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.

RETREAT - a REal-time TREmor Analysis Tool

<p>The EUROVOLC project aims to promote an integrated and harmonised European volcanological community, and one of its main themes focuses on understanding sub-surface processes. Early identification of magma moving towards the surface is very important for the mitigation of risks from volcanic hazards, and joint research activities within the project aim to develop and improve volcano pre-eruptive detection schemes. Volcanic tremor is a sustained seismic signal associated with eruptions and is often linked to movement of magmatic fluids in the subsurface. However, it can occur pre-, syn- and post-eruption, and signals with similar spectral content can also be generated by several other processes (e.g. flooding, rockfalls). Hence one of the best ways of distinguishing between the processes underlying tremor generation is through tracking the evolution of its spatial location. Due to its continuous nature tremor cannot be located using classical seismological methods and so its source must be determined using alternatives such as seismic array analysis.</p><p>This work presents RETREAT, a REal-time TREmor Analysis Tool developed under EUROVOLC, that uses seismic array data and array processing techniques to detect, quantify and locate volcanic tremor signals. It is an open-source python-based tool that utilizes existing routines from the open-source <em>obspy</em> framework to carry out analysis of seismic array data in real-time. The tool performs f-k (frequency-wavenumber) analysis using beamforming to calculate the back azimuth and slowness in overlapping time windows, which can be used to detect and track the location of volcanic tremor sources.</p><p>A graphical and web-based interface has been developed which allows adjustment of highly configurable input parameters. These include options for setting the data source, pre-processing, timing and update options as well as the parameters for the seismic array analysis which must be carefully selected and tuned for the specified array. Once configured the tool fetches waveform data in real time and updates its output accordingly, returning plots of the array processing results (slowness and back azimuth values) as well as plots of the seismic waveform, envelope and spectrogram. The tool has been tested on real-time data using the <em>obspy</em> FDSN (International Federation of Digital Seismograph Networks) client to fetch data from the IRIS datacenter, using example array data from the small aperture SPITS seismic array in Spitsbergen, Svalbard. A 'replay’ mode using existing archive (non real-time) data has also been implemented and tested on array data from the 2014 eruption at Holuhraun and Bardarbunga volcano in Iceland, collected as part of the FUTUREVOLC project. The RETREAT tool is now ready for testing and implementation in a volcano monitoring setting at observatories. It will also be made freely available to download as a EUROVOLC community tool.</p>

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.

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.