Use of botulinum toxin in the management of dystonia in Parkinson's disease.

Botulinum toxin is one of the most potent neurotoxins, but when injected into an overactive muscle, it can transiently alleviate an involuntary movement, such as dystonia. The primary aim of this article is to provide a comprehensive review of the various forms of dystonia observed in patients with Parkinson's disease who can benefit from a therapeutic trial of botulinum toxin. Although most of these indications are not supported by randomized controlled clinical trials and, therefore, not approved by the Food and Drug Administration, there are many open-label trials supporting a large body of empirical experience testifying to the benefits of botulinum toxin treatment in these conditions.

Systemic Symptoms in Huntington's Disease: A Comprehensive Review.

BACKGROUND: Although Huntington's disease (HD) is usually thought of as a triad of motor, cognitive, and psychiatric symptoms, there is growing appreciation of HD as a systemic illness affecting the entire body. OBJECTIVES: This review aims to draw attention to these systemic non-motor symptoms in HD. METHODS: We identified relevant studies published in English by searching MEDLINE (from 1966 to September 2023), using the following subject headings: Huntington disease, autonomic, systemic, cardiovascular, respiratory, gastrointestinal, urinary, sexual and cutaneous, and additional specific symptoms. RESULTS: Data from 123 articles were critically reviewed with focus on systemic features associated with HD, such as cardiovascular, respiratory, gastrointestinal, urinary, sexual and sweating. CONCLUSION: This systematic review draws attention to a variety of systemic and autonomic co-morbidities in patients with HD. Not all of them correlate with the severity of the primary HD symptoms or CAG repeats. More research is needed to better understand the pathophysiology and treatment of systemic and autonomic dysfunction in HD.

Tics emergencies and malignant tourette syndrome: Assessment and management.

Tourette syndrome (TS) is a complex neurodevelopmental disorder characterized by the presence of tics, frequently accompanied by a variety of neuropsychiatric comorbidities. A subset of patients with TS present with severe and disabling symptoms, requiring prompt therapeutic intervention. Some of these manifestations may result in medical emergencies when severe motor or phonic tics lead to damage of anatomical structures closely related to the tic. Examples include myelopathy or radiculopathy following severe neck ("whiplash") jerks or a variety of self-inflicted injuries. In addition to self-aggression or, less commonly, allo-aggression, some patients exhibit highly inappropriate behavior, suicidal tendencies, and rage attacks which increase the burden of the disease and are important components of "malignant TS". This subset of TS is frequently associated with comorbid obsessive-compulsive disorder. Therapeutic measures include intensive behavioral therapy, optimization of oral pharmacotherapy, botulinum toxin injections, and deep brain stimulation.

Current opinions and practices in post-stroke movement disorders: Survey of movement disorders society members.

BACKGROUND: Post-stroke movement disorders (PSMD) encompass a wide array of presentations, which vary in mode of onset, phenomenology, response to treatment, and natural history. There are no evidence-based guidelines on the diagnosis and treatment of PSMD. OBJECTIVES: To survey current opinions and practices on the diagnosis and treatment of PSMD. METHODS: A survey was developed by the PSMD Study Group, commissioned by the International Parkinson's and Movement Disorders Society (MDS). The survey, distributed to all members, yielded a total of 529 responses, 395 (74.7%) of which came from clinicians with experience with PSMD. RESULTS: Parkinsonism (68%), hemiballismus/hemichorea (61%), tremor (58%), and dystonia (54%) were by far the most commonly endorsed presentation of PSMD, although this varied by region. Basal ganglia stroke (76% of responders), symptoms contralateral to stroke (75%), and a temporal relationship (59%) were considered important factors for the diagnosis of PSMD. Oral medication use depended on the phenomenology of the PSMD. Almost 50% of respondents considered deep brain stimulation and ablative surgeries as options for treatment. The lack of guidelines for the diagnosis and treatment was considered the most important gap to address. CONCLUSIONS: Regionally varying opinions and practices on PSMD highlight gaps in (and mistranslation of) epidemiologic and therapeutic knowledge. Multicenter registries and prospective community-based studies are needed for the creation of evidence-based guidelines to inform the diagnosis and treatment of patients with PSMD.

Efficacy and Safety of DaxibotulinumtoxinA for Injection in Cervical Dystonia: ASPEN-1 Phase 3 Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: ASPEN-1 was a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, duration of response, and safety of 2 doses of DaxibotulinumtoxinA for Injection (DAXI), a novel botulinum toxin type A formulation in participants with cervical dystonia (CD). METHODS: Adults (aged 18-80 years) with moderate-to-severe CD (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] total score ≥20) were enrolled at 60 sites across 9 countries in Europe and North America. Participants were randomized (3:3:1) to single-dose intramuscular DAXI 125U, 250U, or placebo and followed for up to 36 weeks after injection. The primary end point was change from baseline in TWSTRS total score averaged across weeks 4 and 6. Key secondary end points included duration of effect, Clinical and Patient Global Impression of Change (CGIC, PGIC), TWSTRS subscale scores, and safety. Multiplicity-adjusted intent-to-treat hypothesis tests with multiple imputation were performed using ANCOVA and Cochran-Mantel-Haenszel analyses. RESULTS: Of 444 individuals screened, 301 were randomized to DAXI 125U (n = 125) or 250U (n = 130) or placebo (n = 46). DAXI 125U and 250U significantly improved the mean TWSTRS total score vs placebo (least squares mean [standard error] difference vs placebo: DAXI 125U, -8.5 [1.93], p < 0.0001; DAXI 250U, -6.6 [1.92], p = 0.0006). The median duration of effect (time from treatment until loss of ≥80% of the peak improvement in average TWSTRS total score achieved at weeks 4 and 6) was 24.0 (95% confidence interval 20.3-29.1) weeks with DAXI 125U and 20.3 (16.7-24.0) weeks with DAXI 250U. Significant improvements were also observed with DAXI in CGIC and PGIC responder rates and TWSTRS subscales. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.6% of participants with DAXI 125U, 23.8% with DAXI 250U, and 17.4% with placebo, with injection site pain being the most common overall. The most frequently reported treatment-related TEAEs of interest in DAXI 125U, DAXI 250U, and placebo, respectively, were muscular weakness (4.8%, 2.3%, 0%), musculoskeletal pain (2.4%, 3.1%, 0%), and dysphagia (1.6%, 3.8%, 0%). DISCUSSION: This study demonstrated that DAXI, at doses of 125U and 250U, is an effective, safe, long-acting, and well-tolerated treatment for CD. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier (NCT03608397, submitted July 11, 2018) and EU Clinical Trials Register (ClinicalTrialsRegister.eu EudraCT identifier 2018-000446-19, submitted September 13, 2018). First participant enrolled on June 11, 2018. Trial registration was performed in accordance with the Food and Drug Administration Amendments Act (FDAAA 801), which stipulates that the responsible party register an applicable clinical trial not later than 21 calendar days after enrolling the first human participant (42 CFR 11.24). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in adults with moderate-to-severe idiopathic cervical dystonia, DAXI reduces dystonia more effectively than placebo.

CADASIL: A NOTCH3-associated cerebral small vessel disease.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease (CSVD), pathologically characterized by a non-atherosclerotic and non-amyloid diffuse angiopathy primarily involving small to medium-sized penetrating arteries and leptomeningeal arteries. In 1996, mutation in the notch receptor 3 gene (NOTCH3) was identified as the cause of CADASIL. However, since that time other genetic CSVDs have been described, including the HtrA serine peptidase 1 gene-associated CSVD and the cathepsin A gene-associated CSVD, that clinically mimic the original phenotype. Though NOTCH3-associated CSVD is now a well-recognized hereditary disorder and the number of studies investigating this disease is increasing, the role of NOTCH3 in the pathogenesis of CADASIL remains elusive. AIM OF REVIEW: This review aims to provide insights into the pathogenesis and the diagnosis of hereditary CSVDs, as well as personalized therapy, predictive approach, and targeted prevention. In this review, we summarize the current progress in CADASIL, including the clinical, neuroimaging, pathological, genetic, diagnostic, and therapeutic aspects, as well as differential diagnosis, in which the role of NOTCH3 mutations is highlighted. KEY SCIENTIFIC CONCEPTS OF REVIEW: In this review, CADASIL is revisited as a NOTCH3-associated CSVD along with other hereditary CSVDs.

Longitudinal predictors of health-related quality of life in isolated dystonia.

OBJECTIVE: To determine longitudinal predictors of health-related quality of life (HR-QoL) in an international multicenter cohort of patients with isolated dystonia. METHODS: Out of 603 dystonia patients prospectively enrolled in the Natural History Dystonia Coalition study, 155 were assessed three times within 2 years for HR-QoL, symptoms of depression, generalized anxiety disorder (GAD), and social anxiety disorder (SAD), as well as dystonia severity and dystonic tremor. In addition, the impact of botulinum neurotoxin (BoNT) injections on HR-QoL was evaluated after 1 year. RESULTS: Depressive symptoms at baseline predicted lower HR-QoL on all subscales after 2 years (all p ≤ 0.001). Higher GAD scores at baseline predicted lower HR-QoL related to general health, pain and emotional well-being, whereas higher SAD scores predicted higher pain-related QoL after 2 years (all p ≤ 0.006). Dystonia severity at baseline predicted social functioning (p = 0.002). Neither dystonic tremor, age, or sex predicted HR-QoL at 2 years. Two latent categories were revealed across the three-time points: Category 1 with higher total HR-QoL scores (mean HR-QoL = 74.4% ± 16.1), susceptible to symptoms of depression and SAD, and Category 2 with lower total HR-QoL scores (mean HR-QoL = 45.5% ± 17.6), susceptible to symptoms of GAD. HR-QoL improved over the course of 1 year irrespective of the use of BoNT. CONCLUSION: The longitudinal impact of psychiatric symptoms on HR-QoL emphasizes the importance of incorporating mental health treatment, in particular also the therapy of anxiety disorders, into treatment regimens for dystonia.

Retinal Thickness in Essential Tremor and Early Parkinson Disease: Exploring Diagnostic Insights.

BACKGROUND: Essential tremor (ET) represents a heterogeneous condition which may overlap with Parkinson disease (PD) even at early stages, by sharing some subtle clinical aspects. Longstanding ET demonstrated also higher risk of developing PD, especially with a Tremor-dominant (TD-PD) phenotype. Therefore, differential diagnosis between ET and early PD could be quite challenging. Optical coherence tomography (OCT) has been recognized as a reliable tool to assess the retina as a proxy of neurodegeneration. We aimed to explore the possible role of retinal assessment in differential diagnosis between ET and early PD. METHODS: Macular layers and peripapillary retinal nerve fiber layer (RNFL) thickness among ET, early PD, and healthy controls (HCs) were assessed using OCT. RESULTS: Forty-two eyes from 23 ET, 41 eyes from 21 early PD, and 33 eyes from 17 HCs were analyzed. Macular RNFL, ganglion cell layer, inner plexiform layer, and inner nuclear layer were thinner in PD as compared with ET and even more in HCs. Differences between ET and PD were more evident when considering the TD-PD subgroup, especially for RNFL. Among ET patients, thickness of the inner macular layers showed negative linear relationship with both age at onset and disease duration. Peripapillary temporal quadrant thinning was found in ET compared with HCs. CONCLUSIONS: Macular inner retina was thinner in patients with ET and early PD compared with HCs. These findings suggest that the retinal assessment may have a utility in the differential diagnosis between ET and PD.

Botulinum toxin treatment in parkinsonism.

Botulinum toxin (BoNT) was approved by the United States Food and Drug Administration (FDA) in 1989 for facial movement disorders and strabismus, but since that time its indications have been expanding beyond neurologic and ophthalmologic disorders. This article is a narrative review of the therapeutic use of BoNT in tremors, dystonia, sialorrhea, bladder and other autonomic symptoms, levodopa-induced dyskinesia and other problems occuring in the setting of parkinsonism. Though FDA approval is lacking for some of these indications, expert experiences have shown that BoNT is often beneficial in this group of patients.

Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: Experience from the MJFF Global Genetic Parkinson's Disease Project.

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.

Linking the cerebellum to Parkinson disease: an update.

Parkinson disease (PD) is characterized by heterogeneous motor and non-motor symptoms, resulting from neurodegeneration involving various parts of the central nervous system. Although PD pathology predominantly involves the nigral-striatal system, growing evidence suggests that pathological changes extend beyond the basal ganglia into other parts of the brain, including the cerebellum. In addition to a primary involvement in motor control, the cerebellum is now known to also have an important role in cognitive, sleep and affective processes. Over the past decade, an accumulating body of research has provided clinical, pathological, neurophysiological, structural and functional neuroimaging findings that clearly establish a link between the cerebellum and PD. This Review presents an overview and update on the involvement of the cerebellum in the clinical features and pathogenesis of PD, which could provide a novel framework for a better understanding the heterogeneity of the disease.

Safety and Efficacy of Long-Term Deutetrabenazine Use in Children and Adolescents with Tics Associated with Tourette Syndrome: An Open-Label Extension Study.

Background: Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and phonic tics. Objective: To assess the safety and efficacy of deutetrabenazine (Teva Neuroscience, Inc, Parsippany, NJ), a vesicular monoamine transporter 2 inhibitor, in children and adolescents with TS. Methods: Alternatives for Reducing Tics in TS (ARTISTS) open-label extension (OLE) (NCT03567291) was a 54-week, global, phase 3, open-label extension study of deutetrabenazine (6-48 mg daily) conducted May 28, 2018 to April 3, 2020 with a 2-week randomized withdrawal period. Participants (6-16 years of age) had TS and active tics causing distress or impairment. Safety (primary outcome) was assessed by treatment-emergent adverse events (TEAEs) and clinical laboratory testing. Efficacy was measured by the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS). Results: The intent-to-treat population (228 participants; mean age, 12.0 years; 79.8% male; 86.4% white) had a median (range) duration of exposure of 28.4 (0.3-52.9) weeks. Of 227 participants in the safety analysis, 161 (70.9%) reported ≥1 TEAE (exposure-adjusted incidence rate, 2.77/patient-year), of which 95 (41.9%) were treatment related. The most frequently reported TEAEs were headaches, somnolence, nasopharyngitis, weight increases, and anxiety. No additional safety signals were observed. Worsening of YGTSS-TTS after the 2-week randomized withdrawal was not statistically significant (least squares mean difference, -0.4; P = 0.78). Several exploratory measures showed sustained improvement throughout the treatment periods. Conclusions: In this long-term, open-label trial, deutetrabenazine was well tolerated with low frequency of TEAEs. There was no significant difference in tics between treatment arms during the 2-week randomized withdrawal period, however, descriptive statistics and comparison with baseline showed a numeric improvement in tics, quality of life, and other measures.

Assessing the Severity of Cervical Dystonia: Ask the Doctor or Ask the Patient?

Background: Assessing disease severity can be performed using either clinician-rated scales (CRS) or patient-rated outcome (PRO) tools. These two measures frequently demonstrate poor correlations. Objectives: To determine if the correlation between a CRS and PRO for motor features of cervical dystonia (CD) improves by accounting for non-motor features. Methods: Subjects with CD (N = 209) were evaluated using a CRS (Toronto Western Spasmodic Torticollis Rating Scale, TWSTRS) and a PRO (Cervical Dystonia Impact Profile, CDIP-58). Results: Linear regression revealed a weak correlation between the two measures, even when considering only the motor subscales of each. The strength of this relationship improved with a regression model that included non-motor symptoms of pain, depression, and disability. Conclusions: These results argue that the results of motor assessments in a PRO for CD cannot be fully appreciated without simultaneous assessment of non-motor co-morbidities. This conclusion might apply to other disorders, especially those with frequent non-motor co-morbidities.

Treatment of cervical dystonia with Botox (onabotulinumtoxinA): Development, insights, and impact.

Cervical dystonia (CD), the most common focal dystonia encountered in neurologic practice, is a chronic disorder in which the muscles of the neck involuntarily contract and cause abnormal postures and movements of the head, neck, and shoulders. Treatment of CD prior to botulinum toxin was unsatisfactory, as existing therapies often did not improve symptoms. The use of botulinum toxin for CD grew out of its success in treating blepharospasm, another type of focal dystonia. On the basis of results from a double-blind, placebo-controlled trial, onabotulinumtoxinA was approved in 2000 in the US for the treatment of CD in adults in order to alleviate abnormal head position and neck pain. A subsequent large observational trial further demonstrated the effectiveness of onabotulinumtoxinA for CD, showing improvements in various rating scales, physician-reported measures, and profound positive effects on patient quality of life, including in amelioration of pain and improvements in work productivity. In addition, onabotulinumtoxinA treatment also reduced the complications of CD, as patients no longer develop contractures (permanent muscle and tendon shortening from prolonged untreated dystonia), which markedly limited the range of neck motion. The onset of onabotulinumtoxinA treatment also accompanied advances in understanding the functional anatomy of neck muscles, basal ganglia physiology, and video and other recording technology. Following the success of onabotulinumtoxinA in the treatment of CD, its use has been expanded into numerous other therapeutic indications, and these advances stimulated educational and training programs by various neurologic and other medical societies.

Real-world experience with VMAT2 inhibitors in Tourette syndrome.

OBJECTIVES: We aimed to review our "real-world" experience with the vesicular monoamine transporter 2 (VMAT2) inhibitors tetrabenazine, deutetrabenazine, and valbenazine for treatment of Tourette syndrome, focusing on therapeutic benefits, side effect profile, and accessibility for the off-label use of these drugs. METHODS: We performed a retrospective chart review, supplemented with a telephone survey, of all our patients treated for their tics with VMAT2 inhibitors over a period of 4 years from January 2017 until January 2021. RESULTS: We identified 164 patients treated with the various VMAT2 inhibitors (tetrabenazine, n = 135; deutetrabenazine, n = 71; valbenazine, n = 20). Data on the mean treatment duration and daily dosages were collected. The response to VMAT2 inhibitors was assessed by a Likert scale by comparing the symptom severity before initiation and while on treatment. Side effects were mild and mostly consisted of depression as the major side effect but there was no suicidality reported. CONCLUSION: VMAT2 inhibitors are effective and safe in the treatment of tics associated with Tourette syndrome but are not readily accessible by patients in the United States, partly because of lack of approval by the Food and Drug Administration.

Spinal cord stimulation for gait disturbances in Parkinson's disease.

INTRODUCTION: Gait disturbances are a major contributor to the disability associated with Parkinson's disease. Although pharmacologic therapies and deep brain stimulation improve most motor parkinsonian features, their effects on gait are highly variable. Spinal cord stimulation, typically used for the treatment of chronic pain, has emerged as a potential therapeutic approach to improve gait disturbances in Parkinson's disease. AREAS COVERED: The authors review the available evidence on the effects of spinal cord stimulation in patients with Parkinson's disease, targeting primarily gait abnormalities. They also discuss possible mechanisms, safety, and methodological implications for future clinical trials. This systematic review of originally published articles in English language was performed using The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA).

The role of the PLA2G6 gene in neurodegenerative diseases.

PLA2G6-associated neurodegeneration (PLAN) represents a continuum of clinically and genetically heterogeneous neurodegenerative disorders with overlapping features. Usually, it encompasses three autosomal recessive diseases, including infantile neuroaxonal dystrophy or neurodegeneration with brain iron accumulation (NBIA) 2A, atypical neuronal dystrophy with childhood-onset or NBIA2B, and adult-onset dystonia-parkinsonism form named PARK14, and possibly a certain subtype of hereditary spastic paraplegia. PLAN is caused by variants in the phospholipase A2 group VI gene (PLA2G6), which encodes an enzyme involved in membrane homeostasis, signal transduction, mitochondrial dysfunction, and α-synuclein aggregation. In this review, we discuss PLA2G6 gene structure and protein, functional findings, genetic deficiency models, various PLAN disease phenotypes, and study strategies in the future. Our primary aim is to provide an overview of genotype-phenotype correlations of PLAN subtypes and speculate on the role of PLA2G6 in potential mechanisms underlying these conditions.

Neutralizing Antibody Formation with OnabotulinumtoxinA (BOTOX®) Treatment from Global Registration Studies across Multiple Indications: A Meta-Analysis.

Though the formation of neutralizing antibodies (NAbs) during treatment with botulinum neurotoxin is rare, their presence may nonetheless affect the biological activity of botulinum toxin and negatively impact clinical response. The goal of this updated meta-analysis was to evaluate and characterize the rate of NAb formation using an expanded dataset composed of 33 prospective placebo-controlled and open-label clinical trials with nearly 30,000 longitudinal subject records prior to and following onabotulinumtoxinA treatment in 10 therapeutic and aesthetic indications. Total onabotulinumtoxinA doses per treatment ranged from 10 U to 600 U administered in ≤15 treatment cycles. The NAb formation at baseline and post-treatment was tested and examined for impact on clinical safety and efficacy. Overall, 27 of the 5876 evaluable subjects (0.5%) developed NAbs after onabotulinumtoxinA treatment. At study exit, 16 of the 5876 subjects (0.3%) remained NAb positive. Due to the low incidence of NAb formation, no clear relationship was discernable between positive NAb results and gender, indication, dose level, dosing interval, treatment cycles, or the site of injection. Only five subjects who developed NAbs post-treatment were considered secondary nonresponders. Subjects who developed NAbs revealed no other evidence of immunological reactions or clinical disorders. This comprehensive meta-analysis confirms the low NAb formation rate following onabotulinumtoxinA treatment across multiple indications, and its limited clinical impact on treatment safety and efficacy.