Ryan A McTaggart

Dehydroascorbic acid, a blood–brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke

Neuronal injury in ischemic stroke is partly mediated by cytotoxic reactive oxygen species. Although the antioxidant ascorbic acid (AA) or vitamin C does not penetrate the blood–brain barrier (BBB), its oxidized form, dehydroascorbic acid (DHA), enters the brain by means of facilitative transport. We hypothesized that i.v. DHA would improve outcome after stroke because of its ability to cross the BBB and augment brain antioxidant levels. Reversible or permanent focal cerebral ischemia was created by intraluminal middle cerebral artery occlusion in mice treated with vehicle, AA, or DHA (40, 250, or 500 mg/kg), either before or after ischemia. Given before ischemia, DHA caused dose-dependent increases in postreperfusion cerebral blood flow, with reductions in neurological deficit and mortality. In reperfused cerebral ischemia, mean infarct volume was reduced from 53% and 59% in vehicle- and AA-treated animals, respectively, to 15% in 250 mg/kg DHA-treated animals (P < 0.05). Similar significant reductions occurred in nonreperfused cerebral ischemia. Delayed postischemic DHA administration after 15 min or 3 h also mediated improved outcomes. DHA (250 mg/kg or 500 mg/kg) administered at 3 h postischemia reduced infarct volume by 6- to 9-fold, to only 5% with the highest DHA dose (P < 0.05). In contrast, AA had no effect on infarct volumes, mortality, or neurological deficits. No differences in the incidence of intracerebral hemorrhage occurred. Unlike exogenous AA, DHA confers in vivo, dose-dependent neuroprotection in reperfused and nonreperfused cerebral ischemia at clinically relevant times. As a naturally occurring interconvertible form of AA with BBB permeability, DHA represents a promising pharmacological therapy for stroke based on its effects in this model of cerebral ischemia.

Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging

Background Thrombectomy is currently recommended for eligible patients with stroke who are treated within 6 hours after the onset of symptoms. Methods We conducted a multicenter, randomized, open‐label trial, with blinded outcome assessment, of thrombectomy in patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted. Patients with proximal middle‐cerebral‐artery or internal‐carotid‐artery occlusion, an initial infarct size of less than 70 ml, and a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more were randomly assigned to endovascular therapy (thrombectomy) plus standard medical therapy (endovascular‐therapy group) or standard medical therapy alone (medical‐therapy group). The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at day 90. Results The trial was conducted at 38 U.S. centers and terminated early for efficacy after 182 patients had undergone randomization (92 to the endovascular‐therapy group and 90 to the medical‐therapy group). Endovascular therapy plus medical therapy, as compared with medical therapy alone, was associated with a favorable shift in the distribution of functional outcomes on the modified Rankin scale at 90 days (odds ratio, 2.77; P<0.001) and a higher percentage of patients who were functionally independent, defined as a score on the modified Rankin scale of 0 to 2 (45% vs. 17%, P<0.001). The 90‐day mortality rate was 14% in the endovascular‐therapy group and 26% in the medical‐therapy group (P=0.05), and there was no significant between‐group difference in the frequency of symptomatic intracranial hemorrhage (7% and 4%, respectively; P=0.75) or of serious adverse events (43% and 53%, respectively; P=0.18). Conclusions Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone among patients with proximal middle‐cerebral‐artery or internal‐carotid‐artery occlusion and a region of tissue that was ischemic but not yet infarcted. (Funded by the National Institute of Neurological Disorders and Stroke; DEFUSE 3 ClinicalTrials.gov number, NCT02586415.)

Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke.

Background and Purpose Although the deleterious role of several proinflammatory mediators, including P-selectin, in reperfused stroke is well established, the role of E-selectin has not been fully characterized. Methods E-selectin mRNA expression was studied at 4, 10, and 24 hours after reperfusion with reverse transcription and polymerase chain reaction in mice (n=18) subjected to transient intraluminal middle cerebral artery occlusion (MCAO). Mice received intravenous injection with anti–E-selectin monoclonal antibody (10, 35, or 50 &mgr;g), nonimmune IgG, or vehicle immediately before MCAO and 90 minutes later (n=85). Others received anti–E-selectin antibody 3 or 6 hours after MCAO (n=32). Myeloperoxidase activity was measured in sham-operated mice and after 10 hours of reperfusion in saline-, nonimmune IgG–, or anti–E-selectin IgG–treated cohorts (n=17). Serial cerebral blood flow was measured with laser-Doppler flowmetry, and outcomes were assessed by neurological deficits and infarct volumes with the use of planimetric analysis of triphenyltetrazolium chloride–stained sections. Results Upregulated E-selectin expression occurred in the ischemic cerebral vasculature within 4 hours of reperfusion and persisted for 24 hours. Anti–E-selectin antibody increased ischemic cortical cerebral blood flow up to 2.6-fold (P <0.05). In addition to dose-dependent reductions in neurological deficits (P <0.05), mortality, and infarct volumes (P <0.01 for 35 and 50 &mgr;g), anti–E-selectin treatment reduced cerebral neutrophil accumulation (P <0.05) and was neuroprotective even if delayed until 3 hours after ischemia (P <0.05). Conclusions These findings establish a functional role for E-selectin in the pathogenesis of tissue injury after cerebral ischemia and reperfusion and suggest that E-selectin blockade may be clinically useful in the treatment of reperfused stroke.

Effect of Collateral Blood Flow on Patients Undergoing Endovascular Therapy for Acute Ischemic Stroke

Background and Purpose— Our aim was to determine the relationships between angiographic collaterals and diffusion/perfusion findings, subsequent infarct growth, and clinical outcome in patients undergoing endovascular therapy for ischemic stroke. Methods— Sixty patients with a thrombolysis in cerebral infarction (TICI) score of 0 or 1 and internal carotid artery/M1 occlusion at baseline were evaluated. A blinded reader assigned a collateral score using a previous 5-point scale, from 0 (no collateral flow) to 4 (complete/rapid collaterals to the entire ischemic territory). The analysis was dichotomized to poor flow (0–2) versus good flow (3–4). Collateral score was correlated with baseline National Institutes of Health Stroke Scale, diffusion-weighted imaging volume, perfusion-weighted imaging volume (Tmax ≥6 seconds), TICI reperfusion, infarct growth, and modified Rankin Scale score at day 90. Results— Collateral score correlated with baseline National Institutes of Health Stroke Scale (P=0.002) and median volume of tissue at Tmax ≥6 seconds (P=0.009). Twenty-nine percent of patients with poor collateral flow had TICI 2B–3 reperfusion versus 65.5% with good flow (P=0.009). Patients with poor collaterals who reperfused (TICI 2B–3) were more likely to have a good functional outcome (modified Rankin Scale score 0–2 at 90 days) compared with patients who did not reperfuse (odds ratio, 12; 95% confidence interval, 1.6–98). There was no difference in the rate of good functional outcome after reperfusion in patients with poor collaterals versus good collaterals (P=1.0). Patients with poor reperfusion (TICI 0–2a) showed a trend toward greater infarct growth if they had poor collaterals versus good collaterals (P=0.06). Conclusions— Collaterals correlate with baseline National Institutes of Health Stroke Scale, perfusion-weighted imaging volume, and good reperfusion. However, target mismatch patients who reperfuse seem to have favorable outcomes at a similar rate, irrespective of the collateral score. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01349946.

Embolectomy for stroke with emergent large vessel occlusion (ELVO): report of the Standards and Guidelines Committee of the Society of NeuroInterventional Surgery

Stroke is the leading cause of adult disability in North America and is the fifth most common cause of death.1 ,2 The natural history of patients with acute ischemic stroke and occlusion of a major intracranial vessel such as the internal carotid artery (ICA), middle cerebral artery (MCA), or basilar artery is dismal, with high rates of mortality and low rates of disability-free survival.3 ,4 We introduce the term ‘Emergent Large Vessel Occlusion (ELVO)’ to describe this clinical scenario. Among acute ischemic stroke, ELVO accounts for the greatest proportion of patients with long-term disability. For the past two decades the use of endovascular therapy has been performed in many centers across the world. The therapies have spanned from infusion of thrombolytic agents5 ,6 to mechanical embolectomy with the introduction of first-generation devices,7 ,8 aspiration-based embolectomy techniques,9 ,10 and the use of stent-retriever based procedures.11 ,12 However, these embolectomy trials were single-arm trials demonstrating safety of the procedure and technique or superiority over another, without direct comparison with standard medical therapy alone. In the past 3 years, several major trials have been published comparing endovascular therapy with standard medical therapy alone. The purpose of this document is to summarize the results of these trials and synthesize the level of evidence supporting the use of embolectomy in patients with ELVO. This document was prepared by the Standards and Guidelines Committee of the Society of NeuroInterventional Surgery, a multidisciplinary society representing the leaders in the field of endovascular therapy for neurovascular disease. The strength of the evidence supporting each recommendation was summarized using a scale previously described by the American Heart Association. ### Role of intravenous thrombolysis In 1996 the FDA approved the use of recombinant tissue plasminogen activator (tPA) for the treatment of acute ischemic stroke …

Alberta Stroke Program Early Computed Tomographic Scoring Performance in a Series of Patients Undergoing Computed Tomography and MRI: Reader Agreement, Modality Agreement, and Outcome Prediction

Background and Purpose— In this study, we compare the performance of pretreatment Alberta Stroke Program Early Computed Tomographic scoring (ASPECTS) using noncontrast CT (NCCT) and MRI in a large endovascular therapy cohort. Methods— Prospectively enrolled patients underwent baseline NCCT and MRI and started endovascular therapy within 12 hours of stroke onset. Inclusion criteria for this analysis were evaluable pretreatment NCCT, diffusion-weighted MRI (DWI), and 90-day modified Rankin Scale scores. Two expert readers graded ischemic change on NCCT and DWI using the ASPECTS. ASPECTS scores were analyzed with the full scale or were trichotomized (0–4 versus 5–7 versus 8–10) or dichotomized (0–7 versus 8–10). Good functional outcome was defined as a 90-day modified Rankin Scale score of 0 to 2. Results— Seventy-four patients fulfilled our study criteria. The full-scale inter-rater agreement for CT-ASPECTS and DWI-ASPECTS was 0.579 and 0.867, respectively. DWI-ASPECTS correlated with functional outcome (P=0.004), whereas CT-ASPECTS did not (P=0.534). Both DWI-ASPECTS and CT-ASPECTS correlated with DWI volume. The receiver operating characteristic analysis revealed that DWI-ASPECTS outperformed both CT-ASPECTS and the time interval between symptom onset and start of the procedure for predicting good functional outcome (modified Rankin Scale score, ⩽2) and DWI volume ≥70 mL. Conclusion— Inter-rater agreement for DWI-ASPECTS was superior to that for CT-ASPECTS. DWI-ASPECTS outperformed NCCT ASPECTS for predicting functional outcome at 90 days.

Initial hospital management of patients with emergent large vessel occlusion (ELVO): report of the standards and guidelines committee of the Society of NeuroInterventional Surgery

Objective To summarize the current literature regarding the initial hospital management of patients with acute ischemic stroke (AIS) secondary to emergent large vessel occlusion (ELVO), and to offer recommendations designed to decrease the time to endovascular treatment (EVT) for appropriately selected patients with stroke. Methods Using guidelines for evidenced-based medicine proposed by the Stroke Council of the American Heart Association, a critical review of all available medical literature supporting best initial medical management of patients with AIS secondary to ELVO was performed. The purpose was to identify processes of care that most expeditiously determine the eligibility of a patient with an acute stroke for interventions including intravenous fibrinolysis with recombinant tissue plasminogen activator (IV tPA) and EVT using mechanical embolectomy. Results This review identifies four elements that are required to achieve timely revascularization in ELVO. (1) In addition to non-contrast CT (NCCT) brain scan, CT angiography should be performed in all patients who meet an institutional threshold for clinical stroke severity. The use of any advanced imaging beyond NCCT should not delay the administration of IV tPA in eligible patients. (2) Activation of the neurointerventional team should occur as soon as possible, based on either confirmation of large vessel occlusion or a prespecified clinical severity threshold. (3) Additional imaging techniques, particularly those intended to physiologically select patients for EVT (CT perfusion and diffusion–perfusion mismatch imaging), may provide additional value, but should not delay EVT. (4) Routine use of general anesthesia during EVT procedures, should be avoided if possible. These workflow recommendations apply to both primary and comprehensive stroke centers and should be tailored to meet the needs of individual institutions. Conclusions Patients with ELVO are at risk for severe neurologic morbidity and mortality. To achieve the best possible clinical outcomes stroke centers must optimize their triage strategies. Strategies that provide patients with ELVO with the fastest access to reperfusion depend upon detail-oriented process improvement.

Extracranial Venous Drainage Patterns in Patients with Multiple Sclerosis and Healthy Controls

BACKGROUND AND PURPOSE: CCSVI hypothesizes an association between impaired extracranial venous drainage and MS. Published sonographic criteria for CCSVI are controversial, and no MR imaging data exist to support the CCSVI hypothesis. Our purpose was to evaluate possible differences in the extracranial venous drainage of MS and healthy controls using both TOF and contrast-enhanced TRICKS MRV. MATERIALS AND METHODS: Healthy subjects (n = 20) and patients with MS (n = 19) underwent axial 2D-TOF neck MRV (to assess flattening) and TRICKS MRV (to assess collaterals) at 3T. Two neuroradiologists blinded to cohort status scored IJV flattening and the severity of non-IJV collaterals by using a 4-point qualitative scale (normal = 0, mild = 1, moderate = 2, severe = 3). κ was used to assess reader agreement. Comparisons between groups were performed by using the Wilcoxon rank sum test. The Spearman rank correlation was used to assess the relationship between IJV flattening and collateral scores and, in patients with MS, EDSS scores. RESULTS: The 2 groups were matched for age and sex (MS, 45 ± 8 years, 79% female; healthy controls, 47 ± 10 years, 65% female). Reader agreement for IJV flattening and collateral severity was good (κ = 0.74) and moderate (κ = 0.58), respectively. While IJV flattening was seen in both patients with MS and healthy controls, scores for the patients with MS were significantly higher (P = .002). Despite a trend, there was no significant difference in collateral scores between groups (P = .063). There was a significant positive correlation between flattening and collateral scores (ρ = 0.32, P = .005) and EDSS and flattening scores (ρ = 0.45, P = .004) but not between EDSS and collateral scores (ρ = 0.01, P = .97). CONCLUSIONS: These results indicate that patients with MS have greater IJV flattening and a trend toward more non-IJV collaterals than healthy subjects. The role that this finding plays in the pathogenesis or progression of MS, if any, requires further study.

Stroke vision, aphasia, neglect (VAN) assessment—a novel emergent large vessel occlusion screening tool: pilot study and comparison with current clinical severity indices

Background Identification of emergent large vessel occlusion (ELVO) stroke has become increasingly important with the recent publications of favorable acute stroke thrombectomy trials. Multiple screening tools exist but the length of the examination and the false positive rate range from good to adequate. A screening tool was designed and tested in the emergency department using nurse responders without a scoring system. Methods The vision, aphasia, and neglect (VAN) screening tool was designed to quickly assess functional neurovascular anatomy. While objective, there is no need to calculate or score with VAN. After training participating nurses to use it, VAN was used as an ELVO screen for all stroke patients on arrival to our emergency room before physician evaluation and CT scan. Results There were 62 consecutive code stroke activations during the pilot study. 19 (31%) of the patients were VAN positive and 24 (39%) had a National Institutes of Health Stroke Scale (NIHSS) score of ≥6. All 14 patients with ELVO were either VAN positive or assigned a NIHSS score ≥6. While both clinical severity thresholds had 100% sensitivity, VAN was more specific (90% vs 74% for NIHSS ≥6). Similarly, while VAN and NIHSS ≥6 had 100% negative predictive value, VAN had a 74% positive predictive value while NIHSS ≥6 had only a 58% positive predictive value. Conclusions The VAN screening tool accurately identified ELVO patients and outperformed a NIHSS ≥6 severity threshold and may best allow clinical teams to expedite care and mobilize resources for ELVO patients. A larger study to both validate this screening tool and compare with others is warranted.

Correlation of AOL recanalization, TIMI reperfusion and TICI reperfusion with infarct growth and clinical outcome.

Objective To understand how three commonly used measures of endovascular therapy correlate with clinical outcome and infarct growth. Methods Prospectively enrolled patients underwent baseline MRI and started endovascular therapy within 12 h of stroke onset. The final angiogram was given a primary arterial occlusive lesion (AOL) recanalization score (0–3), a Thrombolysis in Myocardial Infarction (TIMI) score (0–3) and a Thrombolysis in Cerebral Infarction (TICI) score (0–3). The scores were dichotomized into poor revascularization (AOL 0–2, TIMI 0–1 and TICI 0–2a) versus good revascularization (AOL 3, TIMI 2–3, TICI 2b–3). Patients were classified according to whether or not they had target mismatch (TMM). Good outcome was defined as a 90-day modified Rankin Scale score of 0–2. Results Endovascular treatment was attempted in 100. A good outcome was achieved in 57% of patients with a TICI score of 2b–3 and in 24% of patients with a TICI score of 0–2a (p=0.001). Patients with TIMI scores of 2–3 and an AOL score of 3 had lower rates of good outcome (44% and 47%, respectively), which were not significantly better than those with TIMI scores of 0–1 or AOL scores of 0–2. In patients with TMM, these rates of good outcome improved with all the scoring systems and were significantly better for TIMI and TICI scores. Patients with a TICI score of 2a had rates of good functional outcome and lesion growth which were not different from those with TICI scores of 0–1 but were significantly worse than those with TICI scores of 2b–3. Conclusions TIMI 2–3 and TICI 2b–3 reperfusion scores demonstrated improved outcome in patients with tissue mismatch with a small infarct core and a larger hypoperfused region but AOL scores did not. Patients with a TICI score of 2a had a poorer outcome and more lesion growth than those with TICI scores of 2b–3.