Comprehensive Systematic Review Summary Research Articles

Editors' note: Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

In the special article “Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis,” Rae-Grant et al. reported the findings of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology based on reviewing the evidence on starting, switching, and stopping disease-modifying therapies for clinically isolated syndrome, relapsing-remitting MS, and progressive forms of MS. In response, Dr. Tran, on behalf of Genentech, argues that the report did not make it clear that data on annualized relapse rate reduction and relative risk of in-study disability progression for ocrelizumab (presented along with other therapies in figures 1 and 3) were from direct comparisons with subcutaneous interferon-β-1a 44 μg 3 times weekly in 2 phase 3 randomized, double-blind, double-dummy trials. In response, Dr. Rae-Grant agrees that this information should have been included, but notes that statements in the text of the summary and in a key accompanying table acknowledged the superior efficacy of ocrelizumab compared with interferon- β-1a 3 times weekly. Dr. Rae-Grant also notes that data on subgroup analysis of treatment of highly active MS with ocrelizumab were not available at the time of publication of the systematic review. In the special article “Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis,” Rae-Grant et al. reported the findings of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology based on reviewing the evidence on starting, switching, and stopping disease-modifying therapies for clinically isolated syndrome, relapsing-remitting MS, and progressive forms of MS. In response, Dr. Tran, on behalf of Genentech, argues that the report did not make it clear that data on annualized relapse rate reduction and relative risk of in-study disability progression for ocrelizumab (presented along with other therapies in figures 1 and 3) were from direct comparisons with subcutaneous interferon-β-1a 44 μg 3 times weekly in 2 phase 3 randomized, double-blind, double-dummy trials. In response, Dr. Rae-Grant agrees that this information should have been included, but notes that statements in the text of the summary and in a key accompanying table acknowledged the superior efficacy of ocrelizumab compared with interferon- β-1a 3 times weekly. Dr. Rae-Grant also notes that data on subgroup analysis of treatment of highly active MS with ocrelizumab were not available at the time of publication of the systematic review.

Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

In the special article “Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology,” …

Reader response: Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

Genentech recognizes that high-quality and trustworthy guidelines, such as those published by the American Academy of Neurology, are important both for providers to optimize patient care and for payers to manage appropriate utilization of multiple sclerosis (MS) treatments.

Author response: Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

To review evidence on starting, switching, and stopping disease-modifying therapies (DMTs) for multiple sclerosis (MS) in clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and progressive MS forms.Relevant, peer-reviewed research articles, systematic reviews, and abstracts were identified (MEDLINE, CENTRAL, EMBASE searched from inception to November 2016). Studies were rated using the therapeutic classification scheme. Prior published Cochrane reviews were also used.Twenty Cochrane reviews and an additional 73 full-text articles were selected for data extraction through an updated systematic review (completed November 2016). For people with RRMS, many DMTs are superior to placebo (annualized relapses rates [ARRs], new disease activity [new MRI T2 lesion burden], and in-study disease progression) (see summary and full text publications). For people with RRMS who experienced a relapse on interferon-β (IFN-β) or glatiramer acetate, alemtuzumab is more effective than IFN-β-1a 44 μg subcutaneous 3 times per week in reducing the ARR. For people with primary progressive MS, ocrelizumab is probably more effective than placebo (in-study disease progression). DMTs for MS have varying adverse effects. In people with CIS, glatiramer acetate and IFN-β-1a subcutaneous 3 times per week are more effective than placebo in decreasing risk of conversion to MS. Cladribine, immunoglobulins, IFN-β-1a 30 μg intramuscular weekly, IFN-β-1b subcutaneous alternate day, and teriflunomide are probably more effective than placebo in decreasing risk of conversion to MS. Suggestions for future research include studies considering comparative effectiveness, usefulness of high-efficacy treatment vs stepped-care protocols, and research into predictive biomarkers.

Comprehensive systematic review summary: Treatment of tics in people with Tourette syndrome and chronic tic disorders.

Comprehensive systematic review summary: Treatment of tics in people with Tourette syndrome and chronic tic disorders.

Comprehensive systematic review summary: Treatment of tics in people with Tourette syndrome and chronic tic disorders.

To systematically evaluate the efficacy of treatments for tics and the risks associated with their use. This project followed the methodologies outlined in the 2011 edition of the American Academy of Neurology's guideline development process manual. We included systematic reviews and randomized controlled trials on the treatment of tics that included at least 20 participants (10 participants if a crossover trial), except for neurostimulation trials, for which no minimum sample size was required. To obtain additional information on drug safety, we included cohort studies or case series that specifically evaluated adverse drug effects in individuals with tics. There was high confidence that the Comprehensive Behavioral Intervention for Tics was more likely than psychoeducation and supportive therapy to reduce tics. There was moderate confidence that haloperidol, risperidone, aripiprazole, tiapride, clonidine, onabotulinumtoxinA injections, 5-ling granule, Ningdong granule, and deep brain stimulation of the globus pallidus were probably more likely than placebo to reduce tics. There was low confidence that pimozide, ziprasidone, metoclopramide, guanfacine, topiramate, and tetrahydrocannabinol were possibly more likely than placebo to reduce tics. Evidence of harm associated with various treatments was also demonstrated, including weight gain, drug-induced movement disorders, elevated prolactin levels, sedation, and effects on heart rate, blood pressure, and ECGs. There is evidence to support the efficacy of various medical, behavioral, and neurostimulation interventions for the treatment of tics. Both the efficacy and harms associated with interventions must be considered in making treatment recommendations.

Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

To review evidence on starting, switching, and stopping disease-modifying therapies (DMTs) for multiple sclerosis (MS) in clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and progressive MS forms. Relevant, peer-reviewed research articles, systematic reviews, and abstracts were identified (MEDLINE, CENTRAL, EMBASE searched from inception to November 2016). Studies were rated using the therapeutic classification scheme. Prior published Cochrane reviews were also used. Twenty Cochrane reviews and an additional 73 full-text articles were selected for data extraction through an updated systematic review (completed November 2016). For people with RRMS, many DMTs are superior to placebo (annualized relapses rates [ARRs], new disease activity [new MRI T2 lesion burden], and in-study disease progression) (see summary and full text publications). For people with RRMS who experienced a relapse on interferon-β (IFN-β) or glatiramer acetate, alemtuzumab is more effective than IFN-β-1a 44 μg subcutaneous 3 times per week in reducing the ARR. For people with primary progressive MS, ocrelizumab is probably more effective than placebo (in-study disease progression). DMTs for MS have varying adverse effects. In people with CIS, glatiramer acetate and IFN-β-1a subcutaneous 3 times per week are more effective than placebo in decreasing risk of conversion to MS. Cladribine, immunoglobulins, IFN-β-1a 30 μg intramuscular weekly, IFN-β-1b subcutaneous alternate day, and teriflunomide are probably more effective than placebo in decreasing risk of conversion to MS. Suggestions for future research include studies considering comparative effectiveness, usefulness of high-efficacy treatment vs stepped-care protocols, and research into predictive biomarkers.

Comprehensive systematic review summary: Treatment of cerebellar motor dysfunction and ataxia: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

To systematically review evidence regarding ataxia treatment. A comprehensive systematic review was performed according to American Academy of Neurology methodology. For patients with episodic ataxia type 2, 4-aminopyridine 15 mg/d probably reduces ataxia attack frequency over 3 months (1 Class I study). For patients with ataxia of mixed etiology, riluzole probably improves ataxia signs at 8 weeks (1 Class I study). For patients with Friedreich ataxia or spinocerebellar ataxia (SCA), riluzole probably improves ataxia signs at 12 months (1 Class I study). For patients with SCA type 3, valproic acid 1,200 mg/d possibly improves ataxia at 12 weeks. For patients with spinocerebellar degeneration, thyrotropin-releasing hormone possibly improves some ataxia signs over 10 to 14 days (1 Class II study). For patients with SCA type 3 who are ambulatory, lithium probably does not improve signs of ataxia over 48 weeks (1 Class I study). For patients with Friedreich ataxia, deferiprone possibly worsens ataxia signs over 6 months (1 Class II study). Data are insufficient to support or refute the use of numerous agents. For nonpharmacologic options, in patients with degenerative ataxias, 4-week inpatient rehabilitation probably improves ataxia and function (1 Class I study); transcranial magnetic stimulation possibly improves cerebellar motor signs at 21 days (1 Class II study). For patients with multiple sclerosis-associated ataxia, the addition of pressure splints possibly has no additional benefit compared with neuromuscular rehabilitation alone (1 Class II study). Data are insufficient to support or refute use of stochastic whole-body vibration therapy (1 Class III study).

Rehabilitation in multiple sclerosis: Commentary on the recent AAN systematic review.

We thank Sutliff et al.1 for their commentary on our systematic review (SR), “Summary of comprehensive systematic review: Rehabilitation in multiple sclerosis.”2 We would like to make several points in response. (A more extensive response is available at Neurology.org/cp.) First, contrary to their comment that our panel2 “lacked specialist diversity,” the panel included multiple sclerosis (MS) experts, rehabilitation experts, non-MS neurologists, and guideline methodologists. Furthermore, the National Multiple Sclerosis Society was part of the process.2 Physical and occupational therapists, speech/language therapists, and exercise physiologists were not included; this reflects the guideline development process at the time. Nevertheless, this was an SR,2 not a clinical practice guideline (CPG). An SR makes conclusions based on available evidence, whereas CPGs make practice recommendations. The CPG process lends itself to expert formal consensus; the SR does not. The conclusions of our SR2 would have been the same even with the inclusion of other experts because they are based on the American Academy of Neurology (AAN) risk of bias assessment of each study and not expert opinion. Second, we have highlighted methodologic limitations of the rehabilitation literature in our recommendations for future research.2 We do not deem it appropriate to blame the risk of bias assessment for failure to identify high-level studies in our SR.2 …

Critically re-evaluating a common technique: Accuracy, reliability, and confirmation bias of EMG

Editors' Note: In WriteClick this week, Drs. Charles and Souayah highlight the limitations of EMG in patients with radicular symptoms, in reference to “Critically re-evaluating a common technique: Accuracy, reliability, and confirmation bias of EMG.” In response, the authors discuss situations in which EMG may be clinically useful. Responding to “Summary of comprehensive systematic review: Rehabilitation in multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology,” Jones et al. discuss the possible factors behind the relative lack of quality evidence available and question the effects of this on the study's conclusions. The …

Summary of comprehensive systematic review: Rehabilitation in multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

Objective: To systematically review the evidence regarding rehabilitation treatments in multiple sclerosis (MS). Methods: We systematically searched the literature (1970–2013) and classified articles using 2004 American Academy of Neurology criteria. Results: This systematic review highlights the paucity of well-designed studies, which are needed to evaluate the available MS rehabilitative therapies. Weekly home/outpatient physical therapy (8 weeks) probably is effective for improving balance, disability, and gait (MS type unspecified, participants able to walk ≥5 meters) but probably is ineffective for improving upper extremity dexterity (1 Class I). Inpatient exercises (3 weeks) followed by home exercises (15 weeks) possibly are effective for improving disability (relapsing-remitting MS [RRMS], primary progressive MS [PPMS], secondary progressive MS [SPMS], Expanded Disability Status Scale [EDSS] 3.0–6.5) (1 Class II). Six weeks9 worth of comprehensive multidisciplinary outpatient rehabilitation possibly is effective for improving disability/function (PPMS, SPMS, EDSS 4.0–8.0) (1 Class II). Motor and sensory balance training or motor balance training (3 weeks) possibly is effective for improving static and dynamic balance, and motor balance training (3 weeks) possibly is effective for improving static balance (RRMS, SPMS, PPMS) (1 Class II). Breathing-enhanced upper extremity exercises (6 weeks) possibly are effective for improving timed gait and forced expiratory volume in 1 second (RRMS, SPMS, PPMS, mean EDSS 4.5); this change is of unclear clinical significance. This technique possibly is ineffective for improving disability (1 Class II). Inspiratory muscle training (10 weeks) possibly improves maximal inspiratory pressure (RRMS, SPMS, PPMS, EDSS 2–6.5) (1 Class II).

Summary of comprehensive systematic review: Rehabilitation in multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

To systematically review the evidence regarding rehabilitation treatments in multiple sclerosis (MS). We systematically searched the literature (1970-2013) and classified articles using 2004 American Academy of Neurology criteria. This systematic review highlights the paucity of well-designed studies, which are needed to evaluate the available MS rehabilitative therapies. Weekly home/outpatient physical therapy (8 weeks) probably is effective for improving balance, disability, and gait (MS type unspecified, participants able to walk ≥5 meters) but probably is ineffective for improving upper extremity dexterity (1 Class I). Inpatient exercises (3 weeks) followed by home exercises (15 weeks) possibly are effective for improving disability (relapsing-remitting MS [RRMS], primary progressive MS [PPMS], secondary progressive MS [SPMS], Expanded Disability Status Scale [EDSS] 3.0-6.5) (1 Class II). Six weeks' worth of comprehensive multidisciplinary outpatient rehabilitation possibly is effective for improving disability/function (PPMS, SPMS, EDSS 4.0-8.0) (1 Class II). Motor and sensory balance training or motor balance training (3 weeks) possibly is effective for improving static and dynamic balance, and motor balance training (3 weeks) possibly is effective for improving static balance (RRMS, SPMS, PPMS) (1 Class II). Breathing-enhanced upper extremity exercises (6 weeks) possibly are effective for improving timed gait and forced expiratory volume in 1 second (RRMS, SPMS, PPMS, mean EDSS 4.5); this change is of unclear clinical significance. This technique possibly is ineffective for improving disability (1 Class II). Inspiratory muscle training (10 weeks) possibly improves maximal inspiratory pressure (RRMS, SPMS, PPMS, EDSS 2-6.5) (1 Class II).