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Spencer K. Hutto, M.D. Department of Neurology, Emory University Journal Club August 19, 2016 Speaker Disclosure • I have no potential conflicts of interest to report • No one is even paying me to talk to you today; this is of my own free will without coercion (sort of) Study Question • Do patients with early Parkinson’s Disease benefit from neurostimulation? • Early: • Younger patient age (mean roughly 52-53 years old) • Decreased overall duration of disease (mean 7.5 years) • Decreased duration of motor complications (mean 1.7 years) • Neurostimulation has traditionally been used for patient’s with advanced Parkinson’s disease • In seminal article, mean age 60-61 years old, mean duration of disease of 11.1-13.8 years, and on levodopa for 13-14 years Authors and Potential Sources of Bias • Medtronic provided some degree of funding (major supplier of DBS hardware) • Majority of authors associated with Medtronic (receipt of lecture fees, payment for educational programs, travel support, grant support, consulting fees) as well as the broader pharmaceutical industry BACKGROUND Background • Parkinson’s Disease • Clinical syndrome of bradykinesia, rigidity, tremor, and shuffling gait produced by depletion of dopaminergic neurons in the substantia nigra pars compacta projecting to the striatum of the basal ganglia • Sinemet (carbidopa/levodopa) typically works well early in the disease course though later complicated by motor fluctuations (on/off phenomenon, dyskinesias) • DBS is a surgical therapeutic option usually reserved for advanced cases Deep Brain Stimulation – How It Works • Nobody knows for sure (McIntyre and Hahn 2010) • Originally thought to be due to direct effect of electrodes on the local circuitry rather than an alteration to the network itself (cortico-basal ganglia-thalamo-cortical) • Paradigm now shifting to electrode-induced network changes • Induces changes to the way groups of neurons fire (rate, oscillatory pattern [regular/irregular], burst patterns) • PD associated with beta activity within the basal ganglia, likely as result of the striatum’s impaired ability in the low dopamine state to filter out beta activity from the motor cortex (anti-Parkinsonian meds improve this defect) • STN stimulation produces effects on the hyper-direct pathway as well to regulate the overall network from a cortical perspective Deep Brain Stimulation - Procedure • Electrodes implanted in the STN or the GPi with assistance of MRI, microelectrode recording, and exam • Greater mean decrease in anti-Parkinsonian medications with STN implants in comparison to GPi implants; dyskinesias only improved owing to effect of medication reduction • STN also an area where multiple motor loops of the network converge on a single focused area with separation from non-motor loops; smaller in size than the GPi, requiring less energy demands on the generator • GPi implantation may provide better control over dyskinesias independent of medication changes • No significant difference between the rate of complications for STN vs GPi implantation • Multidisciplinary team required for effective implantation (neurology, neurosurgery, neuropsychiatry, neuroradiology, neurocritical care) Rationale for Deep Brain Stimulation • Waning temporal effectiveness of medical therapy • Surgery effectively targets the GPi/STN, improving bradykinesia and reducing dyskinesias frequently associated with Sinemet • The DBS device is programmable (VA-NIH) in terms of voltage, pulse width, and stimulation frequency (within limits of maximal charge-density) • Must weigh against risks associated with implantation: infection, hemorrhage, failure of generator/leads • Must also consider the cost: • £468,528 per quality-adjusted life year during the 1st year following implantation, £45,189 by year 5, and £70,537 by year 10 METHODS Patient Inclusion Criteria • Ages 18 to 60 • Improvement of motor signs by at least 50% with dopaminergic • • • • • medications (UPDRS*-III) Disease duration of 4 years or more Scores of more than 6 for ADLs in the worst condition despite medication treatment (UPDRS*-II) Disease severity on medication rating below stage 3 (Hoehn and Yahr scale) Fluctuations or dyskinesia present for 3 years or less Mild-to-moderate impairment in social and occupational functioning (Social and Occupational Functioning Assessment Scale) * Unified Parkinson’s Disease Rating Scale Patient Exclusion Criteria • Necessity of determining whether or not patients had typical Parkinson’s disease • Disease duration less than 4 years • Conditions that may impact conduction of study: • Dementia • Major depression with suicidal thoughts • Acute Psychosis • Any other major medical or psychological problem that would interfere with the conduction of study protocol (exact meaning not specified by article) Study Design • Randomized, multicenter, parallel-group, prospective design with centralized data collection and analysis for two year period • Randomized to neurostimulation and medical therapy vs. medical therapy alone • Neurostimulation group underwent bilateral stereotactic surgery of the STN within 6 weeks of randomization • Implantations of electrodes (model 3380, Medtronic) and a pulse generator (Kinetra or Soletra, Medtronic) Study Design • Regular assessments – baseline, 5, 12, and 24 months • Preoperative and postoperative standardized video assessments by experts (with exception of rigidity) • Adjustments to medication and stimulation performed at follow-up according to pre-defined standards Outcome Measures • Primary end point: between group difference in mean change in quality of life from baseline to 2 years (PDQ-39) • Secondary end points (tested sequentially if primary end point found to be significant): • ADLs (UPDRS-II score) • Severity of motor signs (UPDRS-III score) • Severity of treatment-related complications (UPDRS-IV score) • Time with good mobility and no troublesome dyskinesia (patient diary) • Several additional minor secondary outcomes recorded Adverse Events • Defined as any events leading to death, disability, or prolonged or new hospitalization with serious health impairment RESULTS Definitions • Intention-to-treat population – analysis of the entire patient population completing randomization, regardless of if they drop-out or cross-over, with last values carried forward • Per-protocol population – analysis of only those patients completing the study in the portion they were originally randomized to Patient Characteristics • 392 patients assessed; 251 enrolled • 124 assigned to neurostimulation group (120 implanted and completed study) • 127 to the medical-therapy group (123 completed study) • No significant differences in baseline patient characteristics • 25 patients with major protocol deviations • PDQ-39 assessment outside the window, absence of motor fluctuations or dyskinesia, insufficient exposure to treatment, death during study period Primary Outcome on Quality of Life • Neurostimulation • Intention to treat – improved by 26% • Per-protocol – improved by 27% • Medical therapy alone • Intention to treat - declined by 1% • Per-protocol – stable at 0% change QoL: PDQ-39 • Maximum effect achieved at 5 months • All subcomponents show improvement in favor of neurostimulation with exceptions of social support and communication (roughly same as medical therapy) Major Secondary End Points • Severity of motor signs off-medication (UPDRS-III) • Neurostimulation: 53% improvement • Medical therapy: 4% improvement • Mean difference between groups: 16.4 points on UPDRS-III scale • Levodopa-induced complications (UPDRS-IV) • Neurostimulation: 61% improvement • Medical therapy: 13% decline • Mean difference between groups: 4.1 points on UPDRS-IV scale Major Secondary End Points • ADLs in the worse condition (UPDRS-II) • Neurostimulation: 30% improvement • Medical therapy: 12% decline • Mean difference between groups: 6.2 points on UPDRS-II scale • Notably no significant difference when queried on ADLs in the best condition (minor secondary end point) • Time with good mobility and no troublesome dyskinesia • Neurostimulation: 20% improvement • Medical therapy: 2% improvement • Mean difference between groups: 1.9 hours Selected Minor Secondary End Points • Levodopa-equivalent Daily Dose • Neurostimulation: 39% reduction • Medical therapy: 21% increase • Mean difference between groups: 609 mg • No significant differences noted on cognitive assessments (Mattis Dementia Rating Scale or UPDRS-I) • Positive effects noted on mood for the neurostimulation group per the Montgomery and Asberg Depression Raing Scale (administered by examiner) and Beck Depression Invenotry II (patient completed) Adverse Events • Increase in serious adverse events with neurostimulation • Other serious adverse events related to medicine decreased with neurostimulation • Suicide (2 neurostimulation, 1 medical therapy) • Depression more frequent in the neurostimulation group • Motor problems, impulse control disorders, and psychotic manifestations more common in the medical therapy group DISCUSSION Author’s Discussion • Findings of the study were clinically relevant as: • 26% statistically significant improvement in the primary outcome, felt to represent clinically significant outcome as well • Similar to improvement noticed in prior study on patients with advanced PD (25% improvement) • Patients benefited with neurostimulation even while medication was still effective • Felt secondary to the benefit seen in the neurostimulation group as opposed to any deterioration in the medical therapy group Author’s Discussion • More frequent adverse events in the neurostimulation group, principally due to an increase in mild adverse events • Frequency of suicidal behavior high but no significant difference between groups • Strengths of study: • Strict standards for interventions • Small number of withdrawals • Consistency between results of intention-to-treat and per-protocol analyses CRITICAL APPRAISAL Validity • Randomization: • Patient’s were randomized though allocation difficult to conceal in the setting of surgery as the intervention • Patient’s were analyzed via both intention-to-treat and per-protocol methods with comparisons made between analyses • Follow-up was nearly complete for the patient population (only 8 patients did not complete the study out of 251 [3.2%]) • Per-protocol analysis included 116 patients in the neurostimulation group (8 fewer) and 110 in the medicaltherapy group (17 fewer) for a total of 25 major protocol deviations Validity • Evaluators were blinded while reviewing the standardized video encounters • With that noted, it was impossible to blind the patients (due to surgery) • Patients otherwise received equal treatment in terms of medical therapy according to strict guidelines with outside review of adherence to protocol • No major differences in baseline patient characteristics at the start of the trial Conclusions • Notable and extensive conflicts of interest in many of the study investigators • Interesting study question though faced with difficulties related to cost and durability of equipment • Study conducted in a highly regulated fashion in the best way possible given limitations of surgical intervention and inability to blind patients • Methods of intervention effect evaluated by current gold standards utilized for Parkinson’s disease interventions (PDQ-39, UPDRS) • Difficult to know exactly how clinically significant QoL findings were • Significant benefits achievable with comparable degree of adverse events experienced when DBS studied for advanced PD Implications • Probably would not push for early DBS placement in my patients with Parkinson Disease due to following: • High cost per QALYs early in device placement with risk for declining cost effectiveness in future • QoL benefit only truly known for the first two years; with that said, the primary outcome trend after the two years was toward worsening QoL with stability noted for the medication group • Study subject to potential patient bias given the main outcome measure is a patient completed questionnaire in the setting of a nonpatient blinded study • With that said, I may be inclined to consider it with the following reservations: • • • • Early development of Sinemet-induced side effects Potential candidacy for future DBS placement Patient’s ability to mitigate financial/energy/time drains Possibility for durability of equipment with understanding that surgically-related complications and need for re-operation may arise Future Directions • Additional research certainly necessary in terms of DBS durability, its effectiveness, and effect on QoL over time • Cost/benefit analysis of earlier implantation given milder symptoms in the patients enrolled in this study • Research directed at bilateral implantation as centers today predominantly implant unilaterally • Additional DBS studies related to its effect on mood Resources • Anderson WS, Lenz FA. Surgery Insight: deep brain stimulation for movement • • • • • • disorders. Nature Clinical Practice Neurology Nat Clin Pract Neurol. 2006;2(6):310-320. doi:10.1038/ncpneuro0193. Deuschl G, Schade-Brittinger C, Krack P, et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med 2006;355:896-908. Mcintosh E, Gray A, Daniels J, et al. Cost-utility analysis of deep brain stimulation surgery plus best medical therapy versus best medical therapy in patients with Parkinson's: Economic evaluation alongside the PD SURG trial. Movement Disorders. 2016;31(8):1173-1182. doi:10.1002/mds.26423. Mcintyre CC, Hahn PJ. Network perspectives on the mechanisms of deep brain stimulation. Neurobiology of Disease. 2010;38(3):329-337. doi:10.1016/j.nbd.2009.09.022. Okun MS, Zeilman PR. Parkinson's Disease: Guide to Deep Brain Stimulation Therapy. Parkinson's Disease: Guide to Deep Brain Stimulation Therapy. 2014. Schuepbach W, Rau J, Knudsen K, et al. Neurostimulation for Parkinson’s Disease with Early Motor Complications. N Engl J Med 2013; 368:610-622. Tarsy D. Surgical Treatment of Parkinson Disease. UpToDate. http://www.uptodate.com/contents/surgical-treatment-of-parkinson-disease. Published May 19, 2015. Accessed August 14, 2016. Acknowledgements • Jorge Juncos, M.D. – Faculty Advisor • Mary Beth Ramsey, M.D. – Senior Advisor • David Pearce, M.D. – Chief of Education