Neuropathy in Parkinson’s Disease May Be Related to L-Dopa Exposure

S. Andrew Josephson, M.D.


AccessMedicine from McGraw-Hill 

Idiopathic Parkinson’s disease (IPD) is a central nervous system disorder affecting the basal ganglia that is caused by death of dopamine-producing cells in the substantia nigra. Although IPD is thought classically to spare the peripheral nervous system, an association between peripheral neuropathy (PN) and IPD has been demonstrated in some of the rare genetic forms of Parkinson’s disease. A recent study (Toth et al, 2010) aimed to examine the relationship between the more common form of IPD and PN.

The authors conducted a prospective cohort study by randomly selecting patients from a database of IPD patients at a tertiary center in Canada. Patients as well as age- and gender-matched controls underwent detailed clinical assessment, neurophysiologic testing using nerve conduction studies, and a thorough laboratory assessment for causes of neuropathy. Patients who could not tolerate these tests or who had known risk factors for PN such as diabetes were excluded.

A total of 58 IPD patients were included in the study. Symptoms of PN were present in 43% of the IPD patients but in only 5% of the control subjects. There were no significant differences in risk factors for PN between the IPD and control patients. Three IPD patients were excluded because two neurologists, one blinded to the diagnosis of IPD, disagreed as to the diagnosis of PN. Of the remaining 55 IPD patients, 32 (58%) were diagnosed with PN using a standard electrophysiologic and clinical assessment; 24 of these had symptomatic PN. Only 5 of the 58 controls (9%) were diagnosed with PN. Duration of IPD before assessment was similar in the IPD with and without PN groups, although severity of IPD was greater in the IPD with PN patients.

To discern the etiology of PN in IPD patients, the authors examined a number of known causes of neuropathy, most of which were unrevealing. Although similar cobalamin levels were found in the IPD groups with and without PN, fasting homocysteine and methylmalonic acid (MMA) levels were significantly higher in the IPD group with PN.

The odds ratio for exposure to L-dopa in the IPD patients with PN was 12.4 (95% confidence interval, 1.4–109.1). There were no differences between the groups in the use of other PD drugs, including dopamine agonists, COMT inhibitors, anticholinergic agents, and amantadine. Cumulative L-dopa exposure was associated not only with PN, but also with elevated fasting MMA levels across all IPD patients in the study. L-dopa exposure was also associated with PN severity in the IPD patients with PN.

This intriguing study demonstrates a somewhat unexpectedly high prevalence of PN in IPD patients and cites an association with elevated MMA levels, perhaps mediated by exposure to L-dopa. L-dopa may indeed interact with methylation pathways involved in folate metabolism, providing a mechanism for MMA elevation. Although causation is not proven here, if verified, this study may change the way we care for patients with IPD. PN in IPD could substantially contribute to gait disturbance and disability in some patients with IPD, and prevention of PN would be an important advance. Exposure to L-dopa is inevitable in most IPD patients at some point during their course, but perhaps we should be measuring MMA levels in these patients and treating with cobalamin supplementation to reduce MMA levels and prevent neuropathy. Further studies, including treatment trials, seem warranted.


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