Natural history of motor symptoms in Parkinson's disease and the long-duration response to levodopa

Abstract

The natural pattern of progression of Parkinson's disease is largely unknown because patients are conventionally followed on treatment. As Parkinson's disease progresses, the true magnitude of the long-duration response to levodopa remains unknown, because it can only be estimated indirectly in treated patients. We aimed to describe the natural course of motor symptoms by assessing the natural OFF in consecutive Parkinson's disease patients never exposed to treatment (drug-naïve), and to investigate the effects of daily levodopa on the progression of motor disability in the OFF medication state over a 2-year period. In this prospective naturalistic study in sub-Saharan Africa, 30 Parkinson's disease patients (age at onset 58 ± 14 years, disease duration 7 ± 4 years) began levodopa monotherapy and were prospectively assessed using the Unified Parkinson's disease Rating Scale (UPDRS). Data were collected at baseline, at 1-year and 2-years follow-up. First-ever levodopa intake induced a significant improvement in motor symptoms (natural OFF versus ON state UPDRS-III 41.9 ± 15.9 versus 26.8 ± 15.1, respectively; P < 0.001). At 1-year follow-up, OFF state UPDRS-III score after overnight withdrawal of levodopa was considerably lower than natural OFF (26.5 ± 14.9; P < 0 .001). This effect was not modified by disease duration. At the 2-year follow-up, motor signs after overnight OFF (30.2 ± 14.2) were still 30% milder than natural OFF (P = 0.001). The ON state UPDRS-III at the first-ever levodopa challenge was similar to the overnight OFF score at 1-year follow-up and the two conditions were correlated (r = 0.72, P < 0.001). Compared to the natural progression of motor disability, levodopa treatment resulted in a 31% lower annual decline in UPDRS-III scores in the OFF state (3.33 versus 2.30 points/year) with a lower model's variance explained by disease duration (67% versus 36%). Using the equation regressed on pretreatment data, we predicted the natural OFF at 1-year and 2-year follow-up visits and estimated that the magnitude of the long-duration response to levodopa ranged between 60% and 65% of total motor benefit provided by levodopa, independently of disease duration (P = 0.13). Although levodopa therapy was associated with motor fluctuations, overnight OFF disability during levodopa was invariably less severe than the natural course of the disease, independently of disease duration. The same applies to the yearly decline in UPDRS-III scores in the OFF state. Further research is needed to clarify the mechanisms underlying the long-duration response to levodopa in Parkinson's disease. Understanding the natural course of Parkinson's disease and the long-duration response to levodopa may help to develop therapeutic strategies increasing its magnitude to improve patient quality of life and to better interpret the outcome of randomized clinical trials on disease-modifying therapies that still rely on the overnight OFF to define Parkinson's disease progression.

Keywords: Parkinson’s disease; levodopa; long-term response; motor fluctuations.

Figure 1

Progression of Parkinson's disease motor disability according to levodopa status (drug-naive versus stable therapy) and response (LDR and SDR). (A) Scatterplot of UPDRS motor score at natural OFF (solid line) and at 1-year follow-up after overnight withdrawal of levodopa (dotted line). Data are described according to Pearson’s statistic [correlation coefficient (r) and P-value] and linear regression analysis (trend line and equation). (B) Estimation of 12-month and 24-month LDR (grey bars) and SDR (black bars) to levodopa in different disease duration strata (tertiles of distribution). LDR is calculated as the difference between the natural OFF state (predicted from disease duration using the equation regressed from baseline cross-sectional data analysis) and the overnight OFF state, while the SDR is the shift between the overnight OFF and the ON state. White bars represent the changes in UPDRS-III between the natural OFF and the ON state at the first ever levodopa challenge. Trend lines of natural OFF state, overnight OFF and ON state are also included.

Figure 2

Response to levodopa at the first-ever intake (baseline) and at the follow-up visits. Box and whisker plots of UPDRS motor score (A) in the OFF state (dark boxes) and ON state (light boxes) and non-dopaminergic score of the UPDRS-III in the OFF state (B) at the baseline visit and at 1-year and 2-year follow-ups. The box represents the median value (middle line) and the interquartile range (IQR; 25–75th percentile). N.S = not significant.

Figure 3

Relationship between the SDR at baseline and the LDR at follow-up. Correlation between the SDR at the first ever levodopa challenge (ON state UPDRS-III score) and the LDR at 1-year follow-up (overnight OFF).