Factors Predictive Of The Development Of The Levodopa-induced Wearing-off In Parkinson’s Disease

Parkinson’s disease (PD) is a progressive, neurodegenerative disorder, theprimary symptoms of which include bradykinesia, rigidity and resting tremor, as wellas postural instability as the disease progresses. Although motor symptoms classicallydefine the disorder, various non-motor symptoms are frequently seen, includingautonomic dysfunction, cognitive and psychiatric changes, sensory symptoms andsleep disturbances. The average age of PD onset is60years; however, onset can occurat any time throughout adulthood. There are no tests to definitively confirm thediagnosis of PD, which is based upon the experience of the diagnosing healthcareprofessional in assessing symptoms, reviewing patient history and ruling outalternative diagnoses. For the majority of patients, at the time of the initial diagnosis,symptoms are generally mild and multiple treatment options are available that provideadequate symptom control. However, as the disease progresses, symptoms progressand treatment adjustments are necessary.Levodopa is the most effective symptomatic treatment for PD, and eventuallynearly all patients will require levodopa therapy. While levodopa continues to benefitpatients even as PD progresses, chronic use of levodopa is associated with thedevelopment of motor complications, such as dyskinesia and wearing off, that canlead to an increase in disability. The initial complication is commonly wearing-off,which is the re-emergence of motor and non-motor symptoms before the nextscheduled levodopa dose.Objectives：To evaluate factors associated with the development of the wearing-off(WO) in Parkinson’s patients on levodopa(LD) therapy and provide evidence toprevent or delay the WO occurrence clinically.Methods：One hundred thirteen patients with idiopathic Parkinson’s disease(PD) on LDtherapy were enrolled in this study, we recorded age, gender, age at onset of PD,disease duration, presense of wearing-off, treatments with antiparkinsonian drugs．TheUnified Parkinson’s Disease Rating Scale(UPDRS)and Hoehn&Yahr stage wereused to assess the severity of PD. Mean differences between patients with WO andwithout WO were assessed using the independent sample t-tests or theMann–Whitney test for continuous variables with a parametric or non-parametric distribution respectively. Categorical data were compared with the Chi squaretest.Variables with statistically significant differences between patients with WO andwithout WO entered into stepwise multivariate logistic regression analyses with theappearance of WO as the dependent variables to find out the best explanatoryindependent factors. Receiver operating characteristic (ROC) curves were performedto assess the sensitivity and specificity of each variable in predicting WO. The pointthat simultaneously maximized sensitivity and specificity was selected as the cut-offvalue. Kaplan–Meier curves were used to evaluate the relationship between time toonset of WO and the duration of LD use. Survival time was defined as the time fromLD therapy to the appearance of WO, The log-rank test stratified by risk factors (ageat onset of PD, the intial LD dose)were performed to evaluate the effect on theoccurrence of WO during the course of the LD use.Results：(1)Forty-three subjects (38.3%) developed wearing-off，31%patients developedWO in the first five years of LD therapy,of which all the people developed WO withage at onset of30-39years, with age of onset increasing, WO incidence decreased,age of onset after80years without occurence of WO.(2)The mean age at onset of PD were earlier in group with WO(P=0.042). Theduration of PD was longer in group with WO (P<0.001). The time between the firstsymptom and the initiation of LD were not significantly different (P=0.114). Theinitial LD dose was significantly higher in group with WO compared to withoutWO(P<0.001).The time until DA initiation was longer in group with WO (P<0.001).UPDRS Part Ⅲscores and Hoehn and Yahr stage were higher in group withWO(P<0.001). The patients selected DA as the first treatment with significantly lowerrisk of WO than patients were given LD first followed by DA(P=0.002).(3)Age at onset of PD, disease duration, initial LD dose, UPDRS Part Ⅲscoreswere the independent variable most associated with WO.(4)The sensitivity of disease duration79.1%, specificity was70.0%, the UPDRSPart III scores and initial LD dose showed similar accuracy to that of disease durationas predictive factors.(5)Patients who developed Parkinson’s disease with initial LD dose＞300mg/dexperienced WO earlier than≤300mg/d (log-rank, p<0.05).Conclusions：Factors significantly associated with earlier occurrence of wearing-off were young age at onset of PD, longer disease duration, higher initial LD dose, longer LDuse, late DA initiation, higher Hoehn and Yahr stage and more severe UPDRSPartⅢ s cores,but not the timing of LD initiation.The patients selected DA as the firsttreatment with significantly lower risk of WO than patients were given LD firstfollowed by DA. Thus, for early PD patients, especially younger patients, we considerDA starting treatment, adding a small dose of LD according to patients’ need and theprogress of disease, in order to reduce the time of LD use and delay WO occurrence.Patients with age of onset after70years, the WO incidence is not very high, can startLD treatment with a small dose to achieve the purposes of symptom control.