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

Abstract

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 (n528) 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 (p50.006) and at week 32 (p50.014), and in FTM tremor severity scores at week 6 (p50.024). 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.

Botulinum Toxin for the Treatment of Hand Tremor

“…To our knowledge, this is the longest duration of follow-up data reported regarding the use of BoNT for hand tremor, although we previously reported our long-term experience with BoNT in the treatment of dystonia over a period of more than 20 years [ 19 ]. The mean age of our patient population and the male predominance is similar to those reported in recently published studies of BoNT in the treatment of tremor [ 20 , 21 , 22 , 23 , 24 , 25 ]. There was a relatively long period of time between onset of symptoms and first injection (mean 23.2 years, up to 75 years).…”

Botulinum Toxin for the Treatment of Hand Tremor

“…To our knowledge, this is the longest duration of follow-up data reported regarding the use of BoNT for hand tremor, although we previously reported our long-term experience with BoNT in the treatment of dystonia over a period of more than 20 years [ 19 ]. The mean age of our patient population and the male predominance is similar to those reported in recently published studies of BoNT in the treatment of tremor [ 20 , 21 , 22 , 23 , 24 , 25 ]. There was a relatively long period of time between onset of symptoms and first injection (mean 23.2 years, up to 75 years).…”

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

“…However, finger weakness was not viewed to be functionally disabling to terminate treatment. 14 Although the implementation of the treatment algorithm in the current study did reduce the incidence of finger drop as compared with the pilot study, 14 there is an opportunity to improve targeting of the supinator and extensor carpi muscles by using ultrasound and by reducing diffusion by hyper-concentrating BoNT-A during reconstitution (e.g. 0.5 cc saline to 100 U BoNT-A).…”

“…Significant improvements in functional ability and QoL were reported in “De-novo” and in “L-dopa” (treatment-refractory tremor) cohorts following the first injection, with an observed trend of tremor reduction being on average 14.1% greater in the “L-dopa” cohort over the treatment course (weeks 6–42). Interestingly, our previous study of kinematic-guided BoNT-A therapy for PD tremor did not produce sustained QoL and functional improvements, 14 thus highlighting the importance of automating tremor assessment and treatment pattern determination. This immediate QoL and functional improvement in our present study contrasts results reported by another group with a combined 35 years of experience treating upper limb tremor with BoNT-A where three injection cycles were required for treatment optimization.…”

Assessing Digital Health Technologies for Outcome Measurement in Parkinson's Disease Drug Trials: A Systematic Review

“…The majority of the included publications (n = 34, 81.0%) focused on drug‐related interventional trials, comprising both RCTs (n = 25) 6‐30 and nonrandomized trials (n = 9) 31‐39 . These studies comprised a range of trial phases: phase 1 (n = 1), 27 phase 2 (n = 21), 6‐8,10,13,14,16,19‐21,24,25,28‐31,33‐36,39 phase 3 (n = 2), 9,11 and phase 4 (n = 10) 12,15,17,18,22,23,26,32,37,38 .…”

“…Koller and Herbster 30 similarly used a prototype accelerometer on the index finger, correlating the results with clinical scores. Other sensor modalities included electrogoniometers and torsiometers combined with triaxial accelerometers at six upper‐limb locations (shoulder, elbow, wrist, forearm, hand, finger), as used by Samotus et al 33 and Rahimi et al, 34 with outcome variables correlated against the Fahn–Tolosa–Marin (FTM) and UPDRS‐III tremor items. Additionally, Binder et al 39 demonstrated the feasibility of long‐term home monitoring using a wrist‐worn Actiwatch to capture tremor amplitude and duration over 24 h, with data compared against UPDRS‐III scores and patient diaries.…”

Botulinum Toxin for the Treatment of Hand Tremor

“…To our knowledge, this is the longest duration of follow-up data reported regarding the use of BoNT for hand tremor, although we previously reported our long-term experience with BoNT in the treatment of dystonia over a period of more than 20 years [ 19 ]. The mean age of our patient population and the male predominance is similar to those reported in recently published studies of BoNT in the treatment of tremor [ 20 , 21 , 22 , 23 , 24 , 25 ]. There was a relatively long period of time between onset of symptoms and first injection (mean 23.2 years, up to 75 years).…”

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

“…However, finger weakness was not viewed to be functionally disabling to terminate treatment. 14 Although the implementation of the treatment algorithm in the current study did reduce the incidence of finger drop as compared with the pilot study, 14 there is an opportunity to improve targeting of the supinator and extensor carpi muscles by using ultrasound and by reducing diffusion by hyper-concentrating BoNT-A during reconstitution (e.g. 0.5 cc saline to 100 U BoNT-A).…”

“…Significant improvements in functional ability and QoL were reported in “De-novo” and in “L-dopa” (treatment-refractory tremor) cohorts following the first injection, with an observed trend of tremor reduction being on average 14.1% greater in the “L-dopa” cohort over the treatment course (weeks 6–42). Interestingly, our previous study of kinematic-guided BoNT-A therapy for PD tremor did not produce sustained QoL and functional improvements, 14 thus highlighting the importance of automating tremor assessment and treatment pattern determination. This immediate QoL and functional improvement in our present study contrasts results reported by another group with a combined 35 years of experience treating upper limb tremor with BoNT-A where three injection cycles were required for treatment optimization.…”

Assessing Digital Health Technologies for Outcome Measurement in Parkinson's Disease Drug Trials: A Systematic Review

“…The majority of the included publications (n = 34, 81.0%) focused on drug‐related interventional trials, comprising both RCTs (n = 25) 6‐30 and nonrandomized trials (n = 9) 31‐39 . These studies comprised a range of trial phases: phase 1 (n = 1), 27 phase 2 (n = 21), 6‐8,10,13,14,16,19‐21,24,25,28‐31,33‐36,39 phase 3 (n = 2), 9,11 and phase 4 (n = 10) 12,15,17,18,22,23,26,32,37,38 .…”

“…Koller and Herbster 30 similarly used a prototype accelerometer on the index finger, correlating the results with clinical scores. Other sensor modalities included electrogoniometers and torsiometers combined with triaxial accelerometers at six upper‐limb locations (shoulder, elbow, wrist, forearm, hand, finger), as used by Samotus et al 33 and Rahimi et al, 34 with outcome variables correlated against the Fahn–Tolosa–Marin (FTM) and UPDRS‐III tremor items. Additionally, Binder et al 39 demonstrated the feasibility of long‐term home monitoring using a wrist‐worn Actiwatch to capture tremor amplitude and duration over 24 h, with data compared against UPDRS‐III scores and patient diaries.…”

Botulinum Toxin for the Treatment of Hand Tremor

“…To our knowledge, this is the longest duration of follow-up data reported regarding the use of BoNT for hand tremor, although we previously reported our long-term experience with BoNT in the treatment of dystonia over a period of more than 20 years [ 19 ]. The mean age of our patient population and the male predominance is similar to those reported in recently published studies of BoNT in the treatment of tremor [ 20 , 21 , 22 , 23 , 24 , 25 ]. There was a relatively long period of time between onset of symptoms and first injection (mean 23.2 years, up to 75 years).…”

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

“…However, finger weakness was not viewed to be functionally disabling to terminate treatment. 14 Although the implementation of the treatment algorithm in the current study did reduce the incidence of finger drop as compared with the pilot study, 14 there is an opportunity to improve targeting of the supinator and extensor carpi muscles by using ultrasound and by reducing diffusion by hyper-concentrating BoNT-A during reconstitution (e.g. 0.5 cc saline to 100 U BoNT-A).…”

“…Significant improvements in functional ability and QoL were reported in “De-novo” and in “L-dopa” (treatment-refractory tremor) cohorts following the first injection, with an observed trend of tremor reduction being on average 14.1% greater in the “L-dopa” cohort over the treatment course (weeks 6–42). Interestingly, our previous study of kinematic-guided BoNT-A therapy for PD tremor did not produce sustained QoL and functional improvements, 14 thus highlighting the importance of automating tremor assessment and treatment pattern determination. This immediate QoL and functional improvement in our present study contrasts results reported by another group with a combined 35 years of experience treating upper limb tremor with BoNT-A where three injection cycles were required for treatment optimization.…”

Assessing Digital Health Technologies for Outcome Measurement in Parkinson's Disease Drug Trials: A Systematic Review

“…The majority of the included publications (n = 34, 81.0%) focused on drug‐related interventional trials, comprising both RCTs (n = 25) 6‐30 and nonrandomized trials (n = 9) 31‐39 . These studies comprised a range of trial phases: phase 1 (n = 1), 27 phase 2 (n = 21), 6‐8,10,13,14,16,19‐21,24,25,28‐31,33‐36,39 phase 3 (n = 2), 9,11 and phase 4 (n = 10) 12,15,17,18,22,23,26,32,37,38 .…”

“…Koller and Herbster 30 similarly used a prototype accelerometer on the index finger, correlating the results with clinical scores. Other sensor modalities included electrogoniometers and torsiometers combined with triaxial accelerometers at six upper‐limb locations (shoulder, elbow, wrist, forearm, hand, finger), as used by Samotus et al 33 and Rahimi et al, 34 with outcome variables correlated against the Fahn–Tolosa–Marin (FTM) and UPDRS‐III tremor items. Additionally, Binder et al 39 demonstrated the feasibility of long‐term home monitoring using a wrist‐worn Actiwatch to capture tremor amplitude and duration over 24 h, with data compared against UPDRS‐III scores and patient diaries.…”