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Meta-Analysis
. 2017 Dec 12;12(12):CD003633.
doi: 10.1002/14651858.CD003633.pub3.

Botulinum toxin type A therapy for cervical dystonia

Mafalda Castelão  1 , Raquel E Marques, Gonçalo S Duarte, Filipe B Rodrigues, Joaquim Ferreira, Cristina Sampaio, Austen P Moore, João Costa
Affiliations
Meta-Analysis

Botulinum toxin type A therapy for cervical dystonia

Mafalda Castelão et al. Cochrane Database Syst Rev. .

Update in

  • Botulinum toxin type A therapy for cervical dystonia.
    Rodrigues FB, Duarte GS, Marques RE, Castelão M, Ferreira J, Sampaio C, Moore AP, Costa J. Rodrigues FB, et al. Cochrane Database Syst Rev. 2020 Nov 12;11(11):CD003633. doi: 10.1002/14651858.CD003633.pub4. Cochrane Database Syst Rev. 2020. PMID: 33180963 Free PMC article.

Abstract

Background: This is an update of a Cochrane Review first published in 2005. Cervical dystonia is the most common form of focal dystonia and is a highly disabling movement disorder characterised by involuntary, usually painful, head posturing. Currently, botulinum toxin type A (BtA) is considered the first line therapy for this condition.

Objectives: To compare the efficacy, safety, and tolerability of botulinum toxin type A (BtA) versus placebo in people with cervical dystonia.

Search methods: To identify studies for this review we searched Cochrane Movement Disorders' Trials Register, CENTRAL, MEDLINE, Embase, reference lists of articles and conference proceedings. All elements of the search, with no language restrictions, were run in October 2016.

Selection criteria: Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtA versus placebo in adults with cervical dystonia.

Data collection and analysis: Two review authors independently assessed records, selected included studies, extracted data using a paper pro forma, and evaluated the risk of bias. We resolved disagreements by consensus or by consulting a third review author. We performed meta-analyses using a random-effects model for the comparison of BtA versus placebo to estimate pooled effects and corresponding 95% confidence intervals (95% CI). In addition, we performed preplanned subgroup analyses according to BtA dose used, the BtA formulation used, and the use or not of guidance for BtA injection. The primary efficacy outcome was improvement in cervical dystonia-specific impairment. The primary safety outcome was the proportion of participants with any adverse event.

Main results: We included eight RCTs of moderate overall risk of bias, including 1010 participants with cervical dystonia. Six studies excluded participants with poorer responses to BtA treatment, therefore including an enriched population with a higher probability of benefiting from this therapy. Only one trial was independently funded. All RCTs evaluated the effect of a single BtA treatment session, using doses from 150 U to 236 U of onabotulinumtoxinA (Botox), 120 U to 240 U of incobotulinumtoxinA (Xeomin), and 250 U to 1000 U of abobotulinumtoxinA (Dysport).BtA was associated with a moderate-to-large improvement in the participant's baseline clinical status as assessed by investigators, with reduction of 8.06 points in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS total score) at week 4 after injection (95% CI 6.08 to 10.05; I2 = 0%) compared to placebo, corresponding on average to a 18.7% improvement from baseline. The mean difference (MD) in TWSTRS pain subscore at week 4 was 2.11 (95% CI 1.38 to 2.83; I2 = 0%). Overall, both participants and clinicians reported an improvement of subjective clinical status. There were no differences between groups regarding withdrawals due to adverse events. However, BtA treatment was associated with an increased risk of experiencing an adverse event (risk ratio (RR) 1.19; 95% CI 1.03 to 1.36; I2 = 16%). Dysphagia (9%) and diffuse weakness/tiredness (10%) were the most common treatment-related adverse events (dysphagia: RR 3.04; 95% CI 1.68 to 5.50; I2 = 0%; diffuse weakness/tiredness: RR 1.78; 95% CI 1.08 to 2.94; I2 = 0%). Treatment with BtA was associated with a decreased risk of participants withdrawing from trials. We have moderate certainty in the evidence across all of the aforementioned outcomes.We found no evidence supporting the existence of a clear dose-response relationship with BtA, nor a difference between BtA formulations, nor a difference with use of EMG-guided injection.Due to clinical heterogeneity, we did not pool data regarding health-related quality of life, duration of clinical effect, or the development of secondary non-responsiveness.

Authors' conclusions: We have moderate certainty in the evidence that a single BtA treatment session is associated with a significant and clinically relevant reduction of cervical dystonia-specific impairment, including severity, disability, and pain, and that it is well tolerated, when compared with placebo. There is also moderate certainty in the evidence that people treated with BtA are at an increased risk of developing adverse events, most notably dysphagia and diffuse weakness. There are no data from RCTs evaluating the effectiveness and safety of repeated BtA injection cycles. There is no evidence from RCTs to allow us to draw definitive conclusions on the optimal treatment intervals and doses, usefulness of guidance techniques for injection, the impact on quality of life, or the duration of treatment effect.

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Conflict of interest statement

JC, JJF, and CS were investigators in clinical trials in botulinum toxin A and B use in dystonia sponsored by Elan (manufacturer of botulinum toxin type B), Allergan (manufacturer of botulinum toxin type A), and Ipsen (manufacturer of botulinum toxin type A). Searching for studies, selection of studies, data extraction and analysis (including risk of bias), and GRADE assessment were performed by authors (FBR, GSD, MC, REM) who were not trialists. JJF and CS were speakers in symposiums promoted by Elan, Allergan, and Ipsen. APM has received royalties from Ipsen for the use 'LIVEchart' scoring system for botulinum toxin treatment efficacy. He has additionally received consulting fees from Ipsen, Merz (manufacturer of botulinum toxin type A), Eisai (manufacturer of botulinum toxin type B), and Allergan. The same companies have provided for support for travel to meetings for studies or other purposes.

Figures

1
1
Study flow diagram
2
2
Risk of bias of included studies: review authors' judgements about each risk of bias item presented as percentages across all included studies
3
3
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study
1.1
1.1. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 1 Cervical dystonia‐specific improvement.
1.2
1.2. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 2 Cervical dystonia‐specific improvement ‐ TWSTRS subgroup analysis.
1.3
1.3. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 3 Cervical dystonia‐specific severity ‐ as assessed with TWSTRS subscale.
1.4
1.4. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 4 Cervical dystonia‐specific disability ‐ as assessed with TWSTRS subscale.
1.5
1.5. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 5 Cervical dystonia‐specific improvement ‐ doses subgroup analysis.
1.6
1.6. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 6 Cervical dystonia‐specific improvement ‐ BtA formulation subgroup analysis.
1.7
1.7. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 7 Cervical dystonia‐specific improvement ‐ EMG‐guided versus non‐EMG‐guided subgroup analysis.
1.8
1.8. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 8 Adverse events.
1.9
1.9. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 9 Adverse events ‐ doses subgroup analysis.
1.10
1.10. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 10 Adverse events ‐ BtA formulation subgroup analysis.
1.11
1.11. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 11 Adverse events ‐ EMG‐guided vs non‐EMG‐guided subgroup analysis.
1.12
1.12. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 12 Dysphagia.
1.13
1.13. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 13 Diffuse weakness/tiredness.
1.14
1.14. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 14 Neck weakness.
1.15
1.15. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 15 Voice change/hoarseness.
1.16
1.16. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 16 Sore throat/dry mouth.
1.17
1.17. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 17 Vertigo/dizziness.
1.18
1.18. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 18 Malaise/upper respiratory infection.
1.19
1.19. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 19 Local pain (injection site).
1.20
1.20. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 20 Headache.
1.21
1.21. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 21 Any improvement by subjective clinician assessment.
1.22
1.22. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 22 Any improvement by subjective participant assessment.
1.23
1.23. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 23 Any improvement by subjective participant assessment ‐ doses subgroup analysis.
1.24
1.24. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 24 Any improvement by subjective participant assessment ‐ BtA formulation subgroup analysis.
1.25
1.25. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 25 Any improvement by subjective participant assessment ‐ EMG guided vs non‐EMG‐guided subgroup analysis.
1.26
1.26. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 26 Cervical dystonia‐specific pain.
1.27
1.27. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 27 Cervical dystonia‐specific pain ‐ TWSTRS pain subscale subgroup analysis.
1.28
1.28. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 28 Cervical dystonia‐specific pain ‐ BtA formulation subgroup analysis.
1.29
1.29. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 29 Cervical dystonia‐specific pain ‐ EMG‐guided vs non‐EMG‐guided subgroup analysis.
1.30
1.30. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 30 Tolerability ‐ withdrawals.
1.31
1.31. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 31 Tolerability ‐ withdrawals due lack of efficacy subgroup analysis.
1.32
1.32. Analysis
Comparison 1 Botulinum toxin type A versus placebo, Outcome 32 Tolerability ‐ withdrawals due to adverse events subgroup analysis.
See this image and copyright information in PMC

Update of

References

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