Deep Brain Surgery

Posted: Thu Aug 09, 2007 12:54 pm Post subject: DBS

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IN perfiorming DBS which is the better target ?

GPI or STN

What is the determing factor for the selection

Gail

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Dr. Okun



Joined: 19 Jan 2007
Posts: 251
Location: University of Florida
Posted: Fri Aug 10, 2007 1:19 pm Post subject:

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This was a version of an editorial that appeared in Archives recently that Dr. Foote and I wrote. BOTH TARGETS work and so if you have either target that is good. We will learn with ongoing studies which is better for what reason. We do need studies which will be available in the next year or two.

Introduction-

The field of Parkinson’s disease (PD) surgery has again re-emerged as an important area of research and clinical advancement. The notion of the possibility of a surgical treatment for PD and tremors probably started in 1937 with Bucy who favored sectioning procedures. Later surgery was refined by the introduction in the 1950’s of Speigel and Wycis’ stereotactic head frame. Lesions of many basal ganglia structures over the next several years were refined, until surgery halted in the late 1960’s with the introduction of levodopa. After complications of levodopa therapy were realized, PD surgery reemerged as an effective therapy. In the past decade lesions in many centers throughout the world have been replaced by deep brain stimulation (DBS). In addition, the rapid and important advances in our understanding of basal ganglia physiology and neuroanatomy1, 2 have led to a long running debate concerning the best target for Parkinson’s disease (PD) surgery and more specifically for DBS. Since the thalamic target has proven effective for only tremor, this has led to an important showdown between GPi and STN DBS. Historically, GPi has been the preferred target, especially since the resurgence of pallidotomy in the early 1990’s3, and later pallidal DBS4, 5. However, following important physiology and lesioning experiments many investigators quickly embraced the STN6, 7. Thus, by the turn of the millennia the field seemed to be moving toward a singular and unified direction, mainly that STN was a better target. The battle between GPi and STN was so quick and so convincing, that the shock and awe left few doubters of STN’s superiority. The literature was flooded with reports about the successes of STN DBS, while the number of reports on GPi DBS dwindled and almost disappeared. However, many of us, experienced with lesion therapy and DBS were not convinced, and some, as our center, are involved in setting up important rematches between targets. A major goal of clinical science is validation, but there is no validity without reliability. In this issue of Archives of Neurology, Anderson and co-workers detail the rematch between PD surgical targets, GPi and STN. The results were sobering. In this editorial we aim to review these findings, and to summarize as well as evaluate current knowledge about the two surgical targets. Finally, we will discuss the need for future studies that compare GPi and STN DBS.

Results of the Most Recent Trial

Anderson and colleagues who studied patients receiving either GPi or STN DBS report several interesting findings, the most important being that there are no significant differences in the overall benefits of DBS at these two sites. Although bradykinesia tended to improve more in the STN group, it was also worse at baseline in STN (18 versus 15) with the overall improvement resulting in the same UPDRS score (both groups improved to scores of 10). The levodopa dose was reduced more in the STN group, and dyskinesia was improved in both groups, perhaps to a greater degree with GPi DBS. Cognitive and behavioral symptoms however, occurred only in the STN group.

In This Corner… The Challenger and Former Champion- GPi DBS and in
in this Corner… The Reigning Champion- STN DBS

In order to properly set the stage for this rematch of GPi and STN DBS we will directly compare the strengths and weaknesses of each surgical target.

Size of the Target

Size is perhaps the most obvious difference between GPi and STN. The GPi is a much larger (500mm3) target than the STN (200mm3)8-10. The size of the lead and contacts is usually (but not always) identical, despite the large discrepancy in target size. Thus, a smaller target, such as the STN, might be associated with a greater probability of success. Each target is separated into three regions that are roughly equally sized (sensori-motor, limbic, and associative). The goal of the surgery is to implant the lead in the sensori-motor region and to limit current spread into the other 2 areas within the nucleus, because spread into these areas might cause unacceptable side effects. Thus, because the STN is smaller, it may be harder to keep the current sent to this nucleus from spreading into associative, limbic, and adjacent neuroanatomical structures and fiber bundles. Further studies of these nontherapeutic effects are ongoing. Because of these size differences there is an increase in the average charge density required in the GPi target when compared to the STN. Taken together these observations support the potential need for a larger or better suited lead for the GPi target.

Improvement in Dyskinesia and Dystonia

Dyskinesia improves dramatically with both GPi and STN DBS. As suggested by the authors of this study and by others, the mechanism underlying this improvement may be for each target be different11. Although the majority of the anti-dyskinetic benefit of GPi DBS may be due to active stimulation, while the benefits in STN may be as a result of medication reduction. The reasons for these differences remain to be determined. However the anti-dyskinetic effects of GPi DBS seem to be greater than STN DBS.
It is unknown which target is better for PD dystonia, but preliminary experience suggests both may be effective. The recent successes of GPi DBS for primary generalized dystonia have raised the question as to whether GPi is superior to STN for PD dystonia relief, although there is a lack of data at this time to make this determination.

Improvement in Other Parkinsonian Features

DBS in both GPi and STN has been shown effective in improving the cardinal manifestations of PD (tremor, rigidity, bradykinesia, gait disorder)4, 6, 12. DBS in both targets has also been effective in decreasing off time, and in improving motor fluctuations. The majority of published papers suggest STN DBS may be superior particularly in improving motor scores13. There remains however, a lack of comparative trials. The recent report by the DBS for PD study group in 2001 highlights the existing bias to implant the STN target over GPi. Investigators in this study chose target site based on experience and preference only. The bias was reflected when STN DBS was chosen 96 times and GPi only 3813.
Several authors including Anderson et.al. have suggested that STN DBS may be superior in improving bradykinesia. In the current study the baseline bradykinesia score was worse in the STN group (score 18), compared to the GPi group (score 15), and both groups improved to a total score of 10. The difference in the baseline scores in this study could have accounted for this small difference. Thus, more investigation will be needed to answer this question, as well as the question of possible superiority in axial rigidity and gait.
Another difference in GPi and STN DBS may be in the efficacy of tremor improvement. It has been our experience and the experience of others that tremor improves more completely and more consistently with STN DBS. The reasons for this remain unclear. A better understanding of this phenomenon may be gained from exploring the lesion literature where posterior GPi lesions resulted in more tremor benefit. Similarly lesions in different areas of GPi showed differential improvement in specific PD symptoms14. Thus, a lead placed in STN may, based on the size and area it will affect, provide more consistent improvement in tremor, whereas a lead placed in GPi may provide an insufficient area of stimulation, particularly posteriorly. This potential difference will need to be explored.


Medication Reduction

It is now widely accepted that initial medication reduction following surgery is much larger in the STN target5, 6, 13. It will be important in future studies to employ standardized protocols for decreasing doses and medication intervals. Medication reduction should not be the goal of surgery, i.e. if reducing or discontinuing medications makes the patient worse in any PD symptom, reductions should be discontinued. A medication reduction is often required to improve dyskinesia with STN DBS but not GPi DBS. Practitioners should be aware that the initial reports of large-scale medication reductions in STN should be monitored with longer follow-up periods. All of the patients we have treated with STN DBS, who completely discontinued medications, eventually had to restart them. Additionally, many of our patients have required slow increases of dose and interval of medication therapy with disease progression. However, the medication reductions in the STN target constitute an important potential benefit for patients opting for surgery. The long-term differences in medication reduction will require future study.


Cognitive, Behavioral, and Mood Symptoms

Anderson and colleagues point out in their study a potentially important difference between the GPi and STN DBS in the area of cognitive, mood, and behavioral features. Problems in these domains occurred primarily in their STN group. There has been a recent alarm sounded amongst groups implanting DBS with the increasing numbers of reports documenting cognitive, mood and behavioral side effects15-20. Although the initial concern has been with the STN target, as more GPi cases are published, and comparative trials performed, we will get a better idea of these effects with GPi DBS. We have been concerned with leads placed in the STN having the propensity to spread current into associative and limbic regions of the nucleus, as well as into the medial forebrain bundle, zona incerta, lateral hypothalamus, and other regions that have extensive limbic connections. The most concerning side effect reported has been suicide. Currently, our center is randomizing and comparing these targets for mood and cognitive outcomes.


Caution Regarding Interpretation of Comparative Trials of STN and GPi DBS

Comparative studies of GPi and STN DBS will have to be designed to avoid type 2 statistical errors (inadequate power). There are often significant technical difficulties when implanting electrodes in either target and many centers currently have less experience implanting GPi than STN DBS. There also seems to be less of a consensus as to where to place the lead within the GPi. Therefore, large multi-center surgical trials involving several centers that might use different techniques, equipment, patient selection criteria, and have different experience will need to be interpreted with caution.
The issue of microelectrode recording also remains unresolved. An unavoidable weakness of Anderson et. al.’s paper was a delay in the use of microelectrodes on all cases and the failure to use microelectrodes in a systematized fashion. Some groups believe that microelectrodes are unnecessary and increase the surgical hemorrhage risk. We believe however, that given the size of the targets, microelectrodes are necessary to refine implantation and improve outcomes. Further confusing the issue is how they are utilized by different groups. Some use a single or double pass for target verification. We prefer multiple passes in several planes to map borders and construct a three dimensional representation. Still another approach is using many microelectrodes at once, sometimes in a “Ben gun” configuration. The impact of these variables on the therapeutic index is unknown. The impact on the presence or absence of individual team members (particularly a trained neurologist and/or physiologist) in the operating theater is also unknown.

Risk-Benefit Ratio of GPi versus STN

One important deciding factor between GPi and STN DBS will be the incidence of surgical and post-operative complications. Assuming that the rates of the procedure related and device complications are equal, then long-term cognitive, mood, and behavioral problems may become an important consideration.

Depending on what the long-term data reveal about these side effects in GPi and STN DBS, several scenarios are possible. If the motor benefits are equal, but there are many more mood, cognitive, and behavioral side effects with one site versus the other, then the site with less side effects may be a more desirable target. Alternatively, if the motor benefit is greater for one e.g. STN DBS, but the cognitive, mood, and behavioral symptoms are worse, this will constitute a more difficult decision. One factor in this decision that practitioners should consider is that a 10% improvement in UPDRS motor scores (based on a UPDRS score of 50, and looking at the difference between 60% improvement and 50% improvement) of one target over another, may constitute as little as 5 UPDRS points. Will those 5 UPDRS points be worth the risk of a higher complication rate? Further complicating the decision will be other factors including medication reduction, dyskinesia, age, and ease with which side effects can be successfully treated or managed.

The unanswered questions regarding target selection will require several more head to head rematches between GPi and STN. Future improvements in implantation technique and in lead design, may also enhance the benefit in each target. Studies may prove that STN is a better target than GPi, and/or that STN is superior for certain features of disease such as tremor, bradykinesia and medication reduction. Alternatively, studies may also prove that GPi is equal to STN with regard to motor improvements, is a better anti-dyskinesia treatment, but has less cognitive, mood, and behavior side effects. Whatever the outcome, we will need to be open to changes in our current practices, and open to the possibility that individual patient needs will need to be matched to the strengths and weaknesses of individual targets.



References

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Michael S. Okun, M.D.

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