Longitudinal Assessment of Botulinum Toxin Treatment for Lateral Trunk Flexion and Pisa Syndrome in Parkinson's Disease: Real-life, Long-Term Study.

Lateral trunk flexion (LTF) and its severe form, called Pisa syndrome (PS), are highly invalidating axial postural abnormalities associated with Parkinson's disease (PD). Management strategies for LTF lack strong scientific evidence. We present a real-life, longitudinal study evaluating long-term efficacy of botulinum toxin (BoNT) injections in axial muscles to reduce LTF and PS in PD. A total of 13 PD patients with LTF > 5° received ultrasound- and electromyography-guided BoNT injections every 4 months. Seven untreated matched PD patients with LTF served as controls and their changes in posture after 18 months were compared with those of seven patients continuing BoNT over 12 months. 53.8% of patients continued the BoNT injections for at least 12 months. Various individual LTF responses were observed. Overall, BoNT-treated patients obtained a not statistically significant improvement of LTF of 17 ± 41% (p = 0.237). In comparison, the seven untreated PD patients suffered a deterioration in LTF over 12 months by 36 ± 45% (p = 0.116), showing a significantly different trajectory of posture change (p = 0.026). In conclusion, repeated BoNT injections in axial muscles showed varying effects in managing PD-associated LTF, suggesting that: (a) a relevant number of patients with LTF can benefit from BoNT; (b) long-term treatment could prevent LTF worsening; (c) an instrumented, personalized approach is important; and (d) there is a need for prospective, long-term studies.

Perspective of an International Online Patient and Caregiver Community on the Burden of Spasticity and Impact of Botulinum Neurotoxin Therapy: Survey Study.

BACKGROUND: Patient- and caregiver-reported data are lacking on the burden of spasticity, and the impact of botulinum neurotoxin type A (BoNT-A) treatment for this condition, on patients' daily lives. As recommended in recent guidance from the US Food and Drug Administration, online patient communities can represent a platform from which to gather specific information outside of a clinical trial setting on the burden of conditions experienced by patients and caregivers and their views on treatment options in order to inform evidence-based medicine and drug development. OBJECTIVE: The objective of our study is to characterize spasticity symptoms and their associated burdens on Western European and US patients and caregivers in the realms of work, daily activities, quality of life (QoL), as well as the positive and negative impacts of treatment with BoNT-A (cost, time, QoL) using Carenity, an international online community for people with chronic health conditions. METHODS: We performed a noninterventional, multinational survey. Eligible participants were 18 years old or older and had, or had cared for, someone with spasticity who had been treated with BoNT-A for at least 1 year. Patients and caregivers were asked to complete an internet-based survey via Carenity; caregivers reported their own answers and answered on behalf of their patients. Questions included the burden of spasticity on the ability to work, functioning, daily-living activities, and QoL, the impact of BoNT A therapy on patients' lives, and the potential benefits of fewer injections. RESULTS: There were 615 respondents (427 patients and 188 caregivers). The mean age of patients and caregivers was 41.7 years and 38.6 years, respectively, and the most commonly reported cause of spasticity was multiple sclerosis. Caregivers were most often the parents (76/188, 40%) or another family member (51/188, 27%) of their patients. Spasticity had a clear impact on patients' and caregivers' lives, including the ability to work and injection costs. For patients, spasticity caused difficulties with activities of daily living and reduced QoL indices. The median number of BoNT-A injections was 4 times per year, and 92% (393/427) of patients reported that treatment improved their overall satisfaction with life. Regarding the BoNT-A injection burden, the greatest patient-reported challenges were the cost and availability of timely appointments. Overall, 86% (368/427) of patients believed that a reduced injection frequency would be beneficial. Caregivers answering for their patients gave largely similar responses to those reported by patients. CONCLUSIONS: Spasticity has a negative impact on both patients' and caregivers' lives. All respondents reported that BoNT A treatment improved their lives, despite the associated challenges. Patients believed that reducing the frequency of BoNT-A injections could alleviate practical issues associated with treatment, implying that a longer-acting BoNT-A injection would be well received.

The Impact of Socioeconomic Status on Voice Outcomes in Patients With Spasmodic Dysphonia Treated With Botulinum Toxin Injections.

OBJECTIVES:: To determine the impact of socioeconomic status (SES) on voice outcomes for spasmodic dysphonia (SD) patients treated with botulinum toxin injections. METHODS:: This was a prospective cross-sectional study in a tertiary care, academic voice clinic in Canada. Adult SD patients returning to the voice clinic for their botulinum toxin injections were recruited from October 2017 to April 2018. Patients completed a questionnaire on demographic data, the Hollingshead Four-Factor Index for socioeconomic status (validated instrument based on education, occupation, gender, and marital status), and the Voice-Handicap Index 10 (VHI-10) (validated instrument on self-reported vocal handicap). Primary outcome was the association between VHI-10 and Hollingshead Index. Secondary variables were median household income by postal code, duration of disease, gender, age, and professional voice user. Descriptive statistics and multiple linear regression were conducted. RESULTS:: One hundred and one patients (age = 62.8 ± 13.7 years, 20.8% male) were recruited with VHI-10 of 22.1 ± 8.1 (out of 40) and Hollingshead Index of 46.3 ± 11.7 (range, 8-66). Median household income was $75 875 ± $16 393, which was above the Canadian average of $70 336. About 91.1% were Caucasian, 54.4% had university degree, 86.1% spoke English, and 43.5% were employed. In multiple linear regression, there was mild to moderate negative correlation (r = -.292, P = .004) between VHI-10 and Hollingshead Index when controlling for disease duration, age, gender, and professional voice use. CONCLUSION:: SD patients treated with botulinum toxin were mostly affluent, Caucasian, well educated, and English speakers. Lower self-perceived vocal handicap was associated with higher socioeconomic status.

Effectiveness and cost-effectiveness of a patient-initiated botulinum toxin treatment model for blepharospasm and hemifacial spasm compared to standard care: study protocol for a randomised controlled trial.

BACKGROUND: Blepharospasm and hemifacial spasm are debilitating conditions that significantly impact on patient quality of life. Cyclical treatment with botulinum toxin injections offers temporary relief, but the duration of treatment efficacy is variable. The standard model of patient care defines routine fixed-time based scheduled treatment cycles which may lead to unnecessarily frequent treatment for some patients and experience of distressing symptoms in others, if symptoms return before the scheduled follow-up period. METHODS/DESIGN: A randomised controlled trial will compare a patient-initiated model of care, where patients determine botulinum toxin treatment timing, to the standard model of care in which care is scheduled by the clinical team. A sample of 266 patients with blepharospasm or hemifacial spasm will be recruited from Moorfields Eye Hospital (MEH), London. The trial will be accompanied by a mixed-methods evaluation of acceptability of the new service. Patients who meet eligibility criteria will be assessed at baseline and those in the intervention group will be provided with instructions on how to book their own treatment appointments. Patients in both groups will be followed up 3 and 9 months into the trial and all patients will be returned to usual care after 9 months to meet safety protocols. Primary outcome measures include disease severity (questionnaire), functional disability (questionnaire) and patient satisfaction with care (questionnaire). Secondary outcomes include disease-specific quality of life (questionnaire), mood (questionnaire), illness and treatment perceptions (questionnaire and semi-structured interviews), economic impact (questionnaire) and acceptability (questionnaire and semi-structured interviews). DISCUSSION: This trial will assess the effectiveness and cost-effectiveness of a patient-led care model for botulinum toxin therapy. If the new model is shown to be effective in reducing distress and disability in these populations and is found to be acceptable to patients, whilst being cost-effective, this will have significant implications for service organisation across the NHS. TRIAL REGISTRATION: UK Clinical Research Network (UKCRN) Portfolio 18660. Clinicaltrials.gov ID NCT102577224 (registered 29 October 2015).

[Botulinum toxin therapy for spasticity].

Botulinum toxin (BTX) administered as an adjunct to other interventions for spasticity can act as a useful and effective therapeutic tool for treating patients disabled by spasticity. Presence of other non-reflex motor disorders (muscle stiffness, shortness, and contracture) can complicate the clinical course and disturb rehabilitative process of patients with spasticity. Treatment of spasticity using BTX can improve paralysis by correcting muscular imbalance that follows these diseases. In patients with chronic severe spasticity, we also have to address unique and difficult-to-treat clinical conditions such as abnormal posture and movement disorders. The effectiveness of BTX in treating some of these conditions is discussed. Because patients with neurological disabilities can show complex dysfunctions, specific functional limitations, goals, and expected outcomes of treatment should be evaluated and discussed with the patient, family members, and caregivers, prior to initiating BTX therapy. BTX therapy might improve not only care, passive function, but also motor functions in these patients by supplementing intensive rehabilitation with repetitive transcranial magnetic stimulation, transcranial direct-current stimulation, peripheral electrical stimulation, muscle stretching, and other rehabilitation strategies.

The cost-effectiveness of periodic safety update reports for biologicals in Europe.

We analyzed the cost-effectiveness of all Periodic Safety Update Reports (PSURs) submitted for biologicals in Europe from 1995 to 2009 by comparing two regulatory scenarios: full regulation (PSUR reporting) and limited regulation (no PSUR reporting, but all other parts of the pharmacovigilance framework remain in place). During this period, PSUR reporting resulted in the detection of 2 out of a total of 24 urgent safety issues for biologicals: (i) distant spread of botulinum toxin and (ii) edema/fluid collection associated with off-label use of dibotermin-alfa. We used Markov-chain life tables to calculate costs and health effects of PSURs. The incremental cost-effectiveness ratio (ICER) of full regulation (PSUR reporting) vs. limited regulation (no PSUR reporting) for the base-case scenario was \[euro]342,110 per quality-adjusted life year (QALY) gained. It is possible to assess the cost-effectiveness of regulatory requirements using the same methods as those used in assessing the cost-effectiveness of medical interventions.

Continuation of long-term care for cervical dystonia at an academic movement disorders clinic.

Patients with cervical dystonia (CD) receive much of their care at university based hospital outpatient clinics. This study aimed to describe the clinical characteristics and treatment experiences of patients who continued care at our university based movement disorders clinic, and to document the reasons for which a subset discontinued care. Seventy patients (77% female) were recruited from all patients at the clinic (n = 323). Most (93%) were treated with botulinum neurotoxin (BoNT) injection, and onabotulinumtoxinA was initially used in 97%. The average dose of onabotulinumtoxinA was 270.4 U (range 50-500) and the median number of injections was 14 (range: 1-39). Twenty one patients later received at least one cycle of rimabotulinumtoxinB (33%); of those, 10 switched back to onabotulinumtoxinA (48%). The initial rimabotulinumtoxinB dose averaged 11,996 units (range: 3000-25,000 over 1-18 injections). Twenty one patients (30%) discontinued care. Reasons cited included suboptimal response to BoNT therapy (62%), excessive cost (24%), excessive travel burden (10%), and side effects of BoNT therapy (10%). Most patients (76%) did not seek further care after leaving the clinic. Patients who terminated care received fewer treatment cycles (5.5 vs. 13.0, p = 0.020). There were no other identifiable differences between groups in gender, age, disease characteristics, toxin dose, or toxin formulation. These results indicate that a significant number of CD patients discontinue care due to addressable barriers to access, including cost and travel burden, and that when leaving specialty care, patients often discontinue treatment altogether. These data highlight the need for new initiatives to reduce out-of-pocket costs, as well as training for community physicians on neurotoxin injection in order to lessen the travel burden patients must accept in order to receive standard-of-care treatments.

Botulinum toxin assessment, intervention and after-care for lower limb spasticity in children with cerebral palsy: international consensus statement.

Botulinum neurotoxin type-A (BoNT-A) has been used in association with other interventions in the management of spasticity in children with cerebral palsy (CP) for almost two decades. This consensus statement is based on an extensive review of the literature by an invited international committee. The use of BoNT-A in the lower limbs of children with spasticity caused by CP is reported using the American Academy of Neurology Classification of Evidence for therapeutic intervention. Randomized clinical trials have been grouped into five areas of management, and the outcomes are presented as treatment recommendations. The assessment of children with CP and evaluation of outcomes following injection of BoNT-A are complex, and therefore, a range of measures and the involvement of a multidisciplinary team is recommended. The committee concludes that injection of BoNT-A in children with CP is generally safe although systemic adverse events may occur, especially in children with more physical limitations (GMFCS V). The recommended dose levels are intermediate between previous consensus statements. The committee further concludes that injection of BoNT-A is effective in the management of lower limb spasticity in children with CP, and when combined with physiotherapy and the use of orthoses, these interventions may improve gait and goal attainment.

Botulinum toxin assessment, intervention and follow-up for paediatric upper limb hypertonicity: international consensus statement.

The primary objective of this paper was to evaluate the published evidence of efficacy and safety of botulinum neurotoxin (BoNT) injections in paediatric upper limb hypertonia (PULH). Secondary objectives included the provision of clinical context, based on evidence and expert opinion, in the areas of assessment, child and muscle selection, dosing, and adjunctive treatment. A multidisciplinary panel of authors systematically reviewed, abstracted, and classified relevant literature. Recommendations were based on the American Academy of Neurology (AAN) evidence classification. Following a literature search, 186 potential articles were screened for inclusion, and 15 of these met the criteria and were reviewed. Grade A evidence was found to support the use of BoNT to reach individualized therapeutic goals for PULH. There is grade B evidence (probably effective) for tone reduction following BoNT injections and grade U evidence (inconclusive) for improvement in upper limb (UL) activity and function. BoNT injections were generally found to be safe and well tolerated with the most common side effect identified as a transient decrease in grip strength.

Botulinum toxin assessment, intervention and aftercare for cervical dystonia and other causes of hypertonia of the neck: international consensus statement.

Dystonia in the neck region can be safely and effectively reduced with injections of Botulinum neurotoxin-A and B. People with idiopathic cervical dystonia have been studied the most. Benefits following injection include increased range of movement at the neck for head turning, decreased pain, and increased functional capacity (Class I evidence, level A recommendation). The evidence for efficacy and safety in patients with secondary dystonia in the neck is unclear based on the lack of rigorous research conducted in this heterogeneous population (level U recommendation). Psychometrically sound assessments and outcome measures exist to guide decision-making (Class I evidence, level A recommendation). Much less is known about the effectiveness of therapy to augment the effects of the injection (Class IV, level U recommendation). More research is needed to answer questions about safety and efficacy in secondary spastic neck dystonia, effective adjunctive therapy, dosing and favourable injection techniques.

Botulinum neurotoxin: the ugly duckling.

This review presents a brief account of the most significant biological effects and clinical applications of botulinum neurotoxins, in a way comprehensive even for casual readers who are not familiar with the subject. The most toxic known substances in botulinum neurotoxins are polypeptides naturally synthesized by bacteria of the genus Clostridium. These polypeptides inhibit acetylcholine release at neuromuscular junctions, thus causing muscle paralysis involving both somatic and autonomic innervation. There is substantial evidence that this muscle-paralyzing feature of botulinum neurotoxins is useful for their beneficial influence on more than 50 pathological conditions such as spastic paralysis, cerebral palsy, focal dystonia, essential tremor, headache, incontinence and a variety of cosmetic interventions. Injection of adequate quantities of botulinum toxins in spastic muscles is considered as a highly hopeful procedure for the treatment of people who suffer from dystonia, cerebral palsy or have experienced a stroke. So far, numerous and reliable studies have established the safety and efficacy of botulinum neurotoxins and advocate wider clinical therapeutic and cosmetic applications.

Long-term management of strabismus with multiple repeated injections of botulinum toxin.

BACKGROUND: In the healthcare system in the United Kingdom, a number of patients may be offered botulinum toxin as an alternative to surgery in the treatment of their strabismus. We report on our experience of treating those who have received 25 or more injections. METHODS: A retrospective review of the botulinum toxin clinic database was used to identify patients who underwent 25 or more injections between November 1982 and January 2006. All patients with strabismus who met this criterion were included. A statistical analysis was performed in which we compared aspects of this group with those who had received 24 or fewer injections. RESULTS: Fifty-seven patients (0.90%) fulfilled our criteria. There were 37 women and 20 men, with a mean age at first injection of 39 years (range, 15 to 80 years). The number of injections per patient ranged from 25 to 68 (mean, 34). The duration of treatment was between 3 and 22 years. The time interval between injections tended to increase in most patients and the angle tended to reduce. There was no statistical difference between the age at first injection, sex, site injected, diagnosis, and complication rate between the long-term group and the group that received 24 or fewer injections. The long-term group, however, had undergone more previous operations (p < or = 0.001) and had a lower degree of binocularity (p

Assessment protocol for serial casting after botulinum toxin a injections to treat equinus gait.

PURPOSE: The purpose of this study was to investigate feasibility of an assessment protocol for a trial of post-Botox casting to treat equinus gait in cerebral palsy. METHODS: Ten children (ages, 26-75 months) were recruited. Nine were assessed 1 week before botulinum toxin-A injections and reassessed 1 week after removal of the final cast. The assessment protocol included Modified Ashworth Scale (MAS), Modified Tardieu Scale (MTS), Gross Motor Function Measure-66 (GMFM-66), Pediatric Evaluation of Disability Inventory (PEDI), and GAITRite. Feasibility was based on acceptability of the protocol, inter-rater reliability, and responsiveness of outcome measures. RESULTS: The assessment protocol was acceptable and practical. Inter-rater reliability for MAS, MTS, and GMFM ranged from moderate to excellent. Improvements were found in MTS and MAS scores for dorsiflexion and hamstring (p < 0.01), GMFM-66 (p = 0.01), and Pediatric Evaluation of Disability Inventory mobility (p = 0.01), self-care (p = 0.01), and social function (p = 0.00). GAITRite revealed reductions in speed (p = 0.00) and cadence (p = 0.01). CONCLUSIONS: Feasibility was confirmed. Recommendations include raising minimum age and delaying gait analysis.

Prospective manometric assessment of botulinum toxin and its correlation with healing of chronic anal fissure.

INTRODUCTION: The efficacy and pharmacokinetics of botulinum toxin for chronic anal fissure continues to be debated. Addressing both issues we prospectively assessed the manometric impact of botulinum toxin on internal anal sphincter pressure, correlating this impact with chronic anal fissure healing. METHODS: Sixty patients with chronic fissures were assessed. Fifty-seven patients had a total of 20 units of botulinum toxin injected into the intersphincteric groove at four o'clock and eight o'clock. Patients were prospectively assessed with a linear analog pain score, bleeding score, clinical fissure score, modified St. Mark's continence score, and anorectal manometry. Each parameter was reassessed two weeks following treatment and again at three months. RESULTS: Fifty-six patients (30 female), median age 43 (range, 17-80) years, were followed for a median of five (range, 3-15) months with fissure healing assessed 12 weeks after treatment. Physical healing and symptom control were dependent on the baseline maximum anal resting pressure and baseline fissure score (P = 0.003, P = 0.009, respectively). Although maximum anal resting pressure fell by 17 (mean, range, 0-71) percent, pressure reduction did not correlate with clinical outcome (P > 0.2). Seventeen patients reported a mean 17 percent increase in continence score. There was no correlation between deterioration in continence and baseline or subsequent reduction in maximum anal resting pressure. CONCLUSION: Patients with Grade 1 lower-pressure fissures are more likely to heal following treatment with 20 units of botulinum toxin. Healing does not appear to be dependent on a reduction in maximum anal resting pressure.

A pharmacoeconomic evaluation of botulinum toxin in the treatment of spasmodic torticollis.

We performed a prospective study in 21 patients to evaluate the cost of treatment of spasmodic torticollis (cervical dystonia) before and after botulinum toxin type A (BTA) treatment and to assess the impact of BTA treatment on quality of life. Data were recorded for the analysis over a period starting 8 months before and ending 7.2 +/- 0.2 months (mean +/- SEM) after the first injection of BTA. All patients received at least two BTA injections (2.9 +/- 0.2 injections per patient). We studied direct medical costs (drugs, outpatient and inpatient visits, diagnostic procedures, physiotherapy), clinical effects of BTA (clinical rating scale and patient's global assessment), quality of life (French version of the Nottingham Health Profile [NHP]), and adverse reactions. Costs associated with the treatment of spasmodic torticollis before the first BTA injection were 479 +/- 143 French Francs (FF)/patient/month (97 +/- 29 US $/pt/mo). During BTA treatment, costs were 1,126 +/- 147 FF/pt/mo (228 +/- 30 US $/pt/mo), including a mean cost of BTA of 771 +/- 131 FF/pt/mo (157 +/- 27 US $/pt/mo). Treatment with BTA significantly decreased clinical symptoms of spasmodic torticollis and improved the emotional, social, and pain-related domains of the quality of life assessment. Botulinum toxin type A treatment increases the cost of treating spasmodic torticollis but improves quality of life in terms of pain, social, and psychologic functioning in patients with spasmodic torticollis.

The long-term use of botulinum toxin for adult strabismus.

PURPOSE: To characterize patients choosing repeated botulinum toxin injection as a treatment for their strabismus, and assess their demand for it over time (up to 8 years). METHOD: Patients who had undergone at least eight injections were identified and their clinical records analyzed for diagnosis, demographic details, and demand for toxin injections with time. To establish any predictive variables, the details for these cases were compared with those of matched controls who had undergone fewer injections. Lastly, a questionnaire was mailed to research patients' views as to the indications and preferences for regular toxin injection as a method of treatment. RESULTS: Ninety-five patients were identified (34 men, 61 women; median age 37 years), of whom 35 had consecutive exotropia and 16 had secondary exotropia. Other diagnoses represented were residual and primary deviations, restrictive exotropias, and oscillopsias. A trend of fewer injections over the attendance period was seen, and the only complication observed was upper lid ptosis in 1% of injections. Cases exhibited similar demographic composition to matched controls, but were more likely to have consecutive exotropia or secondary esotropia as a diagnosis. Univariate analysis showed evidence (p < 0.001) of an association between the number of previous operations and the odds of being a case. No evidence was found that cases and controls lived at differing distances from our hospital. The questionnaire found that 71% of patients stated appearance as the prime reason for seeking treatment, and 37% stated simplicity of toxin therapy as their reason for reattendance. Twenty-six percent of the patients were disillusioned with the results of previous surgery and preferred toxin therapy as a means of controlling their symptoms. CONCLUSION: Botulinum toxin injection is an appropriate long-term treatment for some strabismus patients who choose not to undergo further surgery. A trend toward fewer injections with time was observed, and no adverse effects were associated with long-term treatment.