Severity of Antipsychotic-Induced Cervical Dystonia Assessed by the Algorithm-Based Rating System.

Background: The severity of antipsychotic-induced cervical dystonia has traditionally been evaluated visually. However, recent advances in information technology made quantification possible in this field through the introduction of engineering methodologies like machine learning.Methods: This study was conducted from June 2021 to March 2023. Psychiatrists rated the severity of cervical dystonia into 4 levels (0: none, 1: minimal, 2: mild, and 3: moderate) for 101 videoclips, recorded from 87 psychiatric patients receiving antipsychotics. The Face Mesh function of the open-source framework MediaPipe was employed to calculate the tilt angles of anterocollis or retrocollis, laterocollis, and torticollis. These were calculated to examine the range of tilt angles for the 4 levels of severity of the different types of cervical dystonia.Results: The tilt angles calculated using Face Mesh for each level of dystonia were 0° ≤ θ < 6° for none, 6° ≤ θ < 11° for minimal, 11° ≤ θ < 25° for mild, and 25° ≤ θ for moderate laterocollis; 0° ≤ θ < 11° for none, 11° ≤ θ < 18° for minimal, 18° ≤ θ <25° for mild, and 25° ≤ θ for moderate anterocollis or retrocollis; and 0° ≤ θ < 9° for none, 9° ≤ θ < 17° for minimal, 17° ≤ θ < 32° for mild, and 32° ≤ θ for moderate torticollis.Conclusion: While further validation with new cases is needed, the range of tilt angles in this study could provide a standard for future artificial intelligence devices for cervical dystonia.

Botulinum Toxin Injections to the Obliquus Capitis Inferioris Muscle for Dynamic Cervical Dystonia Improves Subjective Patient Outcomes.

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.

Spatiotemporal Gait Differences before and after Botulinum Toxin in People with Focal Dystonia: A Pilot Study.

BACKGROUND: The impact of focal dystonia on gait has attracted little attention and remains elusive. Considering the importance of both visual and head control in gait, blepharospasm and cervical dystonia should affect gait. Improvement of cervical/eyelid control following botulinum toxin (BTX) injections would translate into gait changes. OBJECTIVES: To assess gait differences in people with focal dystonia before and after BTX treatment. METHODS: Ten patients with blepharospasm, 10 patients with cervical dystonia, and 20 healthy age- and gender-matched controls were included. Gait was assessed before and 1-month after BTX injections using Biodex Gait Trainer™ 3. Gait velocity, cadence, step length, step asymmetry, and variability of step length were compared between patients and controls, and between the two time-points using non-parametric statistics. RESULTS: At baseline, compared to controls, cervical dystonia patients showed reduced gait velocity, step length, and cadence. After BTX injections, while gait velocity and step length were significantly increased and step length variability reduced, gait parameters still differed between patients and controls. In blepharospasm patients, baseline gait velocity and step length were significantly smaller than in controls. After BTX injections, these gait parameters were significantly increased and variability decreased, so that patients no longer differed from controls. CONCLUSION: Gait differences exist between patients with focal dystonia not directly affecting the lower limbs and healthy controls. These gait abnormalities were improved differently by BTX treatment according to the type of dystonia. These disparities suggest different pathophysiological mechanisms and support the need for changes in rehabilitation routines in cervical dystonia.

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.

KinesioTaping: impact on non-motor symptoms in cervical dystonia patients treated with botulinum toxin injection.

AIM OF THE STUDY: To assess whether combined therapy with botulinum toxin injections (BoNT) and KinesioTaping could be helpful in managing non-motor symptoms (NMS) of cervical dystonia (CD). MATERIAL AND METHODS: Seventeen patients with CD were enrolled in this single-centre, prospective, evaluator-blinded, randomised, crossover trial. We compared three forms of treatment: BoNT treatment alone, or combined with KinesioTaping, or combined with ShamTaping. NMS were assessed using the 14-item self-reported questionnaire proposed by Klingelhoefer, the Hospital Anxiety and Depression Scale (HADS) and the Pittsburgh Sleep Quality Index (PSQI). RESULTS: There were no significant differences between the groups concerning mean results of HADS and PSQI scales, or mean total number of NMS after the procedures. The mean change from baseline HADS and PSQI scores, and total number of NMS after the procedure, also did not differ significantly between groups. ShamTaping combined with BoNT significantly increased the prevalence of pain. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our study did not confirm the effectiveness of combined therapy of BoNT and KinesioTaping in the management of NMS in patients with CD. Due to a potential negative effect of improper taping on pain in CD, patients with CD should only experience KinesioTaping as an adjunctive therapy, and if it is performed by a trained, experienced physiotherapist.

Botulinum toxin and conservative treatment strategies in people with cervical dystonia: an online survey.

Isolated cervical dystonia is a focal, idiopathic dystonia affecting the neck muscles. Treatment usually consists of botulinum neurotoxin (BoNT) injections into the dystonic muscles. Our aim is to investigate the use of BoNT treatment and conservative treatments by people living with cervical dystonia. An online survey in English was conducted between June and August 2022. Participants were eligible to participate if they were living with cervical dystonia, were over 18 years old and could read and understand English. The survey consisted of demographic questions, characteristics of dystonia, questions relating to BoNT use and the perceived utility of conservative treatments. The data were analysed descriptively, and open-ended questions were grouped into similar topics represented by direct quotes. We received 128 responses from people with cervical dystonia, with an average age of 59 years and 77% women. Most participants (52%) described their cervical dystonia as mild to moderate with an average pain score of 5/10. Eighty-two (64%) participants were having regular BoNT injections, with overall positive perceived effects. Common activities reported to improve the symptoms were the use of heat packs, massage, relaxation, physiotherapy and participation in general exercise. Common coping strategies reported were getting sufficient rest, having the support of friends and family, and remaining engaged in enjoyable hobbies. We found that most participants received regular BoNT injections and that heat packs, exercise, massage, physiotherapy and relaxation were mostly perceived as effective in reducing the symptoms of cervical dystonia.

Hypertrophy of the Spinalis Cervicis Muscle in Cervical Dystonia.

Background: Botulinum neurotoxin A (BoNT) is the first line treatment for cervical dystonia (CD) and treatment outcome significantly depends on the correct identification of the muscles involved. Phenomenology shown: In a case with insufficient response to BoNT treatment further work up with magnetic resonance imaging (MRI) of the neck revealed a hypertrophic spinalis cervicis muscle, that is not commonly involved in CD. Educational value: This highlights the use of MRI for muscle selection in treatment refractory CD cases.

Exploring the Interplay between the Clinical and Presumed Effect of Botulinum Injections for Cervical Dystonia: A Pilot Study.

BACKGROUND: Repetitive intramuscular injections of botulinum neurotoxin type A (BoNT/A) are the treatment of choice in patients with cervical dystonia (CD). As soon as BoNT therapy is initiated, the natural course of CD cannot be observed anymore. Nevertheless, the present study focuses on the "presumed" course of disease severity under the assumption that no BoNT therapy had been performed. The "experienced" benefit is compared with the "presumed" worsening. METHODS: Twenty-seven BoNT/A long-term-treated CD patients were recruited. They had to assess the remaining severity of CD in percent of its severity at the start of BoNT therapy (RS-%). Then, they had to draw the course of severity from the onset of symptoms to the start of BoNT/A therapy (CoDB graph), as well as the course of severity from the start of BoNT/A therapy until the day of recruitment (CoDA graph). Then, they were instructed to presume the development of CD severity from the day of the start of BoNT/A therapy until the day of recruitment under the assumption that no BoNT/A therapy had been performed, and to assess the maximal severity they could presume in percent of the severity at the start of BoNT therapy (IS-%). Then, they had to draw the "presumed" development of CD severity (CoDI graph). The "experienced" change in disease severity and the "presumed" change since the start of BoNT/A therapy were compared and correlated with a variety of demographical and treatment-related data, including the actual severity of CD at the day of recruitment, which was assessed using the TSUI score and the actual dose per session (ADOSE). RESULTS: No CD patients expected an improvement without BoNT therapy. "Presumed" worsening ((IS-%)-100) was about 50% in the mean and did not correlate with the "experienced" benefit (100-(RS-%)). However, IS-% was significantly correlated with ATSUI and ADOSE. CONCLUSION: Obviously, CD patients have the opinion that their CD would have further progressed and worsened if no BoNT/A therapy had been performed. Thus, the total benefit of BoNT/A therapy for a patient with CD is a combination of the "experienced" benefit under BoNT/A therapy and the prevented worsening of CD that the patient expects to occur without BoNT/A therapy.

Deep Brain Stimulation for Focal or Segmental Craniocervical Dystonia in Patients Who Have Failed Botulinum Neurotoxin Therapy-A Narrative Review of the Literature.

(1) Background: The first-line treatment for patients with focal or segmental dystonia with a craniocervical distribution is still the intramuscular injection of botulinum neurotoxin (BoNT). However, some patients experience primary or secondary treatment failure from this potential immunogenic therapy. Deep brain stimulation (DBS) may then be used as a backup strategy in this situation. (2) Methods: Here, we reviewed the current study literature to answer a specific question regarding the efficacy and safety of the use of DBS, particularly for cervical dystonia (CD) and Meige syndrome (MS) in patients with documented treatment failure under BoNT. (3) Results: There are only two studies with the highest level of evidence in this area. Despite this clear limitation, in the context of the narrowly defined research question of this paper, it is possible to report 161 patients with CD or MS who were included in studies that were able to show a statistically significant reduction in dystonic symptoms using DBS. Safety and tolerability data appeared adequate. However, much of the information is based on retrospective observations. (4) Conclusions: The evidence base in this area is in need of further scientific investigation. Most importantly, more randomized, controlled and double-blind trials are needed, possibly including a head-to-head comparison of DBS and BoNT.

"Pseudo"-Secondary Treatment Failure Explained via Disease Progression and Effective Botulinum Toxin Therapy: A Pilot Simulation Study.

BACKGROUND: The objective of this study was to provide evidence from a simple simulation. In patients with focal dystonia, an initial good response to botulinum neurotoxin (BoNT) injections followed by a secondary worsening does not necessarily arise from an antibody-induced secondary treatment failure (NAB-STF), but may stem from a "pseudo"-secondary treatment failure (PSEUDO-STF). METHODS: The simulation of the outcome after BoNT long-term treatment was performed in four steps: 1. The effect of the first single BoNT injection (SI curve) was displayed as a 12-point graph, corresponding to the mean improvement from weeks 1 to 12. 2. The remaining severity of the dystonia during the nth injection cycle was calculated by subtracting the SI curve (weighted by the outcome after n - 1 cycles) from the outcome after week 12 of the (n - 1)th cycle. 3. A graph was chosen (the PRO curve), which represents the progression of the severity of the underlying disease during BoNT therapy. 4. The interaction between the outcome during the nth BoNT cycle and the PRO curve was determined. RESULTS: When the long-term outcome after n cycles of BoNT injections (applied every 3 months) was simulated as an interactive process, subtracting the effect of the first cycle (weighted by the outcome after n - 1 cycles) and adding the progression of the disease, an initial good improvement followed by secondary worsening results. This long-term outcome depends on the steepness of the progression and the duration of action of the first injection cycle. We termed this response behavior a "pseudo"-secondary treatment failure, as it can be compensated via a dose increase. CONCLUSION: A secondary worsening following an initial good response in BoNT therapy of focal dystonia might not necessarily indicate neutralizing antibody induction but could stem from a "PSEUDO"-STF (a combination of good response behavior and progression of the underlying disease). Thus, an adequate dose adaptation must be conducted before diagnosing a secondary treatment failure in the strict sense.

Proprioceptive Modulation of Pallidal Physiology in Cervical Dystonia.

BACKGROUND: There is a growing body of evidence suggesting that botulinum toxin can alter proprioceptive feedback and modulate the muscle-spindle output for the treatment of dystonia. However, the mechanism for this modulation remains unclear. METHODS: We conducted a study involving 17 patients with cervical dystonia (CD), seven of whom had prominent CD and 10 with generalized dystonia (GD) along with CD. We investigated the effects of neck vibration, a form of proprioceptive modulation, on spontaneous single-neuron responses and local field potentials (LFPs) recorded from the globus pallidum externus (GPe) and internus (GPi). RESULTS: Our findings demonstrated that neck vibration notably increased the regularity of neck-sensitive GPi neurons in focal CD patients. Additionally, in patients with GD and CD, the vibration enhanced the firing regularity of non-neck-sensitive neurons. These effects on single-unit activity were also mirrored in ensemble responses measured through LFPs. Notably, the LFP modulation was particularly pronounced in areas populated with burst neurons compared to pause or tonic cells. CONCLUSION: The results from our study emphasize the significance of burst neurons in the pathogenesis of dystonia and in the efficacy of proprioceptive modulation for its treatment. Moreover, we observed that the effects of vibration on focal CD were prominent in the α band LFP, indicating modulation of pallido-cerebellar connectivity. Moreover, the pallidal effects of vibration in GD with CD involved modulation of cerebro-pallidal θ band connectivity. Our analysis provides insight into how vibration-induced changes in pallidal activity are integrated into the downstream motor circuit. © 2023 International Parkinson and Movement Disorder Society.

Bilateral globus pallidus internus (GPi) deep brain stimulation for cervical dystonia: Effects on motor and non-motor symptoms within 5 years follow.

BACKGROUND: Cervical Dystonia ("CD") is a movement disorder characterised by sustained muscle contractions in the neck, causing involuntary posturing. Deep brain stimulation ("DBS") of the globus pallidal internus (GPi) is advanced treatment for pharmaco-refractory patients. As CD is a rare disease, cohort studies are often limited to patients of heterogenous disease profile, small sample size or short follow-up. This study firstly aimed to measure the efficacy of GPi-DBS on motor and non-motor symptoms of CD. A secondary aim was to evaluate if clinical factors - such as age, disease duration and baseline disease severity - influence variability of motor outcomes. METHODS: 37 idiopathic CD patients were recruited from movement disorders clinics at The Walton NHS Foundation Trust, Liverpool, UK. Patients were assessed pre-operatively, and 1 year, 3 years and 5 years post-operatively with the following clinical scales: Toronto Western Spasmodic Torticollis Rating Scale ("TWSTRS"), Hospital Anxiety and Depression Scale and EuroQuol-5D. RESULTS: GPI-DBS significantly improved overall TWSTRS scores by 57% from baseline to 5Y FU (p < 0.001). It also significantly improved TWSTRS severity, disability, and pain sub-scores by 72%, 59% and 46% respectively. We did not find a significant improvement in mood or quality of life scores at 5 years. Similarly, clinical factors at baseline did not correlate with variability in motor outcome. CONCLUSION: We concluded that GPi-DBS is an effective treatment for motor symptoms and pain in CD. There was limited effect on mood and QoL, and no clinical predictive factors of outcome were identified.

Botulinum toxin in the management of parkinsonian disorders.

Many studies have shown that botulinum toxin (BoNT) can be an option to treat motor and non-motor symptoms in Parkinson's disease (PD) and parkinsonian syndromes. The advantages of BoNT compared to oral medications include localized action and low incidence of systemic side effects, which is important in treating neurodegenerative disease. Motor symptoms that can be treated with BoNT include blepharospasm, apraxia of eyelid opening, tremor, cervical dystonia and limb dystonia. Other indications with less evidence include camptocormia, freezing of gait and dyskinesia. Non-motor symptoms that may improve with BoNT include sialorrhea, pain, overreactive bladder, dysphagia and constipation. However, the current evidence for use of BoNT in parkinsonism is mostly based on open-label studies and there are few randomized, controlled trials. BoNT can be a valuable tool to treat certain symptoms of PD and parkinsonian syndromes to improve the patient's quality of life. However, many of the uses are not supported by high quality studies and further studies are needed to provide further evidence of efficacy, define the optimal injection protocols such as doses and muscle selection.

Botulinum Toxin Utilization, Treatment Patterns, and Healthcare Costs Among Patients with Spasticity or Cervical Dystonia in the US.

INTRODUCTION: Spasticity and cervical dystonia (CD) are movement disorders with considerable direct and indirect healthcare cost implications. Although several studies have discussed their clinical impact, few have calculated the economic burden of these disorders. This study aimed to understand treatment/injection patterns of botulinum toxins type A (BoNT-As) and the characteristics, healthcare resource utilization (HCRU), and costs among patients with spasticity or CD. METHODS: Retrospective analyses were conducted using administrative healthcare claims from the IQVIA PharMetrics® Plus database, from October 1, 2015 to December 31, 2019. Eligible patients were selected based on Healthcare Common Procedure Coding System codes for BoNT-A (index date) and ICD-10 diagnosis codes for spasticity or CD with 6 months of continuous enrollment pre-index and 12 months post-index. Patients were stratified into adult spasticity, pediatric spasticity, and CD cohorts, and were evaluated for injection patterns, HCRU, and costs in the post-index period. RESULTS: Overall, 2452 adults with spasticity, 1364 pediatric patients with spasticity, and 1529 adults with CD were included. Total mean all-cause healthcare costs were US$42,562 (adult spasticity), $54,167 (pediatric spasticity), and $25,318 (CD). Differences were observed in the cost of BoNT-A injection visits between toxins, with abobotulinumtoxinA (aboBoNT-A) having the lowest injection cost across all indications. CONCLUSIONS: AboBoNT-A had the lowest injection visit costs across indications. These results are suggestive of real-world resource utilization patterns and costs, and, while helpful in informing insurers' BoNT-A management strategies, further research into cost differences is warranted.

Spasticity is an abnormal, involuntary muscle tightness due to extended muscle contraction. This resistance in movement can be caused by stroke, multiple sclerosis, or traumatic injuries to the brain or spinal cord. Cervical dystonia is a form of sustained involuntary muscle contractions that result in abnormal or repetitive muscle movements in the neck and upper shoulders. Spasticity and cervical dystonia are both associated with significant decrease in quality of life and work productivity as well as significant economic burden. It is therefore important to understand how disease management impacts these patients. Many studies have shown that botulinum toxins type A (BoNT-As) are safe and effective in reducing muscle tightness and improving normal range of motion. This study was conducted to better understand BoNT-A injection patterns, use of healthcare services, and the resulting costs in patients with spasticity or cervical dystonia.

Lessons about Botulinum Toxin A Therapy from Cervical Dystonia Patients Drawing the Course of Disease: A Pilot Study.

AIM OF THE STUDY: To compare the course of severity of cervical dystonia (CD) before and after long-term botulinum toxin (BoNT) therapy to detect indicators for a good or poor clinical outcome. PATIENTS AND METHODS: A total of 74 outpatients with idiopathic CD who were continuously treated with BoNT and who had received at least three injections were consecutively recruited. Patients had to draw the course of severity of CD from the onset of symptoms until the onset of BoNT therapy (CoDB graph), and from the onset of BoNT therapy until the day of recruitment (CoDA graph) when they received their last BoNT injection. Mean duration of treatment was 9.6 years. Three main types of CoDB and four main types of CoDA graphs could be distinguished. The demographic and treatment-related data of the patients were extracted from the patients' charts. RESULTS: The best outcome was observed in those patients who had experienced a clear, rapid response in the beginning. These patients had been treated with the lowest doses and with a low number of BoNT preparation switches. The worst outcome was observed in those 17 patients who had drawn a good initial improvement, followed by a secondary worsening. These secondary nonresponders had been treated with the highest initial and actual doses and with frequent BoNT preparation switches. A total of 12 patients were primary nonresponders and did not experience any improvement at all. No relation between the CoDB and CoDA graphs could be detected. Primary and secondary nonresponses were observed for all three CoDB types. The use of initial high doses as a relevant risk factor for the later development of a secondary nonresponse was confirmed. CONCLUSIONS: Patients' drawings of their course of disease severity helps to easily detect "difficult to treat" primary and secondary nonresponders to BoNT on the one hand, but also to detect "golden responders" on the other hand.

No Secondary Treatment Failure during Incobotulinumtoxin-A Long-Term Treatment Demonstrated by the Drawing of Disease Severity.

The aim of this study was to detect clinical hints regarding the development of secondary treatment failure (STF) in patients with focal dystonia who were exclusively treated with incobotulinumtoxin/A (incoBoNT/A). In total, 33 outpatients (26 with idiopathic cervical dystonia, 4 with Meige syndrome and 3 with other cranial dystonia) who were treated with repeated injections of incoBoNT/A for a mean period of 6.4 years without interruptions were recruited to draw the course of their disease severity (CoD) from the onset of symptoms to the onset of BoNT therapy (CoDB graph) and from the onset of BoNT therapy to recruitment (CoDA graph). At the time of recruitment, the patients assessed the change in severity as a percentage of the severity at the onset of BoNT therapy. Blood samples were taken to test the presence of neutralizing antibodies (NABs) using the mouse hemidiaphragm assay (MHDA). Patients reported an improvement of about 70% with respect to the mean. None of the patients tested positive for MHDA. Three different types of CoDB and three different types of CoDA graphs could be distinguished. The patients with different CoDB graphs reported different long-term outcomes, but there was no significant difference in long-term outcomes between patients with different CoDA graphs. None of the patients produced a CoDA graph with an initial improvement and a secondary worsening as a hint for the development of STF. A primary non-response was not observed in any of the patients. During long-term treatment with BoNT/A, NABs and/or STF may develop. However, in the present study on patients with incoBoNT/A long-term monotherapy, no hints for the development of NABs or STF could be detected, underlining the low antigenicity of incoBoNT/A.

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.

Pooled Safety Analysis of IncobotulinumtoxinA in the Treatment of Neurological Disorders in Adults.

The pooled incidences of treatment-emergent adverse events (TEAEs) were examined by indication using the integrated clinical database of Merz-sponsored, placebo-controlled, or repeat-dose studies of incobotulinumtoxinA in adults with cervical dystonia, blepharospasm, limb spasticity, sialorrhea, or essential tremor of the upper limb. Overall incidences of TEAEs, serious TEAEs, TEAEs leading to discontinuation, fatal TEAEs, TEAEs of special interest (TEAESIs; indicating possible toxin spread), and treatment-related (TR) events were determined for incobotulinumtoxinA and placebo after a single injection and for repeated dose cycles of incobotulinumtoxinA. The most frequent events after a single dose of incobotulinumtoxinA are summarized. After a single cycle, incidences of overall TEAEs were similar between incobotulinumtoxinA and the placebo in most indications, although between-indication differences were observed. Few TEAEs led to incobotulinumtoxinA discontinuation; there were no fatal TEAEs with incobotulinumtoxinA. In general, repeated cycles did not increase the incidence of any event. The most frequent TR-TEAEs were indication-dependent, including dysphagia for indications affecting the head or neck. The TR-TEAESIs across all indications were most commonly muscular weakness, dysphagia and dry mouth. Overall, the results of this pooled analysis support and extend the favorable safety and tolerability profile of incobotulinumtoxinA for the treatment of adult neurological disorders established by individual clinical studies.

Improving the Efficacy of Botulinum Toxin for Cervical Dystonia: A Scoping Review.

Cervical dstonia (CD) is a chronic disorder with a significant detrimental impact on quality of life, requiring long-term treatment. Intramuscular injections of botulinum neurotoxin (BoNT) every 12 to 16 weeks have become the first-line option for CD. Despite the remarkable efficacy of BoNT as a treatment for CD, a significantly high proportion of patients report poor outcomes and discontinue the treatment. The reasons that drive sub-optimal response or treatment failure in a proportion of patients include but are not limited to inappropriate muscle targets and/or BoNT dosing, improper method of injections, subjective feeling of inefficacy, and the formation of neutralizing antibodies against the neurotoxin. The current review aims to complement published research focusing on the identification of the factors that might explain the failure of BoNT treatment in CD, highlighting possible solutions to improve its outcomes. Thus, the use of the new phenomenological classification of cervical dystonia known as COL-CAP might improve the identification of the muscle targets, but more sensitive information might come from the use of kinematic or scintigraphic techniques and the use of electromyographic or ultrasound guidance might ensure the accuracy of the injections. Suggestions are made for the development of a patient-centered model for the management of cervical dystonia and to emphasize that unmet needs in the field are to increase awareness about the non-motor spectrum of CD, which might influence the perception of the efficacy from BoNT injections, and the development of dedicated rehabilitation programs for CD that might enhance its effectiveness.

Pain Reduction in Cervical Dystonia Following Treatment with IncobotulinumtoxinA: A Pooled Analysis.

This analysis pooled pain severity data from four phase 3 and 4 studies of incobotulinumtoxinA (incoBoNT-A) for the treatment of cervical dystonia (CD) in adults. CD-related pain severity was assessed at baseline, each injection visit, and 4 weeks after each injection of incoBoNT-A using the Toronto Western Spasmodic Torticollis Rating Scale pain severity subscale or a pain visual analog scale. Both were analyzed using a score range of 0-10 and pain was categorized as mild, moderate, or severe. Data for 678 patients with pain at baseline were assessed and sensitivity analyses evaluated pain responses in the subgroup not taking concomitant pain medication (n = 384 at baseline). At Week 4 after the first injection, there was a mean change of -1.25 (standard deviation 2.04) points from baseline pain severity (p < 0.0001), with 48.1% showing ≥ 30% pain reduction from baseline, 34.4% showing ≥50% pain reduction from baseline, and 10.3% becoming pain free. Pain responses were sustained over five injection cycles with a trend to incremental improvements with each successive cycle. Pain responses in the subgroup not taking concomitant pain medication demonstrated the lack of confounding effects of pain medications. These results confirmed the pain relief benefits of long-term treatment with incoBoNT-A.