Recruitment and Retention in Clinical Trials of Deep Brain Stimulation in Early-Stage Parkinson's Disease: Past Experiences and Future Considerations.

BACKGROUND: Clinical trials are often hindered by inadequate patient recruitment. Overly optimistic investigator predictions of participation can lead to unmet recruitment goals and costly trial extensions. A patient-focused approach estimating recruitment in clinical trials may provide higher accuracy. OBJECTIVE: To assess the feasibility of recruitment in a future deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) multicenter trial by understanding motivations and concerns to participation of past and potential future DBS in early-stage PD clinical trial subjects. METHODS: To identify motivating factors and barriers influencing trial participation, an end-of-trial survey was administered to subjects enrolled in a DBS in early-stage PD pilot trial with subjects randomized to receive DBS plus optimal drug therapy (DBS+ODT) or ODT alone (NCT#00282152, IDE#G050016). Pilot trial survey results were analyzed in conjunction with results of a previously-reported survey querying PD patients about potential participation in a trial for DBS in early-stage PD with similar inclusion/exclusion criteria. RESULTS: Pilot trial subjects reported high levels of satisfaction with their participation in the study. Similar motivations and barriers to participation were expressed in comparable proportions by subjects who successfully completed the pilot trial and patients with early-stage PD considering enrollment in a comparable DBS study. CONCLUSIONS: The FDA has approved a prospective, randomized, double-blind, phase III, multicenter, pivotal clinical trial evaluating DBS in early-stage PD (IDE#G050016). These results suggest that the successful recruitment and retention of early-stage PD subjects, as observed in the pilot trial, is attainable in a future pivotal trial.

Mefloquine induces dose-related neurological effects in a rat model.

Mefloquine is one of the drugs approved by the FDA for malaria chemoprophylaxis. Mefloquine is also approved for the treatment of malaria and is widely used for this purpose in combination with artesunate. However, the clinical utility of the compound has been compromised by reports of adverse neurological effects in some patients. In the present study, the potential neurological effects of mefloquine were investigated with six 7-week-old female rats given a single oral dose of the compound. Potential mefloquine-induced neurological effects were monitored using a standard functional observational battery, automated open field tests, automated spontaneous activity monitoring, a beam traverse task, and histopathology. Plasma mefloquine concentrations were determined 72 h after dosing by using liquid chromatography-mass spectrometry. Mefloquine induced dose-related changes in endpoints associated with spontaneous activity and impairment of motor function and caused degeneration of specific brain stem nuclei (nucleus gracilis). Increased spontaneous motor activity was observed only during the rats' normal sleeping phase, suggesting a correlate to mefloquine-induced sleep disorders. The threshold dose for many of these effects was 187 mg/kg of body weight. This dose yielded plasma mefloquine concentrations after 72 h that are similar to those observed in humans after the treatment dose. Collectively, these data suggest that there may be a biological basis for some of the clinical neurological effects associated with mefloquine.

MR screening for brain stem compression in hypertension.

PURPOSE: To determine the clinical usefulness of MR imaging to screen for vascular compression of the lateral medulla, considered by some to be responsible for neurogenic hypertension. METHODS: MR images and clinical records of 120 adults who had received brain MR imaging for any reason were divided into two groups: group 1 (n = 60) consisted of patients with essential hypertension and group 2 (n = 60) included patients who lacked a diagnosis of hypertension. No patient manifested symptomatic cranial neuralgias. The root entry zone of cranial nerves IX and X into the left lateral medulla was examined by MR imaging for proximity to the ipsilateral vertebral artery or its branches. Images lacking any contact between visible vascular structures and the root entry zone were recorded as normal. Vascular compression was graded according to the degree of proximity to the root entry zone. Lateral medullary contact only (grade I), contact and depression (grade II), or lower brain stem displacement or rotation (grade III) of the root entry zone were recorded in both hypertensive and normotensive patients. Among hypertensive patients, additional data were gathered from electrocardiographic, echocardiographic, and urinary protein reports. RESULTS: We found compression in 34 (57%) of the patients from group 1 and in 33 (55%) of the patients from group 2. Compressions in group 1 were grade I in 22 (37%) of the patients, grade II in 8 (45%), grade II in 4 (7%), and grade III in 2 (3%). There were no statistically significant differences in MR findings between the two groups. Among group 1 patients, MR grading did not predict end-organ changes in the heart (left axis deviation and left ventricular hypertrophy) or kidneys (proteinuria). CONCLUSION: Vascular compression of the root entry zone of cranial nerves IX and X into the left lateral medulla is not an adequate lesion to produce systemic hypertension. This finding is as common among normotensive patients as among hypertensive populations. Neither the presence nor the severity of changes in the root entry zone on MR images increases the occurrence of common end-organ responses in the heart or kidneys among hypertensive patients. MR screening is not warranted among hypertensive patients lacking symptomatic cranial neuralgias.