Is Levodopa Fueling Peripheral Nerve Damage? A Clinical and Neurophysiological Insight Into Polyneuropathy in Parkinson's Disease

ABSTRACT Introduction/Aims Polyneuropathy (PN) in Parkinson's disease (PD) remains underrecognized in clinical practice despite increasing evidence of its prevalence, especially among patients receiving levodopa therapy. Both iatrogenic and neurodegenerative mechanisms have been proposed. This study aimed to assess the prevalence and characteristics of PN in PD patients across different therapeutic regimens, including a longitudinal evaluation of those initiating levodopa–carbidopa intestinal gel (LCIG). Methods We conducted a prospective observational study on 66 PD patients classified into levodopa‐naïve (noLEV), moderate‐dose (modLEV), and high‐dose (highLEV) groups. Clinical, neurophysiological, and biochemical evaluations were performed at baseline. A subgroup of 17 patients initiating LCIG underwent follow‐up assessments after a mean of 40 months. PN diagnosis was based on clinical and nerve conduction study (NCS) criteria. Results At baseline, 22.7% of patients had PN. PN prevalence increased significantly with higher levodopa doses (38.4% in highLEV vs. 10% in noLEV, p = 0.047). Patients with PN had higher homocysteine (Hcy) and lower vitamin B12/folate levels. LEV dosage demonstrated weak positive correlations with Hcy and weak to moderate negative correlations with sensory and motor nerve amplitudes. Among LCIG‐treated patients, PN prevalence rose from 17.6% to 47% at follow‐up, with a 35.7% incidence of new‐onset PN. The change in levodopa dosage was the main predictor of PN development. Discussion This study confirms that PN is a common comorbidity in PD, strongly associated with levodopa exposure, particularly at higher doses or via LCIG. Routine clinical, neurophysiological and biochemical monitoring is essential to identify at‐risk patients and guide preventive strategies, including vitamin supplementation.