Adverse events with botulinum toxin treatment in cervical dystonia: How much should we blame placebo?

INTRODUCTION: Botulinum toxin (BoNT) is the first line therapy for cervical dystonia (CD), with most patients receiving many treatment sessions, and so come to recognize and expect the benefits and harms of BoNT, making it difficult to separate which adverse events (AEs) are driven by BoNT and which come from patients' expectations. METHODS: Using the results of three Cochrane systematic reviews of randomized controlled trials (RCTs) we pooled results to calculate the risk of general and specific AEs associated with BoNT, and the proportion of AEs that cannot be pharmacologically attributed to BoNT. RESULTS: Fifteen RCTs, enrolling 1604 patients, were included. BoNT was associated with an increased risk of AEs, but 79% of this increased risk cannot be pharmacologically attributed to BoNT. CONCLUSIONS: Patients with CD attach a considerable expectation of harm due to BoNT, reflected in the large proportion of non-pharmacologically-mediated AEs

Meta-research metrics matter: letter regarding article “indirect tolerability comparison of Deutetrabenazine and Tetrabenazine for Huntington disease”

Here we discuss the report by Claassen and colleagues describing an indirect treatment comparison between tetrabenazine and deutetrabenazine for chorea in Huntington’s disease using individual patient data. We note the potential for discrepancies in apparently statistically significant findings, due to the rank reversal phenomenon. We provide some cautionary observations and suggestions concerning the limitations of indirect comparisons and the low likelihood that good quality evidence will become available to guide clinical decision comparing these two agents

Deep brain stimulation for dystonia

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To compare the efficacy, safety and tolerability of deep brain stimulation versus placebo, sham intervention, or best medical care, including botulinum neurotoxin and resective/lesional surgery, in people with dystonia

Tetrabenazine versus deutetrabenazine for Huntington's disease: twins or distant cousins?

BACKGROUND: Tetrabenazine is the only US Food and Drug Administration-approved drug for Huntington's disease, and deutetrabenazine was recently tested against placebo. A switching-trial from tetrabenazine to deutetrabenazine is underway, but no head-to-head, blinded, randomized controlled trial is planned. Using meta-analytical methodology, the authors compared these molecules. METHODS: RCTs comparing tetrabenazine or deutetrabenazine with placebo in Huntington's disease were searched. The authors assessed the Cochrane risk-of-bias tool, calculated indirect treatment comparisons, and applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. RESULTS: The evidence network for this report comprised 1 tetrabenazine trial and 1 deutetrabenazine trial, both against placebo. Risk of bias was moderate in both. Participants in the tetrabenazine and deutetrabenazine trials did not differ significantly on motor scores or adverse events. Depression and somnolence scales significantly favored deutetrabenazine. CONCLUSION: There is low-quality evidence that tetrabenazine and deutetrabenazine do not differ in efficacy or safety. It is important to note that these results are likely to remain the only head-to-head comparison between these 2 compounds in Huntington's disease

Botulinum toxin type A versus botulinum toxin type B for cervical dystonia

BACKGROUND: This is an update of a Cochrane review first published in 2003. Cervical dystonia is the most common form of focal dystonia and is a disabling disorder characterised by painful involuntary head posturing. There are two available formulations of botulinum toxin, with botulinum toxin type A (BtA) usually considered the first line therapy for this condition. Botulinum toxin type B (BtB) is an alternative option, with no compelling theoretical reason why it might not be as- or even more effective - than BtA. OBJECTIVES: To compare the efficacy, safety and tolerability of botulinum toxin type A (BtA) versus botulinum toxin type B (BtB) in people with cervical dystonia. SEARCH METHODS: To identify studies for this review we searched the Cochrane Movement Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, reference lists of articles and conference proceedings. All elements of the search, with no language restrictions, were last run in October 2016. SELECTION CRITERIA: Double-blind, parallel, randomised, placebo-controlled trials (RCTs) comparing BtA versus BtB in adults with cervical dystonia. DATA COLLECTION AND ANALYSIS: Two independent authors 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 author. We performed meta-analyses using the random-effects model, for the comparison BtA versus BtB to estimate pooled effects and corresponding 95% confidence intervals (95% CI). No prespecified subgroup analyses were carried out. The primary efficacy outcome was improvement on any validated symptomatic rating scale, and the primary safety outcome was the proportion of participants with adverse events. MAIN RESULTS: We included three RCTs, all new to this update, of very low to low methodological quality, with a total of 270 participants.Two studies exclusively enrolled participants with a known positive response to BtA treatment. This raises concerns of population enrichment, with a higher probability of benefit from BtA treatment. None of the trials were free of for-profit bias, nor did they provide information regarding registered study protocols. All trials evaluated the effect of a single Bt treatment session, and not repeated treatment sessions, using doses from 100 U to 250 U of BtA (all onabotulinumtoxinA, or Botox, formulations) and 5000 U to 10,000 U of BtB (rimabotulinumtoxinB, or Myobloc/Neurobloc).We found no difference between the two types of botulinum toxin in terms of overall efficacy, with a mean difference of -1.44 (95% CI -3.58 to 0.70) points lower on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) for BtB-treated participants, measured at two to four weeks after injection. The proportion of participants with adverse events was also not different between BtA and BtB (BtB versus BtA risk ratio (RR) 1.40; 95% CI 1.00 to 1.96). However, when compared to BtA, treatment with BtB was associated with an increased risk of one adverse events of special interest, namely treatment-related sore throat/dry mouth (BtB versus BtA RR of 4.39; 95% CI 2.43 to 7.91). Treatment-related dysphagia (swallowing difficulties) was not different between BtA and BtB (RR 2.89; 95% CI 0.80 to 10.41). The two types of botulinum toxin were otherwise clinically non-distinguishable in all the remaining outcomes. AUTHORS' CONCLUSIONS: The previous version of this review did not include any trials, since these were still ongoing at the time. Therefore, with this update we are able to change the conclusions of this review. There is low quality evidence that a single treatment session of BtA (specifically onabotulinumtoxinA) and a single treatment session of BtB (rimabotulinumtoxinB) are equally effective and safe in the treatment of adults with certain types of cervical dystonia. Treatment with BtB appears to present an increased risk of sore throat/dry mouth, compared to BtA. Overall, there is no clinical evidence from these single-treatment trials to support or contest the preferential use of one form of botulinum toxin over the other

Botulinum toxin type A therapy for hemifacial spasm

BACKGROUND: This is an update of a Cochrane Review, first published in 2005. Hemifacial spasm (HFS) is characterised by unilateral, involuntary contractions of the muscles innervated by the facial nerve. It is a chronic disorder, and spontaneous recovery is very rare. The two treatments routinely available are microvascular decompression and intramuscular injections with botulinum toxin type A (BtA). OBJECTIVES: To compare the efficacy, safety, and tolerability of BtA versus placebo in people with HFS. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, reference lists of articles, and conference proceedings in July 2020. We ran the electronic database search, with no language restrictions, in July 2020. SELECTION CRITERIA: Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtA versus placebo in adults with HFS. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed records. We planned to select included studies, extract data using a paper pro forma, and evaluate the risk of bias. We resolved disagreements by consensus, or by consulting a third review author. We planned to perform meta-analyses. The primary efficacy outcome was HFS-specific improvement. The primary safety outcome was the proportion of participants with any adverse event. MAIN RESULTS: We found no parallel-group randomised controlled trials comparing BtA and placebo in HFS. AUTHORS' CONCLUSIONS: We did not find any randomised trials that evaluated the efficacy and safety of botulinum toxin type A in people with hemifacial spasm, so we are unable to draw any conclusions. Observational data show a strong association between BtA treatment and symptom improvement, and a favourable safety profile. While it is unlikely that future placebo-controlled RCTs will evaluate absolute efficacy and safety, they should address relevant questions for both people with HFS (such as long-term effects, quality of life, and other patient-reported outcomes), and clinicians (such as relative effectiveness of different BtA formulations and schemes of treatment) to better guide clinical practice.)

Botulinum toxin type B for cervical dystonia

BACKGROUND: This is an update of a Cochrane review first published in 2004, and previously updated in 2009 (no change in conclusions). Cervical dystonia is a frequent and disabling disorder characterised by painful involuntary head posturing. Botulinum toxin type A (BtA) is usually considered the first line therapy for this condition, although botulinum toxin type B (BtB) is an alternative option. OBJECTIVES: To compare the efficacy, safety and tolerability of botulinum toxin type B (BtB) versus placebo in people with cervical dystonia. SEARCH METHODS: We identified studies for inclusion in the review using the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, reference lists of articles and conference proceedings, last run in October 2015. We ran the search from 1977 to 2015. The search was unrestricted by language. SELECTION CRITERIA: Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtB versus placebo in adults with cervical dystonia. DATA COLLECTION AND ANALYSIS: Two independent authors 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 author. We performed one meta-analysis for the comparison BtB versus placebo. We used random-effects models when there was heterogeneity and fixed-effect models when there was no heterogeneity. In addition, we performed pre-specified subgroup analyses according to BtB doses and BtA previous clinical responsiveness. The primary efficacy outcome was overall improvement on any validated symptomatic rating scale. The primary safety outcome was the number of participants with any adverse event. MAIN RESULTS: We included four RCTs of moderate overall methodological quality, including 441 participants with cervical dystonia. Three studies excluded participants known to have poorer response to Bt treatment, therefore including an enriched population with a higher probability of benefiting from Bt treatment. None of the trials were independently funded. All RCTs evaluated the effect of a single Bt treatment session using doses between 2500 U and 10,000 U. BtB was associated with an improvement of 14.7% (95% CI 9.8% to 19.5) in the patients' baseline clinical status as assessed by investigators, with reduction of 6.8 points in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS-total score) at week 4 after injection (95% CI 4.54 to 9.01). Mean difference (MD) in TWSTRS-pain score at week 4 was 2.20 (95% CI 1.25 to 3.15). Overall, both participants and clinicians reported an improvement of subjective clinical status. There were no differences between groups in the withdrawals rate due to adverse events or in the proportion of participants with adverse events. However, BtB-treated patients had a 7.65 (95% CI 2.75 to 21.32) and a 6.78 (95% CI 2.42 to 19.05) increased risk of treatment-related dry mouth and dysphagia, respectively. Statistical heterogeneity between studies was low to moderate for most outcomes. All tested dosages were efficacious against placebo without clear-cut evidence of a dose-response gradient. However, duration of effect (time until return to baseline TWSTRS-total score) and risk of dry mouth and dysphagia were greater in the subgroup of participants treated with higher BtB doses. Subgroup analysis showed a higher improvement with BtB among BtA-non-responsive participants, although there were no differences in the effect size between the BtA-responsive and non-responsive subgroups. AUTHORS' CONCLUSIONS: A single BtB-treatment session is associated with a significant and clinically relevant reduction of cervical dystonia impairment including severity, disability and pain, and is well tolerated, when compared with placebo. However, BtB-treated patients are at an increased risk of dry mouth and dysphagia. There are no data from RCTs evaluating the effectiveness and safety of repeated BtB injection cycles. There are no RCT data to allow us to draw definitive conclusions on the optimal treatment intervals and doses, usefulness of guidance techniques for injection, and impact on quality of life

Botulinum toxin type A therapy for blepharospasm

BACKGROUND: This is an update of a Cochrane Review first published in 2005. Blepharospasm is the second most common form of focal dystonia. It is a disabling disorder, characterised by chronic, intermittent or persistent, involuntary eyelid closure, due to spasmodic contractions of the orbicularis oculi muscles. Currently, botulinum toxin type A (BtA) is considered the first line of therapy for this condition. OBJECTIVES: To compare the efficacy, safety, and tolerability of BtA versus placebo in people with blepharospasm. SEARCH METHODS: We searched Cochrane Movement Disorders' Trials Register, CENTRAL, MEDLINE, Embase, reference lists of included articles, and conference proceedings. We ran all elements of the search, with no language restrictions, in July 2020. SELECTION CRITERIA: Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtA versus placebo in adults with blepharospasm. 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). We did not carry out any prespecified subgroup analyses. The primary efficacy outcome was improvement on any validated symptomatic rating scale. The primary safety outcome was the proportion of participants with any adverse event. MAIN RESULTS: We included three RCTs, assessed at low to moderate overall risk of bias, which randomised 313 participants with blepharospasm. Two studies excluded participants with poorer prior responses to BtA treatment, therefore, they included an enriched population with a higher probability of benefiting from this therapy. All trials were industry-funded. All RCTs evaluated the effect of a single BtA treatment session. BtA resulted in a moderate to large improvement in blepharospasm-specific severity, with a reduction of 0.93 points on the Jankovic Rating Scale (JRS) severity subscale at four to six weeks after injection (95% confidence interval (CI) 0.61 to 1.25; I² = 9%) compared to placebo. BtA was also resulted in a moderate to large improvement in blepharospasm-specific disability and blepharospasm-specific involuntary movements at four to six weeks after injection (disability: 0.69 JRS disability subscale points, 95% CI 0.18 to 1.19; I² = 74%; blepharospasm-specific involuntary movements: standardised mean difference (SMD) 0.79, 0.31 to 1.27; I² = 58%) compared to placebo. BtA did not show a risk of adverse events (risk ratio (RR) 1.18, 95% CI 0.87 to 1.60; I² = 0%). However, BtA increased the risk of vision complaints and eyelid ptosis (vision complaints: RR 5.73, 95% CI 1.79 to 18.36; I² = 51%; eyelid ptosis: RR 4.02, 95% CI 1.61 to 10.00; I² = 39%). There was no distinction between BtA and placebo in the number of participants who dropped out of the trial. A single trial estimated the duration of effects to be 10.6 weeks (range 6.1 to 19.1). We found no evidence supporting the existence of a clear dose-response relationship with BtA. We found no data reporting the impact of BtA on health-related quality of life, or the development of secondary non-responsiveness. AUTHORS' CONCLUSIONS: We are moderately certain that a single BtA treatment resulted in a clinically relevant reduction of blepharospasm-specific severity and disability, and have low certainty that it is well tolerated, when compared with placebo. There is low-certainty evidence that people treated with BtA are not at an increased risk of developing adverse events, though BtA treatment likely increases the risk of visual complaints and eyelid ptosis. 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, or the impact on quality of life

Botulinum toxin type A therapy for cervical dystonia

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 BtA versus placebo, in people with cervical dystonia. SEARCH METHODS: We searched Cochrane Movement Disorders' Trials Register, CENTRAL, MEDLINE, Embase, reference lists of articles, and conference proceedings in July 2020. All elements of the search, with no language restrictions, were last run in July 2020. 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). We performed preplanned subgroup analyses according to BtA dose used, the BtA formulation used, and the use (or not) of guidance for BtA injections. 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 nine RCTs, with moderate, overall risk of bias, that included 1144 participants with cervical dystonia. Seven 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 500 U of onabotulinumtoxinA (Botox), 120 U to 240 U of incobotulinumtoxinA (Xeomin), and 250 U to 1000 U of abobotulinumtoxinA (Dysport). BtA resulted in a moderate to large improvement from the participant's baseline clinical status, assessed by the investigators, with a mean reduction of 8.09 points in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS total score) at week four after injection (95% CI 6.22 to 9.96; I² = 0%) compared to placebo. This corresponded, on average, to a 18.4% improvement from baseline. The mean difference (MD) in TWSTRS pain subscore at week four was 2.11 (95% CI 1.38 to 2.83; I² = 0%) compared to placebo. Overall, both participants and clinicians reported an improvement of subjective clinical status. It was unclear if dropouts due to adverse events differed (risk ratio (RR) 2.51; 95% CI 0.42 to 14.94; I² = 0%) However, BtA treatment increased the risk of experiencing an adverse event (R) 1.23; 95% CI 1.05 to 1.43; I² = 28%). Neck weakness (14%; RR 3.40; 95% CI 1.19 to 9.71; I² = 15%), dysphagia (11%; RR 3.19; 95% CI 1.79 to 5.70; I² = 0%), and diffuse weakness or tiredness (8%; RR 1.80; 95% CI 1.10 to 2.95; I² = 0%) were the most common treatment-related adverse events. Treatment with BtA resulted in a decreased risk of dropouts. We have moderate certainty in the evidence across all of the aforementioned outcomes, with the exception of subjective assessment and tolerability, in which we have high confidence in the evidence. We found no evidence supporting the existence of a clear dose-response relationship between BtA and improvement in cervical dystonia-specific impairment, a destinction between BtA formulations, or a variation with use of EMG-guided injection for efficacy outcomes. Due to clinical heterogeneity, we did not pool health-related quality of life data, duration of clinical effect, or the development of secondary non-responsiveness. AUTHORS' CONCLUSIONS: We are moderately certain in the evidence that a single BtA treatment session resulted in a clinically relevant reduction of cervical dystonia-specific impairment, and pain, and highly certain that it is well tolerated, compared with placebo. There is moderate-certainty evidence that people treated with BtA are at an increased risk of developing adverse events, most notably, dysphagia, neckweakness and diffuse weakness or tiredness. 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, the usefulness of guidance techniques for injection, the impact on quality of life, or the duration of treatment effect

Anterior ischemic optic neuropathy and hematologic malignancy: a systematic review of case reports and case series

OBJECTIVE: Demographic and clinical characteristics associated with nonarteritic anterior ischemic optic neuropathy (NAION) are well described. Patients with hematologic neoplasms may share some of these characteristics, and it may be useful clinically to better understand this set of patients. Our objective is to review systematically the characteristics of patients with both hematologic malignancies and NAION. DESIGN: Systematic review. PARTICIPANTS: Patients with NAION diagnosis related in time to a hematologic neoplasm. METHODS: Data sources for the study included MEDLINE, Web of Science, LILACS, SciELO, and OpenGrey. The study eligibility criteria included case reports and case series. RESULTS: We found 261 records, with 15 studies included plus our case report. A total of 19 patients (8 female) with mean age of 54.6 years (range, 12-87) were analyzed: 37% (7) non-Hodgkin lymphoma; 26% (5) myeloproliferative neoplasms; 21% (4) myelodysplasia; 16% (3) leukemias. The limitations included verification bias, inability to test statistical association between NAION and hematologic neoplasms, the small number of cases, and confounding factors related to medical history and specific interventions in each case limited the robustness of our conclusions. CONCLUSIONS: Our results identified the characteristics of patients with NAION and hematologic neoplasms related in time. Additional observational studies may enlighten the importance of looking for evidence of an occult neoplastic disorder in patients presenting with NAION. A prompt diagnosis would be of invaluable significance for the best management, in terms of follow-up and therapeutics