Functional Ability Improved in Essential Tremor by IncobotulinumtoxinA Injections Using Kinematically Determined Biomechanical Patterns – A New Future

<div><p>Objective</p><p>Effective treatment for functional disability caused by essential tremor is a significant unmet need faced by many clinicians today. Current literature regarding focal therapy by botulinum toxin type A (BoNT-A) injections uses fixed dosing regimens, which cannot be individualized, provides only limited functional benefit and unacceptable muscle weakness commonly occurs. This 38-week open label study, the longest to-date, demonstrates how kinematic technology addressed all these issues by guiding muscle selection.</p><p>Method</p><p>Participants (n = 24) were assessed at weeks 0, 6, 16, 22, 32, and 38 and injected with incobotulinumtoxinA at weeks 0, 16, and 32. Clinical assessments including UPDRS tremor items, Fahn-Tolosa-Marin (FTM) tremor rating scale assessing tremor severity, writing and functional ability, quality of life questionnaire (QUEST) and objective kinematic assessments were completed at every visit. Participants performed two postural and two weight-bearing scripted tasks with motion sensors placed over the wrist, elbow and shoulder joints. These sensors captured angular tremor amplitude (RMS units) and acceleration joint motion that was segmented into directional components: flexion-extension (F/E), pronation-supination and radial-ulnar at the wrist, F/E at the elbow, and F/E and adduction-abduction at the shoulder. Injection parameters were determined using kinematics, followed by the clinician’s determination of which muscles would contribute to the specific upper limb tremor biomechanics and dosing per participant.</p><p>Results</p><p>Multi-joint biomechanical recordings allowed individualized muscle selection and showed significant improvement in whole-arm function, FTM parts A-C scores, at week 6 which continued throughout the study. By week 38, the total FTM score statistically significantly reduced from 16.2±4.6 at week 0 to 9.5±6.3 (p<0.0005). UPDRS item 21 score rating action tremor was significantly reduced from 2.6±0.5 at week 0 to 1.6±1.1 (p = 0.01) at week 32. Quality of life (QUEST) significantly improved from 40.3±15.8 at week 0 to 31.1±15.3 (p = 0.035) at week 32 and to 27.8±15.3 (p = 0.028) at week 38. Kinematics provided an objective, secondary outcome measure, which showed a significant decrease in tremor amplitude in the wrist and shoulder joints (p<0.05). Eight participants (40%) self-reported mild weakness in injected muscles but had no interference in arm function.</p><p>Conclusion</p><p>Kinematic tremor assessments provide the injector unique insight to objectively individualize and personalize injection parameters demonstrating BoNT-A effectively alleviates functional disability caused by essential tremor. Kinematic technology is a promising method for standardizing assessments and for focal upper limb tremor treatment.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT02427646?term=NCT02427646&rank=1" target="_blank">NCT02427646</a></p></div

ET participant demographics and baseline UPDRS, QUEST and FTM parts A to C scores.

<p>ET participant demographics and baseline UPDRS, QUEST and FTM parts A to C scores.</p

CONSORT flow diagram displaying the progress of the study’s design.

<p>CONSORT flow diagram displaying the progress of the study’s design.</p

IncobotulinumtoxinA treatments significantly reduced severity of tremor and provided functional benefit for fine and gross motor tasks with mild muscle weakness in treated muscles.

<p>(A) Tremor severity, FTM part A sub-category score (max: /4 per task), significantly decreased. (B) Handwriting, spiral and line writing tasks showed significant improvement, signified by FTM part B summed score, and functional disability, FTM part C summed score (max: /4 per category, 8 categories in total), was significantly reduced. (C) Quality of life, measured by QUEST tallied 30-items (max: /4 per item), significantly increased. (D) Angular RMS tremor amplitude (primary y-axis) and hand and finger acceleration values (secondary y-axis) at each arm joint was averaged per time-point. Significant reductions in wrist and shoulder tremor amplitudes resembled change in hand and finger acceleration values. (E) Angular wrist tremor RMS amplitude for each scripted-task was significantly reduced. (F) Maximal grip strength (blue) was significantly reduced, but did not impair function, and perceived muscle weakness (red) yielded no significant change at injection visits. All plotted values are means for all participants per each time-point. Asterisks represented statistical significant change (p<0.05) compared to baseline. Error bars represent standard deviation of population.</p

Mean injected dosage per arm muscle treated at each treatment time-point.

<p>Mean injected dosage per arm muscle treated at each treatment time-point.</p

Additional file 1: of Kinematic and kinetic assessment of upper limb movements in patients with writer's cramp

Profiles of the Z-scores of the applied forces (Thumb, Index, and Hand), the measured joint angles (wrist, elbow, and shoulder), and the cramp severities on all surfaces for each individual patient. (PDF 241 kb