Interaction between heme oxygenase‐1 genotypes and exposure to pesticides in Parkinson's disease

Peak-dose levodopa (L-dopa)-induced dyskinesias (LIDs) are disabling side effects of long-term L-dopa therapy in Parkinson’s disease (PD), affecting 45–85% of patients within a few years of treatment initiation. LIDs are a therapeutic challenge for neurologists as limited treatment options exist. Functional chemodenervation with botulinum toxin type A (BTX-A, Botox, Allergan), first-line treatment for cervical dystonia, may be considered a treatment strategy against this motor complication when predominantly affecting the cervical region. Although the pathophysiology of LID is distinct from that of CD, abnormal muscle contractions of antagonistic sets of muscles suggest a phenomenological overlap. We sought to determine the extent to which cervical intramuscular BTX-A injections can reduce cervicalpredominant LID in PD. Twelve consecutive L-dopa-treated PD patients with frequent and bothersome cervical-predominant LID, regardless of previous or concurrent antidyskinetic treatment, were invited to participate in this six-month double-blind, crossover clinical trial. Patients were randomized to receive standardized EMG-guided injections of BTX-A or equal-volume normal saline (placebo) into the sternocleidomastoid (25 U bilaterally), splenius capitis (50 U bilaterally, divided), and trapezius (25 U bilaterally) muscles from a blinded injector. The total BTX-A dose of 200 U (10:1 dilution) was selected as the average optimal dose used in cervical dystonia. Subjects were assessed always in their best ‘‘on’’ state, when maximal benefits and peak-dose LID were expected to occur. The timing for the greatest severity of LID was chosen at enrollment with patient and caregiver input, and all studyrelated assessments were carried out at the same time. Assessments occurred at 0, 1, 3 (crossover visit), 4, and 6 months after enrollment, with blinded injections administered at the 0and 3-month visits. Primary outcome measure was change in the Goetz dyskinesia rating scale (GDRS, 0– 4, higher is worse), modified for the cervical region, 1 month after each injection (1and 4-month study visits). The GDRS was obtained off-line by three blinded raters from randomized videotape sequences. Secondary outcomes included changes in the patient-reported clinical global impression of change (CGIC) and in the duration, severity, and pain of LID using items 32–34 of the UPDRS-IV. Nonparametric analyses to compare BTX-A with baseline and placebo groups were carried out with the Friedman or Wilcoxon ranked test, as appropriate. A two-point difference in the CGIC was prespecified as clinically significant. Institutional Review Board-approved informed consent was administered to all participating subjects. The study was registered in ClinicalTrials.gov as NCT00477802. From 12 eligible PD patients, 8 patients (4 men; 70.3 6 5.6 years; disease duration, 11.1 6 2.7 years; ‘‘on’’ UPDRS-III, 20.2; L-dopa-equivalent dose, 1375 6 601 mg) were randomized. Only 4 patients completed the 6-month study before it was voluntarily stopped due to safety concerns, namely excessive neck weakness (Supporting Information Fig. 1, Consort flow diagram). BTX-A was associated with improved GDRS scores for the resting but not action-induced dyskinesias (1.8 6 0.7 vs. 2.1 6 0.8, P 1⁄4 0.018; Table 1). There was a trend for reduction in ‘‘on’’ time with LID in the BTX-A group compared with baseline (UPDRS-IV, item 32, 1.7 6 1.0 vs. 2.5 6 1.0, P 1⁄4 0.16). CGIC in the BTX-A group ranged from mild worsening to marked improvement. Dyskinesias self-rated as moderately and severely disabling (UPDRS-IV, item 33, n 1⁄4 4/6) became either mildly (n 1⁄4 3/4) or not disabling with BTX-A. This intervention also converted moderately and severely painful dyskinesias (UPDRS-IV, item 34, n 1⁄4 4/6) into mildly or not painful dyskinesias (n 1⁄4 3/4). On average, the BTX-A group showed a one-point difference above placebo in the CGIC (mild improvement vs. unchanged, respectively), falling below the prespecified cutoff for clinical significance. Transient neck weakness was the most frequently reported adverse reaction (2 patients experiencing head drop and moderate dysphagia for 2 weeks). Only 1 subject requested BTX-A injections for ongoing poststudy management of his LID, which, uniquely, were exclusively restricted to the cervical region. Although BTX-A reduced cervical dyskinesia severity and pain, these benefits were outweighed by (1) the development of excessive neck weakness, leading to a larger-than-anticipated dropout rate and forcing a premature termination of the trial; and (2) the lack of a favorable effect on the actioninduced component of LID, which may be the most disabling component. This dichotomy of improvement on resting but not action-induced dyskinesias is similar to the antidyskinetic response reported for clozapine. Overall, the adverse risk-benefit ratio uncovered by the study’s paradigm precludes recommending the use of BTX-A for treatment of cervical LID. We recognize that in considering any future role of BTXA for individual PD patients with focal LID, clinicians will have to balance the discouraging outcome of this truncated randomized clinical trial with the observation that a -----------------------------------------------------------Additional Supporting Information may be found in the online version of this article. Allergan, Inc. had no role in study design, data collection, data analysis, data interpretation, or writing of the report.