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1.
Drug treatment for spinal muscular atrophy types II and III.
Wadman, RI, van der Pol, WL, Bosboom, WM, Asselman, FL, van den Berg, LH, Iannaccone, ST, Vrancken, AF
The Cochrane database of systematic reviews. 2020;(1):CD006282
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Abstract
BACKGROUND Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a (point) mutation in the second SMN1 allele. This results in degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. This is an update of a review first published in 2009 and previously updated in 2011. OBJECTIVES To evaluate if drug treatment is able to slow or arrest the disease progression of SMA types II and III, and to assess if such therapy can be given safely. SEARCH METHODS We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and ISI Web of Science conference proceedings in October 2018. In October 2018, we also searched two trials registries to identify unpublished trials. SELECTION CRITERIA We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a homozygous deletion or hemizygous deletion in combination with a point mutation in the second allele of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis. The primary outcome measure was change in disability score within one year after the onset of treatment. Secondary outcome measures within one year after the onset of treatment were change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full-time ventilation and adverse events attributable to treatment during the trial period. Treatment strategies involving SMN1-replacement with viral vectors are out of the scope of this review, but a summary is given in Appendix 1. Drug treatment for SMA type I is the topic of a separate Cochrane Review. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methodology. MAIN RESULTS The review authors found 10 randomised, placebo-controlled trials of treatments for SMA types II and III for inclusion in this review, with 717 participants. We added four of the trials at this update. The trials investigated creatine (55 participants), gabapentin (84 participants), hydroxyurea (57 participants), nusinersen (126 participants), olesoxime (165 participants), phenylbutyrate (107 participants), somatotropin (20 participants), thyrotropin-releasing hormone (TRH) (nine participants), valproic acid (33 participants), and combination therapy with valproic acid and acetyl-L-carnitine (ALC) (61 participants). Treatment duration was from three to 24 months. None of the studies investigated the same treatment and none was completely free of bias. All studies had adequate blinding, sequence generation and reporting of primary outcomes. Based on moderate-certainty evidence, intrathecal nusinersen improved motor function (disability) in children with SMA type II, with a 3.7-point improvement in the nusinersen group on the Hammersmith Functional Motor Scale Expanded (HFMSE; range of possible scores 0 to 66), compared to a 1.9-point decline on the HFMSE in the sham procedure group (P < 0.01; n = 126). On all motor function scales used, higher scores indicate better function. Based on moderate-certainty evidence from two studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: creatine (median change 1 higher, 95% confidence interval (CI) -1 to 2; on the Gross Motor Function Measure (GMFM), scale 0 to 264; n = 40); and combination therapy with valproic acid and carnitine (mean difference (MD) 0.64, 95% CI -1.1 to 2.38; on the Modified Hammersmith Functional Motor Scale (MHFMS), scale 0 to 40; n = 61). Based on low-certainty evidence from other single studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: gabapentin (median change 0 in the gabapentin group and -2 in the placebo group on the SMA Functional Rating Scale (SMAFRS), scale 0 to 50; n = 66); hydroxyurea (MD -1.88, 95% CI -3.89 to 0.13 on the GMFM, scale 0 to 264; n = 57), phenylbutyrate (MD -0.13, 95% CI -0.84 to 0.58 on the Hammersmith Functional Motor Scale (HFMS) scale 0 to 40; n = 90) and monotherapy of valproic acid (MD 0.06, 95% CI -1.32 to 1.44 on SMAFRS, scale 0 to 50; n = 31). Very low-certainty evidence suggested that the following interventions had little or no effect on motor function: olesoxime (MD 2, 95% -0.25 to 4.25 on the Motor Function Measure (MFM) D1 + D2, scale 0 to 75; n = 160) and somatotropin (median change at 3 months 0.25 higher, 95% CI -1 to 2.5 on the HFMSE, scale 0 to 66; n = 19). One small TRH trial did not report effects on motor function and the certainty of evidence for other outcomes from this trial were low or very low. Results of nine completed trials investigating 4-aminopyridine, acetyl-L-carnitine, CK-2127107, hydroxyurea, pyridostigmine, riluzole, RO6885247/RG7800, salbutamol and valproic acid were awaited and not available for analysis at the time of writing. Various trials and studies investigating treatment strategies other than nusinersen (e.g. SMN2-augmentation by small molecules), are currently ongoing. AUTHORS' CONCLUSIONS Nusinersen improves motor function in SMA type II, based on moderate-certainty evidence. Creatine, gabapentin, hydroxyurea, phenylbutyrate, valproic acid and the combination of valproic acid and ALC probably have no clinically important effect on motor function in SMA types II or III (or both) based on low-certainty evidence, and olesoxime and somatropin may also have little to no clinically important effect but evidence was of very low-certainty. One trial of TRH did not measure motor function.
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2.
Drug treatment for spinal muscular atrophy type I.
Wadman, RI, van der Pol, WL, Bosboom, WM, Asselman, FL, van den Berg, LH, Iannaccone, ST, Vrancken, AF
The Cochrane database of systematic reviews. 2019;(12):CD006281
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Abstract
BACKGROUND Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a point mutation in the second SMN1 allele. This results in degeneration of anterior horn cells, which leads to progressive muscle weakness. By definition, children with SMA type I are never able to sit without support and usually die or become ventilator dependent before the age of two years. There have until very recently been no drug treatments to influence the course of SMA. We undertook this updated review to evaluate new evidence on emerging treatments for SMA type I. The review was first published in 2009 and previously updated in 2011. OBJECTIVES To assess the efficacy and safety of any drug therapy designed to slow or arrest progression of spinal muscular atrophy (SMA) type I. SEARCH METHODS We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and ISI Web of Science conference proceedings in October 2018. We also searched two trials registries to identify unpublished trials (October 2018). SELECTION CRITERIA We sought all randomised controlled trials (RCTs) or quasi-RCTs that examined the efficacy of drug treatment for SMA type I. Included participants had to fulfil clinical criteria and have a genetically confirmed deletion or mutation of the SMN1 gene (5q11.2-13.2). The primary outcome measure was age at death or full-time ventilation. Secondary outcome measures were acquisition of motor milestones, i.e. head control, rolling, sitting or standing, motor milestone response on disability scores within one year after the onset of treatment, and adverse events and serious adverse events attributable to treatment during the trial period. Treatment strategies involving SMN1 gene replacement with viral vectors are out of the scope of this review. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methodology. MAIN RESULTS We identified two RCTs: one trial of intrathecal nusinersen in comparison to a sham (control) procedure in 121 randomised infants with SMA type I, which was newly included at this update, and one small trial comparing riluzole treatment to placebo in 10 children with SMA type I. The RCT of intrathecally-injected nusinersen was stopped early for efficacy (based on a predefined Hammersmith Infant Neurological Examination-Section 2 (HINE-2) response). At the interim analyses after 183 days of treatment, 41% (21/51) of nusinersen-treated infants showed a predefined improvement on HINE-2, compared to 0% (0/27) of participants in the control group. This trial was largely at low risk of bias. Final analyses (ranging from 6 months to 13 months of treatment), showed that fewer participants died or required full-time ventilation (defined as more than 16 hours daily for 21 days or more) in the nusinersen-treated group than the control group (hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.32 to 0.89; N = 121; a 47% lower risk; moderate-certainty evidence). A proportion of infants in the nusinersen group and none of 37 infants in the control group achieved motor milestones: 37/73 nusinersen-treated infants (51%) achieved a motor milestone response on HINE-2 (risk ratio (RR) 38.51, 95% CI 2.43 to 610.14; N = 110; moderate-certainty evidence); 16/73 achieved head control (RR 16.95, 95% CI 1.04 to 274.84; moderate-certainty evidence); 6/73 achieved independent sitting (RR 6.68, 95% CI 0.39 to 115.38; moderate-certainty evidence); 7/73 achieved rolling over (RR 7.70, 95% CI 0.45 to 131.29); and 1/73 achieved standing (RR 1.54, 95% CI 0.06 to 36.92; moderate-certainty evidence). Seventy-one per cent of nusinersen-treated infants versus 3% of infants in the control group were responders on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) measure of motor disability (RR 26.36, 95% CI 3.79 to 183.18; N = 110; moderate-certainty evidence). Adverse events and serious adverse events occurred in the majority of infants but were no more frequent in the nusinersen-treated group than the control group (RR 0.99, 95% CI 0.92 to 1.05 and RR 0.70, 95% CI 0.55 to 0.89, respectively; N = 121; moderate-certainty evidence). In the riluzole trial, three of seven children treated with riluzole were still alive at the ages of 30, 48, and 64 months, whereas all three children in the placebo group died. None of the children in the riluzole or placebo group developed the ability to sit, which was the only milestone reported. There were no adverse effects. The certainty of the evidence for all measured outcomes from this study was very low, because the study was too small to detect or rule out an effect, and had serious limitations, including baseline differences. This trial was stopped prematurely because the pharmaceutical company withdrew funding. Various trials and studies investigating treatment strategies other than nusinersen, such as SMN2 augmentation by small molecules, are ongoing. AUTHORS' CONCLUSIONS Based on the very limited evidence currently available regarding drug treatments for SMA type 1, intrathecal nusinersen probably prolongs ventilation-free and overall survival in infants with SMA type I. It is also probable that a greater proportion of infants treated with nusinersen than with a sham procedure achieve motor milestones and can be classed as responders to treatment on clinical assessments (HINE-2 and CHOP INTEND). The proportion of children experiencing adverse events and serious adverse events on nusinersen is no higher with nusinersen treatment than with a sham procedure, based on evidence of moderate certainty. It is uncertain whether riluzole has any effect in patients with SMA type I, based on the limited available evidence. Future trials could provide more high-certainty, longer-term evidence to confirm this result, or focus on comparing new treatments to nusinersen or evaluate them as an add-on therapy to nusinersen.
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3.
Intravenous Magnesium Sulfate in Acute Stroke.
Avgerinos, KI, Chatzisotiriou, A, Haidich, AB, Tsapas, A, Lioutas, VA
Stroke. 2019;(4):931-938
Abstract
Background and Purpose- Acute stroke treatment is challenging, and stroke remains a major cause of death and disability. The purpose of this meta-analysis is to investigate the effects of postacute stroke intravenous administration of the neuroprotectant magnesium sulfate (MgSO4) on global outcome, functional outcome, and mortality 90 days poststroke (ischemic and nonischemic). Methods- We searched in Pubmed, Science Direct, CENTRAL, and ClinicalTrials.gov, up to November 11, 2017, and we conducted a systematic review and meta-analysis of randomized controlled trials. We synthesized results by using random-effects model, weighted mean differences, standardized mean differences, and odds ratios. Results- Seven randomized controlled trials (4347 patients) met our criteria. Compared with placebo, treatment did not improve functional outcome defined as Barthel Index >60 (odds ratio =1.05; 95% CI, 0.92-1.19) and >95 (odds ratio =0.95; 95% CI, 0.76-1.20), 90 days poststroke. It also did not improve global outcome measured with modified Rankin Scale (standardized mean difference =-0.01; 95% CI, -0.12 to 0.10), 90 days poststroke. In an additional subgroup meta-analysis that exclusively included ischemic stroke patients, intravenous MgSO4 resulted in lower modified Rankin Scale score (improved global outcome; weighted mean difference =-0.96; 95% CI, -1.34 to -0.58; I2=0%], 90 days poststroke. Finally, mortality stayed unaltered (odds ratio =1.10; 95% CI, 0.94-1.29). Conclusions- The findings of our meta-analysis showed that intravenous MgSO4 generally did not improve global/functional outcomes and mortality at 90 days after stroke (combined ischemic stroke and nonischemic stroke). The finding of favorable neurological outcome, selectively in ischemic stroke patients, should be viewed with extreme caution given the limited number of patients included in this subgroup meta-analysis.
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A meta-analysis of the effect of different neuroprotective drugs in management of patients with traumatic brain injury.
El Sayed, I, Zaki, A, Fayed, AM, Shehata, GM, Abdelmonem, S
Neurosurgical review. 2018;(2):427-438
Abstract
Traumatic brain injury is a major problem worldwide. Our objective is to synthesize available evidence in the literature concerning the effectiveness of neuroprotective drugs (cerebrolysin, citicoline, and piracetam) on Glasgow outcome score (GOS), cognitive performance, and survival in traumatic brain injury patients. Comprehensive search of electronic databases, search engines, and conferences proceedings; hand search journals; searching reference lists of relevant articles, theses, and local publications; and contact of authors for incomplete data were performed. Studies included patients in all age groups regardless of severity of trauma. There was no publication date restriction. Two reviewers independently extracted data from each study. Fixed effect or random effects model selection depends on results of statistical tests for heterogeneity. The literature search yielded 13 studies. Patients treated with cerebrolysin (n = 112) had favorable GOS three times more than controls (OR 3.019; 95 % CI 1.76 to 5.16; p = 0.003*). The odds of cognition improvement in the treatment group was 3.4 times more than controls (OR 3.4; 95 % CI 1.82 to 5.21; p < 0.001*). Survival of cerebrolysin-treated patients did not differ from controls (103 patients; OR = 2.81; 95 % CI 0.905 to 8.76). Citicoline did not improve GOS (1355 patients; OR 0.96; 95 % CI 0.830 to 1.129; p = 0.676), cognitive performance (4 studies; 1291 patients; OR 1.35; 95 % CI 0.58 to 3.16; p = 0.478), and survival (1037 patients; OR = 1.38; 95 % CI 0.855 to 2.239). One study showed a positive effect of piracetam on cognition. Further research with high validity is needed to reach a solid conclusion about the use of neuroprotective drugs in cases of brain injury.
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A meta-analysis of pharmacological neuroprotection in noncardiac surgery: focus on statins, lidocaine, ketamine, and magnesium sulfate.
Zeng, ZW, Zhang, YN, Lin, WX, Zhang, WQ, Luo, R
European review for medical and pharmacological sciences. 2018;(6):1798-1811
Abstract
OBJECTIVE Non-cardiac surgery is associated with perioperative cerebral complications (delirium, postoperative cognition dysfunction, stroke). While rare, these complications can lead to disabilities and deaths. Information is ambiguous as to whether pharmacological preoperative treatment exerts neuroprotection. We wished to systematically assess potential modulation by statins, lidocaine, ketamine or magnesium sulfate of the relative risk of cerebral complications in noncardiac surgery. Selection of these pharmacological agents was based on their known neuroprotective abilities. PATIENTS AND METHODS By searching Medline, EMBASE and Cochrane databases, we identified 4 suitable publications that collectively enrolled 1358 patients (intent-to-treat population), of which 679 patients were treated preoperatively with statins (404 patients on atorvastatin and 275 on rosuvastatin) and 679 patients with preoperative placebo. The reported cerebral outcome was stroke, assessed either within 30 days (4 publications) or 6 months (2 publications) after surgery. RESULTS Episodes of stroke within 30 days and 6 months postoperatively were observed in several publications, enabling aggregate analyses. No modulation by statins of the relative risk of stroke at 30 days was observed (risk ratio 1.59, 95% confidence interval 0.08-30.97; p = 0.76). At 6 months, statins showed an insignificant trend toward neuroprotection (risk ratio 0.33, 95% confidence interval 0.05-2.10; p = 0.24). CONCLUSIONS The available clinical data are still scarce. Our analyses indicate no protective effects by statins against perioperative stroke but some favorable trends toward delayed stroke. Further randomized trials are needed to unequivocally assess the neuroprotective potential of current pharmacological agents in non-cardiac surgery.
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Safety and efficacy of Cerebrolysin in early post-stroke recovery: a meta-analysis of nine randomized clinical trials.
Bornstein, NM, Guekht, A, Vester, J, Heiss, WD, Gusev, E, Hömberg, V, Rahlfs, VW, Bajenaru, O, Popescu, BO, Muresanu, D
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2018;(4):629-640
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Abstract
This meta-analysis combines the results of nine ischemic stroke trials, assessing efficacy of Cerebrolysin on global neurological improvement during early post-stroke period. Cerebrolysin is a parenterally administered neuropeptide preparation approved for treatment of stroke. All included studies had a prospective, randomized, double-blind, placebo-controlled design. The patients were treated with 30-50 ml Cerebrolysin once daily for 10-21 days, with treatment initiation within 72 h after onset of ischemic stroke. For five studies, original analysis data were available for meta-analysis (individual patient data analysis); for four studies, aggregate data were used. The combination by meta-analytic procedures was pre-planned and the methods of synthesis were pre-defined under blinded conditions. Search deadline for the present meta-analysis was December 31, 2016. The nonparametric Mann-Whitney (MW) effect size for National Institutes of Health Stroke Scale (NIHSS) on day 30 (or 21), combining the results of nine randomized, controlled trials by means of the robust Wei-Lachin pooling procedure (maximin-efficient robust test), indicated superiority of Cerebrolysin as compared with placebo (MW 0.60, P < 0.0001, N = 1879). The combined number needed to treat for clinically relevant changes in early NIHSS was 7.7 (95% CI 5.2 to 15.0). The additional full-scale ordinal analysis of modified Rankin Scale at day 90 in moderate to severe patients resulted in MW 0.61 with statistical significance in favor of Cerebrolysin (95% CI 0.52 to 0.69, P = 0.0118, N = 314). Safety aspects were comparable to placebo. Our meta-analysis confirms previous evidence that Cerebrolysin has a beneficial effect on early global neurological deficits in patients with acute ischemic stroke.