An injectable implant to stimulate the sphenopalatine ganglion for treatment of acute ischaemic stroke up to 24 h from onset (ImpACT-24B): an international, randomised, double-blind, sham-controlled, pivotal trial.

BACKGROUND: Sphenopalatine ganglion stimulation increased cerebral collateral blood flow, stabilised the blood-brain barrier, and reduced infarct size, in preclinical models of acute ischaemic stroke, and showed potential benefit in a pilot randomised trial in humans. The pivotal ImpACT-24B trial aimed to determine whether sphenopalatine ganglion stimulation 8-24 h after acute ischaemic stroke improved functional outcome. METHODS: ImpACT-24B is a randomised, double-blind, sham-controlled, pivotal trial done at 73 centres in 18 countries. It included patients (men aged 40-80 years and women aged 40-85 years) with anterior-circulation acute ischaemic stroke, not undergoing reperfusion therapy. Enrolled patients were randomly assigned via web-based randomisation to receive active sphenopalatine ganglion stimulation (intervention group) or sham stimulation (sham-control group) 8-24 h after stroke onset. Patients, clinical care providers, and all outcome assessors were masked to treatment allocation. The primary efficacy endpoint was the difference between active and sham groups in the proportion of patients whose 3-month level of disability improved above expectations. This endpoint was evaluated in the modified intention-to-treat (mITT) population (defined as all patients who received one active or sham treatment session) and the population with confirmed cortical involvement (CCI) and was analysed using the Hochberg multi-step procedure (significance in both populations if p<0·05 in both, and in one population if p<0·025 in that one). Safety endpoints at 3 months were all serious adverse events (SAEs), SAEs related to implant placement or removal, SAEs related to stimulation, neurological deterioration, and mortality. All patients who underwent an attempted sphenopalatine ganglion stimulator or sham stimulator placement procedure were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00826059. FINDINGS: Between June 10, 2011, and March 7, 2018, 1078 patients were enrolled and randomly assigned to either the intervention or the sham-control group. 1000 patients received at least one session of sphenopalatine ganglion stimulation or sham stimulation and entered the mITT population (481 [48%] received sphenopalatine ganglion stimulation, 519 [52%] were sham controls), among whom 520 (52%) patients had CCI on imaging. The proportion of patients in the mITT population whose 3-month disability level was better than expected was 49% (234/481) in the intervention group versus 45% (236/519) in the sham-control group (odds ratio 1·14, 95% CI 0·89-1·46; p=0·31). In the CCI population, the proportion was 50% (121/244) in the intervention group versus 40% (110/276) in the sham-control group (1·48, 1·05-2·10; p=0·0258). There was an inverse U-shaped dose-response relationship between attained sphenopalatine ganglion stimulation intensity and the primary outcome in the CCI population: the proportion with favourable outcome increased from 40% to 70% at low-midrange intensity and decreased back to 40% at high intensity stimulation (p=0·0034). There were no differences in mortality or SAEs between the intervention group (n=536) and the sham-control group (n=519) in the safety population. INTERPRETATION: Sphenopalatine ganglion stimulation is safe for patients with acute ischaemic stroke 8-24 h after onset, who are ineligible for thrombolytic therapy. Although not reaching significance, the trial's results support that, among patients with imaging evidence of cortical involvement at presentation, sphenopalatine ganglion stimulation is likely to improve functional outcome. FUNDING: BrainsGate Ltd.

Alpha-linolenic acid: an omega-3 fatty acid with neuroprotective properties-ready for use in the stroke clinic?

Alpha-linolenic acid (ALA) is plant-based essential omega-3 polyunsaturated fatty acids that must be obtained through the diet. This could explain in part why the severe deficiency in omega-3 intake pointed by numerous epidemiologic studies may increase the brain's vulnerability representing an important risk factor in the development and/or deterioration of certain cardio- and neuropathologies. The roles of ALA in neurological disorders remain unclear, especially in stroke that is a leading cause of death. We and others have identified ALA as a potential nutraceutical to protect the brain from stroke, characterized by its pleiotropic effects in neuroprotection, vasodilation of brain arteries, and neuroplasticity. This review highlights how chronic administration of ALA protects against rodent models of hypoxic-ischemic injury and exerts an anti-depressant-like activity, effects that likely involve multiple mechanisms in brain, and may be applied in stroke prevention. One major effect may be through an increase in mature brain-derived neurotrophic factor (BDNF), a widely expressed protein in brain that plays critical roles in neuronal maintenance, and learning and memory. Understanding the precise roles of ALA in neurological disorders will provide the underpinnings for the development of new therapies for patients and families who could be devastated by these disorders.

Gray matter atrophy in patients with ischemic stroke with cognitive impairment.

BACKGROUND AND PURPOSE: Patients with ischemic stroke are at risk for developing vascular cognitive impairment ranging from mild impairments to dementia. MRI findings of infarction, white matter hyperintensities, and global cerebral atrophy have been implicated in the development of vascular cognitive impairment. The present study investigated regional gray matter volume differences between patients with ischemic stroke with no cognitive impairment and those with impairment in at least one domain of cognitive function. METHODS: Ninety-one patients with ischemic stroke participated. Detailed neuropsychological testing was used to characterize cognitive functioning in 7 domains: orientation, attention, working memory, language, visuospatial ability, psychomotor speed, and memory. High-resolution T1-weighted 3-dimensional fast-spoiled gradient recalled structural MRIs were processed using optimized voxel-based morphometry techniques while controlling for lesions. Whole brain voxelwise regional differences in gray matter volume were assessed between patients with stroke with no impaired cognitive domains and patients with stroke with at least one impaired cognitive domain. Logistic regression models were used to assess the contribution of demographic variables, stroke-related variables, and voxel-based morphometry results to classification of cognitive impairment group membership. RESULTS: Fifty-one patients had no impairments in any cognitive domain and 40 patients were impaired in at least one cognitive domain. Logistic regression identified significant contributions to cognitive impairment groups for demographic variables, stroke-related variables, and cognitive domain performance. Voxel-based morphology results demonstrated significant gray matter volume reductions in patients with stroke with one or more cognitive domain impairment compared with patients with stroke without cognitive impairment that was seen mostly in the thalamus with smaller reductions found in the cingulate gyrus and frontal, temporal, parietal, and occipital lobes. These reductions were present after controlling for group differences in age, education, stroke volume, and laterality of stroke. The addition of voxel-based morphometry-derived thalamic volume significantly improved a logistic regression model predicting cognitive impairment group membership when added to demographic variables, stroke-related variables, and cognitive domain performance. CONCLUSIONS: These results suggest a central role for the thalamus and lesser roles for other cortical regions in the development of cognitive impairment after ischemic stroke. Indeed, consideration of thalamic volumes adds significant information to the classification of cognitive impaired versus nonimpaired groups beyond information provided by demographic, stroke-related, and cognitive performance measures.