Cost-Effectiveness and Cost-Utility of Early Levodopa in Parkinson's Disease

Background: In the Levodopa in EArly Parkinson's disease (LEAP) study, 445 patients were randomized to levodopa/carbidopa 100/25 mg three times per day for 80 weeks (early-start) or placebo for 40 weeks followed by levodopa/carbidopa 100/25 mg three times per day for 40 weeks (delayed-start).Objective: This paper reports the results of the economic evaluation performed alongside the LEAP-study.Methods: Early-start treatment was evaluated versus delayed-start treatment, in which the cost-effectiveness analysis (CEA) and the cost-utility analysis (CUA) were performed from the societal perspective, including health care costs among providers, non-reimbursable out-of-pocket expenses of patients, employer costs of sick leave, and lowered productivity while at work. The outcome measure for the CEA was the extra cost per unit decrease on the Unified Parkinson's Disease Rating Scale 80 weeks after baseline. The outcome measure for the CUA was the extra costs per additional quality adjusted life year (QALY) during follow-up.Results: 212 patients in the early-start and 219 patients in the delayed-start group reported use of health care resources. With savings of D 59 per patient (BCa 95% CI: -829, 788) in the early-start compared to the delayed-start group, societal costs were balanced. The early-start group showed a mean of 1.30 QALYs (BCa 95% CI: 1.26, 1.33) versus 1.30 QALYs (BCa 95% CI: 1.27, 1.33) for the delayed-start group. Because of this negligible difference, incremental cost-effectiveness and cost-utility ratios were not calculated.Conclusion: From an economic point of view, this study suggests that early treatment with levodopa is not more expensive than delayed treatment with levodopa.Neurological Motor Disorder

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

Combined and Sequential Treatment with Deep Brain Stimulation and Continuous Intrajejunal Levodopa Infusion for Parkinson’s Disease

(1) Background: Deep brain stimulation (DBS) and continuous intrajejunal levodopa infusion (CLI) are efficacious treatments of medication related motor response fluctuations in advanced Parkinson’s disease (PD). Literature regarding the use of both advanced treatments within one patient is scarce. (2) Methods: We present a retrospective single center case series and a review of the literature. Patients with PD who were treated with both DBS and CLI in our tertiary referral center between 2005 and 2020 were identified and medical records were assessed. Additionally, literature on patients treated with both therapies was systematically searched for in Medline and Embase. (3) Results: Nineteen patients were included. Medication related motor response fluctuations were a major indication for the second therapy in all but one. Of nine patients initially treated with DBS, five reported improvement with CLI. Seven of ten patients initially treated with CLI experienced benefits from DBS. The systematic literature search resulted in fifteen previous publications comprising 66 patients. Of the 59 patients, for whom the effect of the second treatment was known, 57 improved. (4) Conclusions: PD patients, who have persisting medication related motor response fluctuations, despite DBS or CLI treatment, may benefit from an additional or alternative treatment with either CLI or DBS

Ethical Considerations

Since its first applications in humans, DBS has triggered a plethora of ethical questions and concerns and stimulated extensive ethical debates as to its significance and desirability. The main ethical goal is to guide and support responsible decision-making in clinical DBS treatment, as well as related medical research, and to raise awareness about salient ethical issues. Traditional medical ethics consists of the three basic principles of respect for autonomy, beneficence/nonmaleficence and justice. In the context of DBS, these principles require specific attention as to what exactly it means to “respect autonomy,” to safeguard beneficence and nonmaleficence, and to live up to the requirements of justice. Taking the risks and side effects of DBS into account and comparing this treatment to possible alternative treatments is crucial. Given the increasing interest in applying DBS to psychiatric disorders, research ethical questions have been put on the agenda. The status of the brain also gave rise to the expression of profound ethical concerns, particularly regarding potential changes in patients’ personal identity. However, different understandings of this very concept lead to diverging evaluations of the ethical value of potentially identity-modifying techniques. Independent ethical substudies or integral add-on projects in DBS research can advance systematic ethical thought regarding ongoing research endeavors and upcoming new applications

Neuropsychological outcome after deep brain stimulation for Parkinson disease

To assess the neuropsychological outcome 12 months after bilateral deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) or subthalamic nucleus (STN) for advanced Parkinson disease. We randomly assigned patients to receive either GPi DBS or STN DBS. Standardized neuropsychological tests were performed at baseline and after 12 months. Patients and study assessors were masked to treatment allocation. Univariate analysis of change scores indicated group differences on Stroop word reading and Stroop color naming (confidence interval [CI] 1.9-10.0 and 2.1-8.8), on Trail Making Test B (CI 0.5-10.3), and on Wechsler Adult Intelligence Scale similarities (CI -0.01 to 1.5), with STN DBS showing greater negative change than GPi DBS. No differences were found between GPi DBS and STN DBS on the other neuropsychological tests. Older age and better semantic fluency at baseline predicted cognitive decline after DBS. We found no clinically significant differences in neuropsychological outcome between GPi DBS and STN DBS. No satisfactory explanation is available for the predictive value of baseline semantic fluency for cognitive decline. This study provides Class I evidence that there is no large difference in neuropsychological outcome between GPi DBS and STN DBS after 12 months. The study lacks the precision to exclude a moderate difference in outcome