Botulinum toxin type A therapy for cervical dystonia

Mafalda Castelão<sup>a</sup>; Raquel E Marques<sup>a</sup>; Gonçalo S Duarte<sup>a</sup>; Filipe B Rodrigues<sup>a</sup>; Joaquim Ferreira; Cristina Sampaio; Austen P Moore; João Costa

doi:10.1002/14651858.CD003633.pub3

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Figure 1

Study flow diagram

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Figure 2

Risk of bias of included studies: review authors' judgements about each risk of bias item presented as percentages across all included studies

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Figure 3

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study

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Analysis 1.1

Comparison 1 Botulinum toxin type A versus placebo, Outcome 1 Cervical dystonia‐specific improvement.

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Analysis 1.2

Comparison 1 Botulinum toxin type A versus placebo, Outcome 2 Cervical dystonia‐specific improvement ‐ TWSTRS subgroup analysis.

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Analysis 1.3

Comparison 1 Botulinum toxin type A versus placebo, Outcome 3 Cervical dystonia‐specific severity ‐ as assessed with TWSTRS subscale.

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Analysis 1.4

Comparison 1 Botulinum toxin type A versus placebo, Outcome 4 Cervical dystonia‐specific disability ‐ as assessed with TWSTRS subscale.

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Analysis 1.5

Comparison 1 Botulinum toxin type A versus placebo, Outcome 5 Cervical dystonia‐specific improvement ‐ doses subgroup analysis.

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Analysis 1.6

Comparison 1 Botulinum toxin type A versus placebo, Outcome 6 Cervical dystonia‐specific improvement ‐ BtA formulation subgroup analysis.

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Analysis 1.7

Comparison 1 Botulinum toxin type A versus placebo, Outcome 7 Cervical dystonia‐specific improvement ‐ EMG‐guided versus non‐EMG‐guided subgroup analysis.

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Analysis 1.8

Comparison 1 Botulinum toxin type A versus placebo, Outcome 8 Adverse events.

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Analysis 1.9

Comparison 1 Botulinum toxin type A versus placebo, Outcome 9 Adverse events ‐ doses subgroup analysis.

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Analysis 1.10

Comparison 1 Botulinum toxin type A versus placebo, Outcome 10 Adverse events ‐ BtA formulation subgroup analysis.

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Analysis 1.11

Comparison 1 Botulinum toxin type A versus placebo, Outcome 11 Adverse events ‐ EMG‐guided vs non‐EMG‐guided subgroup analysis.

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Analysis 1.12

Comparison 1 Botulinum toxin type A versus placebo, Outcome 12 Dysphagia.

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Analysis 1.13

Comparison 1 Botulinum toxin type A versus placebo, Outcome 13 Diffuse weakness/tiredness.

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Analysis 1.14

Comparison 1 Botulinum toxin type A versus placebo, Outcome 14 Neck weakness.

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Analysis 1.15

Comparison 1 Botulinum toxin type A versus placebo, Outcome 15 Voice change/hoarseness.

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Analysis 1.16

Comparison 1 Botulinum toxin type A versus placebo, Outcome 16 Sore throat/dry mouth.

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Analysis 1.17

Comparison 1 Botulinum toxin type A versus placebo, Outcome 17 Vertigo/dizziness.

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Analysis 1.18

Comparison 1 Botulinum toxin type A versus placebo, Outcome 18 Malaise/upper respiratory infection.

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Analysis 1.19

Comparison 1 Botulinum toxin type A versus placebo, Outcome 19 Local pain (injection site).

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Analysis 1.20

Comparison 1 Botulinum toxin type A versus placebo, Outcome 20 Headache.

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Analysis 1.21

Comparison 1 Botulinum toxin type A versus placebo, Outcome 21 Any improvement by subjective clinician assessment.

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Analysis 1.22

Comparison 1 Botulinum toxin type A versus placebo, Outcome 22 Any improvement by subjective participant assessment.

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Analysis 1.23

Comparison 1 Botulinum toxin type A versus placebo, Outcome 23 Any improvement by subjective participant assessment ‐ doses subgroup analysis.

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Analysis 1.24

Comparison 1 Botulinum toxin type A versus placebo, Outcome 24 Any improvement by subjective participant assessment ‐ BtA formulation subgroup analysis.

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Analysis 1.25

Comparison 1 Botulinum toxin type A versus placebo, Outcome 25 Any improvement by subjective participant assessment ‐ EMG guided vs non‐EMG‐guided subgroup analysis.

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Analysis 1.26

Comparison 1 Botulinum toxin type A versus placebo, Outcome 26 Cervical dystonia‐specific pain.

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Analysis 1.27

Comparison 1 Botulinum toxin type A versus placebo, Outcome 27 Cervical dystonia‐specific pain ‐ TWSTRS pain subscale subgroup analysis.

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Analysis 1.28

Comparison 1 Botulinum toxin type A versus placebo, Outcome 28 Cervical dystonia‐specific pain ‐ BtA formulation subgroup analysis.

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Analysis 1.29

Comparison 1 Botulinum toxin type A versus placebo, Outcome 29 Cervical dystonia‐specific pain ‐ EMG‐guided vs non‐EMG‐guided subgroup analysis.

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Analysis 1.30

Comparison 1 Botulinum toxin type A versus placebo, Outcome 30 Tolerability ‐ withdrawals.

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Analysis 1.31

Comparison 1 Botulinum toxin type A versus placebo, Outcome 31 Tolerability ‐ withdrawals due lack of efficacy subgroup analysis.

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Analysis 1.32

Comparison 1 Botulinum toxin type A versus placebo, Outcome 32 Tolerability ‐ withdrawals due to adverse events subgroup analysis.

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Summary of findings for the main comparison. Botulinum toxin type A compared to placebo for cervical dystonia

Botulinum toxin type A compared to placebo for cervical dystonia
Patient or population: adults with cervical dystonia Setting: hospital‐based, movement disorders clinics Intervention: botulinum toxin type A Comparison: placebo
Outcomes	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**			Certainty in the evidence (GRADE)	What happens
Outcomes	Relative effect (95% CI)	With placebo	With botulinum toxin type A	Difference	Certainty in the evidence (GRADE)	What happens
Cervical dystonia‐specific impairment Number of participants: 522 (4 RCTs) Assessed 3 to 6 weeks post‐injection using TWSTRS total score	‐	3.9 TWSTRS units decrease	12.45 TWSTRS units decrease	The mean change from baseline was 8.06 TWSTRS units higher (6.08 higher to 10.05 higher) in the BtA group compared to the placebo group	⊕⊕⊕⊝ Moderate^a	BtA treatment probably improves cervical dystonia‐specific impairment
Adverse events Number of participants: 952 (7 RCTs) Assessed at any point during follow‐up	RR 1.19 (1.03 to 1.36)	46.5%	55.3% (47.9 to 63.2)	8.8% more (1.4 more to 16.7 more)	⊕⊕⊕⊝ Moderate^a	BtA treatment probably increases the risk of adverse events
Subjective participant assessment Number of participants: 624 (5 RCTs) Assessed 3 to 6 weeks post‐injection	RR 2.30 (1.83 to 2.90)	24.2%	55.7% (44.3 to 70.2)	31.5% more (20.1 more to 46 more)	⊕⊕⊕⊝ Moderate^a	BtA treatment probably increases the likelihood that patients will detect any form of improvement
Pain relief Number of participants: 429 (3 RCTs) Assessed 3 to 6 weeks post‐injection using TWSTRS pain subscore	‐^b	‐^b	‐^b	The mean change from baseline was 2.11 TWSTRS units higher (1.38 higher to 2.83 higher) in the BtA group compared to the placebo group	⊕⊕⊕⊝ Moderate^a	BtA treatment probably improves cervical dystonia‐related pain
Tolerability Number of participants: 574 (4 RCTs) Assessed at any point during follow‐up	RR 0.38 (0.23 to 0.62)	20.5%	7.8% (4.7 to 12.7)	12.7% fewer (15.8 to 7.8)	⊕⊕⊕⊝ Moderate^a	BtA treatment probably slightly decreases the risk of withdrawal of clinical trials
Dysphagia Number of participants: 1007 (8 RCTs) Assessed at any point during follow‐up	RR 3.04 (1.68 to 5.50)	3.0%	9.2% (5.1 to 16.7)	6.2% more (2.1 more to 13.7 more)	⊕⊕⊕⊝ Moderate^a	BtA treatment probably increases the risk of dysphagia
Diffuse weakness/tiredness Number of participants: 823 (6 RCTs) Assessed at any point during follow‐up	RR 1.78 (1.08 to 2.94)	5.6%	10.1% (6.1 to 16.6)	4.4% more (0.5 more to 11 more)	⊕⊕⊕⊝ Moderate^a	BtA treatment probably increases the risk of diffuse weakness/tiredness
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BtA: botulinum toxin type A; CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; TWSTRS: Toronto Western Spasmodic Torticollis Rating Scale
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^a Downgraded one level due to serious study limitations, namely concerns with randomisation procedures and other biases such as 'for‐profit' bias. ^b Data were only available as between‐group differences.

Summary of findings for the main comparison. Botulinum toxin type A compared to placebo for cervical dystonia

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Table 1. Glossary of terms

Term	Definition
BtA‐non‐responsive	People who do not experience the expected benefit from treatment with botulinum toxin type A
Cervical dystonia or spasmodic torticollis	A common movement disorder in which people have abnormal movements or postures of the head and neck that they cannot control. It is frequently accompanied by social embarrassment and pain.
Chemodenervation	The process by which botulinum toxin causes muscular paralysis. Although all the anatomical elements necessary for muscular control are intact (i.e. nerve, synapse and muscle), there is a chemical process that disables the transmission of the electrical signal from the nerve to the muscle.
Dysphagia	A discomfort or difficulty when swallowing.
Electromyography	An examination that displays the electrical activity of muscles using pieces of metal attached to the skin or inserted into the muscle.
Non‐naive	People who have been treated in the past with botulinum toxin.
Voluntary action	Movements that people are able to control, start and stop when they want to.

Table 1. Glossary of terms

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Table 2. Summary of included studies ‐ participants and drug administration

Study ID	Number of participants	Total dropouts	Age mean, range (years)	Baseline CD impairment BtA/placebo	% participants naive to Bt	BtA formulation	Total dose per participant	EMG‐guidance	Study duration (weeks)
Charles 2012	170	35 (11 in BtA)	55, 31‐76	9.2/9.3 (CDSS)	0	Botox (OnaBtA)	236	No	10
Comella 2011	233	14 (8 in BtA)	53	42.4/41.8 (TWSTRS)	39	Xeomin (IncoBtA)	120 or 240	At discretion	20
Greene 1990	55	3 (3 in BtA)	50	21% severe/ 41% severe	100	Botox (OnaBtA)	150 to 165	No	12
Poewe 1998	75	2 (2 in BtA)	47, 26‐82	13.9/14.4 (Tsui scale)	100	Dysport (AboBtA)	250, 500 or 1000	No	8
Poewe 2016	213	N/A	49	46/47 (TWSTRS)	10	Dysport (AboBtA)	500	N/A	12
Truong 2005	80	56 (22 in BtA)	54, 27‐78	45.1/46.2 (TWSTRS)	26	Dysport (AboBtA)	500	At discretion	20
Truong 2010	116	33 (10 in BtA)	53, 20‐79	43.8/45.8 (TWSTRS)	17	Dysport (AboBtA)	500	At discretion	12
Wissel 2001	68	0	48, 18‐75	11.1/11.5 (Tsui scale)	31	Dysport (AboBtA)	500	No	16
Bt: botulinum toxin; CD: cervical dystonia; CDSS: Cervical Dystonia Severity Scale; EMG: electromyography; TWSTRS: Toronto Western Spasmodic Torticollis Rating Scale

Table 2. Summary of included studies ‐ participants and drug administration

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Comparison 1. Botulinum toxin type A versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Cervical dystonia‐specific improvement Show forest plot	7	833	Std. Mean Difference (Random, 95% CI)	0.70 [0.52, 0.89]

2 Cervical dystonia‐specific improvement ‐ TWSTRS subgroup analysis Show forest plot	4	522	Mean Difference (IV, Random, 95% CI)	8.06 [6.08, 10.05]

3 Cervical dystonia‐specific severity ‐ as assessed with TWSTRS subscale Show forest plot	3	429	Mean Difference (IV, Random, 95% CI)	3.13 [2.15, 4.11]

4 Cervical dystonia‐specific disability ‐ as assessed with TWSTRS subscale Show forest plot	3	429	Mean Difference (IV, Random, 95% CI)	2.52 [1.72, 3.31]

5 Cervical dystonia‐specific improvement ‐ doses subgroup analysis Show forest plot	6	777	Std. Mean Difference (Random, 95% CI)	0.84 [0.68, 1.00]

5.1 Low dose	1	39	Std. Mean Difference (Random, 95% CI)	1.24 [0.55, 1.94]
5.2 Medium dose	6	545	Std. Mean Difference (Random, 95% CI)	0.76 [0.59, 0.94]
5.3 High dose	2	193	Std. Mean Difference (Random, 95% CI)	1.08 [0.53, 1.63]
6 Cervical dystonia‐specific improvement ‐ BtA formulation subgroup analysis Show forest plot	7	833	Std. Mean Difference (Random, 95% CI)	0.70 [0.52, 0.89]

6.1 Botox	1	170	Std. Mean Difference (Random, 95% CI)	0.38 [0.08, 0.69]
6.2 Dysport	5	430	Std. Mean Difference (Random, 95% CI)	0.75 [0.54, 0.96]
6.3 Xeomin	1	233	Std. Mean Difference (Random, 95% CI)	0.82 [0.53, 1.10]
7 Cervical dystonia‐specific improvement ‐ EMG‐guided versus non‐EMG‐guided subgroup analysis Show forest plot	7	833	Std. Mean Difference (Random, 95% CI)	0.70 [0.52, 0.89]

7.1 EMG‐guided injection	4	522	Std. Mean Difference (Random, 95% CI)	0.71 [0.52, 0.89]
7.2 Non‐EMG‐guided injection	3	311	Std. Mean Difference (Random, 95% CI)	0.79 [0.27, 1.31]
8 Adverse events Show forest plot	7	952	Risk Ratio (M‐H, Random, 95% CI)	1.19 [1.03, 1.36]

9 Adverse events ‐ doses subgroup analysis Show forest plot	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

9.1 Low dose	1	39	Risk Ratio (M‐H, Random, 95% CI)	1.47 [0.56, 3.85]
9.2 Medium dose	6	664	Risk Ratio (M‐H, Random, 95% CI)	1.23 [1.06, 1.44]
9.3 High dose	2	193	Risk Ratio (M‐H, Random, 95% CI)	1.90 [0.72, 5.02]
10 Adverse events ‐ BtA formulation subgroup analysis Show forest plot	7	952	Risk Ratio (M‐H, Random, 95% CI)	1.19 [1.03, 1.36]

10.1 Botox	1	170	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.78, 1.30]
10.2 Dysport	5	549	Risk Ratio (M‐H, Random, 95% CI)	1.30 [1.02, 1.66]
10.3 Xeomin	1	233	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.92, 1.62]
11 Adverse events ‐ EMG‐guided vs non‐EMG‐guided subgroup analysis Show forest plot	7	952	Risk Ratio (M‐H, Random, 95% CI)	1.19 [1.03, 1.36]

11.1 EMG‐guided injection	4	640	Risk Ratio (M‐H, Random, 95% CI)	1.19 [1.03, 1.36]
11.2 Non‐EMG‐guided injection	3	312	Risk Ratio (M‐H, Random, 95% CI)	1.43 [0.82, 2.50]
12 Dysphagia Show forest plot	8	1007	Risk Ratio (M‐H, Random, 95% CI)	3.04 [1.68, 5.50]

13 Diffuse weakness/tiredness Show forest plot	6	823	Risk Ratio (M‐H, Random, 95% CI)	1.78 [1.08, 2.94]

14 Neck weakness Show forest plot	4	277	Risk Ratio (M‐H, Random, 95% CI)	3.23 [0.95, 10.91]

15 Voice change/hoarseness Show forest plot	2	154	Risk Ratio (M‐H, Random, 95% CI)	1.83 [0.37, 8.95]

16 Sore throat/dry mouth Show forest plot	3	222	Risk Ratio (M‐H, Random, 95% CI)	1.66 [0.78, 3.51]

17 Vertigo/dizziness Show forest plot	2	154	Risk Ratio (M‐H, Random, 95% CI)	1.47 [0.38, 5.73]

18 Malaise/upper respiratory infection Show forest plot	7	952	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.63, 2.64]

19 Local pain (injection site) Show forest plot	7	837	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.88, 2.02]

20 Headache Show forest plot	6	706	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.59, 1.86]

21 Any improvement by subjective clinician assessment Show forest plot	4	544	Risk Ratio (M‐H, Random, 95% CI)	1.91 [1.47, 2.49]

22 Any improvement by subjective participant assessment Show forest plot	5	624	Risk Ratio (M‐H, Random, 95% CI)	2.30 [1.83, 2.90]

23 Any improvement by subjective participant assessment ‐ doses subgroup analysis Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

23.1 Low dose	1	39	Risk Ratio (M‐H, Random, 95% CI)	1.58 [0.30, 8.43]
23.2 Medium dose	4	336	Risk Ratio (M‐H, Random, 95% CI)	2.44 [1.82, 3.25]
23.3 High dose	2	193	Risk Ratio (M‐H, Random, 95% CI)	3.39 [2.16, 5.33]
24 Any improvement by subjective participant assessment ‐ BtA formulation subgroup analysis Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

24.1 Botox	1	170	Risk Ratio (M‐H, Random, 95% CI)	1.99 [1.34, 2.94]
24.2 Dysport	3	221	Risk Ratio (M‐H, Random, 95% CI)	2.13 [1.49, 3.04]
24.3 Xeomin	1	233	Risk Ratio (M‐H, Random, 95% CI)	3.23 [2.03, 5.14]
25 Any improvement by subjective participant assessment ‐ EMG guided vs non‐EMG‐guided subgroup analysis Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

25.1 EMG‐guided injection	2	313	Risk Ratio (M‐H, Random, 95% CI)	2.97 [1.99, 4.43]
25.2 Non‐EMG‐guided injection	3	311	Risk Ratio (M‐H, Random, 95% CI)	2.03 [1.53, 2.69]
26 Cervical dystonia‐specific pain Show forest plot	6		Std. Mean Difference (Random, 95% CI)	0.50 [0.35, 0.65]

27 Cervical dystonia‐specific pain ‐ TWSTRS pain subscale subgroup analysis Show forest plot	3		Mean Difference (Random, 95% CI)	2.11 [1.38, 2.83]

28 Cervical dystonia‐specific pain ‐ BtA formulation subgroup analysis Show forest plot	6		Std. Mean Difference (Random, 95% CI)	0.50 [0.35, 0.65]

28.1 Botox	2		Std. Mean Difference (Random, 95% CI)	0.51 [0.01, 1.02]
28.2 Dysport	3		Std. Mean Difference (Random, 95% CI)	0.52 [0.28, 0.77]
28.3 Xeomin	1		Std. Mean Difference (Random, 95% CI)	0.55 [0.27, 0.83]
29 Cervical dystonia‐specific pain ‐ EMG‐guided vs non‐EMG‐guided subgroup analysis Show forest plot	6	654	Std. Mean Difference (Random, 95% CI)	0.50 [0.35, 0.65]

29.1 EMG‐guided injection	3	429	Std. Mean Difference (Random, 95% CI)	0.53 [0.33, 0.73]
29.2 Non‐EMG‐guided injection	3	225	Std. Mean Difference (Random, 95% CI)	0.50 [0.20, 0.80]
30 Tolerability ‐ withdrawals Show forest plot	4	574	Risk Ratio (IV, Random, 95% CI)	0.38 [0.23, 0.62]

31 Tolerability ‐ withdrawals due lack of efficacy subgroup analysis Show forest plot	3	519	Risk Ratio (IV, Random, 95% CI)	0.30 [0.17, 0.53]

32 Tolerability ‐ withdrawals due to adverse events subgroup analysis Show forest plot	2	288	Risk Ratio (IV, Random, 95% CI)	3.10 [0.36, 26.74]

Comparison 1. Botulinum toxin type A versus placebo

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