Surgical Treatment of ParkinsonDisease: Past, Present, and Future

Andrew P. Duker, MD*, Alberto J. Espay, MD, MSc

KEYWORDS

� Parkinson disease � Deep brain stimulation � Patient selection� Beta band oscillations

KEY POINTS

� The surgical treatment of Parkinson disease (PD) has progressed from destructive and le-sional procedures to focused and targeted brain stimulation.

� The effects of deep brain stimulation (DBS) typically mirror the benefits of levodopa, how-ever with the benefit of reducing motor fluctuations and off time, as well as decreasingdyskinesia.

� The 2 main targets for DBS in PD, the subthalamic nucleus (STN) and internal segment ofthe globus pallidus (GPi), appear to give similar outcomes, although individual patient fac-tors and surgeon expertise may be important.

� Developing concepts in DBS, including closed loop paradigms and segmented elec-trodes, promise to further refine this therapy.

INTRODUCTION

The surgical treatment of Parkinson disease (PD) has evolved sporadically over thepast century. Early attempts at relieving parkinsonian symptoms included bilateralposterior cervical rhizotomy by Leriche in 19121 and later by others in an attempt toimprove rigidity and tremor. Later surgeries focused on interruption of the pyramidaltracts (motor cortex,2 cervical spinal cord,3 and cerebral peduncle).4 Surgery on the

Disclosures: Dr Duker has nothing to disclose. Dr Espay is supported by the K23 career devel-opment award (NIMH, 1K23MH092735); has received grant support from CleveMed/GreatLakes Neurotechnologies and Michael J Fox Foundation; personal compensation as a consul-tant/scientific advisory board member for Solvay (Abbot/Abbvie), Chelsea Therapeutics,TEVA, Impax, Merz, Solstice Neurosciences, Eli Lilly, and USWorldMeds; and honoraria fromNovartis, UCB, TEVA, the American Academy of Neurology, and the Movement Disorders Soci-ety. He serves as Associate Editor of Movement Disorders and Frontiers in Movement Disordersand is on the editorial board of The European Neurologic Journal.Department of Neurology and Rehabilitation Medicine, James J. and Joan A. Gardner Centerfor Parkinson’s Disease and Movement Disorders, University of Cincinnati Neuroscience Insti-tute, University of Cincinnati, 260 Stetson Street, Suite 2300, Cincinnati, OH 45267-0525, USA* Corresponding author.E-mail address: Andrew.Duker@uc.edu

Neurol Clin 31 (2013) 799–808http://dx.doi.org/10.1016/j.ncl.2013.03.007 neurologic.theclinics.com0733-8619/13/$ – see front matter � 2013 Elsevier Inc. All rights reserved.

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basal ganglia for PD, particularly the pallidofugal fibers, was initially explored byMeyers in 1951,5 and given support by the favorable outcome on a parkinsonian pa-tient whose anterior choroidal artery was serendipitously ligated by Cooper when per-forming a pedunculotomy.6 With the advent of stereotactic surgery, reports by Spiegeland colleagues7 and others on the benefits of pallidotomy began to surface, and even-tually thalamotomy was found to reduce parkinsonian tremor. In the 1960s, levodopawas found to dramatically improve the symptoms of PD8 and there was a temporaryhiatus in the surgical treatment of PD. Despite the profound efficacy of levodopa, com-plications, such as dyskinesias and motor fluctuations, prompted a renewed interestin the surgical treatment of PD in the early 1990s, primarily through the previously usedlesional surgeries. Although stimulation of the deep structures of the brain had beenperformed previously,9 the modern era of chronic deep brain stimulation (DBS) wasled by the reports of Benabid and colleagues,10 first of the ventral intermediate nu-cleus of the thalamus (Vim), then later the subthalamic nucleus (STN)11 and the internalsegment of the globus pallidus (GPi).12 Thalamic DBS was approved by the US Foodand Drug Administration in 1997 for the treatment of tremor associated with essentialtremor and PD, and STN and pallidal DBS in 2002 for the treatment of PD. In a shorttime, DBS became an established treatment for advanced PD. Evidence has accumu-lated supporting the long-term efficacy of DBS, and at the same time new technologyhas continued to refine the procedure.

Case study

A 66-year-old man presents to the Movement Disorders Center for evaluation and treatment ofworsening symptoms from his PD. He had the onset of right-hand resting tremor at the age of58 years, followed by micrographia, decreased dexterity when typing, then later slowness andshuffling of gait. He ultimately had good improvement with levodopa for several years. Overtime, however, the duration of benefit from his medication doses shortened, and he requiredincreasing doses of medication to obtain the same benefit. Adjunctive medications including acatechol-O-methyl transferase inhibitor, dopamine agonist, and a monoamine oxidase-B inhib-itor yielded modest improvement, but motor fluctuations became progressively more difficultto control, alternating between “on” periods with good function and “off” periods marked byfreezing of gait and near-immobility. Sleep was disrupted by painful off-period symptomsreturning in the middle of the night. Moderate to severe dyskinesia complicated his func-tioning in the “on” periods, partially attenuated by the addition of amantadine. Depressionwas present but adequately treated with an antidepressant.

PATIENT SELECTION

The Core Assessment Program for Intracerebral Transplantations (CAPIT) was devel-oped and published in 1992,13 in an attempt to standardize patient selection, inclu-sionary criteria, and reporting of outcomes in studies of intracerebral transplantation(originally, fetal dopamine neurons). This protocol was later updated and adapted toboth ablative and neurostimulation procedures in the Core Assessment Program forSurgical Interventional Therapies (CAPSIT) protocol.14 From this protocol, and withexperience over time, a set of standardized evaluations have evolved, identifying can-didates who will derive lasting benefits from the procedure, while being cognitively,emotionally, and socially prepared for DBS.15 It is important for centers to evaluatepatients in a standardized fashion to accurately identify those patients in whom thebenefits of the surgery will outweigh the potential risks. A decision-making algorithmmay be helpful (Fig. 1).DBS performed in a patient with an atypical parkinsonism may not benefit and, in

fact, may accelerate the symptomatic decline of these conditions.16 Therefore, a

Fig. 1. Decision-making algorithm for patient selection for DBS surgery in PD.

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diagnosis of idiopathic PD is a prerequisite for consideration of functional neurosur-gery. Disability that requires consideration for DBS after a disease duration of 5 yearsor less suggests the presence of a PD mimic, most often an atypical parkinsonism,such as the parkinsonian variant of multiple system atrophy. A preoperative evaluation

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of levodopa responsiveness is mandatory, with a 33% decrease in the Unified Parkin-son’s Disease Rating Scale (UPDRS) part III motor score often suggested as thethreshold beyond which surgical benefits materialize. DBS mostly benefits symptomsthat are improved with levodopa, with the possible exception of medication-resistanttremor (in which benefit from DBS may exceed that of medication). The presurgicalevaluation helps to establish a patient’s realistic expectations from surgery.Preoperative cognitive assessments should be performed to exclude patients with

dementia. In addition, behavioral assessments are necessary to identify significantdepression, given the small but serious risk of attempted suicide reported in somecases.17 Finally, a sufficient social support network is essential to help care for the pa-tient during the postoperative and stimulation titration process, which can take severalmonths.An “appropriate DBS candidate” may come from 3major categories. The previously

mentioned case, a cognitively intact patient with idiopathic PD, good response tolevodopa, but with motor fluctuations, including shortened duration of benefit fromthe medication and bothersome dyskinesia despite optimal medical management,should be considered for DBS. Alternatively, a patient with well-controlled PD exceptfor medication-resistant tremor may also benefit from the procedure. Finally, patientswith poor symptom control because of inability to tolerate adequate doses of levo-dopa may also benefit from surgical intervention. Except in the latter, less commonscenario, response to levodopa remains the best predictor for surgical response, asmagnitude of benefit to DBS matches but does not outperform that of levodoparesponse.

SURGICAL TARGET SELECTION

Thalamic stimulation is effective at reducing tremor in PD, and although the benefit issustained, Vim DBS does not address bradykinesia or other PD symptoms, whichinvariably progress over time.18,19 Preferred targets include the STN and GPi, andthe choice between them depends on individual patient factors and the experienceof the surgeon. STN stimulation has consistently across studies been shown to allowfor greater reduction in dopaminergic medication postoperatively. GPi stimulation isoften more effective at reducing dyskinesia directly, unaccounted for by a reductionin dopaminergic medications. Although there is some suggestion that GPi DBS is“safer” from a neurocognitive standpoint,20 leading some to suggest this target forcognitively impaired patients who are otherwise good candidates,21 controlled clinicaltrials have not demonstrated significant cognitive differences in outcomes betweenthe 2 targets.

OPERATIVE PROCEDURE

The location of the surgical target is typically chosen preoperatively on magnetic reso-nance imaging (MRI) by the neurosurgeon, based on visual landmarks. Coregistrationwith a standardized brain atlas can also be used. Brain mapping software determinesthe 3-dimensional coordinates of the target, which can then be entered into a framesecured to the patient’s skull. If a frameless system is used, the angle and depth ofthe target is calculated with respect to skull fiducial markers. After burr hole place-ment, a microelectrode is slowly passed along the trajectory, and the depth of thetarget is identified based on microelectrode recording. The stimulating macroelec-trode is then placed (Fig. 2) and tested intraoperatively to verify the threshold forside effects (depending on the target, these can include paresthesias, muscle contrac-tion, conjugate eye deviation, visual phosphenes). The macroelectrode is secured into

Fig. 2. Intraoperative placement of the DBS electrode.

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position and the contralateral target is approached in a similar manner if a bilateral pro-cedure is being performed. The electrodes are then connected to an implantable pulsegenerator (IPG), often in a separate procedure.

POSTOPERATIVE PROGRAMING

Initial programing of the DBS stimulators often takes place several weeks after implan-tation, to permit the “lesion effect” of improved function following lead implantation todissipate, allowing for easier identification of symptoms and improvements fromstimulation. The quadripolar electrode has contacts spaced 1.5 mm or 0.5 mm apartdepending on the lead used, and stimulation can be delivered in a monopolar (oneactive electrode contact as cathode with the IPG as anode) or bipolar (different elec-trode contacts used for both cathode and anode) fashion. Themost effective electrodecontact configurationgives thegreatest benefitwith the least amountof sideeffects dueto current spread to surrounding structures. Stimulation amplitude is started at a lowsettingand increasedgradually over time,whichcanallow for a reduction inmedication.Programing optimization can take up to 4 to 6 months andmay require multiple adjust-ment sessions.

OUTCOMES

STN and GPi DBS have been shown in several randomized controlled clinical trials tobe superior to medical management alone.22–24 Patients receiving DBS gained onaverage 4.4 to 4.6 hours of “on” time without troublesome dyskinesia, had 1.0 to2.6 fewer hours per day of “on” time with troublesome dyskinesia, and 2.4 to 4.2 fewerhours per day of “off” time. Quality of life, off-medication UPDRS motor scores, andsleep have also been reported to improve. Recent randomized trials comparingSTN to GPi DBS showed no differences in motor function between groups, in both uni-lateral25 and bilateral26 stimulation. Given the similar outcome, it has been recommen-ded that individual patient factors (eg, STN if greater medication reduction is desired,GPi if greater antidyskinetic effect is pursued) and surgeon preference dictate targetselection. Another randomized trial did find a significant difference in motor scoresas a secondary outcome favoring STN compared with GPi DBS, but no differencein the primary outcomes of functional health (disability score) or cognitive, mood, orbehavioral effects.27

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DBS COMPLICATIONS

The incidence of serious adverse events related to DBS varies depending on the study.In 3 large multicenter trials,24,26,27 intracranial or intracerebral hemorrhage occurred in2% of patients, ischemic stroke in 0% to 1%, implantation site infection in 3% to 8%,and seizures in 0% to 3%. A postoperative confusional state was also seen in up to21% in one of the trials,26 although this required additional hospitalization in only2%. Lead fracture and device malfunction are also possible complications, whichcan cause loss of clinical benefit.28

The prevalence of suicidal ideation may increase after DBS, with a multicenterretrospective survey finding a rate of 0.90% suicide attempts and 0.45% suicidecompletions.29 Declines in cognition in longitudinal follow-up have been docu-mented30,31; however, it remains unclear whether DBS hastens this decline. Smallerseries initially suggested that DBS may have a negative impact on frontal executivefunctioning, in some patients leading to a “mental state comparable to progressivesupranuclear palsy.”32 However, larger studies comparing patients receiving DBSto best medical management found overall cognitive scores (eg, Mattis dementiarating scale) to be similar, although found declines in verbal fluency (both semanticand phonemic), working memory, and processing speed.23,33 Verbal fluency hasbeen the most consistently decreased outcome following STN DBS across manystudies and meta-analyses.34

EMERGING CONCEPTSAxial Features of PD

Although DBS is very helpful in reducing motor fluctuations and dyskinesia, it may beless effective in treating certain axial symptoms, such as freezing of gait and falls, and,indeed, these symptoms are often less responsive to dopaminergic therapy as well.DBS of the pendunculopontine nucleus (PPN), known from animal research to be animportant center for locomotion, has been studied as one treatment approach forthese resistant symptoms. Thus far, data from only small open-label trials are avail-able,35–38 and although all of the trials reported improvement in duration of freezingand falls, blinded assessments in one trial37 did not show improvements. Limiting fac-tors in these studies were the small sample size (4–6 patients in each study) and thechallenge of targeting a location that can be difficult to visualize on MRI sequencesand does not as of yet have a clearly defined microelectrode recording signature.Further research is needed to determine if the PPN will fulfill the promise of a targetto improve postural instability and other axial symptoms.

Early Versus Late DBS

AlthoughDBS is currently recommended for patientswithPDwith at least 5 years of dis-ease duration and motor disability that does not improve with optimization of medica-tion therapy, there has been growing interest in examining whether earlier implantationof DBSmay be associatedwith larger and longer-lasting improvements in quality of life,before social and occupational activities are threatened.39 A recent clinical trial of251 patients with PD and “early” motor complications (after a mean disease durationof 7.5 years) randomized to STN DBS plus medical therapy or medical therapy alone,demonstrated greater quality of life, asmeasured by theParkinson’sDiseaseQuestion-naire (PDQ-39), in the DBSplusmedical therapy group after 2 years, comparedwith themedical therapy alone group.40 However the definition of “early” has been subject todebate and the long-termefficacy (andpotential diseasemodification) of earlier implan-tation remains unknown.

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Intermediate-Frequency Stimulation

High-frequency stimulation has long been held as the necessary mechanism for DBS-based improvement since it was first investigated.10 Later research confirmed thatstimulation frequencies more than 130 Hz were the most effective in the STN.41 Fre-quencies less than 20 Hz appear to worsen bradykinesia,41,42 but there is some evi-dence that frequencies in the 60-Hz to 80-Hz range could improve freezing andgait,43 although the duration of this benefit may be transient.44

Rate Versus Pattern of Neuronal Firing

Updated models of basal ganglia physiology suggest that motor benefit from DBSresults fromchanges in the pattern of neuronal firing, particularly related to the synchro-nicity of intrinsic neuronal oscillations in thebasal ganglia, rather than simple changes tothe firing rate.45 This synchronicity can manifest as an increase in the power of specificfrequencies of local field potentials (LFPs) when recording from particular nucleiwithin the basal ganglia. In theSTNandGPi, LFPoscillations in the beta band frequency(11–30 Hz) are associated with worsened motor function in the off-medicationstate,46 and the power of these oscillations is attenuated by voluntary movement,and dopamine,47,48 suggesting that the beta band may be “pathologic” in PD. It hasbeen demonstrated that DBS also attenuates the beta band synchrony,49 leading toresearch into “closed-loop” or adaptive DBS.50 Suppression of oscillatory activitythrough a closed-loop paradigm was more effective than standard open-loop stimula-tion in controlling parkinsonian motor symptoms in the MPTP-treated African greenmonkey.51 Other advances in DBS technology, such as segmented electrodes, mayprovide the ability to “steer” the direction of stimulation and shape the electrical fieldto better encompass desired structures but exclude spread to fibers contributing toside effects of stimulation.52,53

SUMMARY

DBS surgery is a very effective treatment for the appropriately selected patient with PDand can afford decreased motor fluctuations, reduced “off” time, and improvement indyskinesia. Outcomes for STN and GPi targets appear to be largely similar, and thechoice of target is best made based on individual patient factors and surgeon prefer-ence. The inner workings of the basal ganglia, or the “dark basement” of the mind asWilson referred to them,54 are slowly yielding their secrets, led in large part by researchbased on surgically implanted patients. Adaptive, “closed-loop” DBS and new tech-nologies, including segmented electrodes, may help to further refine and improvethis procedure.

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