Anna L. Molinari

Subthalamic nucleus deep brain stimulation in early stage Parkinson's disease.

BACKGROUND Deep brain stimulation (DBS) is an effective and approved therapy for advanced Parkinsons disease (PD), and a recent study suggests efficacy in mid-stage disease. This manuscript reports the results of a pilot trial investigating preliminary safety and tolerability of DBS in early PD. METHODS Thirty subjects with idiopathic PD (Hoehn & Yahr Stage II off medication), age 50-75, on medication ≥6 months but ≤4 years, and without motor fluctuations or dyskinesias were randomized to optimal drug therapy (ODT) (n = 15) or DBS + ODT (n = 15). Co-primary endpoints were the time to reach a 4-point worsening from baseline in the UPDRS-III off therapy and the change in levodopa equivalent daily dose from baseline to 24 months. RESULTS As hypothesized, the mean UPDRS total and part III scores were not significantly different on or off therapy at 24 months. Medication requirements in the DBS + ODT group were lower at all time points with a maximal difference at 18 months. With a few exceptions, differences in neuropsychological functioning were not significant. Two subjects in the DBS + ODT group suffered serious adverse events; remaining adverse events were mild or transient. CONCLUSIONS This study demonstrates that subjects with early stage PD will enroll in and complete trials testing invasive therapies and provides preliminary evidence that DBS is well tolerated in early PD. The results of this trial provide the data necessary to design a large, phase III, double-blind, multicenter trial investigating the safety and efficacy of DBS in early PD.

Pilot Study Assessing the Feasibility of Applying Bilateral Subthalamic Nucleus Deep Brain Stimulation in Very Early Stage Parkinson's Disease: Study design and rationale

BACKGROUND Deep brain stimulation provides significant symptomatic benefit for people with advanced Parkinsons disease whose symptoms are no longer adequately controlled with medication. Preliminary evidence suggests that subthalamic nucleus stimulation may also be efficacious in early Parkinsons disease, and results of animal studies suggest that it may spare dopaminergic neurons in the substantia nigra. OBJECTIVE We report the methodology and design of a novel Phase I clinical trial testing the safety and tolerability of deep brain stimulation in early Parkinsons disease and discuss previous failed attempts at neuroprotection. METHODS We recently conducted a prospective, randomized, parallel-group, single-blind pilot clinical trial of deep brain stimulation in early Parkinsons disease. Subjects were randomized to receive either optimal drug therapy or deep brain stimulation plus optimal drug therapy. Follow-up visits occurred every six months for a period of two years and included week-long therapy washouts. RESULTS Thirty subjects with Hoehn & Yahr Stage II idiopathic Parkinsons disease were enrolled over a period of 32 months. Twenty-nine subjects completed all follow-up visits; one patient in the optimal drug therapy group withdrew from the study after baseline. Baseline characteristics for all thirty patients were not significantly different. CONCLUSIONS This study demonstrates that it is possible to recruit and retain subjects in a clinical trial testing deep brain stimulation in early Parkinsons disease. The results of this trial will be used to support the design of a Phase III, multicenter trial investigating the efficacy of deep brain stimulation in early Parkinsons disease.

Subthalamic Nucleus Deep Brain Stimulation May Reduce Medication Costs in Early Stage Parkinson’s Disease

Background: Subthalamic nucleus deep brain stimulation (STN-DBS) is well-known to reduce medication burden in advanced stage Parkinson’s disease (PD). Preliminary data from a prospective, single blind, controlled pilot trial demonstrated that early stage PD subjects treated with STN-DBS also required less medication than those treated with optimal drug therapy (ODT). Objective: The purpose of this study was to analyze medication cost and utilization from the pilot trial of DBS in early stage PD and to project 10 year medication costs. Methods: Medication data collected at each visit were used to calculate medication costs. Medications were converted to levodopa equivalent daily dose, categorized by medication class, and compared. Medication costs were projected to advanced stage PD, the time when a typical patient may be offered DBS. Results: Medication costs increased 72% in the ODT group and decreased 16% in the DBS+ODT group from baseline to 24 months. This cost difference translates into a cumulative savings for the DBS+ODT group of

Methods for Surgical Targeting of the STN in Early-Stage Parkinson’s Disease

7,150 over the study period. Projected medication cost savings over 10 years reach

Continuation of Long-Term Care for Cervical Dystonia at an Academic Movement Disorders Clinic

64,590. Additionally, DBS+ODT subjects were 80% less likely to require polypharmacy compared with ODT subjects at 24 months (p <  0.05; OR = 0.2; 95% CI: 0.04–0.97). Conclusions: STN-DBS in early PD reduced medication cost over the two-year study period. DBS may offer substantial long-term reduction in medication cost by maintaining a simplified, low dose medication regimen. Further study is needed to confirm these findings, and the FDA has approved a pivotal, multicenter clinical trial evaluating STN-DBS in early PD.

Barriers to Conducting Research With Community-Dwelling Adults Who Have Intellectual Disabilities

Patients with Parkinson’s disease (PD) experience progressive neurological decline, and future interventional therapies are thought to show most promise in early stages of the disease. There is much interest in therapies that target the subthalamic nucleus (STN) with surgical access. While locating STN in advanced disease patients (Hoehn–Yahr Stage III or IV) is well understood and routinely performed at many centers in the context of deep brain stimulation surgery, the ability to identify this nucleus in early-stage patients has not previously been explored in a sizeable cohort. We report surgical methods used to target the STN in 15 patients with early PD (Hoehn–Yahr Stage II), using a combination of image guided surgery, microelectrode recordings, and clinical responses to macrostimulation of the region surrounding the STN. Measures of electrophysiology (firing rates and root mean squared activity) have previously been found to be lower than in later-stage patients, however, the patterns of electrophysiology seen and dopamimetic macrostimulation effects are qualitatively similar to those seen in advanced stages. Our experience with surgical implantation of Parkinson’s patients with minimal motor symptoms suggest that it remains possible to accurately target the STN in early-stage PD using traditional methods.

Neuropsychological Effects of Deep Brain Stimulation in Subjects with Early Stage Parkinson's Disease in a Randomized Clinical Trial

Patients with cervical dystonia (CD) receive much of their care at university based hospital outpatient clinics. This study aimed to describe the clinical characteristics and treatment experiences of patients who continued care at our university based movement disorders clinic, and to document the reasons for which a subset discontinued care. Seventy patients (77% female) were recruited from all patients at the clinic (n = 323). Most (93%) were treated with botulinum neurotoxin (BoNT) injection, and onabotulinumtoxinA was initially used in 97%. The average dose of onabotulinumtoxinA was 270.4 U (range 50–500) and the median number of injections was 14 (range: 1–39). Twenty one patients later received at least one cycle of rimabotulinumtoxinB (33%); of those, 10 switched back to onabotulinumtoxinA (48%). The initial rimabotulinumtoxinB dose averaged 11,996 units (range: 3000–25,000 over 1–18 injections). Twenty one patients (30%) discontinued care. Reasons cited included suboptimal response to BoNT therapy (62%), excessive cost (24%), excessive travel burden (10%), and side effects of BoNT therapy (10%). Most patients (76%) did not seek further care after leaving the clinic. Patients who terminated care received fewer treatment cycles (5.5 vs. 13.0, p = 0.020). There were no other identifiable differences between groups in gender, age, disease characteristics, toxin dose, or toxin formulation. These results indicate that a significant number of CD patients discontinue care due to addressable barriers to access, including cost and travel burden, and that when leaving specialty care, patients often discontinue treatment altogether. These data highlight the need for new initiatives to reduce out-of-pocket costs, as well as training for community physicians on neurotoxin injection in order to lessen the travel burden patients must accept in order to receive standard-of-care treatments.

Effects of deep brain stimulation on rest tremor progression in early stage Parkinson disease

Research on individuals with intellectual and developmental disabilities continues to be an underinvestigated area of medicine. Even after the Surgeon General’s report (Office of the Surgeon General, 2002) emphasizing the need to develop specific, achievable goals to improve the quality of life of people with intellectual and developmental disabilities, there is insufficient research with these individuals. Now more than ever, it is imperative that adequate research efforts be focused on the population of individuals with intellectual and developmental disabilities in order to better understand and define their specific needs, and, ultimately, to improve their quality of life. With the evolution of modern medicine and the introduction of novel medical concepts and treatments, these individuals are living longer (McCausland et al., 2010), but they continue to face clear challenges in maintaining good health because they have poor health status compared to individuals in the general population (Lennox, Beange, & Edwards, 2000). Researchers have shown that the needs of this population differ significantly from those of the general population and that they are at an increased risk of developing comorbidities. However, their specific needs have not been well-defined (Parish, Moss, & Richman, 2008). To date, few large epidemiological studies have been conducted to assess the prevalence of specific medical conditions in individuals with intellectual and developmental disabilities (Beange, McElduff, & Baker, 1995). Furthermore, only 14% of individuals with intellectual and developmental disabilities currently live in public or private institutions (Smith, Lakin, Larson, & Salmi, 2011), making community-based research increasingly important.

Subthalamic Nucleus Deep Brain Stimulation in Early Stage Parkinson’s Disease Is Not Associated with Increased Body Mass Index

BACKGROUND Deep brain stimulation (DBS) is an effective treatment for patients with advanced Parkinsons disease (PD) and motor symptom complications. Recently, attention has been focused on whether offering DBS earlier in the course of PD is beneficial. OBJECTIVE The purpose of this study was to determine the effects of DBS on neuropsychological functioning in subjects with early stage PD. METHODS Thirty subjects with early PD (Hoehn & Yahr Stage II off medication) were randomized to optimal drug therapy (ODT) (n = 15) or bilateral subthalamic nucleus (STN) DBS+ODT (n = 15) after completing an expanded informed consent process specially designed for the study and administered by a medical ethicist and the study team. Comprehensive neuropsychological testing was completed in the treatment-withdrawn state at baseline and at 12 month and 24 month follow-ups. RESULTS Two serious adverse events occurred in the DBS+ODT group. One subject experienced a stroke and another developed infected hardware that contributed to specific declines in cognitive functioning. However, compared to the ODT group, the remaining subjects in the DBS+ODT group exhibited modest reductions on a few measures of attention, executive function, and word fluency at 12 months. These differences were largely diminished at 24 months, especially when those with the adverse events were excluded. CONCLUSIONS The results of this trial provide novel data regarding the effects of DBS on cognitive function in early PD. We believe that the findings and insights from this trial can help guide the safety analysis and risk-benefit evaluations in future discussions of DBS in early stage PD.

Recruitment and Retention in Clinical Trials of Deep Brain Stimulation in Early-Stage Parkinson’s Disease: Past Experiences and Future Considerations

Objective To evaluate whether the progression of individual motor features was influenced by early deep brain stimulation (DBS), a post hoc analysis of Unified Parkinsons Disease Rating Scale–III (UPDRS-III) score (after a 7-day washout) was conducted from the 2-year DBS in early Parkinson disease (PD) pilot trial dataset. Methods The prospective pilot trial enrolled patients with PD aged 50–75 years, treated with PD medications for 6 months–4 years, and no history of dyskinesia or other motor fluctuations, who were randomized to receive optimal drug therapy (ODT) or DBS plus ODT (DBS + ODT). At baseline and 6, 12, 18, and 24 months, all patients stopped all PD therapy for 1 week (medication and stimulation, if applicable). UPDRS-III “off” item scores were compared between the ODT and DBS + ODT groups (n = 28); items with significant between-group differences were analyzed further. Results UPDRS-III “off” rest tremor score change from baseline to 24 months was worse in patients receiving ODT vs DBS + ODT (p = 0.002). Rest tremor slopes from baseline to 24 months favored DBS + ODT both “off” and “on” therapy (p < 0.001, p = 0.003, respectively). More ODT patients developed new rest tremor in previously unaffected limbs than those receiving DBS + ODT (p = 0.001). Conclusions These results suggest the possibility that DBS in early PD may slow rest tremor progression. Future investigation in a larger cohort is needed, and these findings will be tested in the Food and Drug Administration–approved, phase III, pivotal, multicenter clinical trial evaluating DBS in early PD. Classification of evidence This study provides Class II evidence that for patients with early PD, DBS may slow the progression of rest tremor.