Objective: To analyze the resistance to high levodopa doses of FoG, posture, speech, and gait features in PD patients during a daily-ON therapeutic condition.

Background: Management of freezing of gait (FoG) and other axial symptoms in Parkinson’s disease (PD) is challenging, since their response to dopaminergic therapies is complex. Systematic assessments of their response to progressively increasing levodopa doses are lacking.

Method: We conducted a pre-post interventional study in patients treated with levodopa/carbidopa intestinal gel (LCIG) infusion and with good control of motor symptoms and fluctuations, experiencing disabling FoG in daily-ON condition. Patients were evaluated in three consecutive therapeutic regimens, i.e. at the usual LCIG infusion rate (T1), and one hour after 1.5x (T2) and 2x (T3) increase of the LCIG infusion rate. Primary outcome was the FoG improvement, defined as the blinded, video-assessed reduction in the count of FoG episodes during a video-recorded two-minute walk test. As secondary endpoints, we evaluated posture and speech improvement, objectively quantified by means of standardized test by a blinded rater. We also used inertial motion sensors to evaluate gait parameters in a subgroup of patients. Finally, changes in motor symptoms, dyskinesia, and plasma levodopa concentrations were analyzed at T1, T2, and T3.

Results: We evaluated sixteen patients (10 males, 6 females) with a mean age of 69 ± 9.4 years and treated with LCIG for a mean of 2.2 ± 2.1 years. FoG improved in 83.3% of patients. The number of FoG episodes significantly decreased at each study phase, ranging from a mean of 2.3 at T1 to 1.7 at T2 and 1.2 at T3 (p:0.013). Posture and speech parameters did not show significant changes, while gait and balance analysis in twelve patients showed a significant improvement of stride length (p: 0.049), turn duration (p: 0.001), and turn velocity (p: 0.024) after doubling the levodopa infusion dose.

Conclusion: The increase of levodopa doses can improve ‘dopa-resistant’ FoG and gait issues in most PD patients with overall optimal control of motor symptoms and fluctuations, in the absence of clinically significant dyskinesia worsening. The lack of posture and speech improvements could be due to their different pathophysiology. Our results suggest the existence of a higher threshold for the efficacy of levodopa on FoG than on cardinal motor symptoms in advanced PD.

References: [1] Lau B, Meier N, Serra G, et al. Axial symptoms predict mortality in patients with Parkinson disease and subthalamic stimulation. Neurology. 2019;92(22):e2559-e2570; doi: 10.1212/WNL.0000000000007562.
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[4] Nonnekes J, Bereau M, Bloem BR. Freezing of Gait and Its Levodopa Paradox. JAMA Neurol. 2020;77(3):287-288; doi: 10.1001/jamaneurol.2019.4006.
[5] Doherty KM, van de Warrenburg BP, Peralta MC, et al. Postural deformities in Parkinson’s disease. Lancet Neurol. 2011;10(6):538-549; doi: 10.1016/S1474-4422(11)70067-9.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/response-of-freezing-posture-and-voice-to-increasing-levodopa-doses-in-parkinsons-disease/