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By Claire Henchcliffe, MD
Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College
Dr. Henchcliffe reports she is on the speakers bureau and advisory boards for Teva, IMPAX, and ACADIA; and receives grant/research support from Biogen and Kaneka.
Synopsis: Truncal vagotomy was associated with a reduced risk for Parkinson’s disease with a hazard ratio of 0.58 for those with more than 20 years’ follow-up. This suggests the vagus nerve as a possible route of entry into the central nervous system for this neurodegenerative process.
Source: Svensson E, et al. Vagotomy and subsequent risk of Parkinson’s disease. Ann Neurol 2015;78:522-529.
Parkinson’s disease (PD) pathology, as demonstrated by abnormal alpha-synuclein deposition, may begin in the enteric nervous system and the olfactory bulb many years prior to appearance of motor symptoms. Therefore, it has been proposed that these structures are “portals of entry” for external triggers of PD pathology. A compelling hypothesis is that spread from the gastrointestinal tract to the central nervous system might then occur via the vagus nerve. Vagotomy is a procedure that has been undertaken for peptic ulcer disease, allowing this hypothesis to be tested. Moreover, in treating peptic ulcers either truncal vagotomy may be performed or superselective vagotomy in which only nerves supplying the fundus and body of the stomach are resected, leaving the route to the brain from other regions relatively intact. Svensson and colleagues compared rates of occurrence of PD in those undergoing the two types of vagotomy procedures, and additionally compared each group with population-based controls.
Patients who had undergone truncal vagotomy or superselective vagotomy between 1977-1995 who had > 5 years’ follow-up (truncal vagotomy: n = 5339; superselective vagotomy: n = 5870) were identified and compared with more than 120,000 individuals who had not. This latter group, with 10 individuals matched for age and gender to each vagotomy patient, was randomly selected from the general population. Diagnosis of PD was made on the basis of records from the Danish National Patient Registry. Multiple potential confounders were examined, including rheumatologic disease, cardiovascular disease, diabetes, and others. Median age was 56 years (truncal vagotomy) and 47 years (superselective vagotomy) at the time of index date. Of those with truncal vagotomy, 61% were men vs 69% of those with superselective vagotomy, and those who had undergone truncal vagotomy had a higher prevalence of comorbidities. The investigators found that fewer cases of PD were identified in those undergoing truncal vagotomy (n = 45) vs superselective vagotomy (n = 59) or vs the general population cohort, with hazard ratios (HR) of 0.85 (95% confidence interval [CI], 0.56-1.27) and 0.84 (95% CI, 0.63-1.14), respectively. More robust associations were determined in those with > 20 years follow-up in whom HR was 0.58 (95% CI, 0.28-1.20) for truncal vagotomy vs superselective vagotomy, and 0.53 (95% CI, 0.28-0.99) for truncal vagotomy vs the general population cohort. Smoking had not been measured, but attempts to adjust for this potential confounder still resulted in adjusted risk ratios from 0.61 and 0.66 depending on assumptions for the percentage of the truncal vagotomy cohort who smoked (between 75-85% vs 60% of the general population cohort).
The gastrointestinal tract has been proposed as a “portal of entry” for potential pathogenic agents in PD. This, as well as entry via the olfactory system, is a compelling argument, given data suggesting environmental risk factors such as pesticides. The question is how the pathogenic process, as tracked by alpha-synuclein-based pathology, spreads to the central nervous system where more specific and recognizable effects lead to characteristic motor symptoms of PD such as bradykinesia, tremor, and rigidity. The vagus nerve represents a potential route, and in animal studies spread of alpha-synuclein pathology induced by rotenone has been observed to spread from the enteric nervous system through the vagus nerve to the brainstem. The strength of this study by Svensson and colleagues is in examining long-term follow-up of patients who underwent not only truncal vagotomy, but also superselective vagotomy in which only nerves supplying the fundus and body of the stomach are resected. This population-based, registry-linkage, cohort study takes advantage of a national health registry and civil registration system to facilitate access to substantial numbers of patients and healthy individuals. The major finding that severing the vagus nerve is associated with lower risk of subsequent development of PD indeed supports the hypothesis that spread of PD pathogenesis occurs from the gut and that the vagus nerve plays a critical role in its transmission. However, there are some points that temper excitement. Statistical significance was not reached for most of the group comparisons. Diagnoses and procedure codes may be inaccurate. It is difficult to adequately control for all confounders, including known PD associations such as smoking or caffeine intake. And it does not, of course, address other potential origins and routes of spread. PD was not reduced to zero in those who had undergone truncal vagotomy. Nonetheless, this study has major implications and should quickly prompt efforts to replicate its findings in other populations.