Levodopa‐Induced Neuropathy: A Systematic Review

Abstract

Background Background: Clinical, neurophysiological, and pathological evidence suggest an association between Parkinson's disease (PD) and peripheral neuropathy (PNP), with a possible causative role of levodopa metabolic products, such as homocysteine and methylmalonic acid. Methods Methods: We conducted a systematic review of studies reporting cases of PNP in L-dopa-treated PD patients indexed in PubMed between January 1990 and March 2018. ResultsResults: We identified 38 articles reporting cases of PNP in PD patients treated with oral L-dopa or with L-dopa/ carbidopa intestinal gel infusion (LCIG). Prevalence of PNP was 30.2% in the former group and 42.1% in the latter. Oral L-dopa was mostly associated with slowly progressive PNP, whereas LCIG showed an acute or subacute onset in 35.7% of cases. In both groups, there was an association between PNP and higher L-dopa doses, as well as with the following biochemical alterations: increased homocysteine; reduced vitamin B12; increased methylmalonic acid; and reduced vitamin B6. A skin biopsy was performed in 181 patients, showing signs of small fibers neuropathy in 169 (93.4%). Positive, yet preliminary, results were observed in patients receiving periodic vitamin supplementation. Conclusions Conclusions: Over one third of PD patients in treatment with L-dopa may develop PNP, with a significantly higher prevalence of acute and subacute forms in those receiving LCIG. Pathogenic mechanisms remain unclear, but possibly related to a complex interplay between peripheral neurodegenerative processes and L-dopa neurotoxic metabolites. Prospective, randomized, clinical trials are required to identify factors associated with the onset and progression of PD-associated PNP and clarify the protective role of B-group vitamin supplementation.

<p>Levodopa-Carbidopa Intestinal Gel Infusion Therapy Discontinuation: A Ten-Year Retrospective Analysis of 204 Treated Patients</p>

“…39,40 A recent systematic review revealed that over one-third of PD patients in treatment with L-dopa may develop polyneuropathy, with a significantly higher prevalence of acute and subacute forms in those receiving LCIG. 41 It has been hypothesized that a high-dose of LD favors high levels of homocysteine and methylmalonic acid or reduces the absorption of vitamins (B6, B12) and folate. Vitamin B6 and folate deficiency in the setting of LCIG infusion have been associated with weight loss and subacute axonal sensorimotor polyneuropathy.…”

Safety of Levodopa-Carbidopa Intestinal Gel Treatment in Patients with Advanced Parkinson’s Disease Receiving ≥2000 mg Daily Dose of Levodopa

“…Other studies have indicated a link between polyneuropathy and a higher levodopa equivalent daily dose [28]. However, other factors may be linked to levodopa-related polyneuropathy, including a disruption in the metabolic breakdown of levodopa, causing low levels of vitamin B12, vitamin B6, and folate [28,29] and high homocysteine and methylmalonic acid [28][29][30] and/or BMI reduction [30]. Levodopa-related polyneuropathy is evidently a complex phenomenon that requires careful monitoring of neuropathic symptoms and vitamin deficiencies, particularly when higher levodopa doses are used.…”

“…Some studies have suggested that the frequency of polyneuropathy is more likely to be associated with the duration of the cumulative exposure than with peak doses during LCIG therapy [26,27]. Other studies have indicated a link between polyneuropathy and a higher levodopa equivalent daily dose [28]. However, other factors may be linked to levodopa-related polyneuropathy, including a disruption in the metabolic breakdown of levodopa, causing low levels of vitamin B12, vitamin B6, and folate [28,29] and high homocysteine and methylmalonic acid [28][29][30] and/or BMI reduction [30].…”

Polyneuropathie im Alter

“…Es hat sich gezeigt, dass Höhe und Dauer der L-DOPA-Dosierung mit Hinweisen auf einen Vitamin-B12-Mangel und auch mit der Wahrscheinlichkeit einer Neuropathie korrelieren [7]. Daher sollte vor allem bei Patienten mit Morbus Parkinson, Langzeit-L-DOPA-Therapie und PNP an einen Vitamin-B12-Mangel gedacht werden [33].…”