Characterization and personalization of botulinum toxin type A therapy for upper limb tremor in Parkinson disease and Essential tremor patients using multi-sensor kinematic technology

Tremor commonly affects the upper extremities in essential tremor (ET) and Parkinson disease (PD) patients where many experience functional disability and ultimately seek therapy. As ET and PD tremor features overlap and clinical assessment is challenging due to its highly complex nature, misdiagnosis is common resulting in unsuitable therapies and prognosis. Current treatment options for ET and PD tremor include pharmacotherapy, focal therapy with botulinum toxin type A (BoNT-A) injections, and surgical interventions which provide modest relief of tremor. However, such therapies are commonly associated with significant adverse events and lack long-term efficacy and tolerability. Hence lack of standardized, objective measures of tremor and suboptimal treatment options are two significant unmet needs faced by neurologists today. The hypothesis of this thesis was to determine whether joint tremor amplitude can differentiate between ET and PD tremor types and can be applied towards improving BoNT-A tremor therapy. The first objective was to apply motion sensor kinematic technology to investigate the role of paired tasks in modulating tremor biomechanics in 24 ET and 28 PD participants. Paired tasks involved variating limb positioning while at rest, posture, and under weight-bearing conditions. Motion sensor devices were placed over the wrist, elbow and shoulder joints capturing joint angular tremor amplitude in multiple degrees of freedom (DOF). Kinematic measures of tremor allowed detailed segmentation of tremor into directional components, which cannot be performed visually. The relationship of joint tremor severity between paired tasks and across all tasks generated unique tremor profiles and provided a simple method to differentiate ET and PD tremor types. The second objective was to apply tremor kinematics to better tailor BoNT-A injection parameters. Participants were injected in the upper limb, which exhibited their most bothersome tremor, every 16 weeks, a total of 3 injection cycles, and attended follow-up visits six weeks following treatment, for a total of 6 study visits. Clinical rating scales and kinematic recordings were conducted at each visit. Dosing was based on clinician’s experience and kinematic data, and muscle site of injection was determined kinematically. A significant decrease in mean clinical tremor rating scores during rest and action tasks and significant improvement in arm function was observed at week 6 and continued throughout the study in both ET and PD individuals. Ten PD participants and eight ET participants reported mild weakness in injected muscles that had no interference with arm function. Kinematic technology is a promising method for standardizing assessments and for personalizing BoNT-A therapy