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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.

Abstract Background Neuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to investigate the relative contribution of white matter hyperintensities and cortical thickness to NPS in participants across neurodegenerative and cerebrovascular diseases. Methods Five hundred thirteen participants with one of these conditions, i.e. Alzheimer’s Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson’s Disease, or Cerebrovascular Disease, were included in the study. NPS were assessed using the Neuropsychiatric Inventory – Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter loss. Results Although NPS were frequent across the five disease groups, participants with frontotemporal dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both frontotemporal dementia and Parkinson’s disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities. Conclusions In participants with neurodegenerative and cerebrovascular diseases, our results suggest that smaller cortical thickness and white matter hyperintensity burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed.

Speech rate reduction is a global speech therapy approach for speech deficits in Parkinson’s disease (PD) that has the potential to result in changes across multiple speech subsystems. While the overall goal of rate reduction is usually improvements in speech intelligibility, not all people with PD benefit from this approach. Speech rate is often targeted as a means of improving articulatory precision, though less is known about rate-induced changes in other speech subsystems that could help or hinder communication. The purpose of this study was to quantify phonatory changes associated with speech rate modification across a broad range of speech rates from very slow to very fast in talkers with and without PD. Four speaker groups participated: younger and older healthy controls, and people with PD with and without deep brain stimulation of the subthalamic nucleus (STN-DBS). Talkers read aloud standardized sentences at 7 speech rates elicited using magnitude production: habitual, three slower rates, and three faster rates. Acoustic measures of speech intensity, cepstral peak prominence, and fundamental frequency were measured as a function of speech rate and group. Overall, slower rates of speech were associated with differential effects on phonation across the four groups. While all talkers spoke at a lower pitch in slow speech, younger talkers showed increases in speech intensity and cepstral peak prominence, while talkers with PD and STN-DBS showed the reverse pattern. Talkers with PD without STN-DBS and older healthy controls behaved in between these two extremes. At faster rates, all groups uniformly demonstrated increases in cepstral peak prominence. While speech rate reductions are intended to promote positive changes in articulation to compensate for speech deficits in dysarthria, the present results highlight that undesirable changes may be invoked across other subsystems, such as at the laryngeal level. In particular, talkers with STN-DBS, who often demonstrate speech deterioration following DBS surgery, demonstrated more phonatory detriments at slowed speech rates. Findings have implications for speech rate candidacy considerations and speech motor control processes in PD.

Abstract Sensorimotor control (SMC) is a complex function that involves sensory, cognitive, and motor systems working together to plan, update and execute voluntary movements. Any abnormality in these systems could lead to deficits in SMC, which would negatively impact an individual's ability to execute goal-directed motions. Recent studies have shown that patients diagnosed with Parkinson's disease (PD) have dysfunctions in sensory, motor, and cognitive systems, which could give rise to SMC deficits. However, SMC deficits in PD and how they affect a patient's upper-limb movements have not been well understood. The objective of the study was to investigate SMC deficits in PD and how they affect the planning and correction of upper-limb motions. This was accomplished using a robotic manipulandum equipped with a virtual-reality system. Twenty age-matched healthy controls and fifty-six PD patients (before and after medication) completed an obstacle avoidance task under dynamic conditions (target and obstacles in moving or stationary form, with and without mechanical perturbations). Kinematic information from the robot was used to extract eighteen features that evaluated the SMC functions of the participants. The findings show that the PD patients before medication were 32% slower, reached 16% fewer targets, hit 41% more obstacles, and were 26% less efficient than the control participants, and the difference in these features was statistically significant under dynamic conditions. In addition to the motor deficits, the PD patients also showed deficits in handling high cognitive loads and interpreting sensory cues. Further, the PD patients after medication exhibited worse sensory and cognitive performance than before medication under complex testing conditions. The PD patients also showed deficits in following the computational models leading to poor motor planning.

The obliquus capitis inferioris (OCI) muscle is a significant driver of cervical dystonia with torticaput movements and a no–no head tremor. Limited data are available on the efficacy of OCI injections on patient outcomes. Our study aims to determine whether the botulinum toxin injection into OCI improves subjective patient quality of life in those with dystonic head tremors. A retrospective chart review was performed for 25 patients receiving injections into the OCI for a dystonic head tremor at the London Movement Disorders Clinic between January 2020 and January 2022. Toronto Western Spasmodic Torticollis Scale-2 (TWSTRS-2) subscale scores for disability and pain, TWSTRS-PSYCH scores, and the global impression of severity were extracted. The average TWSTRS-2 disability subscale change was −2.8 points (p < 0.003). The average TWSTRS-2 pain subscale change was −4.6 points (p < 0.003). The average TWSTRS-PSYCH score prior to injection was 5.6. After injection, the average score was 3.7 (p < 0.004). The patient self-reported average global impression of severity before injection was 7.0; after this, it was 4.2 (p < 0.0003). The OCI injection showed significant improvement in retrospective patient self-reported outcomes; it should be considered early in the treatment plan for cervical dystonia with a no–no head tremor.

Biallelic intronic repeat expansion in the replication factor complex unit 1 (RFC1) gene has recently been described as a cause of late onset ataxia with degeneration of the cerebellum, sensory pathways and the vestibular apparatus. This condition is termed cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). Since the identification of this novel gene mutation, the phenotypic spectrum of RFC1 mutations continues to expand and includes not only CANVAS but also slowly progressive cerebellar ataxia, ataxia with chronic cough (ACC), isolated sensory neuropathy and multisystemic diseases. We present a patient with a genetically confirmed intronic repeat expansion in the RFC1 gene with a symptom complex not described previously.

Abstract Genetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consider the clinical and pathological overlap observed across neurodegenerative diseases and the potential for genetic overlap between the phenotypes. Here, we leveraged rare variant association analyses (RVAAs) to elucidate the genetic overlap among multiple neurodegenerative diagnoses, including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson’s disease (PD), as well as cerebrovascular disease, using the data generated with a custom-designed neurodegenerative disease gene panel in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). As expected, only ~3% of ONDRI participants harboured a monogenic variant likely driving their disease presentation. Yet, when genes were binned based on previous disease associations, we observed an enrichment of putative loss of function variants in PD genes across all ONDRI cohorts. Further, individual gene-based RVAA identified significant enrichment of rare, nonsynonymous variants in PARK2 in the FTD cohort, and in NOTCH3 in the PD cohort. The results indicate that there may be greater heterogeneity in the genetic factors contributing to neurodegeneration than previously appreciated. Although the mechanisms by which these genes contribute to disease presentation must be further explored, we hypothesize they may be a result of rare variants of moderate phenotypic effect contributing to overlapping pathology and clinical features observed across neurodegenerative diagnoses.

Abstract Background Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied. Methods Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative (n = 519). Results In total, we identified and validated four CNVs in the cohort, including: (1) a heterozygous deletion of exon 5 in OPTN in an Alzheimer's disease participant; (2) a duplication of exons 1–5 in PARK7 in an amyotrophic lateral sclerosis participant; (3) a duplication of >3 Mb, which encompassed ABCC6, in a cerebrovascular disease (CVD) participant; and (4) a duplication of exons 7–11 in SAMHD1 in a mild cognitive impairment participant. We also identified 43 additional CNVs that may be candidates for future replication studies. Conclusion The identification of the CNVs suggests a portion of the apparent missing heritability of the phenotypes may be due to these structural variants, and their assessment is imperative for a thorough understanding of the genetic spectrum of neurodegeneration.

Scientific and technological advances achieved with industrial expansion have led to an ever-increasing demand for heavy metals. This demand has, in turn, led to increased contamination of soil, water and air with these metals. Chronic exposure to metals may be detrimental not only to occupational workers but also to the nonoccupational population exposed to these metals. Manganese (Mn), a commonly used heavy metal, is an essential cofactor for many enzymatic processes that drive biological functions. However, it is also a potential source of neurotoxicity, particularly in the field of movement disorders. The typical manifestation of Mn overexposure is parkinsonism, which may be difficult to differentiate from the more common idiopathic Parkinson’s disease. In addition to environmental exposure to Mn, other potential etiologies causing hypermanganesemia include systemic health conditions, total parenteral nutrition and genetic mutations causing Mn dyshomeostasis. In this review, we critically analyze Mn and discuss its sources of exposure, pathophysiology and clinical manifestations. We have highlighted the global public health impact of Mn and emphasize that movement disorder specialists should record a detailed social and occupational history to ensure that a toxic etiology is not misdiagnosed as a neurodegenerative disease. In the absence of a definite therapeutic option, early diagnosis and timely institution of preventive measures are the keys to managing its toxic effects.

Assessing biomechanics of upper limb movement is essential for guiding targeted therapy to treat conditions such as spasticity and dystonia. Targeted therapy, including injections of medications into specific muscles (e.g., lidocaine, botulinum toxin type A), requires accurate identification (activity) and contribution of as many muscles as possible. Currently, this is achieved by visual clinical assessment or using surface electromyography (sEMG). Although sEMG could provide a reasonable estimate of muscle activity for certain superficial muscles after an intense filtering process, they are unable to provide separated activity and contribution for every superficial and deep muscle. Other proposed musculoskeletal and machine learning models similarly do not provide a detailed and accurate activity of every muscle. The objective of the study is to design a subject-specific musculoskeletal model to predict the activity and contribution of each muscle pertaining to any upper limb movement with improved detail and accuracy over existing methodologies. Performance metrics were calculated for validation by comparing the predicted muscle activity with the normalized sEMG data computed from 8 superficial muscles, while the deeper muscles were not included in the validation as the sEMG is unable to provide a separated activity for those muscles. The results show that the proposed model has a mean R2 value of 0.8190 and also indicated a statistically significant correlation ( $P < 0.0001$ ) between the calculated (normalized sEMG data) and predicted activity value. Additionally, and significantly, compared to earlier studies, the proposed model predicts the individual muscle activity and contribution of deeper muscles.

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.

The spectrum of tauopathy encompasses heterogenous group of neurodegenerative disorders characterized by neural or glial deposition of pathological protein tau. Clinically they can present as cognitive syndromes, movement disorders, motor neuron disease, or mixed. The heterogeneity in clinical presentation, genetic background, and underlying pathology make it difficult to classify and clinically approach tauopathy. In the literature, tauopathies are thus mostly highlighted from pathological perspective. From clinical standpoint, cognitive syndromes are often been focussed while reviewing tauopathies. However, the spectrum of tauopathy has also evolved significantly in the domain of movement disorders and has transgressed beyond the domain of primary tauopathies. Secondary tauopathies from neuroinflammation or autoimmune insults and some other “novel” tauopathies are increasingly being reported in the current literature, while some of them are geographically isolated. Because of the overlapping clinical phenotypes, it often becomes difficult for the clinician to diagnose them clinically and have to wait for the pathological confirmation by autopsy. However, each of these tauopathies has some clinical and radiological signatures those can help in clinical diagnosis and targeted genetic testing. In this review, we have exposed the heterogeneity of tauopathy from a movement disorder perspective and have provided a clinical approach to diagnose them ante mortem before confirmatory autopsy. Additionally, phenotypic variability of these disorders (chameleons) and the look-alikes (mimics) have been discussed with potential clinical pointers for each of them. The review provides a framework within which new and as yet undiscovered entities can be classified in the future.

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

Altered gene expression related to Parkinson's Disease (PD) has not been described in the living brain, yet this information may support novel discovery pertinent to disease pathophysiology and treatment. This study compared the transcriptome in brain biopsies obtained from living PD and Control patients. To evaluate the novelty of this data, a comprehensive literature review also compared differentially expressed gene (DEGs) identified in the current study with those reported in PD cadaveric brain and peripheral tissues. RNA was extracted from rapidly cryopreserved frontal lobe specimens collected from PD and Control patients undergoing neurosurgical procedures. RNA sequencing (RNA-Seq) was performed and validated using quantitative polymerase chain reaction. DEG data was assessed using bioinformatics and subsequently included within a comparative analysis of PD RNA-Seq studies. 370 DEGs identified in living brain specimens reflected diverse gene groups and included key members of trophic signaling, apoptosis, inflammation and cell metabolism pathways. The comprehensive literature review yielded 7 RNA-Seq datasets generated from blood, skin and cadaveric brain but none from a living brain source. From the current dataset, 123 DEGs were identified only within the living brain and 267 DEGs were either newly found or had distinct directional change in living brain relative to other tissues. This is the first known study to analyze the transcriptome in brain tissue from living PD and Control patients. The data produced using these methods offer a unique, unexplored resource with potential to advance insight into the genetic associations of PD.

Dysfunction within large-scale brain networks as the basis for movement disorders is an accepted hypothesis. The treatment options for restoring network function are limited. Non-invasive brain stimulation techniques such as repetitive transcranial magnetic stimulation are now being studied to modify the network. Transcranial electrical stimulation (tES) is also a portable, cost-effective, and non-invasive way of network modulation. Transcranial direct current stimulation and transcranial alternating current stimulation have been studied in Parkinson’s disease, dystonia, tremor, and ataxia. Transcranial pulsed current stimulation and transcranial random noise stimulation are not yet studied enough. The literature in the use of these techniques is intriguing, yet many unanswered questions remain. In this review, we highlight the studies using these four potential tES techniques and their electrophysiological basis and consider the therapeutic implication in the field of movement disorders. The objectives are to consolidate the current literature, demonstrate that these methods are feasible, and encourage the application of such techniques in the near future.

Wearable global position system (GPS) technology can help those working with older populations and people living with movement disorders monitor and maintain their mobility level. Health research using GPS often employs inconsistent recording lengths due to the lack of a standard minimum GPS recording length for a clinical context. Our work aimed to recommend a GPS recording length for an older clinical population. Over 14 days, 70 older adults with Parkinson’s disease wore the wireless inertial motion unit with GPS (WIMU-GPS) during waking hours to capture daily “time outside”, “trip count”, “hotspots count” and “area size travelled”. The longest recording length accounting for weekend and weekdays was ≥7 days of ≥800 daily minutes of data (14 participants with 156, 483.9 min recorded). We compared the error rate generated when using data based on recording lengths shorter than this sample. The smallest percentage errors were observed across all outcomes, except “hotspots count”, with daily recordings ≥500 min (8.3 h). Eight recording days will capture mobility variability throughout days of the week. This study adds empirical evidence to the sensor literature on the required minimum duration of GPS recording.

Over the past 30 years, botulinum toxin (BoNT) has seen an ever-expanding use in disorders afflicting the nervous system [...]

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.

The simple definition of tone as the resistance to passive stretch is physiologically a complex interlaced network encompassing neural circuits in the brain, spinal cord, and muscle spindle. Disorders of muscle tone can arise from dysfunction in these pathways and manifest as hypertonia or hypotonia. The loss of supraspinal control mechanisms gives rise to hypertonia, resulting in spasticity or rigidity. On the other hand, dystonia and paratonia also manifest as abnormalities of muscle tone, but arise more due to the network dysfunction between the basal ganglia and the thalamo-cerebello-cortical connections. In this review, we have discussed the normal homeostatic mechanisms maintaining tone and the pathophysiology of spasticity and rigidity with its anatomical correlates. Thereafter, we have also highlighted the phenomenon of network dysfunction, cortical disinhibition, and neuroplastic alterations giving rise to dystonia and paratonia.

In this first, double-blind, randomized, placebo-controlled exploratory trial, we evaluate the efficacy and safety of incobotulinumtoxinA and feasibility of using kinematic tremor assessment to aid in the planning of muscle selection in a multicenter setting. Reproducibility of the planning technology to other clinical sites was explored. In this trial (NCT02207946), patients with upper-limb essential tremor (ET) were randomized 2:1 to a single treatment cycle of incobotulinumtoxinA or placebo. A tremor kinematic analytics investigational device was used to define a customized muscle set for injection, related to the pattern of the wrist, forearm, elbow, and shoulder tremor for each patient, and the incobotulinumtoxinA dose per muscle (total ≤ 200 U). Fahn–Tolosa–Marin (FTM) Part B motor performance score, Global Impression of Change Scale (GICS), and kinematic analysis-based efficacy evaluations were assessed. Thirty patients were randomized (incobotulinumtoxinA, n = 19; placebo, n = 11). FTM motor performance scores showed greater improvement with incobotulinumtoxinA versus placebo at Week 4 (p= 0.003) and Week 8 (p= 0.031). The physician-rated GICS score indicated improvement with incobotulinumtoxinA versus placebo at Week 4 (p < 0.05). IncobotulinumtoxinA also decreased accelerometric hand-tremor amplitude versus placebo from baseline to Week 4 (p= 0.004) and Week 8 (p < 0.001), with persistent tremor reduction up to 24 weeks post-injection. IncobotulinumtoxinA produced a slight and transient reduction of maximal grip strength versus placebo; two patients reported localized finger muscle weakness. Customized incobotulinumtoxinA injections decreased tremor severity and improved hand motor function in patients with upper-limb ET after a single injection cycle, with a favorable tolerability profile. The study showed that tremor kinematic analytics technology could be successfully scaled for use in other clinical sites.

Cervical dystonia (CD) is a neurological movement disorder characterized by sustained involuntary muscle contractions. First-line therapy for CD is intramuscular injections of botulinum neurotoxin (e.g., abobotulinumtoxinA) into the affected muscles. The objective of this systematic literature review is to assess the clinical evidence regarding the effects of abobotulinumtoxinA for treatment of CD in studies of safety, efficacy, patient-reported outcomes, and economic outcomes. Using comprehensive electronic medical literature databases, a search strategy was developed using a combination of Medical Subject Heading terms and keywords. Results were reviewed by two independent reviewers who rated the level of evidence. The search yielded 263 publications, of which 232 were excluded for being duplicate publications, not meeting the selection criteria, or failing to meet predefined eligibility criteria, leaving a total of 31 articles. Clinical efficacy, patient-reported outcomes, and safety data were in 6 placebo-controlled trials (8 articles), 6 active-controlled trials, and 16 observational studies (17 articles). Data on health economic outcomes were provided in one of the clinical trials, in two of the observational studies, and in one specific cost-analysis publication. This review demonstrated that the routine use of abobotulinumtoxinA in CD is well-established, effective, and generally well-tolerated, with a relatively low cost of treatment.

BackgroundThe levodopa challenge test is routinely used in Parkinson disease (PD) to determine a patient’s motor improvement following levodopa administration [levodopa response (LR)]. LR is most commonly reported as a percent OFF to ON change in the Unified Parkinson Disease Rating Scale (UPDRS) part III score, and occasionally as an absolute difference in score. This inconsistency in LR determination alters how clinical factors such as patient age and disease duration are understood in relation to LR in PD.ObjectiveThe aim of this study was to compare the calculation of the LR as either a percent change or difference in UPDRS-III motor score between OFF and ON medication. These two scores were then used to correlate to disease duration, patient age, levodopa duration, levodopa equivalent dose (LED), OFF score, cognition, mood, gait, and quality of life (QOL).Methods70 PD patients underwent the levodopa challenge test. The UPDRS-III motor examination was performed in the defined OFF and ON medication states to determine LR. Each patient was assessed after 12–14 h without anti-parkinsonian medication and then given three 100/25 mg levodopa/carbidopa tablets. LR was reported as both a difference in score [OFF − ON; absolute LR (aLR)] and as a percent change in score [(OFF − ON)/OFF*100%; %LR]. Patients completed the following non-motor symptom assessment scales: Montreal Cognitive Assessment, Freezing of Gait Questionnaire, Activities-specific Balance Confidence Scale, Parkinson’s Disease Questionnaire, and Geriatric Depression Scale. The effect of the LR calculation method was correlated to the clinical measures.ResultsThe aLR was significantly associated with disease duration (r = 0.40), levodopa duration (r = 0.47), OFF motor score (r = 0.58), and LED (r = 0.31), but not age. The aLR was also found to have a significant relationship with clinical scales assessing cognition (r = 0.41), freezing of gait (r = 0.35), QOL (r = 0.40), and depression (r = 0.30). By contrast, the more commonly used %LR demonstrated no significant relationships with any of the variables tested.ConclusionAlthough the %LR is more commonly employed in clinical protocols and research studies, the aLR is the superior method for reporting motor response to levodopa in PD given its significant associations with the clinical factors evaluated.

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.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.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.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.

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.

Introduction: Writer's cramp is a specific focal hand dystonia causing abnormal posturing and tremor in the upper limb. The most popular medical intervention, botulinum neurotoxin type A (BoNT-A) therapy, is variably effective for 50–70% of patients. BoNT-A non-responders undergo ineffective treatment and may experience significant side effects. Various assessments have been used to determine response prediction to BoNT-A, but not in the same population of patients. Methods: A comprehensive assessment was employed to measure various symptom aspects. Clinical scales, full upper-limb kinematic measures, self-report, and task performance measures were assessed for nine writer's cramp patients at baseline. Patients received two BoNT-A injections then were classified as responders or non-responders based on a quantified self-report measure. Baseline scores were compared between groups, across all measures, to determine which scores predicted a positive BoNT-A response. Results: Five of nine patients were responders. No kinematic measures were predictably different between groups. Analyses revealed three features that predicted a favorable response and separated the two groups: higher than average cramp severity and cramp frequency, and below average cramp latency. Discussion: Non-kinematic measures appear to be superior in making such predictions. Specifically, measures of cramp severity, frequency, and latency during performance of a specific set of writing and drawing tasks were predictive factors. Since kinematic was not used to determine the injection pattern and the injections were visually guided, it may still be possible to use individual patient kinematics for better outcomes.

Background: Neuroferritinopathy (NF) is a rare autosomal dominant disease caused by mutations in the ferritin light chain 1 (FTL1) gene leading to abnormal excessive iron accumulation in the brain, predominantly in the basal ganglia. Methods: A literature search was performed on Pubmed, for English-language articles, utilizing the terms iron metabolism, neurodegeneration with brain iron accumulation, and NF. The relevant articles were reviewed with a focus on the pathophysiology, clinical presentation, differential diagnoses, and management of NF. Results: There have been nine reported mutations worldwide in the FTL1 gene in 90 patients, the most common mutation being 460InsA. Chorea and dystonia are the most common presenting symptoms in NF. There are specific features, which appear to depend upon the genetic mutation. We discuss the occurrence of specific mutations in various regions along with their associated presenting phenomenology. We have compared and contrasted the commonly occurring syndromes in the differential diagnosis of NF to guide the clinician. Discussion: NF must be considered in patients presenting clinically as a progressive movement disorder with variable phenotype and imaging evidence of iron deposition within the brain, decreased serum ferritin, and negative genetic testing for other more common movement disorders such as Huntington’s disease. In the absence of a disease-specific treatment, symptomatic drug therapy for specific movement disorders may be used, although with variable success.

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

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.

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.