Neurology · Medical Literature
Time course of motor recovery after stroke with and without levodopa: a post hoc 6-month longitudinal analysis of the ESTREL trial.
Abstract
Levodopa did not enhance early motor recovery at 3 months after stroke in the Enhancement of Stroke Rehabilitation with Levodopa (ESTREL) trial. However, whether levodopa modifies the time course of recovery, leading to a delayed benefit remains unclear. Here, we examined levodopa's effects on the trajectories of motor recovery up to 6 months after stroke. The ESTREL trial, a double-blind, randomised controlled clinical trial, compared a 39-day regimen of levodopa/carbidopa (100 mg/25 mg, 3×/day) to placebo alongside standardised task-oriented training. We longitudinally analysed Fugl-Meyer Motor Assessment (FMA) total scores (primary outcome), mRS and NIHSS (secondary outcomes) at baseline (0-7 days post stroke), 5 weeks, 3 and 6 months using linear mixed-effects models including timepoint, treatment allocation and their interaction. In total, 576 of 610 (94%) participants (median age 73 years; 40% female) were analysed. FMA scores improved over time in both groups (P < .001), with no overall levodopa effect across visits (estimate 0.65 points, 95% CI, -3.3 to 4.6; P = .75). There was no indication that levodopa modified the recovery trajectory (χ2 = 0.52, df = 3, P = .91), and estimated levodopa-placebo differences in FMA changes across visit intervals were small, ranging from -0.7 to +0.8 points, with confidence intervals crossing zero. Secondary outcomes showed similar longitudinal improvement, without evidence of a treatment effect. In this post hoc analysis of ESTREL participants with repeated FMA assessments, motor impairment improved from the first days after stroke up to 6 months. Levodopa added to task-oriented inpatient rehabilitation did not improve motor recovery or alter its trajectory over this period. NCT03735901, available at ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT03735901?cond=NCT03735901&rank=1.
Clinical relevance
This study addresses the clinically important question of whether levodopa, a dopaminergic agent with proposed neuromodulatory effects on motor plasticity, confers a delayed or sustained benefit on post-stroke motor recovery beyond its previously null 3-month primary endpoint in the ESTREL trial. The patient population includes acute ischemic stroke survivors (n=576, median age 73 years, 40% female) undergoing standardized inpatient task-oriented rehabilitation—a representative and high-burden population. These findings are timely given ongoing interest in pharmacological augmentation of stroke rehabilitation and the need to close the evidence gap on delayed levodopa effects.
Key findings
1. FMA total scores improved significantly over time in both levodopa and placebo groups from baseline (0–7 days post-stroke) through 5 weeks, 3 months, and 6 months (P < .001), confirming robust spontaneous and rehabilitation-driven motor recovery. 2. There was no statistically significant overall effect of levodopa on FMA scores across all visits (estimated difference: 0.65 points; 95% CI, −3.3 to 4.6; P = .75), indicating no clinically or statistically meaningful between-group advantage. 3. Levodopa did not modify the trajectory of motor recovery at any time interval (χ² = 0.52, df = 3, P = .91), providing strong evidence against a delayed or time-varying treatment benefit. 4. Estimated levodopa-placebo differences in FMA change across individual visit intervals were negligible, ranging from −0.7 to +0.8 points, with all 95% confidence intervals crossing zero—well below any clinically meaningful threshold. 5. Secondary outcomes (mRS and NIHSS) showed longitudinal improvement in both groups without evidence of a treatment effect at any timepoint, corroborating the null primary outcome across multiple functional domains. 6. The analysis included 576 of 610 (94%) ESTREL participants with repeated FMA assessments, ensuring high data completeness and minimizing attrition bias in this post hoc longitudinal evaluation.
Practice implications
Clinicians should not prescribe levodopa/carbidopa (100 mg/25 mg three times daily for 39 days) as an adjunct to task-oriented inpatient rehabilitation with the expectation of enhancing motor recovery at any point up to 6 months post-stroke, as this well-powered RCT post hoc analysis demonstrates no benefit in trajectory or magnitude of FMA improvement. The absence of both early and delayed levodopa effects across motor impairment (FMA), disability (mRS), and neurological severity (NIHSS) outcomes argues against further routine clinical use of this regimen for motor rehabilitation augmentation in the acute-to-subacute stroke period. Future research should focus on identifying biologically or genetically defined subpopulations (e.g., by dopaminergic pathway integrity on neuroimaging) who may respond differentially, rather than applying levodopa broadly to unselected stroke rehabilitation patients.