Is Botulinum Toxin Type A Efficacious, Safe, and Tolerable in Cervical Dystonia?

The aim of this commentary is to discuss in a rehabilitation perspective the published Cochrane Review “Botulinum toxin type A therapy for cervical dystonia” by Castelão et al.1 (https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003633.pub3/full), under the direct supervision of Cochrane Movement Disorders Group. This Cochrane Corner is produced in agreement with the American Journal of Physical Medicine & Rehabilitation by Cochrane Rehabilitation. BACKGROUND Cervical dystonia is one of the most frequently encountered focal dystonias, which is characterized by continuous muscle contractions that produce repetitive and patterned movements and force the head and neck into abnormal postures such as twisting and tilting to different directions.2 Cervical dystonia is not only associated with neurological motor problems but also associated with nonmotor sequela, such as pain, fatigue, anxiety, depression, and problems in sleep, self-efficacy, and working ability.3,4 All of these problems could contribute to the resultant disability and reduced health-related quality of life (HRQoL), which makes cervical dystonia challenging to treat in rehabilitation medicine. Botulinum toxin injections are considered as a first-line treatment2 and widely used in the treatment of cervical dystonia with favorable outcomes in HRQoL.4 An update of a Cochrane Review, which was published previously in 2005,5 looked at studies to provide more recent evidence on the efficacy and safety of botulinum toxin type A (BtA) for the treatment of this disabling health condition.1 BOTULINUM TOXIN TYPE A THERAPY FOR CERVICAL DYSTONIA (Castelão et al., 2017)1 What Is the Aim of this Cochrane Review? The aim was to assess the efficacy, safety, and tolerability of BtA in comparison with placebo in individuals with cervical dystonia. What Was Studied in the Cochrane Review? The population addressed in this review was adults 18 yrs and older with cervical dystonia. The intervention studied was intramuscularly injected BtA. The comparator was placebo. Primary outcomes studied included cervical dystonia–specific improvement (assessed as improvement in specific symptomatic rating scale/subscale scores, such as Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS], Tsui Scale, and Cervical Dystonia Severity Scale, and also TWSTRS Severity and Disability subscales) and adverse events. Secondary outcomes studied were subjective assessment of clinical status (performed by clinicians, participants [pts], or both), pain relief, HRQoL, tolerability, and effect duration. Search Methodology and Up-to-Dateness of the Cochrane Review The review authors searched for studies that had been published up to October 6, 2016, using the databases of Cochrane Movement Disorders’ Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, as well as searches in reference lists of relevant studies and hand searches for relevant abstracts presented in international congresses. What Are the Main Results of the Cochrane Review? The review included eight parallel-design, double-blind, randomized, placebo-controlled trials involving 1010 adult pts (mean age = 52.3 yrs, 64% female pts) with cervical dystonia, which assessed the effects of a single BtA treatment session using either onabotulinumtoxinA (150–236 U), or incobotulinumtoxinA (120–240 U), or abobotulinumtoxinA (250–1000 U). The review shows the following results when comparing BtA treatment with placebo: Cervical dystonia–specific improvement (as assessed at 4 wks after injection) Botulinum toxin type A treatment resulted in a moderate-to-large improvement as measured using either TWSTRS, Tui Scale, or Cervical Dystonia Severity Scale scores (standardized mean difference 0.70; 95% confidence interval [CI], 0.52–0.89) (7 studies, 833 pts; moderate-certainty evidence). Botulinum toxin type A improved overall “severity, pain, and disability” by 18.7% from baseline as measured using TWSTRS (with three subscales assessing these) with a mean difference of 8.06 points (95% CI, 6.08–10.05) in total score (4 studies, 522 pts; moderate-certainty evidence). Adverse events (as assessed at any point of follow-up) Botulinum toxin type A treatment increased adverse event risk by 20% with the proportion of pts experiencing any treatment-related adverse events being higher in BtA than in placebo groups (55.3% vs. 46.5%) with an estimated risk ratio (RR) of 1.19 (95% CI, 1.03–1.36) (7 studies, 952 pts; moderate-certainty evidence). Two adverse events predominated with BtA treatment: both dysphagia risk (RR 3.04; 95% CI, 1.68–5.50) (8 studies, 1007 pts) and diffuse weakness/tiredness risk (RR 1.78; 95% CI, 1.08–2.94) (6 studies, 823 pts) increased (both moderate certainty evidence). Other adverse events reported in studies included pain at the injection site, headache, dizziness/vertigo, weakness of neck, sore throat/dry mouth, voice changes/hoarseness, and a general feeling of bodily discomfort (malaise)/infection of upper respiratory tract, however, with no difference between BtA and placebo groups. No deaths were considered related to BtA in any trial. Subjective clinical status (assessed at 4 and 20 wks after injection) Botulinum toxin type A treatment improved clinical status as subjectively assessed by the patients (RR 2.30; 95% CI, 1.83–2.90) (5 studies, 624 pts; moderate certainty evidence). Pain relief (assessed as the change from baseline to 4 to 6 wks after injection) Botulinum toxin type A was more effective in relieving pain (standardized mean difference 0.50; 95% CI, 0.35–0.65) as assessed using combination of pain scales (6 studies, 722 pts; moderate-certainty evidence). Botulinum toxin type A showed a favorable difference in pain relief (mean difference 2.11 points; 95% CI, 1.38–2.83) as measured using only TWSTRS pain subscale (3 studies, 429 pts; moderate-certainty evidence). Tolerability (defined as the number of withdrawals) Botulinum toxin type A treatment slightly decreased withdrawal risk from studies in general (RR 0.36; 95% CI, 0.21–0.61) (4 studies, 574 pts; moderate certainty evidence). Although withdrawals due to lack of efficacy decreased with BtA (RR 0.30; 95% CI, 0.17–0.53) (3 studies, 519 pts), those due to adverse events did not differ between BtA and placebo (RR 3.10; 95% CI, 0.36–26.74) (2 studies, 288 pts). HRQoL (data not pooled—results from single studies) There were reports of significant improvement with BtA in total and in all eight Cervical Dystonia Impact Profile-58 subscale scores (1 study, 213 pts), an improvement in Short Form 36 physical function, but not in social function domain at 8 wks (2 different studies, 80 and 116 pts). Effect duration (data not pooled—results from single studies) There were reports of need for reinjection at eighth week in pts ranging from 39% to 94% depending on the dose from high to low (75 pts), 22.8 wks as the mean effect duration until symptom recurrence (80 pts), 14.4 wks as the mean time for retreatment (116 pts), and longer than 85 days from the second to the fifth treatment cycles, regardless of the dose (369 pts). How Did the Authors Conclude on the Evidence? The authors concluded that a single BtA treatment session is more effective in reducing impairments specific to cervical dystonia including severity of the health condition as well as associated pain and disability in comparison with placebo. There is also pts’ assessed subjective meaningful clinical benefit of BtA. Tolerability to BtA is well; however, it increases the risk of developing adverse events, specifically dysphagia and diffuse weakness/tiredness (all with moderate certainty in the evidence). There is no conclusive/clear evidence with regard to the optimal doses and intervals for BtA treatment, comparative utility of BtA formulations and injection guidance techniques, its influence on HRQoL aspects such as social or mental functions, or treatment effect duration. What Are the Implications of the Cochrane Evidence for Practice in Rehabilitation? If we interpret the evidence in Cochrane language,6 moderate-certainty evidence tells us that BtA probably reduces cervical dystonia–specific disability and pain, improves subjectively assessed clinical well-being of the patients, and increases adverse events with implications that it is likely that the actual effect is close to the estimated effect. This conveys the message that BtA could be a useful treatment option to reduce disability in patients affected by cervical dystonia. However, great caution is needed for adverse events. On the other hand, we do not know whether BtA improves all aspects of HRQoL, which dose, formulation, or the injection guidance technique is the best, how long the treatment effect lasts, and what the long-term effects, as well as the effects on poorer responders such as those with pure anterocollis or retrocollis who were not included in the studies, are; thus, further research needs to be conducted to elucidate effects on these. From a rehabilitation medicine point of view, we also do not know the influence of BtA on specific components of disability, such as activity limitations, and participation restrictions as defined in the International Classification of Functioning, Disability and Health.7 For example, we do not have information from an improved single total score and/or subscale score of TWSTRS on whether the improvement was related to “carrying out daily routine,” “walking,” “remunerative employment,” or “recreation and leisure” as mapped to the International Classification of Functioning, Disability and Health category titles.8 There is also a need to include “interpersonal interactions and relations” and attitudes such as “social stigmatization” as outcomes because these are highly relevant to individuals with cervical dystonia.4,8 For defining outcomes in future research, the use of International Classification of Functioning, Disability and Health7 could be recommended to identify the effects of BtA on specific functioning domains.

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