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 .).

Background It is uncertain if endovascular stroke therapy leads to improved clinical outcomes due to a paucity of data from randomized placebo-controlled trials. The aim of this study was to determine if MRI can be used to identify patients who are most likely to benefit from endovascular reperfusion. Methods Consecutive patients, scheduled to undergo endovascular therapy within 12 hours of stroke onset, were enrolled in a multi-center prospective cohort study. Aided by an automated image analysis software program, investigators interpreted the baseline MRI. They determined, prior to endovascular treatment, if the patient had an MRI profile (Target Mismatch) that suggested salvageable tissue was present. Reperfusion was assessed on an early follow-up MRI and defined as a >50% reduction in the volume of the baseline perfusion lesion. A favorable clinical response was defined as a ≥8 point improvement on the NIH Stroke Scale (NIHSS) between baseline and day 30 or an NIHSS score of 0–1 at 30 days. Findings Following endovascular therapy reperfusion occurred in 46 of 78 (59%) Target Mismatch patients and in 12 of 21 (57%) No Target Mismatch patients. The adjusted odds ratio for favorable clinical response associated with reperfusion was 8·5 (95% CI 2·6 – 28) in the Target Mismatch group and 0·2 (95% CI 0·0 – 1·6) in the No Target Mismatch group (p=0·003 for difference between odds ratios). Reperfusion was associated with an increased odds of good functional outcome at 90 days (OR is 5.2, 95% CI 1.4–19) and attenuation of infarct growth at 5 days (30 ml of median growth with reperfusion vs. 73 ml without reperfusion, p=0·01) in the Target Mismatch group but not in patients without Target Mismatch. Interpretation Target Mismatch patients who achieved early reperfusion following endovascular stroke therapy had more favorable clinical outcomes and less infarct growth. No association between reperfusion and favorable outcomes was present in patients without Target Mismatch. These data support a randomized controlled trial of endovascular treatment in patients with the Target Mismatch profile.

Background and Purpose-We sought to assess whether the volume of the ischemic penumbra can be estimated more accurately by altering the threshold selected for defining perfusion-weighting imaging (PWI) lesions. Methods-DEFUSE is a multicenter study in which consecutive acute stroke patients were treated with intravenous tissue-type plasminogen activator 3 to 6 hours after stroke onset. Magnetic resonance imaging scans were obtained before, 3 to 6 hours after, and 30 days after treatment. Baseline and posttreatment PWI volumes were defined according to increasing Tmax delay thresholds (Ͼ2, Ͼ4, Ͼ6, and Ͼ8 seconds). Penumbra salvage was defined as the difference between the baseline PWI lesion and the final infarct volume (30-day fluid-attenuated inversion recovery sequence). We hypothesized that the optimal PWI threshold would provide the strongest correlations between penumbra salvage volumes and various clinical and imaging-based outcomes. Results-Thirty-three patients met the inclusion criteria. The correlation between infarct growth and penumbra salvage volume was significantly better for PWI lesions defined by Tmax Ͼ6 seconds versus Tmax Ͼ2 seconds, as was the difference in median penumbra salvage volume in patients with a favorable versus an unfavorable clinical response. Among patients who did not experience early reperfusion, the Tmax Ͼ4 seconds threshold provided a more accurate prediction of final infarct volume than the Ͼ2 seconds threshold. Conclusions-Defining PWI lesions based on a stricter Tmax threshold than the standard Ͼ2 seconds delay appears to provide more a reliable estimate of the volume of the ischemic penumbra in stroke patients imaged between 3 and 6 hours after symptom onset. A threshold between 4 and 6 seconds appears optimal for early identification of critically hypoperfused tissue.

Background and Purpose We evaluate associations between the severity of magnetic resonance perfusion-weighted imaging abnormalities, as assessed by the hypoperfusion intensity ratio (HIR), on infarct progression and functional outcome in the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study 2 (DEFUSE 2). Methods Diffusion-weighted magnetic resonance imaging and perfusion-weighted imaging lesion volumes were determined with the RAPID software program. HIR was defined as the proportion of TMax >6 s lesion volume with a Tmax >10 s delay and was dichotomized based on its median value (0.4) into low versus high subgroups as well as quartiles. Final infarct volumes were assessed at day 5. Initial infarct growth velocity was calculated as the baseline diffusion-weighted imaging (DWI) lesion volume divided by the delay from symptom onset to baseline magnetic resonance imaging. Total Infarct growth was determined by the difference between final infarct and baseline DWI volumes. Collateral flow was assessed on conventional angiography and dichotomized into good and poor flow. Good functional outcome was defined as modified Rankin Scale ≤2 at 90 days. Results Ninety-nine patients were included; baseline DWI, perfusion-weighted imaging, and final infarct volumes increased with HIR quartiles (P<0.01). A high HIR predicted poor collaterals with an area under the curve of 0.73. Initial infarct growth velocity and total infarct growth were greater among patients with a high HIR (P<0.001). After adjustment for age, DWI volume, and reperfusion, a low HIR was associated with good functional outcome: odds ratio=4.4 (95% CI, 1.3–14.3); P=0.014. Conclusions HIR can be easily assessed on automatically processed perfusion maps and predicts the rate of collateral flow, infarct growth, and clinical outcome.

Background Therapeutic hypothermia is commonly used in comatose survivors’ post-cardiopulmonary resuscitation (CPR). It is unknown whether outcome predictors perform accurately after hypothermia treatment. Methods Post-CPR comatose survivors were prospectively enrolled. Six outcome predictors [pupillary and corneal reflexes, motor response to pain, and somatosensory-evoked potentials (SSEP) >72 h; status myoclonus, and serum neuron-specific enolase (NSE) levels <72 h] were systematically recorded. Poor outcome was defined as death or vegetative state at 3 months. Patients were considered “sedated” if they received any sedative drugs ≤12 h prior the 72 h neurological assessment. Results Of 85 prospectively enrolled patients, 53 (62%) underwent hypothermia. Furthermore, 53 of the 85 patients (62%) had a poor outcome. Baseline characteristics did not differ between the hypothermia and normothermia groups. Sedative drugs at 72 h were used in 62 (73%) patients overall, and more frequently in hypothermia than in normothermia patients: 83 versus 60% (P = 0.02). Status myoclonus <72 h, absent cortical responses by SSEPs >72 h, and absent pupillary reflexes >72 h predicted poor outcome with a 100% specificity both in hypothermia and normothermia patients. In contrast, absent corneal reflexes >72 h, motor response extensor or absent >72 h, and peak NSE >33 ng/ml <72 h predicted poor outcome with 100% specificity only in non-sedated patients, irrespective of prior treatment with hypothermia. Conclusions Sedative medications are commonly used in proximity of the 72-h neurological examination in comatose CPR survivors and are an important prognostication confounder. Patients treated with hypothermia are more likely to receive sedation than those who are not treated with hypothermia.

Objective-Outcome prediction is challenging in comatose post-cardiac arrest survivors. We assessed the feasibility and prognostic utility of brain diffusion-weighted MRI (DWI) during the first week.Corresponding Author Christine AC Wijman, MD, PhD, Stanford Stroke Center, 701 Welch Road, B325, Palo Alto, CA 94304, Fax: (650) Tel: (650) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMethods-Consecutive comatose post-cardiac arrest patients were prospectively enrolled. MRI data of patients who met predefined specific prognostic criteria were used to determine distinguishing ADC thresholds. Group 1: death at 6 months and absent motor response or absent pupillary reflexes or bilateral absent cortical responses at 72 hours, or vegetative at 1 month. Group 2A: Glasgow outcome scale (GOS) score of 4 or 5 at 6 months. Group 2B: GOS of 3 at 6 months. The percentage of voxels below different apparent diffusion coefficient (ADC) thresholds was calculated at 50 × 10 −6 mm 2 /sec intervals.Results-Overall, 86% of patients underwent MR imaging. Fifty-one patients with 62 brain MRIs were included in the analyses. Forty patients met the specific prognostic criteria. The percentage of brain volume with an ADC value below 650-700 × 10 −6 mm 2 /sec best differentiated between group 1 and groups 2A and 2B combined (p<0.001), while the 400-450 × 10 −6 mm 2 /sec threshold best differentiated between groups 2A and 2B (p=0.003). The ideal time window for prognostication using DWI was between 49 to 108 hours after the arrest. When comparing MRI in this time window with the 72 hour neurological examination MRI improved the sensitivity for predicting poor outcome by 38% while maintaining 100% specificity (p=0.021).Interpretation-Quantitative DWI in comatose post-cardiac arrest survivors holds great promise as a prognostic adjunct.Approximately 350,000 cardiac arrests occur annually in the United States1. Up to half of these patients are successfully resuscitated. In the past, only 10% to 30% of comatose postcardiac arrest patients had good functional recovery. These numbers will likely improve with the increasing use of therapeutic hypothermia2 , 3.Post-cardiac arrest brain injury is a common cause of morbidity and mortality. Many comatose post-cardiac arrest patients die or survive with severe disability after a prolonged intensive care unit stay associated with a tremendous cost burden4 , 5. Conversely, the potential for premature withdrawal of life support from patients who may have a chance of functional recovery represents an additional ethical dilemma. Thus, early accurate identification of patients who have no likelihood of meaningful recovery is a very important health care issue.Although several prognostic variables have been studied in comatose post-cardiac arrest patients, the currently accepted variables (neurological examination, neurophysiologic tests, and serum markers) have substantive limitations. First, they identify only a subset of poor outcome patients with high specificity. Se...

Background and Purpose-Knowledge on the natural history and clinical impact of perihematomal edema (PHE) associated with intracerebral hemorrhage is limited. We aimed to define the time course, predictors, and clinical significance of PHE measured by serial magnetic resonance imaging. Methods-Patients with primary supratentorial intracerebral hemorrhage Ն5 cm 3 underwent serial MRIs at prespecified intervals during the first month. Hematoma (H v ) and PHE (E v ) volumes were measured on fluid-attenuated inversion recovery images. Relative PHE was defined as E v /H v . Neurologic assessments were performed at admission and with each MRI. Barthel Index, modified Rankin scale, and extended Glasgow Outcome scale scores were assigned at 3 months. Results-Twenty-seven patients with 88 MRIs were prospectively included. Median H v and E v on the first MRI were 39 and 46 cm 3 , respectively. Median peak absolute E v was 88 cm 3 . Larger hematomas produced a larger absolute E v (r 2 ϭ0.6) and a smaller relative PHE (r 2 ϭ0.7). Edema volume growth was fastest in the first 2 days but continued until 12Ϯ3 days. In multivariate analysis, a higher admission hematocrit was associated with a greater delay in peak PHE (Pϭ0.06). Higher admission partial thromboplastin time was associated with higher peak rPHE (Pϭ0.02). Edema volume growth was correlated with a decline in neurologic status at 48 hours (81 vs 43

Rationale Early reperfusion in patients experiencing acute ischemic stroke is effective in patients with large vessel occlusion. No randomized data are available regarding the safety and efficacy of endovascular therapy beyond 6 h from symptom onset. Aim The aim of the study is to demonstrate that, among patients with large vessel anterior circulation occlusion who have a favorable imaging profile on computed tomography perfusion or magnetic resonance imaging, endovascular therapy with a Food and Drug Administration 510 K-cleared mechanical thrombectomy device reduces the degree of disability three months post stroke. Design The study is a prospective, randomized, multicenter, phase III, adaptive, blinded endpoint, controlled trial. A maximum of 476 patients will be randomized and treated between 6 and 16 h of symptom onset. Procedures Patients undergo imaging with computed tomography perfusion or magnetic resonance diffusion/perfusion, and automated software (RAPID) determines if the Target Mismatch Profile is present. Patients who meet both clinical and imaging selection criteria are randomized 1:1 to endovascular therapy plus medical management or medical management alone. The individual endovascular therapist chooses the specific device (or devices) employed. Study outcomes The primary endpoint is the distribution of scores on the modified Rankin Scale at day 90. The secondary endpoint is the proportion of patients with modified Rankin Scale 0–2 at day 90 (indicating functional independence). Analysis Statistical analysis for the primary endpoint will be conducted using a normal approximation of the Wilcoxon–Mann–Whitney test (the generalized likelihood ratio test).