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Truncal vagotomy might help delay Parkinson’s disease

Publish date: April 26, 2017

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Consider implications of findings

The current study provides an independent dataset suggesting that truncal vagotomy may be protective in Parkinson’s disease. Therefore, the time has come to seriously consider the implications of these findings.

Could it be true that alpha-synuclein misfolding in PD may originate in the autonomic nerve terminals of the gastrointestinal tract? For the moment, more research is needed. One may consider studying the effects of vagotomy in patients with mutations in the leucine-rich repeat kinase-2 gene (LRRK2), which dramatically increases the risk of developing neurodegenerative parkinsonism. Some of these mutations have a penetrance of up to 80% in the very elderly. However, it is largely unknown whether alpha-synuclein aggregates are present in gastrointestinal nerve endings of these patients. At this stage, we have insufficient knowledge to propose vagotomy as a putative treatment for PD. Although vagotomy will likely never become a widespread treatment for PD, strategies to prevent alpha-synuclein misfolding in the gastrointestinal tract may be proposed, because nerve terminals are reachable by oral therapeutic interventions.

Per Borghammer, MD, PhD, is in the department of nuclear medicine and PET Centre, Aarhus University Hospital, Denmark. Clement Hamani, MD, PhD, is at the division of neurosurgery, Toronto Western Hospital, University of Toronto, and the department of neuroimaging, Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto. They reported no conflicts of interest. These comments are excerpted from their editorial (Neurology. 2017 Apr 26. doi: 10.1212/WNL.0000000000003969).

Patients who were followed for more than 5 years after truncal vagotomy had about a 40% lower risk of being diagnosed with Parkinson’s disease, compared with matched population controls, according to the results of a cohort registry study.

Selective vagotomy did not decrease the risk of Parkinson’s disease (PD), however, reported Bojing Liu of Karolinska Institutet, Stockholm, and her associates. The findings, which reflect those from a prior Danish study, “provide preliminary and indirect support” for the idea that Lewy pathology in PD begins in peripheral nerves and spreads to the central nervous system through “prion-like mechanisms,” they added.

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Gastrointestinal symptoms such as constipation are among the most frequent nonmotor symptoms in PD, and cell-to-cell transmission of alpha-synuclein has been observed in grafted neurons from PD patients and in a transgenic mouse model of PD. Importantly, resecting the vagus nerve before treating mice with rotenone to induce alpha-synuclein accumulation “stopped the spread of PD-like pathology,” the researchers noted. Because few data existed to help determine whether vagotomy reduced the risk of PD in humans, they used national Swedish registries between 1970 and 2010 to compare 9,430 vagotomy patients with 377,200 population controls matched by age and sex (Neurology. 2017 Apr 26. doi: 10.1212/WNL.0000000000003961). A total of 101 (1.07%) vagotomy patients developed PD, as did 4,829 (1.28%) controls over 7.3 million person-years of follow-up. Crude rates of PD per 100,000 person-years were 61.8 for vagotomy overall, 80.4 for truncal vagotomy, 55.1 for selective vagotomy, and 67.5 for controls. Vagotomy overall was not linked to PD risk in the unadjusted model (hazard ratio, 0.96, 95% confidence interval, 0.78-1.17) or after the researchers controlled for country of birth, chronic obstructive pulmonary disease, diabetes mellitus, vascular diseases, rheumatologic disease, osteoarthritis, and comorbidities. However, truncal vagotomy trended toward a protective effect in the adjusted model (HR, 0.78; 95% CI, 0.55-1.09), and this association reached statistical significance after researchers restricted the analysis to patients who were followed for more than 5 years (HR, 0.59; 95% CI, 0.37-0.93). A similar trend existed among patients who were followed for more than 10 years after truncal vagotomy (HR, 0.62; 95% CI, 0.36-1.08). In contrast, selective vagotomy “was not related to Parkinson’s disease risk in any analyses,” the investigators wrote.

The findings reflect a prior registry study that found a 15% decrease in the risk of PD compared with the general population more than 5 years after truncal vagotomy (Ann Neurol. 2015 Oct. 78[4];522-9). “This Danish study, however, did not differentiate truncal from selective vagotomy and thus might have underestimated the association of truncal vagotomy with PD,” the researchers said.

Another study found that truncal vagotomy exhibited a nonsignificant protective effect overall and an insignificantly increased risk of PD more than 20 years after surgery (Neurology Today 2015 Dec 3;15[23]:27-30). Likewise, the current study yielded “stronger evidence for PD risk reduction more than 5 or 10 years after truncal vagotomy,” and the protective effect appeared to weaken with longer follow-up, the investigators noted. If PD started at multiple sites within the peripheral nervous system, “even truncal vagotomy may delay, rather than eliminate, the risk for PD,” they emphasized. “Indeed, abnormal alpha-synuclein accumulation has been found throughout the digestive tract of patients with PD with descending pattern of density, and even in the submandibular gland in patients with preclinical PD.”

The study was funded by the Swedish Research Council for Health, Working Life and Welfare, the Parkinson Research Foundation in Sweden, the Karolinska Institutet, the Swedish Society for Medical Research, the Stockholm County Council, and Karolinska Institutet–NIH Doctoral Partnership Program in Neuroscience. The investigators had no relevant disclosures.

Truncal vagotomy might help delay Parkinson’s disease

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