Traumatic brain injury-related attention deficits: treatment outcomes with lisdexamfetamine dimesylate (Vyvanse).

BACKGROUND AND OBJECTIVES: Attention deficits are often among the most persistent and debilitating impairments resulting from traumatic brain injury (TBI). This study examined the effects of lisdexamfetamine dimesylate (Vyvanse) in treating attention deficits due to moderate-to-severe TBI. It was the first study of lisdexamfetamine dimesylate with this population and, in fact, was the first controlled trial in this area examining a stimulant medication option other than methylphenidate. METHODS: This was a 12-week, randomized, double-blind, placebo-controlled, cross-over trial. A total of 22 rigorously selected cases were enrolled, 13 of whom completed the trial. They were 16-42 years of age and had newly acquired attention deficits persisting for 6-34 months post-injury. They were assessed on a broad range of neuropsychological and behavioural measures at baseline, 6-weeks and at 12-weeks. RESULTS AND CONCLUSIONS: Positive treatment effects were found involving selective measures of sustained attention, working memory, response speed stability and endurance and in aspects of executive functioning. No major problems with safety or tolerability were observed. Some moderating treatment effects were found from a broad range of pre-treatment subject characteristics and injury variables examined. Avenues for further research and treatment applications in this area are discussed.

Long-term neuropsychological outcomes of deep brain stimulation in early-stage Parkinson's disease.

INTRODUCTION: The pilot trial of deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) randomized 30 patients (medication duration 0.5-4 years; without dyskinesia or motor fluctuations) to receive optimal drug therapy alone (early ODT) or subthalamic nucleus (STN) DBS plus ODT (early DBS + ODT). This study reports long-term neuropsychological outcomes from the early DBS pilot trial. METHODS: This is an extension of an earlier study that examined two-year neuropsychological outcomes in the pilot trial. The primary analysis was conducted on the five-year cohort (n = 28), and a secondary analysis was conducted on the 11-year cohort (n = 12). Linear mixed effects models for each analysis compared overall trend in outcomes for randomization groups. All subjects who completed the 11-year assessment were also pooled to evaluate long-term change from baseline. RESULTS: There were no significant differences between groups in either the five- or 11-year analyses. Across all PD patients who completed the 11-year visit, there was significant decline in Stroop Color and Color-Word and Purdue Pegboard from baseline to 11 years. CONCLUSIONS: Previous significant differences between the groups in phonemic verbal fluency and cognitive processing speed showing more decline for early DBS + ODT subjects one year after baseline diminished as PD progressed. No cognitive domains were worse for early DBS + ODT subjects compared to standard of care subjects. There were shared declines across all subjects on cognitive processing speed and motor control, likely reflecting disease progression. More study is needed to understand the long-term neuropsychological outcomes associated with early DBS in PD.

Deep brain stimulation for early-stage Parkinson's disease: an illustrative case.

OBJECTIVES: Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective intervention in advanced Parkinson's disease (PD), but its efficacy and safety in early PD are unknown. We are conducting a randomized pilot trial investigating DBS in early PD. This report describes one participant who received bilateral STN-DBS. MATERIALS AND METHODS: Thirty subjects have been randomized to either optimal drug therapy (ODT) or DBS + ODT. Microelectrode recordings from the STN and substantia nigra are collected at implantation. The Unified Parkinson's Disease Rating Scale Motor Subscale (UPDRS-III) is administered in the ON and OFF states semi-annually and neuropsychological function and quality of life are assessed annually. We describe a 54-year-old man with a two-year history of PD who was randomized to DBS + ODT and followed for two years. RESULTS: The subject showed a lower STN to substantia nigra ratio of neuronal activity than advanced PD patients, and higher firing rate than non-PD patients. The subject's total UPDRS and UPDRS-III scores improved during the two-year follow-up, while his OFF UPDRS-III score and levodopa equivalent daily dose increased. Quality of life, verbal fluency, and verbal learning improved. He did not experience any serious adverse events. CONCLUSIONS: This report details the first successful application of bilateral STN-DBS for early-stage PD during a clinical trial.

Traumatic Brain Injury-Related Attention Deficits in Children: A Controlled Treatment Trial with Lisdexamfetamine Dimesylate (Vyvanse).

Attention deficits are among the most common and persistent impairments resulting from traumatic brain injury (TBI). This study was the first to examine the effects of lisdexamfetamine dimesylate (LDX, Vyvanse) in treating TBI-related attention deficits in children. It was an extension of a previous controlled trial with adults. This was a 12-week, randomized, double-blind, placebo-controlled, dose-titration, crossover trial. In addition to weekly safety monitoring, there were assessments on a broad range of neuropsychological and behavioral measures at baseline, 6-weeks, and 12-weeks. A total of 20 carefully selected children were enrolled, ranging from 10 to 16 years of age. The sample consisted of cases with mainly mild TBI (based on the known details regarding their injuries), but they had persisting attention deficits and other post-concussion symptoms lasting from 2 to 29 months by the time of enrollment. A total of 16 children completed the trial. One of the children withdrew due to a mild anxiety reaction while on LDX. There were no other adverse effects. Positive treatment results were found on both formal testing of sustained attention and in terms of parent ratings of attention, emotional status, behavioral controls, and various aspects of executive functioning. The findings also served to highlight broader insights into the nature of attention deficits and their treatment in children with TBI.

Depression and intelligence in patients with Parkinson's disease and deep-brain stimulation.

The goal of this study is to examine the association of depression with intelligence and education in patients with Parkinson's disease treated with bilateral subthalamic nucleus stimulation (STN-DBS). The literature has been contradictory concerning depression in Parkinson's disease patients. Some studies have shown less depression in Parkinson's disease patients with more education not treated with STN-DBS. Other recently published studies indicate that STN-DBS improves the depression associated with Parkinson's disease. No studies have examined the correlation of these factors with depression in Parkinson's disease patients treated with STN-DBS. We administered the Beck Depression Inventory (BDI) pre- and postoperatively to 21 Parkinson's disease patients (seven women, 14 men, ages 49-75) who underwent STN-DBS. The postoperative scores of the lower 50th percentile (n=8) of the Verbal Comprehensive Index of the Wechsler Adult Intelligence Scale (WAIS-III) decreased significantly (P=0.036), while the upper 50th percentile (n=13) remained nearly constant (P=0.802). Furthermore, as the education increased from highschool to graduate level, patients demonstrated less improvement in depressive symptoms postoperatively. These findings suggest that Parkinson's disease patients with lower intelligence test scores and less education benefit more with regards to depressive symptomatology after STN-DBS than patients with higher scores and education.

Neuropsychological effects of deep brain stimulation in subjects with early stage Parkinson's disease in a randomized clinical trial.

BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for patients with advanced Parkinson's 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.

Deep brain stimulation of the subthalamic nucleus reduces antiparkinsonian medication costs.

This study reports a retrospective analysis of 16 patients to determine changes in medication costs associated with deep brain stimulation of the bilateral subthalamic nucleus (DBS B-STN). Antiparkinsonian medication (APMED) costs were evaluated pre- and post-operatively at 1 and 2 years, based on prescribed dosages. After treatment with DBS, patients experienced a 32% reduction in APMED costs after 1 year and a 39% reduction after 2 years. Hypothetical projections of total potential savings are presented, accounting for increasingly complex medication regimens and medication cost inflation. DBS patients may experience a significant long-term reduction in the cost of their pharmacologic treatment.

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

BACKGROUND: Deep brain stimulation (DBS) is an effective and approved therapy for advanced Parkinson's 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 Parkinson's disease whose symptoms are no longer adequately controlled with medication. Preliminary evidence suggests that subthalamic nucleus stimulation may also be efficacious in early Parkinson's 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 Parkinson's 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 Parkinson's 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 Parkinson's 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 Parkinson's 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 Parkinson's disease.