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Cervical dystonia is the most common form of dystonia encountered in a movement disorders clinic. Botulinum toxin has been a long-established first line therapy. Several studies, including nearly two dozen randomized clinical trials, have shown that botulinum toxin is safe and effective in reducing the clinical severity of cervical dystonia. Longitudinal data have demonstrated decades of sustained benefit and safety. Although there is a potential for the development of botulinum toxin immunoresistance, this is quite rare, and partly determined by frequency of administration, cumulative dosage, and properties of the injected product. When immunoresistance does occur, switching to an alternative type of botulinum toxin (e.g., from type A to type B) usually restores the efficacy. In this evidence-based review we highlight the results of published double blind, placebo-controlled studies. We also briefly discuss injection techniques and some unmet needs, such as the development of practical assays to detect immunoresistance and longer-acting formulations of botulinum toxin.
Botulinum toxin (BoNT) is a neurotoxin derived from the anaerobic bacterium,
Capitalizing on the ability of BoNT to produce weakness by modulating the release of acetylcholine, this most potent biologic toxin known to man has emerged as one of the most multipurposed treatments for a large variety of neurologic and non-neurologic disorders (
A comprehensive literature review of PubMed database was conducted with search criteria including the following key words: botulinum toxin treatment, cervical dystonia, randomized controlled trials (RCTs). Filters were set to RCTs between the years of 1980–2022. We excluded articles not published in the English language and those which were based on non-human subjects. The query resulted in 66 articles. Those were further reviewed to include both safety and efficacy data. Any ongoing trials or those that were beyond the scope of BoNT in treatment of CD were excluded.
Before reviewing the findings from the published studies of treatment with BoNT in CD, we wish to briefly describe the pharmacology and properties of the different formulations of BoNT as this is critical to the interpretation of the published results. Structurally, BoNT is composed 100 kD heavy chain and 50 kD light chain, linked by a disulfide bond (
Though most clinical trials have utilized BoNT type A and B, there are eight immunologically distinct forms of BoNT (A–H). There are four different preparations of BoNT that have been approved by the FDA: BoNTA onabotulinumtoxinA (Botox®), abobotulinumtoxinA (Dysport®), incobotulinumtoxinA (Xeomin®), and BoNTB rimabotulinumtoxinB (Myobloc®) (
Generally, the effects of BoNT become evident within 1 week after injection, last 3–4 months, and then the benefits gradually wane. It has been proposed that the relatively short-lived effects are due to axonal sprouting at the presynaptic nerve terminal after injection with return of neuromuscular junction function that correlates with re-establishment of normal (baseline) muscle strength (
One of the potential risks associated with long-term BoNT use is the emergence of immunoresistance associated with the development of neutralizing antibodies (NABs) (
The possibility of immunoresistance should be considered when patients have at least two to three consecutive treatments without at least a 25% improvement. One of the biggest unmet needs in BoNT therapeutics is the lack of reliable assays to measure NABs. Currently available assays include the mouse protection assay (MPA) and mouse hemidiaphragm assay (MHDA) but these are difficult to perform and require sacrificing animals (
CD (also referred to as spasmodic torticollis) is a form of focal dystonia manifested by abnormal postures or movements produced by involuntary contractions of muscles in the neck, often associated with tremor (
An interesting phenomenon in CD, as in other forms of dystonia, is the alleviating maneuver, also referred to as “sensory trick” or “geste antogniste” (
The assessment of BoNT efficacy largely relies on clinical rating scales, such as the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and Tsui score (
Several RCTs and long-term observational studies (
Randomized controlled trials of botulinum toxin in cervical dystonia.
Study | Study design and endpoint | Methods | Results | Class of evidence |
---|---|---|---|---|
( |
RDBPC assessing effectiveness of BoNTA in spasmodic torticollis |
|
BoNTA was found to be objectively and subjectively effective; 14 of 16 patients had significant pain reduction. No increased incidence of SEs in treatment group | II |
( |
RDBPC assessing BoNT in patients with torticollis |
|
80% of patients reported subjective improvement with at least 1 dose, 55% reported substantial improvement. No objective improvement in torticollis; 4 patients reported transient dysphagia | II |
( |
Randomized, double-blind, placebo-controlled crossover study of BoNT in spasmodic torticollis |
|
At 1 year follow up, statistically significant benefit in treatment arm ( |
I |
( |
Randomized prospective, double-blind study assessing effectiveness of BoNTA to trihexyphenidyl in CD |
|
BoNTA more effective than trihexyphenidyl in treatment of CD | I |
( |
RDBPC assessing the efficacy of BoNTB in BoNTA responsive and resistant patients with CD |
|
Total TWSTRS scores were higher in all three dosage groups, dose dependent response observed. BoNTB found to be effective in treatment of CD | I |
( |
RDBPC assessing efficacy of BoNTB in patients with CD resistant to BoNTA |
|
At weeks 4, 8, and 12 TWSTRS scores improved in the BoNTB treatment arm. BoNTB found to be effective in patients resistant to BoNTA | I |
( |
RDBPC for dose ranging in CD |
|
Good response was noted in 72% of 1,000 U arm, 44% of 500 U arm, 39% of 250 U arm and 10% of placebo; more side effects at 1,000 U dose compared to 250 U and placebo | I |
( |
RDBPC assessing efficacy of BoNTB in patients with CD previously treated with BoNTA |
|
TWSTRS scores significantly improved with 10,000 U treatment ( |
I |
( |
Summary of three clinical trials evaluating safety and efficacy of BoNTB in CD | Patients received 2,500–10,000 U of BoNTB | In all 3 trials, there was a statistically significant reduction in TWSTRS scores compared to placebo. In BoNTA responsive and resistant patients, BoNTB effects lasted 12–16 weeks. Side effects were mild, transient and anticipated. BoNTB is safe and effective in treatment of CD | I |
( |
RDBPC assessing the efficacy of ABOA 500 units in CD with Tsui score ≥ 9 |
|
There was a 49% reduction in pain in the treatment arm and 33% in placebo; 86% of treatment group and 42% of placebo were considered responders; adverse effects were reported in 42.9% of treatment and 27.3% of placebo groups; 500 U of ABOA is safe and effective for CD | I |
( |
Randomized, double-blind, crossover study comparing old ONA to new ONA in CD |
|
TWSTRS scores improved by −5.34 points in old ONA and −6.20 points in new ONA group. Nearly equivalent adverse events reported; new and old formulations of ONA have similar effects in treatment of CD | I |
( |
Randomized, double-blind trial assessing the efficacy of low dose BoNT in CD |
|
At 4 weeks, both groups had similar improvement in TWSTRS scores; marginally higher duration of effect in higher dosing group (65.8 days v. 57.4 days) | II |
( |
Randomized, double-blind trial comparing NT201 to ONA in CD |
|
TWSTRS score improved by −6.6 in NT201 and −6.4 in ONA groups from same mean starting score; 28.1% of NT201 and 24.1% of ONA groups reported SEs. Safety and tolerability were similar for both groups | I |
( |
Randomized, double-blind trial assessing BoNTA versus BoNTB in CD |
|
TWSTRS scores improved by −9.3 in the BoNTA and −10.2 in the BoNTB groups; duration of effect was longer in the BoNTA, on average 14 weeks and reduced incidence of adverse SEs | I |
( |
RDBPC assessing ABOA safety and efficacy in CD (in United States of America) |
|
38% of ABOA and 16% of placebo groups reported benefit; mean duration of ABOA was 18.5 weeks and increased reporting of SEs | I |
( |
Randomized, double-blind trial comparing BoNTA to BoNTB in CD |
|
TWSTRS score improved by −11 in BoNTA and −8.8 in BoNTB groups. Severe SEs similarly reported in both groups. Dry mouth more common in BoNTB group. Both formulations found to be effect in treating CD | I |
( |
Randomized prospective, double-blind trial comparing Prosigne to ONA |
|
ONA and Prosigne have the same safety profiles | II |
( |
RDBPC assessing the safety and efficacy of ABOA in CD |
|
TWSTRS score improved −15.6 ± 2 in the treatment arm and −6.7 ± 2 in the placebo arm; ABOA was found to be safe and effective in CD | I |
( |
Prospective, RDBPC comparing INCA to placebo in CD |
|
TWSTRS score improved by −2.2, −9.9, −10.9, respectively. SEs including dysphagia, neck pain, and muscle weakness occurred at higher rates in the higher dose treatment group. INCA was found to be safe and effective | I |
( |
RDBPC, single dose study assessing RIMAB in CD (Japanese population) | Patients stratified into placebo, 2,500 U, 5,000 U or 10,000 U groups | At 4 weeks, TWSTRS scores improved in all treatment groups when compared to placebo; for disability and pain sub scores, only the 10,000 U showed significant improvement when compared to placebo. Dose dependent SEs reported | I |
( |
Randomized, double-blind crossover trial assessing ABOA to ONA at 2.5:1 ratio in CD |
|
ABOA at a ratio of 2.5:1 had similar efficacy and safety profile compared to ONA | I |
( |
RDBPC comparing ABOA to placebo in CD |
|
At 4-week endpoint, treatment group achieved statistically significant improvement in TWSTRS score ( |
I |
( |
RDBPC assessing the efficacy and safety of BoNTA in CD in dyskinetic cerebral palsy |
|
At 4 weeks, TWSTRS score significantly improved in treatment arm ( |
I |
( |
RDBPC phase 3b trial assessing efficacy of 2 ml ABOA injection at 12 weeks in CD |
|
At 12 weeks, mean TWSTRS score improved −7.1 in the treatment compared to −2 in the placebo group; Pain scale improved −1 vs. −0.2 in the treatment arm. Patients in treatment arm reported being “somewhat satisfied” more than placebo group. No new or serious SEs | I |
Class of evidence was determined by the criteria outlined by the Quality and Standards subcommittee of the American Academy of Neurology (
RDBPC, randomized, double-blind, placebo-controlled study; CD, cervical dystonia; ST, spasmodic torticollis; BoNT, botulinum toxin (type A or B;, ABOA, abobotulinumtoxinA; INCA, incobotulinumtoxinA; ONA, onabotulinumtoxinA; RIMAB, rimabotulinumtoxinB; U = unit; SE, side effect; TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale.
While most studies involve BoNTA, trials assessing the safety and efficacy of BoNTB have found similar results (
A Cochrane review conducted in 2016 that included three RCTs found no difference between the two types of BoNT but BoNTB had a higher frequency of dry mouth (
Numerous short-term RCT studies and long-term observational studies have demonstrated that the efficacy of BoNT can be sustained for decades along with continued safety (
Dysphagia is the most frequently cited adverse effect of BoNT, reported in 5%–42% of patients, followed by muscle weakness in 3%–4%, injection pain 1%–9%, generalized weakness 0.3%, speech difficulties 0.3%, head drop 0.3%, rigidity 0.3%–3%, weight loss 0.3%, xerostomia (or dry mouth) 56%–71% (
Although BoNT has clearly improved the quality of life of patients with CD, up to 30% of patients discontinue treatment (
One of the major limitations of BoNT is its relatively short duration (about 2–4 months) of benefit. In a survey of 209 patients, 88% reported re-emergence of symptoms in between treatments at an average of 10.5 weeks from injection (
Though most studies use primary endpoints of improvement in clinical rating scales, few evaluate for patient satisfaction or quality of life measures as surrogates for treatment efficacy. This has been highlighted by others, creating a need for improved rating systems that consider the complexity of achieving desirable results with minimal side effects (
Clinicians must always strive to optimize the response to BoNT by recognizing the full phenomenology of the patient’s CD and by making certain that they target the most relevant (agonist) muscles and avoid injecting compensatory (antagonist) muscles. Although EMG, ultrasound, kinematic guidance and other techniques have been found to improve accuracy of BoNT injections and possibly reduce the risk of BoNT-related side effects (
Adjunctive treatment has an important role in overall patient satisfaction. Several studies have shown that anticholinergic drugs, baclofen, benzodiazepines and other muscles relaxants provide ancillary benefits in patients with CD treated with BoNT (
Despite efforts to optimize efficacy by selecting appropriate targets, mitigating side effects, and reducing immunogenicity, some patients with CD remain refractory to BoNT. In these cases, advanced therapies such as deep brain stimulation (DBS) may provide benefit. A randomized, sham-controlled study conducted in Europe, which included 62 patients (32 assigned to neurostimulation vs. 30 assigned to sham stimulation), found that pallidal neurostimulation for 3 months is more effective than sham stimulation in reducing symptoms of CD (
Although BoNT is generally effective and safe for the treatment of CD, other adjunct therapies and physical therapy may be needed to optimize the response (
Treatment algorithm for cervical dystonia.
BoNT has been shown, through numerous open-label and controlled trials, to be safe and effective in the treatment of CD. These benefits, which clearly translate into improved quality of life, are usually sustained indefinitely. There are currently four formulations of BoNT (three types A and one type B) approved in the United States, but other formulations are available elsewhere and more are in development. The most important factor in favorable outcome following BoNT injection is the identification and appropriate selection of dose in the target muscle. It is likely that in the near future novel formulation of BoNT will be developed with improved properties such as longer duration of action, less diffusibility and immunogenicity, and lower cost which will lead to wider accessibility.
NH was responsible for data collection and manuscript writing. JJ was responsible for manuscript writing and editing.
JJ has received research or training grants from AbbVie Inc., CHDI Foundation, Dystonia Coalition, Emalex Biosciences, Inc., Medtronic Neuromodulation, Michael J Fox Foundation for Parkinson Research, National Institutes of Health, Parkinson’s Foundation, Revance Therapeutics, Inc., and Teva Pharmaceutical Industries Ltd. JJ has served as a consultant for AbbVie Inc., Aeon BioPharma, Neurocrine; Revance Therapeutics, and Teva Pharmaceutical Industries Ltd.
The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.