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

Poor sleep quality and oral health among older Brazilian adults

Objectives: This study evaluates the association between normative and subjective oral health measures and poor self‐reported sleep quality among community‐dwelling older adults in Brazil. / Methods: This was a cross‐sectional study with data from the Brazilian Longitudinal Study of Aging. The dependent variable was the poor sleep quality. Independent variables of interest included number of teeth and self‐reported impact of oral health on eating/chewing and on maintaining emotional stability. / Results: Poor sleep quality was reported by 17.8 (95% CI 16.6; 19.2) of the participants, 29% of the participants were edentulous, and 30% had 20 or more teeth. Impacts of oral health on eating and maintaining emotional stability was found among 33.3% and 20% of the older adults, respectively. After adjusting for all oral health measures and covariates, the magnitude of the associations between the number of teeth and sleep quality was attenuated. Sleep quality was related to oral health impacts on eating (OR 1.19 [95% CI 1.00; 1.41]) and on emotional stability (OR 1.51 [95% CI 1.21; 1.87]). / Conclusions: This study found an association between oral health and sleep quality emphasizing the importance of oral health to general health

Endovascular treatment versus medical care alone for ischaemic stroke: systematic review and meta-analysis

Objectives: To evaluate the efficacy and safety of endovascular treatment, particularly adjunctive intra-arterial mechanical thrombectomy, in patients with ischaemic stroke. / Design: Systematic review and meta-analysis. / Data sources: Medline, Embase, Cochrane Central Register of Controlled Trials, Web of Science, SciELO, LILACS, and clinical trial registries from inception to December 2015. Reference lists were crosschecked. / Eligibility criteria for selecting studies: Randomised controlled trials in adults aged 18 or more with ischaemic stroke comparing endovascular treatment, including thrombectomy, with medical care alone, including intravenous recombinant tissue plasminogen activator (rt-PA). Trial endpoints were functional outcome (modified Rankin scale scores of ≤2) and mortality at 90 days after onset of symptoms. No language or time restrictions applied. / Results: 10 randomised controlled trials (n=2925) were included. In pooled analysis endovascular treatment, including thrombectomy, was associated with a higher proportion of patients experiencing good (modified Rankin scale scores ≤2) and excellent (scores ≤1) outcomes 90 days after stroke, without differences in mortality or rates for symptomatic intracranial haemorrhage, compared with patients randomised to medical care alone, including intravenous rt-PA. Heterogeneity was high among studies. The more recent studies (seven randomised controlled trials, published or presented in 2015) proved better suited to evaluate the effect of adjunctive intra-arterial mechanical thrombectomy on its index disease owing to more accurate patient selection, intravenous rt-PA being administered at a higher rate and earlier, and the use of more efficient thrombectomy devices. In most of these studies, more than 86% of the patients were treated with stent retrievers, and rates of recanalisation were higher (>58%) than previously reported. Subgroup analysis of these seven studies yielded a risk ratio of 1.56 (95% confidence interval 1.38 to 1.75) for good functional outcomes and 0.86 (0.69 to 1.06) for mortality, without heterogeneity among the results of the studies. All trials were open label. Risk of bias was moderate across studies. The full results of two trials are yet to be published. / Conclusions: Moderate to high quality evidence suggests that compared with medical care alone in a selected group of patients endovascular thrombectomy as add-on to intravenous thrombolysis performed within six to eight hours after large vessel ischaemic stroke in the anterior circulation provides beneficial functional outcomes, without increased detrimental effects. / Systematic review registration: PROSPERO CRD42015019340

Does undiagnosed diabetes mitigate the association between diabetes and cognitive impairment? Findings from the ELSI‐Brazil study

Background: Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment. However, most of the evidence has been based on self‐reported T2DM, and undiagnosed diabetes has not been considered as a separate category. We aimed to examine the extent to which undiagnosed diabetes modifies the association between diabetes and cognitive impairment in a representative sample of Brazilian adults aged 50 years and older. / Methods: We analyzed baseline data from 1944 participants of the Brazilian Longitudinal Study of Aging (ELSI‐Brazil) conducted from 2015 to 2016. Diabetes was evaluated based on self‐reported doctor diagnosis and glycosylated hemoglobin levels. Participants were classified as diabetics (D), undiagnosed diabetics (UDD), or nondiabetics (ND). Cognitive function was assessed by word list learning and verbal fluency tests. Three multiple logistic regression models were used to evaluate the changes in the strength of the associations. / Results: Participants with diabetes had 49% greater odds of exhibiting impaired memory than nondiabetics (odds ratio [OR] = 1.49; 95% CI: 1.01‐2.20). By combining UDD and ND, the association between diabetes and impaired memory was attenuated by 2.0%, losing its statistical significance (OR = 1.46; 95% CI: 0.98‐2.17). By combining UDD and D, the association was attenuated by 7.4% (OR = 1.38; 95% CI: 1.01‐1.90). No significant association was found between T2DM and impaired verbal fluency. / Conclusion: This study found an association between T2DM and impaired memory but not with impaired verbal fluency. When UDD individuals are considered diabetics, this association is attenuated; when UDD individuals are considered as ND, this association is attenuated to the extent that it loses its statistical significance, affecting thus the clinical interpretation

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

Differences in the prevalence of prediabetes, undiagnosed diabetes and diagnosed diabetes and associated factors in cohorts of Brazilian and English older adults

OBJECTIVE: To analyse differences in the prevalence of prediabetes (PD), undiagnosed diabetes (UDD) and diagnosed diabetes (DD) and associated factors between Brazilian and English older adults. DESIGN: Cross-sectional study. SETTING: England and Brazil. PARTICIPANTS: 5301 participants of the English Longitudinal Study of Ageing study and 1947 participants of the Brazilian Longitudinal Study of Aging study classified as non-diabetics, PD, UDD and DD. RESULTS: The prevalence of PD, UDD and DD was 48·6, 3 and 9·6 % in England and 33, 6 and 20 % in Brazil. In England, the increase in age, non-white skin colour, smoking, general obesity and abdominal obesity were associated with PD, UDD and DD, whereas hypertriglyceridaemia, low HDL levels, hypertension and stroke were associated with UDD and DD. In Brazil, the increase in age was associated with DD and UDD, non-white skin colour and smoking were associated with UDD and abdominal obesity and hypertriglyceridaemia were associated with all three conditions. CVD in England and schooling in Brazil were associated with PD and DD. A sedentary lifestyle was associated with DD in both samples. CONCLUSIONS: The prevalence of diabetes was higher in the Brazilian sample. Different associated factors were found in the two samples, which may be related to differences in nutritional transition, access to healthcare services and the use of such services