Extracranial-Intracranial Bypass and Risk of Stroke and Death in Patients With Symptomatic Artery Occlusion: The CMOSS Randomized Clinical Trial.

Importance: Prior trials of extracranial-intracranial (EC-IC) bypass surgery showed no benefit for stroke prevention in patients with atherosclerotic occlusion of the internal carotid artery (ICA) or middle cerebral artery (MCA), but there have been subsequent improvements in surgical techniques and patient selection. Objective: To evaluate EC-IC bypass surgery in symptomatic patients with atherosclerotic occlusion of the ICA or MCA, using refined patient and operator selection. Design, Setting, and Participants: This was a randomized, open-label, outcome assessor-blinded trial conducted at 13 centers in China. A total of 324 patients with ICA or MCA occlusion with transient ischemic attack or nondisabling ischemic stroke attributed to hemodynamic insufficiency based on computed tomography perfusion imaging were recruited between June 2013 and March 2018 (final follow-up: March 18, 2020). Interventions: EC-IC bypass surgery plus medical therapy (surgical group; n = 161) or medical therapy alone (medical group; n = 163). Medical therapy included antiplatelet therapy and stroke risk factor control. Main Outcomes and Measures: The primary outcome was a composite of stroke or death within 30 days or ipsilateral ischemic stroke beyond 30 days through 2 years after randomization. There were 9 secondary outcomes, including any stroke or death within 2 years and fatal stroke within 2 years. Results: Among 330 patients who were enrolled, 324 patients were confirmed eligible (median age, 52.7 years; 257 men [79.3%]) and 309 (95.4%) completed the trial. For the surgical group vs medical group, no significant difference was found for the composite primary outcome (8.6% [13/151] vs 12.3% [19/155]; incidence difference, -3.6% [95% CI, -10.1% to 2.9%]; hazard ratio [HR], 0.71 [95% CI, 0.33-1.54]; P = .39). The 30-day risk of stroke or death was 6.2% (10/161) in the surgical group and 1.8% (3/163) in the medical group, and the risk of ipsilateral ischemic stroke beyond 30 days through 2 years was 2.0% (3/151) and 10.3% (16/155), respectively. Of the 9 prespecified secondary end points, none showed a significant difference including any stroke or death within 2 years (9.9% [15/152] vs 15.3% [24/157]; incidence difference, -5.4% [95% CI, -12.5% to 1.7%]; HR, 0.69 [95% CI, 0.34-1.39]; P = .30) and fatal stroke within 2 years (2.0% [3/150] vs 0% [0/153]; incidence difference, 1.9% [95% CI, -0.2% to 4.0%]; P = .08). Conclusions and Relevance: Among patients with symptomatic ICA or MCA occlusion and hemodynamic insufficiency, the addition of bypass surgery to medical therapy did not significantly change the risk of the composite outcome of stroke or death within 30 days or ipsilateral ischemic stroke beyond 30 days through 2 years. Trial Registration: ClinicalTrials.gov Identifier: NCT01758614.

Diagnostic accuracy of acute infarcts in multiple cerebral circulations for cardioembolic stroke: Literature review and meta-analysis.

OBJECTIVE: To determine the diagnostic value of acute infarcts in multiple cerebral circulations (AIMCC) on MRI diffusion-weighted imaging (DWI) for cardioembolism (CE) stroke subtype in adult patients hospitalized with acute ischemic stroke, we conducted a systematic literature review and meta-analysis. METHODS: MEDLINE was searched via PubMed for articles reporting patients hospitalized with acute ischemic stroke with MRI DWI categorized as AIMCC vs other and use of Trial of Org 10172 in Acute Stroke Treatment (TOAST) Criteria for cardioembolism subtype. Measures of diagnostic accuracy were calculated from the retrieved studies. RESULTS: Seven eligible articles comprised 5813 patients. Bivariate random effects models estimated sensitivity 0.19 (95% CI, 0.13 to 0.27), specificity 0.89 (0.86 to 0.91), positive predictive value 0.37 (0.30 to 0.45), negative predictive value 0.76 (0.7 to 0.82), positive likelihood ratio 1.70 (1.13 to 2.57) and negative likelihood ratio 0.91 (0.83 to 1). INTERPRETATION: The pattern of AIMCC on DWI is of limited diagnostic value. It is not sufficiently accurate to exclude cardiac pathology by a negative test nor does a positive test indicate a major increase in the probability of identifying a potential cardioembolic source.

Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.

Background and Purpose- The purpose of these guidelines is to provide an up-to-date comprehensive set of recommendations in a single document for clinicians caring for adult patients with acute arterial ischemic stroke. The intended audiences are prehospital care providers, physicians, allied health professionals, and hospital administrators. These guidelines supersede the 2013 Acute Ischemic Stroke (AIS) Guidelines and are an update of the 2018 AIS Guidelines. Methods- Members of the writing group were appointed by the American Heart Association (AHA) Stroke Council's Scientific Statements Oversight Committee, representing various areas of medical expertise. Members were not allowed to participate in discussions or to vote on topics relevant to their relations with industry. An update of the 2013 AIS Guidelines was originally published in January 2018. This guideline was approved by the AHA Science Advisory and Coordinating Committee and the AHA Executive Committee. In April 2018, a revision to these guidelines, deleting some recommendations, was published online by the AHA. The writing group was asked review the original document and revise if appropriate. In June 2018, the writing group submitted a document with minor changes and with inclusion of important newly published randomized controlled trials with >100 participants and clinical outcomes at least 90 days after AIS. The document was sent to 14 peer reviewers. The writing group evaluated the peer reviewers' comments and revised when appropriate. The current final document was approved by all members of the writing group except when relationships with industry precluded members from voting and by the governing bodies of the AHA. These guidelines use the American College of Cardiology/AHA 2015 Class of Recommendations and Level of Evidence and the new AHA guidelines format. Results- These guidelines detail prehospital care, urgent and emergency evaluation and treatment with intravenous and intra-arterial therapies, and in-hospital management, including secondary prevention measures that are appropriately instituted within the first 2 weeks. The guidelines support the overarching concept of stroke systems of care in both the prehospital and hospital settings. Conclusions- These guidelines provide general recommendations based on the currently available evidence to guide clinicians caring for adult patients with acute arterial ischemic stroke. In many instances, however, only limited data exist demonstrating the urgent need for continued research on treatment of acute ischemic stroke.

2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.

BACKGROUND AND PURPOSE: The purpose of these guidelines is to provide an up-to-date comprehensive set of recommendations for clinicians caring for adult patients with acute arterial ischemic stroke in a single document. The intended audiences are prehospital care providers, physicians, allied health professionals, and hospital administrators. These guidelines supersede the 2013 guidelines and subsequent updates. METHODS: Members of the writing group were appointed by the American Heart Association Stroke Council's Scientific Statements Oversight Committee, representing various areas of medical expertise. Strict adherence to the American Heart Association conflict of interest policy was maintained. Members were not allowed to participate in discussions or to vote on topics relevant to their relations with industry. The members of the writing group unanimously approved all recommendations except when relations with industry precluded members voting. Prerelease review of the draft guideline was performed by 4 expert peer reviewers and by the members of the Stroke Council's Scientific Statements Oversight Committee and Stroke Council Leadership Committee. These guidelines use the American College of Cardiology/American Heart Association 2015 Class of Recommendations and Levels of Evidence and the new American Heart Association guidelines format. RESULTS: These guidelines detail prehospital care, urgent and emergency evaluation and treatment with intravenous and intra-arterial therapies, and in-hospital management, including secondary prevention measures that are appropriately instituted within the first 2 weeks. The guidelines support the overarching concept of stroke systems of care in both the prehospital and hospital settings. CONCLUSIONS: These guidelines are based on the best evidence currently available. In many instances, however, only limited data exist demonstrating the urgent need for continued research on treatment of acute ischemic stroke.

Reperfusion Beyond 6 Hours Reduces Infarct Probability in Moderately Ischemic Brain Tissue.

BACKGROUND AND PURPOSE: We aimed to examine perfusion changes between 3 and 6 and 6 and 24 hours after stroke onset and their impact on tissue outcome. METHODS: Acute ischemic stroke patients underwent perfusion magnetic resonance imaging at 3, 6, and 24 hours after stroke onset and follow-up fluid-attenuated inversion recovery at 1 month to assess tissue fate. Mean transit time prolongation maps (MTTp=MTT-[median MTT of contralateral hemisphere]) were obtained at 3 (MTTp3 h), 6 (MTTp6 h), and 24 hours (MTTp24 h). Perfusion changes between 3 and 6 hours (ΔMTTp3_6) and 6 and 24 hours (ΔMTTp6_24) were calculated. A 2-step analysis was performed to evaluate the impact of ΔMTTp3_6 and ΔMTTp6_24 on tissue fate. First, a voxel-based multivariable logistic regression was performed for each individual patient with MTTp3 h, ΔMTTp3_6, and ΔMTT6_24 as independent variables and tissue fate as outcome. Second, Wilcoxon signed-rank tests on logistic regression coefficients were performed across patients to evaluate whether ΔMTTp3_6 and ΔMTT6_24 had significant impact on tissue fate for varying severities of baseline perfusion. RESULTS: Perfusion change was common during both time periods: 85% and 81% of patients had perfusion improvement during 3- to 6- and 6- and 24-hour time intervals, respectively. ΔMTT3_6 significantly influenced 1-month infarct probability across a wide range of baseline perfusion (MTTp 0-15 s). ΔMTT6_24 also impacted 1-month infarct probability, but its influence was restricted to tissue with milder baseline ischemia (MTTp 0-10 s). CONCLUSIONS: Brain tissue with mild to moderate ischemia can be salvaged by reperfusion even after 6 hours. Such tissue could be targeted for intervention beyond current treatment windows.

Effect of High-Dose Simvastatin on Cerebral Blood Flow and Static Autoregulation in Subarachnoid Hemorrhage.

BACKGROUND: Statins may promote vasodilation following subarachnoid hemorrhage (SAH) and improve the response to blood pressure elevation. We sought to determine whether simvastatin increases cerebral blood flow (CBF) and alters the response to induced hypertension after SAH. METHODS: Statin-naïve patients admitted <72 h after WFNS ≥2 aneurysmal SAH were randomly assigned to 80 mg simvastatin/day or placebo for 21 days. Regional CBF was measured with quantitative (15)O PET on SAH day 7-10 before and after raising mean arterial pressure (MAP) 20-25 %. Autoregulatory index (AI) was calculated as the ratio of % change in resistance (MAP/CBF) to % change in MAP. Angiography was performed within 24 h of PET. Results are presented as simvastatin vs. placebo. RESULTS: Thirteen patients received simvastatin and 12 placebo. Clinical characteristics were similar. Moderate or severe angiographic vasospasm occurred in 42 vs. 45 % and delayed cerebral ischemia in 14 vs. 55 % (p = 0.074). During PET studies, MAP (110 ± 10 vs. 111 ± 12), global CBF (41 ± 12 vs. 43 ± 13), and CVR (2.95 ± 1.0 vs. 2.81 ± 1.0) did not differ at baseline. When MAP was raised to 135 ± 7 mm Hg vs. 137 ± 15, global CBF did not change. Global AI did not differ (107 ± 59 vs. 0. 89 ± 52 %, p = 0.68). CBF did not change in regions with low baseline flow or in regions supplied by vessels with angiographic vasospasm in either group. Six-month modified Rankin Scale scores did not differ. CONCLUSIONS: Our data indicate that initiation of therapy with high-dose simvastatin does not alter baseline CBF or response to induced hypertension.

Relative Mean Transit Time Predicts Subsequent Stroke in Symptomatic Carotid Occlusion.

BACKGROUND: Mean transit time (MTT) measurements to assess cerebral hemodynamics are easily obtained by computed tomography and magnetic resonance imaging. We reviewed hemodynamic and clinical outcome data from the St. Louis Carotid Occlusion Study to determine if increased MTT was associated with an increased risk of stroke in patients with symptomatic complete carotid artery occlusion. METHODS: Positron emission tomography (PET) studies of cerebral blood volume-to-cerebral blood flow ratios were used to calculate MTTs. Mean ipsilateral (side of the occluded internal carotid artery)-to-contralateral ratios of MTTs in the middle cerebral artery territories were determined. MTT was tested as a predictor of stroke risk using Cox regression analysis. Receiver operating characteristic curves for stroke risk prediction were generated by varying the mean ispilateral-to-contralateral MTT ratio to identify an optimal cutpoint. RESULTS: Increased MTT ratio was associated with an increased risk of ipsilateral stroke (P < .001). The maximum combination of sensitivity (.778) and specificity (.763) was obtained at a cutpoint ratio of 1.387 or higher. Subjects with a MTT ratio of 1.387 or higher had a 29.3% 2-year risk of ipsilateral stroke compared to 4.6% for those without (P < .001). CONCLUSIONS: PET relative MTT ratio identified patients with symptomatic complete internal artery occlusion who were at high risk for subsequent ipsilateral stroke. Confirmation using measurements of relative MTT from other imaging modalities in a patient cohort receiving contemporary medical management is needed.

2015 American Heart Association/American Stroke Association Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.

PURPOSE: The aim of this guideline is to provide a focused update of the current recommendations for the endovascular treatment of acute ischemic stroke. When there is overlap, the recommendations made here supersede those of previous guidelines. METHODS: This focused update analyzes results from 8 randomized, clinical trials of endovascular treatment and other relevant data published since 2013. It is not intended to be a complete literature review from the date of the previous guideline publication but rather to include pivotal new evidence that justifies changes in current recommendations. Members of the writing committee were appointed by the American Heart Association/American Stroke Association Stroke Council's Scientific Statement Oversight Committee and the American Heart Association/American Stroke Association Manuscript Oversight Committee. Strict adherence to the American Heart Association conflict of interest policy was maintained throughout the consensus process. Recommendations follow the American Heart Association/American Stroke Association methods of classifying the level of certainty of the treatment effect and the class of evidence. Prerelease review of the draft guideline was performed by 6 expert peer reviewers and by the members of the Stroke Council Scientific Statement Oversight Committee and Stroke Council Leadership Committee. RESULTS: Evidence-based guidelines are presented for the selection of patients with acute ischemic stroke for endovascular treatment, for the endovascular procedure, and for systems of care to facilitate endovascular treatment. CONCLUSIONS: Certain endovascular procedures have been demonstrated to provide clinical benefit in selected patients with acute ischemic stroke. Systems of care should be organized to facilitate the delivery of this care.

Defining the ischemic penumbra using magnetic resonance oxygen metabolic index.

BACKGROUND AND PURPOSE: Penumbral biomarkers promise to individualize treatment windows in acute ischemic stroke. We used a novel magnetic resonance imaging approach that measures oxygen metabolic index (OMI), a parameter closely related to positron emission tomography-derived cerebral metabolic rate of oxygen utilization (CMRO2), to derive a pair of ischemic thresholds: (1) an irreversible-injury threshold that differentiates ischemic core from penumbra and (2) a reversible-injury threshold that differentiates penumbra from tissue not-at-risk for infarction. METHODS: Forty patients with acute ischemic stroke underwent magnetic resonance imaging at 3 time points after stroke onset: <4.5 hours (for OMI threshold derivation), 6 hours (to determine reperfusion status), and 1 month (for infarct probability determination). A dynamic susceptibility contrast method measured cerebral blood flow, and an asymmetrical spin echo sequence measured oxygen extraction fraction, to derive OMI (OMI=cerebral blood flow×oxygen extraction fraction). Putative ischemic threshold pairs were iteratively tested using a computation-intensive method to derive infarct probabilities in 3 tissue groups defined by the thresholds (core, penumbra, and not-at-risk tissue). An optimal threshold pair was chosen based on its ability to predict infarction in the core, reperfusion-dependent survival in the penumbra, and survival in not-at-risk tissue. The predictive abilities of the thresholds were then tested within the same cohort using a 10-fold cross-validation method. RESULTS: The optimal OMI ischemic thresholds were found to be 0.28 and 0.42 of normal values in the contralateral hemisphere. Using the 10-fold cross-validation method, median infarct probabilities were 90.6% for core, 89.7% for nonreperfused penumbra, 9.95% for reperfused penumbra, and 6.28% for not-at-risk tissue. CONCLUSIONS: OMI thresholds, derived using voxel-based, reperfusion-dependent infarct probabilities, delineated the ischemic penumbra with high predictive ability. These thresholds will require confirmation in an independent patient sample.

The safety of aeroplane travel in patients with symptomatic carotid occlusion.

OBJECTIVE: Patients with carotid stenosis or occlusion may be at increased risk for stroke during air travel. Records from the Carotid Occlusion Surgery Study (COSS), a randomised trial of surgical revascularisation for complete carotid artery occlusion and haemodynamic ischaemia, were examined for evidence of stroke related to air travel. METHODS: COSS subjects who travelled by aeroplane to a regional Positron Emission Tomography (PET) centre for a screening of cerebrovascular haemodynamic evaluation were identified. Maximum altitude and total flight time were estimated based on the distance between origin and destination. Ischaemic events were determined by a structured telephone interview within 24 h of travel. Patient demographics, comorbidities, oxygen extraction fraction (OEF) data and 24 h interview responses were recorded. RESULTS: Seventy-seven patients with symptomatic carotid occlusion travelled by aeroplane to a single PET centre (174 flights). Fifty-two (67.5%) were men and 25 (32.5%) were women. The average age was 58.7±1.4 years. Twenty-seven patients (35.1%) demonstrated evidence of ipsilateral haemodynamic cerebral ischaemia as measured by PET OEF, while 50 (64.9%) had normal OEF. Patients flew an average distance of 418.9±25.9 miles for 107.1±4.7 min per trip. No patient reported symptoms of a transient ischaemic attack or stroke during or within 24 h after aeroplane travel (95% CI 0% to 2.0%). CONCLUSIONS: The risk of stroke as a consequence of air travel is low, even in a cohort of patients at high risk for future stroke owing to haemodynamic impairment. These patients with symptomatic carotid occlusion should not be discouraged from air travel.

Extracranial-intracranial bypass for ischemic cerebrovascular disease: what have we learned from the Carotid Occlusion Surgery Study?

Extracranial-intracranial (EC-IC) arterial bypass has been used in the treatment of various neurosurgical pathologies including skull base tumors requiring sacrifice of a large intracranial artery; complex intracranial aneurysms requiring trapping; and distal revascularization, moyamoya disease, and symptomatic cerebrovascular stenoocclusive disease. The latter indication has been the subject of intense investigations in several large randomized controlled trials, most recently the Carotid Occlusion Surgery Study (COSS). In the present literature review and synthesis, the authors examine the current evidence available for EC-IC arterial bypass for the treatment of ischemic cerebrovascular disease including both extracranial carotid artery occlusive disease and intracranial atherosclerotic disease. They focus particular attention on EC-IC arterial bypass for the treatment of symptomatic hemodynamic cerebral ischemia and how lessons learned from the COSS might guide future investigations into the treatment of this disease.