Review Calls for Further Research on Surgical Approaches to Parkinson Disease Modification

A review published in NPJ Parkinson’s Disease found that further research is needed to evaluate the effectiveness of surgical treatments in slowing the progression of Parkinson disease (PD). The aim of the review was to compare clinical outcomes of surgical treatments proposed to alter the progression of PD.

The researchers used existing literature for this review. To find studies, they searched keywords, including surgical, Parkinson’s disease, disease modification, cell transplantation, dopamine growth factors, deep brain stimulation, and abdominal vagotomy. The authors reviewed each article for context and emphasized trial outcomes within the past 20 years.

The authors first highlighted cell transplantation as a potential treatment for patients with PD. A cell transplantation would replace cells through grafting of dopamine neurons, in hopes of the grafted cells integrating within the host and restoring damaged neural circuits. Questions on appropriate donor cells, where to place the cells in the brain, and the mechanism of action within the grafted cells still remain. In early clinical trials, autologous adrenal autografts resulted in only modest improvement in motor symptoms.

Grafting embryonic dopaminergic neurons has had variable outcomes in human trials. According to a study the researchers cited, the Lund group observed improvement in motor function and PET imaging after grafting of embryonic mesencephalic tissue into the striatum of patients with PD. However, in 2 separate trials, some patients demonstrated dyskinesia.

Some complications of these trial outcomes include the inherent neurodegenerative nature of PD, potential host-to-graft transfer of Lewy body pathology, barriers to availability, quality control concerns, and embryonic allograft inconsistency.

For this method, younger PD patients without tremor may be more responsive to this treatment, as tremors did not reliably improve in cell transplantation studies. Although the grafted dopamine will likely undergo the same pathological changes as the host, the numbers are low enough (2% at 11 years, 5% at 16 years, and 11% at 24 years post transplantation according to a cited autopsy analysis) that the potential benefit outweighs the risk. Feasibility and pivotal trials will help identify efficacy and cost in these methods.

Another surgical treatment identified by the researchers was glial-derived neurotrophic factor (GDNF), which has the potential to rescue and regenerate dopaminergic neurons. However, administration of GDNF has had unanticipated adverse effects of nausea and paresthesias. Subsequent trials have since administered GDNF through parenchymal infusions into the striatum or through gene therapy.

Recent trials of GDNF infusions had similar results to earlier trials in which treatment effects were clouded by placebo responses. Re-analysis of patients with PD treated with GDNF gene therapy who were less than 5 years past diagnosis of PD did show a significant improvement compared with the placebo group. The researchers suggested that future trials be aimed at patients who were recently diagnosed with PD.

Third, the authors discussed deep brain stimulation (DBS) for tremors in patients with PD, which was identified to help control symptoms of bradykinesia, rigidity, tremor, and dyskinesias in the 1980s. Lesions in the subthalamic nucleus demonstrated similar results. Multiple DBS studies have confirmed symptomatic benefit. However, the numbers in these studies were small, which prompted the authors to recommend a pivotal, multicenter trial to evaluate whether this treatment could slow the progression of motor signs and symptoms of PD. They also said that research should include approaches that target lesions in the internal segment of the globus pallidus.

Last, the researchers highlighted abdominal vagotomies, which are used to improve refractory peptic ulcer disease. Given this result, abdominal vagotomies that sever the connection between the gut and the brainstem could be a disease-modifying or preventive approach to PD development.

In a Swedish matched-cohort study that the researchers cited, there was no association between vagotomies and reduced PD risk overall (HR, 0.96), but the truncal vagotomy cohort saw decreased risk of PD development (HR, 0.78). In a separate Danish study, the truncal vagotomy cohort saw decreased risk of PD compared with the general population (HR, 0.53) and the selective vagotomy cohort (HR, 0.58). The researchers recommended developing accurate predictive biomarkers of PD before considering an invasive study of this magnitude.

The researchers concluded that all these methods need individual and comparative pivotal trials to assess the feasibility and effectiveness of each method.

“If potential treatments are not explored with critical trials and due diligence, we will continue to ask the same questions 10, 20, or 30 years from now, with persistent claims of ‘promise’ rather than demonstrated efficacy,” the authors wrote.

Reference

Rahimpour S, Zhang SC, Vitek JL, Mitchell KT, Turner DA. Comparative efficacy of surgical approaches to disease modification in Parkinson disease. npf Parkinson’s Dis. 2022;8:33. doi:10.1038/s41531-022-00296-w