but this is probably due to decreased levodopa dose The same device can be placed in other aspects of the brain in Parkinson’s disease. Subthalamic nucleus deep brain stimulation is gaining acceptance because is seems to improve essentially all cardinal manifestations of PD in the “off” state. It does not significantly improve these features over optimum dosed levodopa; however, its use can significantly reduce drug therapy and thus can significantly reduce dyskinesias. There are also speculations that STN DBS may have some neuroprotective effect, however, there is as of yet no clincal evidence of this. www.wemove.org

Bilateral Subthalamic DBS Bilateral placement appears to be superior to unilateral placement Theorized neuroprotective mechanism, but no clinical evidence supporting this AE: confusion and hallucinations, increased dyskinesia before medication adjustments, eyelid opening apraxia, weight gain, surgical complications Recent clinical trials have shown bilateral placement to be superior to unilateral placement. The clinical effect of unilateral DBS may be less lateralized compared to VIM DBS. Most larger studies have only evaluated bilateral placement. Adverse events from subthalamic DBS include confusion and hallucination, which are worse immediately after implantation; increased dyskinesias prior to the reduction of levodopa doses; eyelid opening apraxia; weight gain; and the usual surgical complications. The exact placement of this device is considered to be more technically demanding than when placed into the VIM thalamic nucleus. www.wemove.org

Globus Pallidus internus DBS Effects tend to mimic those of pallidotomy Significant improvement in dyskinesia Moderate improvement in cardinal “off” signs No comparison between unilateral and bilateral Bilateral DBS may be better tolerated than bilateral pallidotomy AE: surgical complications When the same device is placed in the globus pallidus internus it seems to generally mimic the effects of pallidotomy. Therefore, there is some significant improvement in dyskinesias scores, and moderate improvement in “off” UPDRS motor scores. The bilateral pallidal DBS may be better tolerated than bilateral pallidotomy, however, there is little formal data comparing the two. Adverse events include the same surgical complications, weakness, and visual field deficits, however, the last two tend to be adjustable. www.wemove.org

Cell Transplants Autologous adrenal transplants No efficacy Allogenic human fetal transplants Initial encouraging clinical results Xenogenic fetal transplant (porcine and bovine) Preliminary results pending Genetically engineered cells Research ongoing A variety of cell transplantation techniques have been attempted and are currently ongoing for further studies for the treatment of Parkinson’s disease. Autologous adrenal transplants of dopaminergic producing cells from the adrenal gland of the same individual have not proven to be efficacious and have been largely abandoned. Allogenic human fetal transplants have showed encouraging results and study of these continue. Xenogenic fetal transplants from porcine and bovine brains studies are beginning, but results are still pending. Finally, genetically engineered stem cell technology research is ongoing; however, no cells have been actually transplanted to date into a human with Parkinson’s disease. www.wemove.org

Human Fetal Transplants Efficacy Encouraging preliminary results in young (<60) PD pts Patients greater than 50 years did not improve PET studies consistent with cell functioning Autopsies (2) show cell survival Problems 4-10 embryos < 10 weeks gestation needed Immunosuppression requirements unknown Numerous technical problems Potential for dyskinesias, even without any PD medications Regarding human fetal transplantation, several studies have shown encouraging preliminary clinical results. The largest controlled study demonstrated clear improvement in younger, but not older, patients. PET studies have showed increase dopaminergic function consistent with cell survival and two autopsies of patients who have died subsequent to transplant, and related causes have demonstrated that at least 1% of the cells have survived and ovularized. The many practical problems with human fetal transplantation include the high number of embryos that are required for cell transplantation of variety of unclear technical parameters including exact placement of the cells and poor understanding regarding the necessity for immunosuppression. www.wemove.org

Faculty for the WE MOVE Parkinson’s Disease Teaching Slide Set Mark Stacy, MD Barrow Neurological Institute Phoenix, Arizona, USA Charles H. Adler, MD, PhD Mayo Clinic Scottsdale Scottsdale, Arizona, USA Kathleen Albany, PT, MPH WE MOVE New York, New York, USA Richard B. Dewey, Jr., MD University of Texas Southwestern Medical Center Dallas, Texas, USA William G. Ondo, MD Baylor College of Medicine Houston, Texas, USA Rajesh Pahwa, MD University of Kansas Medical Center Kansas City, Kansas, USA Ali H. Rajput, MD Royal University Hospital Saskatoon, Saskatchewan, Canada Lisa M. Shulman, MD Health Policy Fellow U.S. House of Representatives Washington, DC, USA Celia Stewart, PhD Mount Sinai Medical Center New York, New York, USA Reviewed by the Education Committee of the Movement Disorder Society www.wemove.org