Distribution of cerebral age-related white matter changes in relation to risk factors in stroke patients.

INTRODUCTION: The distribution of cerebral age-related white matter changes (ARWMC) may be indicative of the underlying etiology and could suggest optimal interventions. We aimed to determine if left ventricular hypertrophy (LVH), a marker of uncontrolled hypertension, along with additional risk factors are associated with the distribution of cerebral ARWMC. METHODS: We analyzed data of 172 patients from a hospital stroke registry who had acute stroke and brain MRI. We classified lesion location as superficial (frontal, parieto-occipital, or temporal) or deep (basal nuclei) using the ARWMC scale. We defined a superficial ARWMC index as the superficial minus the deep score. We excluded infratentorial lesions and patients with bilateral strokes. Regression analysis analyzed LVH and other relevant clinical factors for independent association with the superficial ARWMC index. RESULTS: The superficial ARWMC scores ranged from 0 to 6, the deep scores from 0 to 3, and the superficial ARWMC index from -2 to 6. We categorized the superficial ARWMC index as -2 to 1 (n = 65), 2 (n = 50), and 3 - 6 (n = 57). In bivariate analysis, ARWMC distribution was significantly associated with older age, lower household income (HI), and lower serum triglyceride (TG) levels. In multiple logistic regression analysis, higher superficial ARWMC index was significantly associated with lower HI (OR 10.72, 95 % CI 2.30-49.85), lower serum low density cholesterol (LDL) (OR 0.86, 95 % CI 0.75-0.98, per 10 mg/dL), and lower serum TG levels (OR 0.91, 95 % CI 0.85-0.99, per 10 mg/dL). The area under the curve in receiver operating characteristic analysis (95 % CI) for HI was 0.63 (0.49-0.76), LDL level 0.64 (0.51-0.77), and TG level 0.77 (0.65-0.88). CONCLUSION: In this study, LVH was not associated with the distribution of cerebral ARWMC. Using an alternate classification of ARWMC distribution and analyzing additional risk factors in larger studies may yield further discoveries.

Pre-stroke Adherence to Hypertension Medications in a Bi-racial United States Stroke Belt.

INTRODUCTION: Blood pressure is not optimally reduced in 3 of 4 patients with hypertension (HTN) in the United States. AIM: We analyzed for factors associations with premorbid non-adherence to HTN medications in acute stroke patients. METHODS: This cross-sectional study included 225 acute stroke patients with self-reported adherence to HTM medications in a stroke registry in the Southeastern United States. We defined medication non-adherence as < 90% of prescribed. Logistic regression analyzed demographic and socioeconomic factors for prediction of adherence. RESULTS: There were 145 (64%) patients with adherence and 80 (36%) with non-adherence. The likelihood of adherence to HTN medications was decreased among black patients, OR 0.49 (95% CI 0.26-0.93), p = 0.03, and those without health insurance, OR 0.29 (95% CI 0.13-0.64), p = 0.002. Specific reasons for non-adherence were high medication cost in 26 (33%), side effects in 8 (10%), and other unspecified reasons in 46 (58%) patients. CONCLUSION: In this study, adherence to HTN medications was significantly lower among black patients and those without health insurance.

Collateral status, hyperglycemia, and functional outcome after acute ischemic stroke.

BACKGROUND: Mixed data exist regarding the association between hyperglycemia and functional outcome after acute ischemic stroke when accounting for the impact of leptomeningeal collateral flow. We sought to determine whether collateral status modifies the association between treatment group and functional outcome in a subset of patients with large vessel occlusion enrolled in the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial. METHODS: In this post-hoc analysis, we analyzed patients enrolled into the SHINE trial with anterior circulation large vessel occlusion who underwent imaging with CT angiography prior to glucose control treatment group assignment. The primary analysis assessed the degree to which collateral status modified the effect between treatment group and functional outcome as defined by the 90-day modified Rankin Scale score. Logistic regression was used to model the data, with adjustments made for thrombectomy status, age, post-perfusion thrombolysis in cerebral infarction (TICI) score, tissue plasminogen activator (tPA) use, and baseline National Institutes of Health Stroke Scale (NIHSS) score. Five SHINE trial centers contributed data for this analysis. Statistical significance was defined as a p-value < 0.05. RESULTS: Among the 1151 patients in the SHINE trial, 57 with angiographic data were included in this sub-analysis, of whom 19 had poor collaterals and 38 had good collaterals. While collateral status had no effect (p = 0.855) on the association between glucose control treatment group and functional outcome, patients with good collaterals were more likely to have a favorable functional outcome (p = 0.001, OR 5.02; 95% CI 1.37-16.0). CONCLUSIONS: In a post-hoc analysis using a subset of patients with angiographic data enrolled in the SHINE trial, collateral status did not modify the association between glucose control treatment group and functional outcome. However, consistent with prior studies, there was a significant association between good collateral status and favorable outcome in patients with large vessel occlusion stroke. TRIAL REGISTRATION: ClinicalTrials.gov Identifier is NCT01369069. Registration date is June 8, 2011.

Pre-diabetes, Diabetes, Hyperglycemia, and Stroke: Bittersweet Therapeutic Opportunities.

PURPOSEOF REVIEW: Diabetes mellitus (DM) causes systemic vascular complications. Chronic hyperglycemia is a hallmark of DM and appears to be at least partially responsible for the vascular complications. In addition, hyperglycemia during acute tissue injury has been postulated to augment the injury. This review addresses the potential therapeutic benefits related to ischemic stroke from lowering hyperglycemia in two settings, in chronic hyperglycemia and during acute ischemic stroke. RECENT FINDINGS: A recent efficacy trial to lower hyperglycemia during acute ischemic stroke showed no significant benefit overall as well as in patient subgroups. This finding helps to establish good clinical practice protocols for patients with acute ischemic stroke and hyperglycemia. Hyperglycemia appears to be a key mediator of the systemic vascular complications of DM. Despite current lack of evidence that lowering hyperglycemia during acute ischemic stroke improves functional outcome, unanswered questions remain in specific acute ischemic stroke settings that warrant additional research.

Pilot Study of Remote Ischemic Conditioning in Acute Spontaneous Intracerebral Hemorrhage.

Spontaneous Intracerebral hemorrhage (ICH) is a devastating injury that accounts for 10-15% of all strokes. The rupture of cerebral blood vessels damaged by hypertension or cerebral amyloid angiopathy creates a space-occupying hematoma that contributes toward neurological deterioration and high patient morbidity and mortality. Numerous protocols have explored a role for surgical decompression of ICH via craniotomy, stereotactic guided endoscopy, and minimally invasive catheter/tube evacuation. Studies including, but not limited to, STICH, STICH-II, MISTIE, MISTIE-II, MISTIE-III, ENRICH, and ICES have all shown that, in certain limited patient populations, evacuation can be done safely and mortality can be decreased, but functional outcomes remain statistically no different compared to medical management alone. Only 10-15% of patients with ICH are surgical candidates based on clot location, medical comorbidities, and limitations regarding early surgical intervention. To date, no clearly effective treatment options are available to improve ICH outcomes, leaving medical and supportive management as the standard of care. We recently identified that remote ischemic conditioning (RIC), the non-invasive, repetitive inflation-deflation of a blood pressure cuff on a limb, non-invasively enhanced hematoma resolution and improved neurological outcomes via anti-inflammatory macrophage polarization in pre-clinical ICH models. Herein, we propose a pilot, placebo-controlled, open-label, randomized trial to test the hypothesis that RIC accelerates hematoma resorption and improves outcomes in ICH patients. Twenty ICH patients will be randomized to receive either mock conditioning or unilateral arm RIC (4 cycles × 5 min inflation/5 min deflation per cycle) beginning within 48 h of stroke onset and continuing twice daily for one week. All patients will receive standard medical care according to latest guidelines. The primary outcome will be the safety evaluation of unilateral RIC in ICH patients. Secondary outcomes will include hematoma volume/clot resorption rate and functional outcomes, as assessed by the modified Rankin Scale (mRS) at 1- and 3-months post-ICH. Additionally, blood will be collected for exploratory genomic analysis. This study will establish the feasibility and safety of RIC in acute ICH patients, providing a foundation for a larger, multi-center clinical trial.

Intensive Versus Standard Treatment of Hyperglycemia in Acute Ischemic Stroke Patient: A Randomized Clinical Trial Subgroups Analysis.

BACKGROUND: Benefit from blood glucose (BG) control during acute ischemic stroke may depend on glycemic parameters. We evaluated for associations between the SHINE (Stroke Hyperglycemia Insulin Network Effort) randomized treatment group and the SHINE predefined 90-day functional outcome, within-patient subgroups defined by various glycemic parameters. METHODS: The SHINE Trial randomized 1151 patients within 12 hours with acute ischemic stroke and hyperglycemia to standard (target BG 80-179 mg/dL) or intensive (target BG 80-130 mg/dL) BG control for 72 hours. We predefined 6 glycemic parameters: acute BG level, absence versus presence of diagnosed and undiagnosed diabetes, hemoglobin A1c, glycemic gap (acute BG-average daily hemoglobin A1c based BG), stress hyperglycemia ratio (acute BG/average daily hemoglobin A1c based BG), and BG variability (SD). Favorable functional outcome was defined by the SHINE Trial and based on the modified Rankin Scale score at 90 days, adjusted for stroke severity. We computed relative risks adjusted for baseline stroke severity and thrombolysis use. RESULTS: Likelihood for favorable outcome was lowest among patients with undiagnosed diabetes compared to patients with true nondiabetes (adjusted relative risk, 0.42 [99% CI, 0.19-0.94]). We did not find any relationship between the favorable outcome rate and baseline BG or any of the glycemic parameters. No differences between SHINE treatment groups were identified among any of these patient subgroups. CONCLUSIONS: In this exploratory subgroup analysis, intensive versus standard insulin treatment of hyperglycemia in acute ischemic stroke patient subgroups, did not influence the 90-day functional outcomes, nor did we identify associations between these glycemic parameters and 90-day functional outcomes.

Expanding the horizon of research into the pathogenesis of the white matter diseases: Proceedings of the 2021 Annual Workshop of the Albert Research Institute for White Matter and Cognition.

White matter pathologies are critically involved in the etiology of vascular cognitive impairment-dementia (VCID), Alzheimer's disease (AD), and Alzheimer's disease and related diseases (ADRD), and therefore need to be considered a treatable target ( Roseborough A, Hachinski V, Whitehead S. White matter degeneration - a treatable target? Roseborough et al. JAMA Neurol [Internet]. 2020 Apr 27;77(7):793-4, [1] . To help address this often-missed area of research, several workshops have been sponsored by the Leo and Anne Albert Charitable Trust since 2015, resulting in the incorporation of "The Albert Research Institute for White Matter and Cognition" in 2020. The first annual "Institute" meeting was held virtually on March 3-4, 2021. The Institute provides a forum and workspace for communication and support of the advancement of white matter science and research to better understand the evolution and prevention of dementia. It serves as a platform for young investigator development, to introduce new data and debate biology mechanisms and new ideas, and to encourage and support new research collaborations and directions to clarify how white matter changes, with other genetic and health risk factors, contribute to cognitive impairment. Similar to previous Albert Trust-sponsored workshops (Barone et al. in J Transl Med 14:1-14, [2]; Sorond et al. in GeroScience 42:81-96, [3]), established expert investigators were identified and invited to present. Opportunities to attend and present were also extended by invitation to talented research fellows and younger scientists. Also, updates on institute-funded research collaborations were provided and discussed. The summary that follows is a synopsis of topics and discussion covered in the workshop.

Predicting Functional Outcome After Decompressive Craniectomy for Malignant Hemispheric Infarction: Clinical and Novel Imaging Factors.

OBJECTIVE: Decompressive craniectomy (DC) is an established optional treatment for malignant hemispheric infarction (MHI). We analyzed relevant clinical factors and computed tomography (CT) measurements in patients with DC for MHI to identify predictors of functional outcome 3-6 months after stroke. METHODS: This study was performed at 2 comprehensive stroke centers. The inclusion criteria required DC for MHI, no additional intraoperative procedures (strokectomy or cerebral ventricular drain placement), and documented functional status 3-6 months after the stroke. We classified functional outcome as acceptable if the modified Rankin Scale score was <5, or as unacceptable if it was 5 or 6 (bedbound and totally dependent on others or death). Multiple logistic regression analyzed relevant clinical factors and multiple perioperative CT measurements to identify predictors of acceptable functional outcome. RESULTS: Of 87 identified consecutive patients, 66 met the inclusion criteria. Acceptable functional outcome occurred in 35 of 66 (53%) patients. Likelihood of acceptable functional outcome decreased significantly with increasing age (OR 0.92, 95% CI 0.82-0.97, P = 0.004) and with increasing post-DC midline brain shift (OR 0.78, 95% CI 0.64-0.96, P = 0.016), and decreased non-significantly with left-sided stroke (OR 0.30, 95% CI 0.08-1.10, P = 0.069) and with increasing craniectomy barrier thickness (OR 0.92, 95% CI 0.85-1.01, P = 0.076). CONCLUSIONS: Patient age and the post-DC midline shift may be useful in prognosticating functional outcome after DC for MHI. Stroke side and craniectomy barrier thickness merit further ideally prospective outcome prediction testing.

Coagulation markers and functional outcome in acute ischemic stroke: Impact of intensive versus standard hyperglycemia control.

OBJECTIVE: Alterations in coagulation could mediate functional outcome in patients with hyperglycemia after acute ischemic stroke (AIS). We prospectively studied the effects of intensive versus standard glucose control on coagulation markers and their relationships to functional outcomes in patients with AIS. APPROACH: The Insights on Selected Procoagulation Markers and Outcomes in Stroke Trial measured the coagulation biomarkers whole blood tissue factor procoagulant activity (TFPCA); plasma factors VII (FVII), VIIa (FVIIa), and VIII (FVIII); thrombin-antithrombin (TAT) complex; D-dimer; tissue factor pathway inhibitor, and plasminogen activator inhibitor-1 (PAI-1) antigen in patients enrolled in the Stroke Hyperglycemia Insulin Network Effort trial of intensive versus standard glucose control on functional outcome at 3 months after AIS. Changes in biomarkers over time (from baseline ≈12 hours after stroke onset) to 48 hours, and changes in biomarkers between treatment groups, functional outcomes, and their interaction were analyzed by two-way analysis of variance. RESULTS: A total of 125 patients were included (57 in the intensive treatment group and 68 in the standard treatment group). The overall mean age was 66 years; 42% were women. Changes from baseline to 48 hours in coagulation markers were significantly different between treatment groups for TFPCA (P = 0.02) and PAI-1 (P = .04) and FVIIa (P = .04). Increases in FVIIa and decreases in FVIII were associated with favorable functional outcomes (P = .04 and .04, respectively). In the intensive treatment group, reductions in TFPCA and FVIII and increases in FVIIa were greater in patients with favorable than unfavorable outcomes (P = .02, 0.002, 0.03, respectively). In the standard treatment group, changes in FVII were different by functional outcome (P = .006). CONCLUSIONS: Intensive glucose control induced greater alterations in coagulation biomarkers than standard treatment, and these were associated with a favorable functional outcome at 3 months after AIS.

Limiting Brain Shift in Malignant Hemispheric Infarction by Decompressive Craniectomy.

OBJECTIVE: Decompressive craniectomy (DC) improves functional outcomes in selected patients with malignant hemispheric infarction (MHI), but variability in the surgical technique and occasional complications may be limiting the effectiveness of this procedure. Our aim was to evaluate predefined perioperative CT measurements for association with post-DC midline brain shift in patients with MHI. METHODS: At two medical centers we identified 87 consecutive patients with MHI and DC between January 2007 and December 2019. We used our previously tested methods to measure the craniectomy surface area, extent of transcalvarial brain herniation, thickness of tissues overlying the craniectomy, diameter of the cerebral ventricle atrium contralateral to the stroke, extension of infarction beyond the craniectomy edges, and the pre and post-DC midline brain shifts. To avoid potential confounding from medical treatments and additional surgical procedures, we excluded patients with the first CT delayed >30 hours post-DC, resection of infarcted brain, or insertion of an external ventricular drain during DC. The primary outcome in multiple linear regression analysis was the postoperative midline brain shift. RESULTS: We analyzed 72 qualified patients. The average midline brain shift decreased from 8.7 mm pre-DC to 5.4 post-DC. The only factors significantly associated with post-DC midline brain shift at the p<0.01 level were preoperative midline shift (coefficient 0.32, standard error 0.10, p=0.002) and extent of transcalvarial brain herniation (coefficient -0.20, standard error 0.05, p <0.001). CONCLUSIONS: In patients with MHI and DC, smaller post-DC midline shift is associated with smaller pre-DC midline brain shift and greater transcalvarial brain herniation. This knowledge may prove helpful in assessing DC candidacy and surgical success. Additional studies to enhance the surgical success of DC are warranted.

Targeting autophagy in ischemic stroke: From molecular mechanisms to clinical therapeutics.

Stroke constitutes the second leading cause of death and a major cause of disability worldwide. Stroke is normally classified as either ischemic or hemorrhagic stroke (HS) although 87% of cases belong to ischemic nature. Approximately 700,000 individuals suffer an ischemic stroke (IS) in the US each year. Recent evidence has denoted a rather pivotal role for defective macroautophagy/autophagy in the pathogenesis of IS. Cellular response to stroke includes autophagy as an adaptive mechanism that alleviates cellular stresses by removing long-lived or damaged organelles, protein aggregates, and surplus cellular components via the autophagosome-lysosomal degradation process. In this context, autophagy functions as an essential cellular process to maintain cellular homeostasis and organismal survival. However, unchecked or excessive induction of autophagy has been perceived to be detrimental and its contribution to neuronal cell death remains largely unknown. In this review, we will summarize the role of autophagy in IS, and discuss potential strategies, particularly, employment of natural compounds for IS treatment through manipulation of autophagy.

Initial testing of an electronic application of the simplified modified Rankin Scale questionnaire (e-smRSq).

INTRODUCTION AND PURPOSE: To facilitate modified Rankin scale (mRS) assessments, we developed and tested a smartphone/web application of the simplified mRS questionnaire (e-smRSq). The e-smRSq guides raters towards a final score according to the smRSq algorithm, and offers hints for scoring based on the conventional mRS concepts. METHODS: Initially, three experienced mRS certified raters prepared 30 vignettes of unstructured stroke patient interviews, and determined consensus reference scores. Using the e-smRSq, 16 raters of varied professional backgrounds without mRS training scored the mRS for 24 randomly selected vignettes. Subsequently, 5 certified and 5 uncertified raters using the e-smRSq scored 23 mRS certification vignettes developed and used in the Strategies to Innovate Emergency Care Clinical Trials Network-Neurological Emergencies Treatment Trials (SIREN-NETT). Cohen's and Fleiss's kappa (κ), weighted kappa (κw), and intra-class correlation (ICC) compared rater scores with reference scores and assessed interrater reliability. RESULTS: For the 16 initial raters using the e-smRSq with 24 vignettes, the κ (Fleiss) was 0.62 and ICC 0.87 (CI 0.80-0.93). Comparing raters' scores with reference scores, Cohen's κ was 0.68 and κw 0.90. For the 10 subsequent raters using the e-smRSq on SIREN-NETT vignettes, κ (Fleiss) was 0.8 and ICC 0.95 (CI 0.91-0.97). Comparing all 10 raters scores with SIREN-NETT reference scores, Cohen's κ was 0.88 and κw 0.97. There was no significant difference between certified and uncertified raters. CONCLUSIONS: The e-smRSq appears to have good reproducibility and validity metrics among both certified and non-certified mRS raters, possibly owing to its simplicity. Further testing in stroke patients in warranted.

The reliability and validity of a novel Chinese version simplified modified Rankin scale questionnaire (2011).

BACKGROUND: The modified Rankin Scale (mRS) is a key global outcome measure after stroke internationally. The latest English version of the simplified modified Rankin scale questionnaire (smRSq)(2011) is a reliable and valid tool in scoring the mRS after stroke. In order to use this tool in Chinese patients, we translated it into Chinese and tested its clinimetric properties. METHODS: The English version smRSq (2011) was translated into Chinese by a standard process. We recruited 300 consecutive hospitalized ischemic stroke patients in the department of neurology, Beijing Chaoyang Hospital. Six randomly paired raters scored the conventional mRS, the novel Chinese version smRSq (2011), the National Institutes of Health Stroke Scale (NIHSS), and the Barthel index (BI) in-person. Inter-rater reliability and validity were assessed. RESULTS: Among the 300 ischemic stroke patients, mean age was 64.9 ± 12.1 years, and 220 (73%) were male. For inter-rater reliability of the smRSq (2011), the percent agreement among the paired raters was 87%, the kappa (κ) was 0.84 (95% CI, 0.79-0.88), and the weighted kappa (κw) was 0.96 (95% CI, 0.95-0.98). The percent agreement between the smRSq (2011) scores and the conventional mRS scores was 55%, κ = 0.47 (95% CI, 0.40-0.54), and κw = 0.91 (95% CI, 0.89-0.93). In construct validity testing, the Spearman's correlation coefficients comparing the smRSq (2011) scores with the NIHSS and the BI scores were 0.83 (P < 0.001) and - 0.86 (P < 0.001), respectively. CONCLUSIONS: Our results show good to excellent clinimetric properties of the novel Chinese version smRSq (2011) in scoring the mRS in Chinese stroke patients. Further validation in other clinical settings, including in communities and by remote methods in China is warranted.

New CT measurements to assess decompression after hemicraniectomy: A two-center reliability study.

OBJECTIVES: To test the reliability of three simplified measurements made after decompressive hemicraniectomy (DHC) for malignant hemispheric infarction on computed tomography (CT) scan. PATIENTS AND METHODS: We defined new simple methods to measure the thickness of the soft tissues overlying the craniectomy defect and the extent of infarction beyond the anterior and posterior craniectomy edges on post-DHC CT. Multiple raters independently made the three new CT measurements in 49 patients from two institutions. The Intraclass Correlation Coefficient (ICC) compared the raters for interrater agreements (reliability). RESULTS: Between two raters at Augusta University Medical Center, each measuring 21 CT scans, the ICC coefficient point estimates were good to excellent (0.83 - 0.92). Among four raters at University of Virginia Medical Center, with three raters measuring each of 28 CT scans, the ICC coefficient point estimates were good to excellent (0.87 - 0.95). CONCLUSIONS: The proposed simple methods to obtain three additional CT measurements after DHC in malignant hemispheric infarction have good to excellent reliability in two independent patient samples. The clinical usefulness of these measurements should be investigated.

Intensive vs Standard Treatment of Hyperglycemia and Functional Outcome in Patients With Acute Ischemic Stroke: The SHINE Randomized Clinical Trial.

Importance: Hyperglycemia during acute ischemic stroke is common and is associated with worse outcomes. The efficacy of intensive treatment of hyperglycemia in this setting remains unknown. Objectives: To determine the efficacy of intensive treatment of hyperglycemia during acute ischemic stroke. Design, Setting, and Participants: The Stroke Hyperglycemia Insulin Network Effort (SHINE) randomized clinical trial included adult patients with hyperglycemia (glucose concentration of >110 mg/dL if had diabetes or ≥150 mg/dL if did not have diabetes) and acute ischemic stroke who were enrolled within 12 hours from stroke onset at 63 US sites between April 2012 and August 2018; follow-up ended in November 2018. The trial included 1151 patients who met eligibility criteria. Interventions: Patients were randomized to receive continuous intravenous insulin using a computerized decision support tool (target blood glucose concentration of 80-130 mg/dL [4.4-7.2 mmol/L]; intensive treatment group: n = 581) or insulin on a sliding scale that was administered subcutaneously (target blood glucose concentration of 80-179 mg/dL [4.4-9.9 mmol/L]; standard treatment group: n = 570) for up to 72 hours. Main Outcomes and Measures: The primary efficacy outcome was the proportion of patients with a favorable outcome based on the 90-day modified Rankin Scale score (a global stroke disability scale ranging from 0 [no symptoms or completely recovered] to 6 [death]) that was adjusted for baseline stroke severity. Results: Among 1151 patients who were randomized (mean age, 66 years [SD, 13.1 years]; 529 [46%] women, 920 [80%] with diabetes), 1118 (97%) completed the trial. Enrollment was stopped for futility based on prespecified interim analysis criteria. During treatment, the mean blood glucose level was 118 mg/dL (6.6 mmol/L) in the intensive treatment group and 179 mg/dL (9.9 mmol/L) in the standard treatment group. A favorable outcome occurred in 119 of 581 patients (20.5%) in the intensive treatment group and in 123 of 570 patients (21.6%) in the standard treatment group (adjusted relative risk, 0.97 [95% CI, 0.87 to 1.08], P = .55; unadjusted risk difference, -0.83% [95% CI, -5.72% to 4.06%]). Treatment was stopped early for hypoglycemia or other adverse events in 65 of 581 patients (11.2%) in the intensive treatment group and in 18 of 570 patients (3.2%) in the standard treatment group. Severe hypoglycemia occurred only among patients in the intensive treatment group (15/581 [2.6%]; risk difference, 2.58% [95% CI, 1.29% to 3.87%]). Conclusions and Relevance: Among patients with acute ischemic stroke and hyperglycemia, treatment with intensive vs standard glucose control for up to 72 hours did not result in a significant difference in favorable functional outcome at 90 days. These findings do not support using intensive glucose control in this setting. Trial Registration: ClinicalTrials.gov Identifier: NCT01369069.