1. 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.

2. 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.

3. 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.

4. Improvements with Pallidotomy
Specific Features:
Dyskinesia %
Wearing off dystonia %
Tremor %
Rigidity %
Bradykinesia %
Gait %
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.

5. 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.

6. 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.

7. 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.

8. 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.

9. Pallidotomy Complications
Hemorrhage (2 - 6 %)
Weakness (2 - 8 %)
Visual field deficit ( %)
Confusion (0 - 8 %)
Weight gain ( %)
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.

10. 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.

11. 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.

12. Adjustable Features Voltage (1-7 volts) Pulse width (65-450 msec)
Frequency ( 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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