Force Control Issues in Upper and Lower Limbs in Parkinson's Disease and Freezing of Gait.

Parkinson's Disease (PD) has been found to cause force control deficits in upper and lower limbs. About 50% of patients with advanced PD develop a debilitating symptom called freezing of gait (FOG), which has been linked to force control problems in the lower limbs, and some may only have a limited response to the gold standard pharmaceutical therapy, levodopa, resulting in partially levodopa-responsive FOG (PLR-FOG). There has been limited research on investigating upper-limb force control in people with PD with PLR-FOG, and without FOG. In this pilot study, force control was explored using an upper-and-lower-limb haptics-enabled robot in a reaching task while people with PD with and without PLR-FOG were on their levodopa medication. A healthy control group was used for reference, and each cohort completed the task at three different levels of assistance provided by the robot. Similar significant proportional force control deficits were found in the upper and lower limbs in patients with PLR-FOG versus those without FOG. Some aspects of force control were found to be retained, including an ability to increase or decrease force in response to changes in resistance while completing a reaching task. Overall, these results suggest there are force control deficits in both the upper and lower limbs in people with PLR-FOG.

Conversion to AbobotulinumtoxinA Increases Waning Time and Efficacy for Cervical Dystonia.

Background: Symptom re-emergence before re-injection negatively impacts cervical dystonia (CD) patients receiving botulinum toxin type A (BoNT-A) therapy. Longer waning time is associated with abobotulinumtoxinA (abo-BoNT-A) as compared to onabotulinumtoxinA (ona-BoNT-A)/incobotulinumtoxinA (inco-BoNT-A) formulations. Objectives: To compare waning time and treatment outcomes when chronically injected CD patients experiencing early waning despite being optimized on BoNT-A (ona-BoNT-A/inco-BoNT-A) were converted to abo-BoNT-A. Methods: Thirty-three chronically injected CD participants with a waning time of ≤8 weeks were converted to abo-BoNT-A (1:2.5 dose ratio) for three injections every 12-weeks. The second and third injection patterns were kinematically optimized. Participants were converted back to their original BoNT-A for the fourth injection (1:2.5) using the same third abo-BoNT-A pattern. Participant-perceived waning times were collected post-injections. Clinical scales (Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)) and kinematic measures were collected 12-weeks post-injection and at three peak effect time-points. Results: Compared to baseline, waning time (12-22 days) significantly increased following all abo-BoNT-A treatments (P < 0.005) but was not significantly different at the fourth injection (original BoNT-A reconversion). TWSTRS sub-scores significantly reduced following all abo-BoNT-A treatments (P < 0.0001) and at peak effect following the third injection compared to original BoNT-A. Dysphagia and muscle weakness were reported and comparable to safety of original BoNT-A formulations. Conclusions: Optimized patients experiencing waning had significant improvement in the peak benefit as well as the duration of effect when converted to abo-BoNT-A. This effect was toxin dependent as reconversion to the original BoNT-A using the kinematically optimized pattern failed to produce an improvement in waning.

Real-World Longitudinal Experience of Botulinum Toxin Therapy for Parkinson and Essential Tremor.

BACKGROUND: Botulinum toxin type A (BoNT-A) therapy for upper-limb tremor has emerged as a promising option. However, it is unclear in real-world practices whether a technology-guided approach can compare with expert clinical assessments (including surface anatomy and palpation) for improving outcomes. This retrospective study aims to review our clinical outcomes of treating essential tremor (ET) and Parkinson's disease (PD) tremor using either clinical- or kinematic-based injection pattern determination methods. METHODS: 68 ET and 45 PD patients received at least one injection for their upper-limb tremor (unilateral or bilateral) in the last 7 years. Demographics of patients and BoNT-A injections were collected. A Mann-Whitney U statistical test was used to compare outcome measures between ET and PD cohorts. RESULTS: Mean age (72 ± 9 years), number of injections (5), years receiving therapy (~2 years), clinic- (~57%) or kinematic-based patterns, and self-paying (52%) were similar between both cohorts. BoNT-A as a monotherapy in both upper limbs was received in more ET than PD patients. Double reconstitution of Xeomin® in the wrist flexors/extensors, supinator, biceps, and triceps were most injected. Discontinuation due to no benefit/weakness was not dependent on the injection pattern determination approach. CONCLUSIONS: Kinematic-based BoNT-A injections produced similar treatment outcomes to injections based on the clinical expertise of the expert injector. This suggests that kinematics could be used by a non-expert to attain equivalent efficacy potentially improving access to this treatment.

Changes in Cortical Excitability and Parkinson Tremor After Botulinum Toxin Therapy.

OBJECTIVES: This study investigated the relationship between botulinum toxin type A (BoNT-A) administration, tremor amplitude, and modulation of intracortical excitability and sensorimotor processing using paired-pulse transcranial magnetic stimulation (pp-TMS) in early, tremor-dominant Parkinson's disease (PD) patients. METHODS: Twelve "De-novo" (naïve to anti-PD medications) and seven "L-dopa" (optimized on levodopa) PD participants with tremor affecting one arm were recruited. All participants received 4 serial BoNT-A treatments for tremor every 12-weeks and peak effect was assessed 6-weeks post-treatment, totaling 8 visits over 42-weeks. Injection parameters were based on kinematic tremor analysis. Short interval intracortical inhibition (SICI), intracortical facilitation (ICF), long interval intracortical inhibition (LICI), and measures of sensorimotor interaction (short- (SAI) and long- (LAI) latency afferent stimulation) were assessed in both hemispheres using pp-TMS paradigms at each time-point. Linear mixed models analyzed the effect of each pp-TMS measure and tremor severity within each cohort and the association between pp-TMS and tremor severity in the "De-novo" cohort over 42-weeks. T-tests compared pp-TMS measures between hemispheres per time-point. RESULTS: Baseline SICI, LICI, and SAI was reduced (higher MEP ratio) on the tremulous/treated-side compared to the non-tremulous-side in "De-novo" participants. On the treated-side in the "De-novo" cohort, BoNT-A treatment significantly reduced ICF and increased LICI, SAI and LAI (lower MEP ratio) at peak BoNT-A time-points. The change in tremor severity was significantly associated with changes in SICI, LICI and LAI. CONCLUSIONS: Our findings suggest that tremor severity in early PD may be related to impaired intracortical inhibition and defective sensorimotor integration.

Developing a Consistent, Reproducible Botulinum Toxin Type A Dosing Method for Upper Limb Tremor by Kinematic Analysis.

Botulinum toxin type A (BoNT-A) injection patterns customized to each patient's unique tremor characteristics produce better efficacy and lower adverse effects compared to the fixed-muscle-fixed-dose approach for Essential Tremor (ET) and Parkinson's disease (PD) tremor therapy. This article outlined how a kinematic-based dosing method to standardize and customize BoNT-A injections for tremors was developed. Seven ET and eight PD participants with significant tremor reduction and minimal perceived weakness using optimized BoNT-A injections determined by clinical and kinematic guidance were retrospectively selected to develop the kinematic-based dosing method. BoNT-A dosages allocated per joint were paired to baseline tremor amplitudes per joint. The final kinematic-based dosing method was prospectively utilized to validate BoNT-A injection pattern selection without clinical/visual assessments in 31 ET and 47 PD participants with debilitating arm tremors (totaling 122 unique tremor patterns). Whole-arm kinematic tremor analysis was performed at baseline and 6-weeks post-injection. Correlation and linear regression analyses between baseline tremor amplitudes and the change in tremor amplitude 6-weeks post-injection, with BoNT-A dosages per joint, were performed. Injection patterns determined using clinical assessment and interpretation of kinematics produced significant associations between baseline tremor amplitudes and optimized BoNT-A dosages in all joints. The change in elbow tremor was only significantly associated with the elbow total dose as the change in the wrist and shoulder tremor amplitudes were not significantly associated with the wrist and shoulder dosages from the selected 15 ET and PD participants. Using the kinematic-based dosing method, significant associations between baseline tremor amplitudes and the change (6-weeks post-first treatment) in tremor at each joint with BoNT-A dosages for all joints was observed in all 78 ET and PD participants. The kinematic-based dosing method provided consistency in dose selection and subsequent tremor reduction and can be used to standardize tremor assessments for whole-arm tremor treatment planning.

Spinal cord stimulation therapy for gait dysfunction in progressive supranuclear palsy patients.

BACKGROUND: There are no effective symptomatic treatments for progressive supranuclear palsy (PSP). Recent studies report benefits of spinal cord stimulation (SCS) for freezing of gait (FOG) and gait disorders in Parkinson's disease and atypical Parkinsonism patients. This is the first study to report therapeutic effects of SCS in Richardson's syndrome PSP (PSP-RS) patients. METHODS: Epidural SCS was implanted in three female PSP-RS participants (3.2 ± 1.3 years with disease). Six programs (300-400 µs/30-130 Hz) were randomly tested at suprathreshold intensity on separate days. The setting that best improved gait/FOG was used daily by each participant in the study. Protokinetics walkway captured spatiotemporal gait measures and FOG episodes (turning on the spot and while walking) and clinical scales including FOG questionnaire, UPDRS-III (OFF-/ON-L-dopa), and participant-perceived global impression of change (GISC) were collected at pre-SCS, and 3, 6, 12 months post-SCS. RESULTS: Participant #1 demonstrated the highest GISC score (6.5/10) with a consistent reduction of FOGs by 43.8%, UPDRS-III score (- 5 points), and improved step length and stride velocity (33.6%) while maintaining a L-dopa response of ~ 12% over the 12 months. Participant #2, walking FOG frequency and turning duration was reduced by 39.0% (OFF-L-dopa), and ON-L-dopa UPDRS-III score worsened (+ 5 points) at 12 months. Participant #3, FOG frequency reduced by 75% up to 6 months rating a GISC 3/10 score, however disease severity worsened at 12 months. Ambulatory gait parameters universally improved by 29.6% in all participants. CONCLUSION: The results support the benefit of SCS for FOG and gait symptoms in PSP-RS and suggests early SCS intervention for dopaminergic-resistant gait should be considered.

Standardized algorithm for muscle selection and dosing of botulinum toxin for Parkinson tremor using kinematic analysis.

BACKGROUND: Inadequate efficacy and significant side effect profile makes pharmacological treatment of Parkinson's disease (PD) tremor challenging. Personalized dosing of botulinum toxin type A (BoNT-A) using tremor analysis has shown efficacy and safety for treating upper limb tremor. This study incorporated a novel, standardized treatment algorithm for determining injection pattern and BoNT-A dosing, customizable by the physician, in PD patients with disabling tremor in one or both arms. METHODS: This open-label study included 47 PD participants (25 "De-novo" and 22 "L-dopa") who received 4 serial BoNT-A treatments with follow-ups at 6 weeks post-treatment over 42 weeks. The treatment algorithm utilized kinematic tremor analysis of each participant's whole arm tremor and determined the physician's injection pattern of BoNT-A. Endpoints included changes in angular tremor amplitude, Fahn-Tolosa-Marin (FTM C) tremor scale, Movement Disorder Society-Unified Parkinson's disease rating scale (MDS-UPDRS) tremor-related score, tremor-related quality of life questionnaire, Likert ratings of perceived weakness, and maximal grip strength. RESULTS: BoNT-A significantly (p < 0.05) improved tremor amplitude (41.6%), quality of life (23.0%), UPDRS tremor score (29.6%), and arm function (FTM C; 24.6%) for both treatment cohorts from weeks 6 to 42. Maximum grip strength was reduced between 7.4% and 23.0% at follow-up visits and did not impact activities of daily living. Efficacy was obtained with first injection and remained without adjustment over two serial injection in 45% of participants. CONCLUSIONS: This is the first study to use a fully standardized treatment algorithm for personalization of BoNT-A injection patterns for disabling PD tremor over serial treatments. A sustained alleviation of tremor severity and improved arm function and quality of life fulfills an important unmet need for the treatment of PD tremor. This study demonstrated that BoNT-A can be administered as a monotherapy in tremor-dominant PD or as an add-on therapy for refractory PD tremor.

PHTNet: Characterization and Deep Mining of Involuntary Pathological Hand Tremor using Recurrent Neural Network Models.

The global aging phenomenon has increased the number of individuals with age-related neurological movement disorders including Parkinson's Disease (PD) and Essential Tremor (ET). Pathological Hand Tremor (PHT), which is considered among the most common motor symptoms of such disorders, can severely affect patients' independence and quality of life. To develop advanced rehabilitation and assistive technologies, accurate estimation/prediction of nonstationary PHT is critical, however, the required level of accuracy has not yet been achieved. The lack of sizable datasets and generalizable modeling techniques that can fully represent the spectrotemporal characteristics of PHT have been a critical bottleneck in attaining this goal. This paper addresses this unmet need through establishing a deep recurrent model to predict and eliminate the PHT component of hand motion. More specifically, we propose a machine learning-based, assumption-free, and real-time PHT elimination framework, the PHTNet, by incorporating deep bidirectional recurrent neural networks. The PHTNet is developed over a hand motion dataset of 81 ET and PD patients collected systematically in a movement disorders clinic over 3 years. The PHTNet is the first intelligent systems model developed on this scale for PHT elimination that maximizes the resolution of estimation and allows for prediction of future and upcoming sub-movements.

Personalized Bilateral Upper Limb Essential Tremor Therapy with Botulinum Toxin Using Kinematics.

Variability of multi-joint essential tremor (ET) between patients and within the two upper limbs makes a visual assessment for the determination of botulinum toxin type A (BoNT-A) injections challenging. Kinematic tremor analysis guidance has succeeded in overcoming this challenge by making effective long-term unilateral BoNT-A injections for disabling ET. In this open-label study, 31 ET participants received three bilateral arm BoNT-A injection cycles over 30 weeks with follow-ups six-weeks post-treatment. Whole-arm kinematic assessment of tremor using a customized, automated algorithm provided muscle selection and dosing per muscle without clinician's assessment. Efficacy endpoints included Fahn-Tolosa-Marin tremor scale, quality of life (QoL) questionnaire, and maximum grip strength. BoNT-A reduced tremor amplitude by 47.7% in both the arms at week-6 (p < 0.005) that persisted from weeks 18⁻30. QoL was improved by 26.5% (p < 0.005) over the treatment period. Functional interference due to tremor was reduced by 30% (p < 0.005) from weeks 6⁻30. Maximum grip strength was reduced at week 6 (p = 0.001) but was not functionally impaired for the participants. Effective bilateral ET therapy by personalized BoNT-A injections could be achieved using computer-assisted tremor analysis. By removing variability inherent within the clinical assessments, this standardized tremor analysis method enabled patients to have improved bimanual upper limb functionality after the first treatment.

Transitioning from Unilateral to Bilateral Upper Limb Tremor Therapy for Parkinson's Disease and Essential Tremor Using Botulinum Toxin: Case Series.

Botulinum toxin type A (BoNT-A) injections guided by kinematic analysis for unilateral upper limb essential tremor (ET) and Parkinson's disease (PD) tremor therapy has demonstrated efficacy, improvements in quality of life (QoL) and arm functionality. In this open-label pilot trial, 5 ET and 2 PD participants decided to switch from receiving long-term unilateral arm treatment to now bilateral BoNT-A arm therapy in their other tremulous arm which worsened over time. Injection patterns were based on kinematic analysis. Efficacy endpoints including kinematic analysis, Fahn-Tolosa-Marin tremor rating scale, QoL questionnaire, and maximal grip strength were collected over 2 treatments and 2 follow-up visits totaling 18-weeks. BoNT-A decreased wrist tremor amplitude by 84.6% and 89.6% 6-weeks following the 1st injection in the newly-treated limb in ET and PD participants, respectively. PD participants started with worse QoL but demonstrated an additional improvement in QoL by 29.9% for switching to bilateral treatment, whereas ET participants did not. Left and right arm tremor also did not share commonalities in severity or dose. This preliminary finding suggests trends for transitioning to bilateral therapy and warrants further studies to evaluate efficacy of bilateral tremor BoNT-A therapy in a larger cohort of PD and ET patients.

Personalized botulinum toxin type A therapy for cervical dystonia based on kinematic guidance.

BACKGROUND: Botulinum toxin type A (BoNT-A) injections is the accepted first-line therapy for cervical dystonia (CD), however, numerous patients discontinue treatment early due to perceived sub-optimal relief. To improve BoNT-A therapy for CD, proper assessment of neck motion and selection of relevant muscles and dosing must be met. Kinematic technology may improve treatment outcomes by guiding physicians to better tailor muscle selection and BoNT-A dosing for CD therapy. METHODS: 28 CD participants were placed into either group: expert injector determined injection patterns by visual assessment ("vb") versus injection patterns based on kinematics interpreted by an expert injector ("kb"). Injections occurred at weeks 0, 16 and 32 with follow-ups at weeks 6, 22 and 38. Kinematics utilized four sensors to capture the severity of multiaxial, static neck posturing (e.g., torticollis) and dynamic, spasmodic/tremor movements while participants were seated. Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score changes were evaluated over 38 weeks. RESULTS: For the "kb" participants, there was a significant 28.8% (- 11.25 points) reduction in TWSTRS total score at week 6, as well as significant reduction in severity and disability TWSTRS sub-scores (parts I and II) with maintained improvement at subsequent visits. As for the "vb" participants had a significant reduction in total TWSTRS score by 28.5% (- 9.84 points) after week 22. Disability score for the "vb" group trended towards improvement over 38 weeks. CONCLUSION: Clinical judgement guided by kinematic analysis of CD biomechanics can result in faster optimal muscle selections and minimize use of higher BoNT-A doses as compared to visual determination, thereby achieving comparable and potentially better treatment outcomes.

Spinal Cord Stimulation Therapy for Gait Dysfunction in Advanced Parkinson's Disease Patients.

BACKGROUND: Benefits of dopaminergic therapy and deep brain stimulation are limited and unpredictable for axial symptoms in Parkinson's disease. Dorsal spinal cord stimulation may be a new therapeutic approach. The objective of this study was to investigate the therapeutic effect of spinal cord stimulation on gait including freezing of gait in advanced PD patients. METHODS: Five male PD participants with significant gait disturbances and freezing of gait underwent midthoracic spinal cord stimulation. Spinal cord stimulation combinations (200-500 µs/30-130 Hz) at suprathreshold intensity were tested over a 1- to 4-month period, and the effects of spinal cord stimulation were studied 6 months after spinal cord stimulation surgery. Protokinetics Walkway measured gait parameters. Z scores per gait variable established each participant's best spinal cord stimulation setting. Timed sit-to-stand and automated freezing-of-gait detection using foot pressures were analyzed. Freezing of Gait Questionnaire (FOG-Q), UPDRS motor items, and activities-specific balance confidence scale were completed at each study visit. RESULTS: Spinal cord stimulation setting combinations of 300-400 µs/30-130 Hz provided gait improvements. Although on-medication/on-stimulation at 6 months, mean step length, stride velocity, and sit-to-stand improved by 38.8%, 42.3%, and 50.3%, respectively, mean UPDRS, Freezing of Gait Questionnaire, and activities-specific balance confidence scale scores improved by 33.5%, 26.8%, and 71.4%, respectively. The mean number of freezing-of-gait episodes reduced significantly from 16 presurgery to 0 at 6 months while patients were on levodopa and off stimulation. CONCLUSIONS: By using objective measures to detect dynamic gait characteristics, the therapeutic potential of spinal cord stimulation was optimized to each participant's characteristics. This pilot study demonstrated the safety and significant therapeutic outcome of spinal cord stimulation in advanced PD patients, and thus a larger and longer clinical study will be conducted to replicate these results. © 2018 International Parkinson and Movement Disorder Society.

Botulinum Toxin Type A Injections as Monotherapy for Upper Limb Essential Tremor Using Kinematics.

BACKGROUND: There is a significant need for a targeted therapy for essential tremor (ET), as medications have not been developed specifically for ET, and the ones prescribed are often not well-tolerated, so that many patients remain untreated. Recent work has shown that, unlike previous experience, kinematically guided individualized botulinum toxin type A (BoNT-A) injections provide benefit along with minimal weakness. Ours is the first long-term (96-week) safety and efficacy study of BoNT-A as monotherapy for ET using kinematically driven injection parameters. METHODS: Ten ET patients were administered six serial BoNT-A treatments every 16 weeks and were assessed at 6 weeks following treatment. During each study visit, the Fahn-Tolosa-Marin (FTM) scale, the Unified Parkinson's Disease Rating Scale, and the Quality of Life for Essential Tremor Questionnaire (QUEST) were administered along with kinematic assessment of the treated limb. Participants performed scripted tasks with motion sensors placed over each arm joint. Dosing patterns were determined using the movement disorder neurologist's interpretation of muscles contributing to the kinematically analyzed upper limb tremor biomechanics. RESULTS: There was a 33.8% (p<0.05) functional improvement (FTM part C) and a 39.8% (p<0.0005) improvement in QUEST score at week 96 compared to pretreatment scores at week 0. Although there was a 44.6% (p<0.0005) non-dose-dependent reduction in maximal grip strength, only 2 participants complained of mild weakness. Following the fourth serial treatment, mean action tremor score was reduced by 62.9% (p=0.001) in the treated and by 44.4% (p=0.03) in the untreated arm at week 96 compared to week 48. CONCLUSIONS: Individualized BoNT-A dosing patterns to each individual's tremor biomechanics provided an effective monotherapy for ET as function improved without functionally limiting muscle weakness.

Long-term tremor therapy for Parkinson and essential tremor with sensor-guided botulinum toxin type A injections.

OBJECTIVE: Current pharmacological agents used to treat Parkinson disease (PD) tremor and essential tremor (ET) provide suboptimal benefit and are commonly associated with significant adverse effects. Botulinum toxin type A (BoNT-A) has been shown to be effective for wrist tremor though functionally bothersome muscle weakness frequently occurs. This is the longest study to date demonstrating that BoNT-A therapy coupled with kinematic guidance can provide efficacious outcomes for upper limb tremor with minimized unwanted weakness. METHODS: A total of 28 PD and 24 ET participants with bothersome, disabling tremor, received six serial BoNT-A treatments every 16 weeks starting at week 0 with a follow-up visit 6 weeks following a treatment, totaling 96 weeks. Clinical scales, including Fahn-Tolosa-Marin tremor rating scale (FTM), and sensor-based tremor assessments were conducted at each visit. Kinematics was utilized to identify which arm muscles contributed to the tremulous movements and the experienced injector used clinical expertise in determining BoNT-A dosages. RESULTS: Following BoNT-A treatment, clinical ratings of tremor severity and functional ability (FTM) showed significant improvements following the first treatment which was maintained up to week 96 in PD and ET. Kinematics detected a significant reduction in PD and ET tremor amplitudes by 70% and 76% over the treatment course, respectively. By objectively distinguishing tremulous muscles and tremor severity, adverse effects were limited to mild perceived weakness by participants in injected muscles during follow-ups. Following the fourth treatment, BoNT-A dosages in flexor and extensor wrist muscles and biceps were reduced for those experiencing residual weakness which ultimately did not interfere with tremor relief or arm function. CONCLUSIONS: Kinematics is an objective method that can aid clinicians in assessing and determining optimal BoNT-A parameters to alleviate both PD and ET tremor. BoNT-A injections are tolerable and effective when focal therapy regimens are determined and optimized kinematically over a long-term.

Haptic Feedback Manipulation During Botulinum Toxin Injection Therapy for Focal Hand Dystonia Patients: A Possible New Assistive Strategy.

Abnormality of sensorimotor integration in the basal ganglia and cortex has been reported in the literature for patients with task-specific focal hand dystonia (FHD). In this study, we investigate the effect of manipulation of kinesthetic input in people living with writer's cramp disorder (a major form of FHD). For this purpose, severity of dystonia is studied for 11 participants while the symptoms of seven participants have been tracked during five sessions of assessment and Botulinum toxin injection (BoNT-A) therapy (one of the current suggested therapies for dystonia). BoNT-A therapy is delivered in the first and the third session. The goal is to analyze the effect of haptic manipulation as a potential assistive technique during BoNT-A therapy. The trial includes writing, hovering, and spiral/sinusoidal drawing subtasks. In each session, the subtasks are repeated twice when (a) a participant uses a normal pen, and (b) when the participant uses a robotics-assisted system (supporting the pen) which provides a compliant virtual writing surface and manipulates the kinesthetic sensory input. The results show (p-value using one-sample t-tests) that reducing the writing surface rigidity significantly decreases the severity of dystonia and results in better control of grip pressure (an indicator of dystonic cramping). It is also shown that (p-value based on paired-samples t-test) using the proposed haptic manipulation strategy, it is possible to augment the effectiveness of BoNT-A therapy. The outcome of this study is then used in the design of an actuated pen as a writing-assistance tool that can provide compliant haptic interaction during writing for FHD patients.

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

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.

Effective Management of Upper Limb Parkinsonian Tremor by IncobotulinumtoxinA Injections Using Sensor-based Biomechanical Patterns.

BACKGROUND: Focal treatment of Parkinson's disease tremor by botulinum toxin type A incobotulinumtoxinA (BoNT-A) injections has been inadequately investigated and at best provides modest relief with significant muscle weakness. Complexity of multi-joint tremulous movements results in non-individualized dosing regimens. This 38-week open-label study used kinematic technology to guide muscle selection and improve efficacy of incobotulinumtoxinA (BoNT-A) injections for Parkinson's disease tremor. METHODS: Participants (n=28) attended study visits at weeks 0, 6, 16, 22, 32, and 38, and were injected with BoNT-A at weeks 0, 16, and 32. During each visit, clinical tremor scales, the Unified Parkinson's Disease Rating Scale (UPDRS) and the Fahn-Tolosa-Marin (FTM), and kinematic assessments were conducted. Participants performed rest and postural scripted tasks with motion sensors placed over the wrist, elbow, and shoulder joints where tremor was quantified by angular root mean square (RMS) amplitude in multiple degrees of freedom at each joint. Injection parameters were determined using the clinician's interpretation of which muscles would contribute to the upper limb tremor biomechanics analyzed kinematically. RESULTS: Kinematic measures of tremor amplitude allowed detailed segmentation of tremor into directional components at each arm joint permitting a statistically significant decrease in mean UPDRS item 20 (rest tremor) at week 16 (p=0.006) and at week 32 (p=0.014), and in FTM tremor severity scores at week 6 (p=0.024). Ten participants perceived mild muscle weakness following the third treatment, which did not interfere with performing activities of daily living. DISCUSSION: Kinematics is a simple method for standardizing assessments and treatment of upper limb Parkinson's disease tremor, thereby personalizing tremor therapy and optimizing the effect of BoNT-A injections for Parkinson's disease tremor.