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s deep brain stimulation neuroprotective if applied early in the course of PD? P David Charles*, Chandler E Gill, Thomas L Davis, Peter E Konrad and Alim-Louis Benabid About the authors Correspondence *Department of Neurology, Vanderbilt University Medical Center, A-0118 MCN, Nashville, TN 37232–2551, USA Email [log in to unmask] Parkinson's disease (PD) is a progressive and disabling disorder that affects millions worldwide and is characterized by tremor, bradykinesia, rigidity and balance difficulties. Nonmotor features, including cognitive decline, autonomic disorders and sleep disruption, are present in a considerable minority of individuals with PD and dramatically increase disability. Although PD was first described 200 years ago, we have not yet identified the cause or developed a cure or treatment to slow progression. Hundreds of putative neuroprotective agents have been tested in clinical trials over the past two decades, but none of these agents has been successful at preventing the progression of PD. Deep brain stimulation (DBS) of the bilateral subthalamic nucleus (B-STN) is a safe, effective and cost-effective treatment for the motor symptoms of advanced PD,1, 2 and recent literature has suggested that DBS may also provide a neuroprotective benefit.3, 4 We believe that DBS will be the first therapy proven to slow PD progression, and that it must be applied in the earliest stages of the disease to have such an effect. Pioneered at the University of Grenoble in the 1980s, B-STN DBS provides long-term symptomatic benefit and improves quality of life for many patients with PD.2, 5 However, despite the technique's widespread use, we do not fully understand its mechanism of action—neither the proven symptomatic benefit nor the potential neuroprotective effect. Several theories have been proposed to explain the neuroprotective properties of DBS. One such theory is based on the idea that PD develops after initial injury to the substantia nigra, mainly its pars compacta, causing the substantia nigra to become hypoactive. Other areas of the basal ganglia, including the STN, become hyperactive as a result of loss of inhibition. The STN is the main relay of the indirect pathway of the basal ganglia; it influences motor output through the globus pallidus internus and substantia nigra. The hyperactive STN may promote glutamate excitotoxicity, further accelerating dopaminergic cell death in the substantia nigra. It has been proposed that high-frequency B-STN DBS alters STN activity, resulting in the removal of a source of toxic glutamate input to the substantia nigra, which in turn leads to the preservation of dopaminergic cells. Two recent reports provide evidence in support of this theory. Temel et al. found that B-STN DBS protected nigral neurons in the 6-hydroxydopamine rat model of PD—cell loss in the substantia nigra of DBS-treated animals was 28– 30% lower than that in controls.4 The animals received DBS during ongoing neurodegeneration, which more accurately represents clinical practice than previous animal experiments in which lesioning or stimulation was performed before treatment with 6-hydroxydopamine. Kainic-acid-induced lesion of the STN also reduces the loss of nigral dopaminergic cells in the 6-hydroxydopamine rat model,6 supporting the hypothesis that DBS at high frequency has inhibitory effects. Wallace and colleagues made similarly exciting observations when using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in primates. These authors found that STN stimulation both before and after MPTP injury prevented further neuronal loss (MPTP-treated animals that received STN stimulation had 20% more dopaminergic cells in the substantia nigra than animals that did not receive stimulation).3 In this study, kainic-acid-induced lesion of the STN also had neuroprotective effects that were comparable to those of STN DBS. Clinical results, on the other hand, are conflicting. During the initial clinical trials that investigated the efficacy of DBS in PD, some patients seemed to stabilize after implantation of the DBS electrodes (AL Benabid, unpublished data). A more-recent trial of DBS in patients with advanced PD confirmed this observation,7 although neuroprotection was not a stated end point. The authors noted no significant clinical deterioration during 4 years of DBS therapy,7 which is clearly different from the expected natural progression of PD. Many trials, however, have noted clinically and statistically significant deterioration of motor symptoms after initiation of DBS therapy. For example, off-medication Unified Parkinson Disease Rating Scale motor scores of the first 49 patients who were treated with DBS therapy in Grenoble deteriorated by 7 points from year 1 to year 5 of the follow-up period.2 In 2005, Hilker et al. used serial 18F-fluorodopa PET as a surrogate marker for disease progression and found that dopaminergic function had continued to decline in patients with advanced PD after 16 months of clinically effective B-STN DBS therapy.8 Several factors limit the capacity of the clinical results to date to rule out DBS as a neuroprotective therapy. First, continued functional decline does not eliminate the possibility of positive disease modification—it only eliminates the possibility that DBS might result in a complete halt in progression. Furthermore, none of the studies so far has included a control group that was treated with standard drug therapy, and, thus, progression rates between the two groups have not been compared. An additional limitation is that all studies to date have been in patients with features of advanced PD, including motor complications of therapy. A majority of nigral neurons have died by the time patients with PD first present to a neurologist. Currently, patients do not receive DBS therapy until they have developed intractable symptoms and motor complications of therapy; electrode implantation both in clinical trials and in standard of care takes place at an average of 11 years after diagnosis, at which point considerable cell death has occurred, and potentially neuroprotective strategies are unlikely to demonstrate a clear benefit. Animal data seem to be in agreement with this view; in general, studies that report a lack of neuroprotection with the use of DBS have employed extensive neurological injuries to model PD (resulting in the death of 75–90% of all nigral cells), whereas other authors who have induced lesser injuries have found positive results.3, 9 A nigral cell death rate of 85% is representative of a patient with advanced disease who receives DBS through current standard of care, whereas a nigral cell death rate of 50% is representative of a patient in the earliest symptomatic stages. The fact that studies to date have tested the therapy in patients with advanced disease may partially explain why many of these trials have failed to document neuroprotection.2, 8 We believe that DBS slows the progression of PD, and we are currently conducting a pilot clinical trial of B-STN DBS in early-stage PD (ClinicalTrials.gov identifier NCT00282152), collecting preliminary data necessary to launch a multicenter phase III trial to definitively test this hypothesis. When designing our pilot study, we took into account several lessons from previous DBS and neuroprotection trials. Only patients with early-stage disease, who hold the greatest potential for disease modification, will enroll. They must be in Hoehn and Yahr stage II, have been on anti-PD medications for less than 4 years, and cannot have developed motor fluctuations. The trial is designed as a single-blind, randomized, parallel-group study, with 30 patients randomized to either optimal drug therapy alone or optimal drug therapy plus B-STN DBS. Patients undergo 8-day inpatient evaluations at baseline and at 6-month intervals for 2 years. During each evaluation, medications and stimulation are withdrawn and motor scales are administered daily. The purpose of this design is to fully characterize the washout of stimulation plus medication versus the washout of medication alone, and to determine the minimum time necessary for patients to remain off drugs or stimulation to assess underlying disease. The data from this trial will provide essential information for the design of any phase III trial that will test neuroprotection. If our data support the safety of DBS in early PD, the current study will be extended into a delayed-start design, with surgery offered to patients in the drug therapy only arm 3 years after original randomization. While our trial addresses many criticisms of recent neuroprotection and DBS trials, there are considerable hurdles to overcome before any therapy can be definitively proven to modify human disease progression. Most notable are the lack of an accepted biomarker of PD progression,10 and the difficulty in separating symptomatic benefit from actual prevention of cell death and from the maintenance or facilitation of mechanisms that compensate for the loss of dopaminergic neurons. These barriers may take years to overcome. Being able to prove that a therapy halts or slows progression of clinical symptoms, however, is a worthwhile and achievable goal. Our hypothesis is bold and ambitious and, if correct, would enable achievement of a goal held by both physicians and patients. Any treatment for PD that proves to be neuroprotective will be applied as soon as the diagnosis is reasonably confirmed. These clinical trials represent the essential steps toward finally developing a treatment that slows this relentlessly progressive and disabling illness. http://www.nature.com/ncpneuro/journal/v4/n8/full/ncpneuro0848.html ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn