Time to angiographic reperfusion and clinical outcome after acute ischaemic stroke: an analysis of data from the Interventional Management of Stroke (IMS III) phase 3 trial

Background

The IMS III trial did not show a clinical benefit of endovascular treatment compared with intravenous alteplase (recombinant tissue plasminogen activator) alone for moderate or severe ischaemic strokes. Late reperfusion of tissue that was no longer salvageable could be one explanation, as suggested by previous exploratory studies that showed an association between time to reperfusion and good clinical outcome. We sought to validate this association in a preplanned analysis of data from the IMS III trial.

Methods

We used data for patients with complete proximal arterial occlusions in the anterior circulation who received endovascular treatment and achieved angiographic reperfusion (score on Thrombolysis in Cerebral Infarction scale of grade 2—3) during the endovascular procedure (within 7 h of symptom onset). We used logistic regression to model good clinical outcome (defined as a modified Rankin Scale score of 0—2 at 3 months) as a function of the time to reperfusion. We prespecified variables to be considered for adjustment, including age, baseline National Institutes of Health Stroke Scale score, sex, and baseline blood glucose concentration.

Findings

Of 240 patients who were otherwise eligible for inclusion in our analysis, 182 (76%) achieved angiographic reperfusion. Mean time from symptom onset to reperfusion (ie, procedure end) was 325 min (SD 52). Increased time to reperfusion was associated with a decreased likelihood of good clinical outcome (unadjusted relative risk for every 30-min delay 0·85 [95% CI 0·77—0·94]; adjusted relative risk 0·88 [0·80—0·98]).

Interpretation

Delays in time to angiographic reperfusion lead to a decreased likelihood of good clinical outcome in patients after moderate to severe stroke. Rapid reperfusion could be crucial for the success of future acute endovascular trials.

Lancet Neurology 2014

Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study

Background

Subcutaneous pegylated interferon (peginterferon) beta-1a is being developed for treatment of relapsing multiple sclerosis, with less frequent dosing than currently available first-line injectable treatments. We assessed the safety and efficacy of peginterferon beta-1a after 48 weeks of treatment in the placebo-controlled phase of the ADVANCE trial, a study of patients with relapsing-remitting multiple sclerosis.

Methods

We did this 2-year, double-blind, parallel group, phase 3 study, with a placebo-controlled design for the first 48 weeks, at 183 sites in 26 countries. Patients with relapsing-remitting multiple sclerosis (age 18—65 years, with Expanded Disability Status Scale score ≤5) were randomly assigned (1:1:1) via an interactive voice response or web system, and stratified by site, to placebo or subcutaneous peginterferon beta-1a 125 μg once every 2 weeks or every 4 weeks. The primary endpoint was annualised relapse rate at 48 weeks. This trial is registered with ClinicalTrials.gov, number NCT00906399.

Findings

We screened 1936 patients and enrolled 1516, of whom 1512 were randomly assigned (500 to placebo, 512 to peginterferon every 2 weeks, 500 to peginterferon every 4 weeks); 1332 (88%) patients completed 48 weeks of treatment. Adjusted annualised relapse rates were 0·397 (95% CI 0·328—0·481) in the placebo group versus 0·256 (0·206—0·318) in the every 2 weeks group and 0·288 (0·234—0·355) in the every 4 weeks group (rate ratio for every 2 weeks group 0·644, 95% CI 0·500—0·831, p=0·0007; rate ratio for the every 4 weeks group 0·725, 95% CI 0·565—0·930, p=0·0114). 417 (83%) patients taking placebo, 481 (94%) patients taking peginterferon every 2 weeks, and 472 (94%) patients taking peginterferon every 4 weeks reported adverse events including relapses. The most common adverse events associated with peginterferon beta-1a were injection site reactions, influenza-like symptoms, pyrexia, and headache. 76 (15%) patients taking placebo, 55 (11%) patients taking study drug every 2 weeks, and 71 (14%) patients taking study drug every 4 weeks reported serious adverse events; relapse, pneumonia, and urinary tract infection were the most common.

Interpretation

After 48 weeks, peginterferon beta-1a significantly reduced relapse rate compared with placebo. The drug might be an effective treatment for relapsing-remitting multiple sclerosis with less frequent administration than available treatments

Lancet Neurology 2014

Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack

The aim of this updated guideline is to provide comprehensive and timely evidence-based recommendations on the prevention of future stroke among survivors of ischemic stroke or transient ischemic attack. The guideline is addressed to all clinicians who manage secondary prevention for these patients. Evidence-based recommendations are provided for control of risk factors, intervention for vascular obstruction, antithrombotic therapy for cardioembolism, and antiplatelet therapy for noncardioembolic stroke. Recommendations are also provided for the prevention of recurrent stroke in a variety of specific circumstances, including aortic arch atherosclerosis, arterial dissection, patent foramen ovale, hyperhomocysteinemia, hypercoagulable states, antiphospholipid antibody syndrome, sickle cell disease, cerebral venous sinus thrombosis, and pregnancy. Special sections address use of antithrombotic and anticoagulation therapy after an intracranial hemorrhage and implementation of guidelines.

Stroke 2014

Reconciling the clinical practice guidelines on Bell palsy from the AAO-HNSF and the AAN

Bell palsy, named after the Scottish anatomist Sir Charles Bell, is the most common acute mononeuropathy, or disorder affecting a single nerve, and is the most common diagnosis associated with facial nerve weakness/paralysis. In the past 2 years, both the American Academy of Neurology and the Academy of Otolaryngology–Head and Neck Surgery Foundation have published clinical practice guidelines aimed at improving the quality of care and outcomes for patients diagnosed with Bell palsy. This commentary aims to address the similarities and differences in the scope and final recommendations made by each guideline development group.

Neurology 2014

Anti-agrin autoantibodies in myasthenia gravis

Objective: Because the extracellular matrix protein agrin is essential for neuromuscular junction formation and maintenance, we tested the hypothesis that autoantibodies against agrin are present in sera from patients with myasthenia gravis (MG).

Methods: We determined the presence of anti-agrin antibodies in 54 sera from patients with generalized MG using a solid-phase ELISA with purified mini-agrin protein. Thirty of the 54 sera were seronegative for antibodies against the acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK), 15 had elevated levels of anti-MuSK, and 9 had elevated levels of anti-AChR autoantibodies. Sixteen sera from healthy volunteers served as control.

Results: Five sera with elevated levels of anti-agrin antibodies were identified. The concentration of the antibodies ranged between 0.04 and 0.12 nM. Four of the 5 agrin-positive sera were also positive for anti-MuSK, one was positive for anti-AChR, and 2 had elevated levels of anti–low-density lipoprotein receptor-related protein 4 (LRP4) autoantibodies. Some of the sera stained adult mouse neuromuscular junctions and reacted with native mini-agrin expressed in 293HEK cells.

Conclusions: The results provide evidence for agrin as a novel target protein for autoantibodies in patients with MG. Anti-agrin antibodies were always detected in combination with autoantibodies against MuSK, LRP4, or AChRs, indicating a high incidence of autoantibodies against several neuromuscular proteins in the agrin-positive MG cases.

Neurology 2014

Phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathy

Objective: To clarify the phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathies.

Methods: We screened for TRPV4 mutations in 169 French unrelated patients with inherited axonal peripheral neuropathy. Ninety-five patients had dominant Charcot-Marie-Tooth type 2 (CMT2) disease, and 74 patients, including 39 patients with distal hereditary motor neuropathy, 14 with congenital spinal muscular atrophy and arthrogryposis, 13 with CMT2, and 8 with scapuloperoneal spinal muscular atrophy, presented with additional vocal cord paralysis and/or skeletal dysplasia.

Results: No deleterious TRPV4 mutation was identified in the 95 patients with “pure” CMT2 (0/95). In contrast, 12 of 74 patients (16%) with neuropathy and vocal cord paralysis and/or skeletal dysplasia presented pathogenic TRPV4mutations, including 7 patients with distal hereditary motor neuropathy, 2 with scapuloperoneal spinal muscular atrophy, 2 with congenital spinal muscular atrophy and arthrogryposis, and one with CMT2. Investigation of affected relatives allowed us to study 17 patients. All patients had childhood-onset motor neuropathy and showed a variety of associated findings, including foot deformities (100% of cases), kyphoscoliosis (100%), elevated serum creatine kinase levels (100%), vocal cord paralysis (94%), scapular winging (53%), respiratory insufficiency (29%), hearing loss (24%), skeletal dysplasia (18%), and arthrogryposis (12%). Eight missense mutations were observed in these 12 families, including 2 previously unreported. Six mutations were de novo events, and 2 asymptomatic carriers were identified.

Conclusion: With 16% of patients affected in our series, this study demonstrates that TRPV4 mutations are a major cause of inherited axonal neuropathy associated with a large spectrum of additional features.

Neurology 2014

AAN Guidelines: Efficacy and safety of medical marijuana in selected neurologic disorders

Objective: To determine the efficacy of medical marijuana in several neurologic conditions.

Methods: We performed a systematic review ofmedicalmarijuana (1948–November 2013) to address

treatment of symptoms of multiple sclerosis (MS), epilepsy, and movement disorders. We graded the studies according to the American Academy of Neurology classification scheme for therapeutic articles. Results: Thirty-four studies met inclusion criteria; 8 were rated as Class I. 

Conclusions: The following were studied in patients with MS: (1) Spasticity: oral cannabis extract (OCE) is effective, and nabiximols and tetrahydrocannabinol (THC) are probably effective, for reducing patientcentered measures; it is possible both OCE and THC are effective for reducing both patient-centered and objective measures at 1 year. (2) Central pain or painful spasms (including spasticity-related pain, excluding neuropathic pain): OCE is effective; THC and nabiximols are probably effective. (3) Urinary dysfunction: nabiximols is probably effective for reducing bladder voids/day; THC and OCE are probably ineffective for reducing bladder complaints. (4) Tremor: THC and OCE are probably ineffective; nabiximols is possibly ineffective. (5) Other neurologic conditions: OCE is probably ineffective for treating levodopa-induced dyskinesias in patientswith Parkinson disease. Oral cannabinoids are of unknown efficacy in non–chorea-related symptoms of Huntington disease, Tourette syndrome, cervical dystonia, and epilepsy. The risks and benefits of medical marijuana should be weighed carefully. Risk of serious adverse psychopathologic effects was nearly 1%. Comparative effectiveness of medical marijuana vs other therapies is unknown for these indications.

Neurology 2014