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

Abstract

Objective: 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.

Method: 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.

Results: 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT02427646.

Conflict of interest statement

Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Jog has non-financial support from Allergan Inc., Teva Pharmaceuticals, and AbbVie. In addition, Dr. Jog, who is commercializing this medical device, has a patent PCT/CA2013/000804 pending to MDDT Inc., and a patent PCT/CA2014/050893 pending to MDDT Inc. Dr. Rahimi has a patent PCT/CA2013/000804 pending to MDDT Inc., and a patent PCT/CA2014/050893 pending to MDDT Inc., and was a former post-doctoral fellow and now performs contract work with MDDT Inc. to continue commercial development. Mr. Lee is a former research associate and now is a MDDT Inc. employee. Ms. Samotus reports a government industrial MITACS grant in collaboration with Merz Pharma during the conduct of the study. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. CONSORT flow diagram displaying the progress of the study’s design.

Fig 2

Sample kinematic data showing (A) presence of tremor in the wrist, elbow and shoulder joints and (B) the ideal injection parameters determined using the kinematics with the injector’s best clinical judgement. (A) Total tremor severity (plot 1) is displayed in angular RMS amplitude and the percent distribution of tremulous movement (plot 2) by 3 DOFs in the wrist and by 2 DOFs in the shoulder joint. Error bars indicate standard deviation over three trials. (B) Injector’s interpretation of the kinematic results showing selection of total dose allocated to wrist, elbow and shoulder muscle groups based on tremor severity and the muscles selected based on the amount of tremor present in each degree of freedom that each arm joint moves in.

Fig 3. IncobotulinumtoxinA treatments significantly reduced severity of tremor and provided functional benefit for fine and gross motor tasks with mild muscle weakness in treated muscles.

(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