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Background and Purpose— EG-1962 is a sustained release formulation of nimodipine administered via external ventricular drain in patients with aneurysmal subarachnoid hemorrhage. A randomized, open-label, phase 1/2a, dose-escalation study provided impetus for this study to evaluate efficacy and safety of a single intraventricular 600 mg dose of EG-1962 to patients with aneurysmal subarachnoid hemorrhage, compared with standard of care oral nimodipine. Methods— Subjects were World Federation of Neurological Surgeons grades 2–4, modified Fisher grades 2–4 and had an external ventricular drain inserted as part of standard of care. The primary end point was the proportion of subjects with favorable outcome at day 90 after aneurysmal subarachnoid hemorrhage (extended Glasgow outcome scale 6–8). The proportion of subjects with favorable outcome at day 90 on the Montreal cognitive assessment, as well as the incidence of delayed cerebral ischemia and infarction, use of rescue therapy and safety were evaluated. Results— The study was halted by the independent data monitoring board after planned interim analysis of 210 subjects (289 randomized) with day 90 outcome found the study was unlikely to achieve its primary end point. After day 90 follow-up of all subjects, the proportion with favorable outcome on the extended Glasgow outcome scale was 45% (65/144) in the EG-1962 and 42% (62/145) in the placebo group (risk ratio, 1.01 [95% CI, 0.83–1.22], P =0.95). Consistent with its mechanism of action, EG-1962 significantly reduced vasospasm (50% [69/138] EG-1962 versus 63% [91/144], P =0.025) and hypotension (7% [9/138] versus 10% [14/144]). Analysis of prespecified subject strata suggested potential efficacy in World Federation of Neurological Surgeons 3–4 subjects (46% [32/69] EG-1962 versus 32% [24/75] placebo, odds ratio, 1.22 [95% CI, 0.94–1.58], P =0.13). No safety concerns were identified that halted the study or that preclude further development. Conclusions— There was no significant increase in favorable outcome for EG-1962 compared with standard of care in the overall study population. The safety profile was acceptable. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02790632.

Background: There are limited data on the baseline characteristics and clinical outcomes of patients who have recurrent hemispheric syndromes in the territory of symptomatic atherosclerotic internal carotid artery occlusion (AICAO). Methods: Baseline characteristics and clinical outcomes were compared between patients with (rHEM+) and without (rHEM-) recurrent ipsilateral hemispheric syndromes at the time of randomization into the Carotid Occlusion Surgery Study (COSS) based on local investigator clinical impression. Results: Of 195 participants who were randomized, 100 (51%) were rHEM+ (50 in each study arm) and 95 were rHEM-(48 nonsurgical, 47 surgical). Baseline characteristics between rHEM+ and rHEM- participants were similar except that rHEM+ participants were more likely to have had a previous stroke prior to entry event (59% vs 22%, p < 0.001) and to have had TIA vs stroke as the entry event (61% vs 20%, p 0.10). For the nonsurgical participants, there was no statistically significant difference in the primary endpoint for those rHEM+ vs rHEM- (26.3% vs 18.9%, p=.410) Conclusion: Patients with recurrent hemispheric stroke syndromes enrolled in the COSS trial were more likely to have had previous stroke and to have TIAs as the entry event to randomization. Given the lack of surgical treatment benefit seen in these patients, early aggressive risk factor measures should be prioritized to reduce recurrent strokes, including blood pressure control which was associated with a 70% reduction in stroke in the nonsurgical group in COSS ( Neurology 2014; 82:1027-1032).

Purpose— Our goal is to provide an overview of the current evidence about components of the evaluation and treatment of adults with acute ischemic stroke. The intended audience is physicians and other emergency healthcare providers who treat patients within the first 48 hours after stroke. In addition, information for healthcare policy makers is included. Methods— Members of the panel were appointed by the American Heart Association Stroke Council’s Scientific Statement Oversight Committee and represented different areas of expertise. The panel reviewed the relevant literature with an emphasis on reports published since 2003 and used the American Heart Association Stroke Council’s Levels of Evidence grading algorithm to rate the evidence and to make recommendations. After approval of the statement by the panel, it underwent peer review and approval by the American Heart Association Science Advisory and Coordinating Committee. It is intended that this guideline be fully updated in 3 years. Results— Management of patients with acute ischemic stroke remains multifaceted and includes several aspects of care that have not been tested in clinical trials. This statement includes recommendations for management from the first contact by emergency medical services personnel through initial admission to the hospital. Intravenous administration of recombinant tissue plasminogen activator remains the most beneficial proven intervention for emergency treatment of stroke. Several interventions, including intra-arterial administration of thrombolytic agents and mechanical interventions, show promise. Because many of the recommendations are based on limited data, additional research on treatment of acute ischemic stroke is needed.

Relative mean transit time (MTT) is readily obtainable from dynamic susceptibility contrast MRI of the brain. While it has received much attention in acute ischemic stroke as a possible means to identify patients for reperfusion therapies, little has been done to determine if it has clinical significance outside the acute setting. To determine if relative MTT could be used to identify patients who are at high risk for subsequent stroke, we analyzed data from the St. Louis Carotid Occlusion Study. This prospective study was carried out from 1992-1997 to determine if PET measurement of oxygen extraction fraction could identify medically treated patients with recently symptomatic carotid artery occlusion at high risk for subsequent stroke. Sixty-eight of the participants in the study had quantitative PET measurements of cerebral blood flow (CBF) and cerebral blood volume (CBV). From these we calculated the MTT (CBV/CBF) in each middle cerebral artery territory and determined the MTT ratio of the ipsilateral to the contralateral hemisphere (I/C MTT ratio). Nine of the 68 participants had a subsequent ipsilateral ischemic stroke during mean follow-up of 2.6 years (range .5 - 5 years). The I/C MTT ratio was significantly associated with subsequent stroke as a continuous variable by Cox regression analysis (HR 65, 95%CI 7-613, p < .001). The maximum combination of sensitivity (.778) and specificity (.763) was obtained with a cutpoint of ≥ 1.387 which identified 7/9 subsequent strokes (PPV .333, NPV .957). Relative MTT shows great promise as a means to identify patients with large artery disease who are at high risk for subsequent stoke. These results need to be confirmed using MRI in a cohort receiving contemporary medical management.

Background and Purpose— To describe baseline clinical features and outcomes of adults with moyamoya phenomenon treated at a single North American institution. Methods— We identified 34 adults with moyamoya phenomenon by review of angiographic records. Clinical presentation and baseline stroke risk factors were obtained by chart review. Follow-up was obtained prospectively. A 5-year Kaplan-Meier stroke risk was calculated. Results— The median age was 42 (range 20 to 79) years. Twenty-five were women. The initial symptom was ischemia, hemorrhage, or asymptomatic in 24, 7, and 3 patients, respectively. Twenty-two had bilateral involvement and 12 had unilateral moyamoya vessels. Baseline stroke risk factors were similar between groups. The median follow-up in 31 living patients was 5.1 (range 0.2 to 19.6) years. Fourteen patients were treated with surgical revascularization (20 total hemispheres). In medically treated symptomatic hemispheres, the 5-year risk of recurrent ipsilateral stroke was 65% after the initial symptom and 27% after angiographic diagnosis. Patients with bilateral involvement presenting with ischemic symptoms were at the highest risk of subsequent stroke (n=17, 5-year risk of stroke with medical treatment after first symptom of 82%). In surgically treated hemispheres, the 5-year risk of perioperative or subsequent ipsilateral stroke or death was 17%. This was significantly different compared with medical treatment after first symptom ( P =0.02) but not after angiographic diagnosis. Conclusion— Moyamoya phenomenon in North American adults is associated with a high risk of recurrent stroke, particularly those with bilateral involvement and ischemic symptoms. These data suggest a potential benefit with surgery if diagnosis could be made earlier.

Background and Purpose— The optimal treatment of patients with symptomatic carotid stenosis who are poor surgical candidates is uncertain. The purposes of this study were to report the long-term outcome after angioplasty in a series of these patients and to compare these data with historical control data from the North American Symptomatic Carotid Endarterectomy Trial (NASCET). Methods— We identified 42 consecutive patients with >70% carotid stenosis and ipsilateral ischemic symptoms within 120 days of treatment with angioplasty. All were considered poor surgical candidates by experienced surgeons. Baseline epidemiological stroke risk factors were obtained from review of medical records. Follow-up was from clinic records and by telephone. Results— Baseline epidemiological stroke risk factors were similar to those of medically treated NASCET patients. Angioplasty patients tended to have higher degrees of stenosis (45% with >90% stenosis versus 24% in NASCET) and more frequent contralateral stenosis or occlusion (30% versus 9%) than NASCET patients. Three patients suffered procedural strokes; 2 of the 3 made nearly complete recoveries. One additional patient suffered a central retinal occlusion 48 hours after angioplasty. No ipsilateral strokes occurred during the mean follow-up period of 1.7 years. Three patients were lost to follow-up. The cumulative risk of stroke was 9.5% (4 of 42) compared with 26% at 2 years for medically treated patients in NASCET. Conclusions— These pilot data suggest a beneficial effect of angioplasty for patients with high-grade symptomatic carotid stenosis who are not good surgical candidates.

Background and Purpose —Misery perfusion, identified by increased oxygen extraction fraction (OEF), predicts subsequent stroke in patients with carotid occlusion. The purpose of this investigation was to determine the relationship of angiographic findings to increased OEF in these patients. Methods —Forty-seven patients with carotid occlusion were studied with cerebral angiography and positron emission tomography (PET). The following angiographic data were collected blind to PET results: (1) pial collateralization, defined as retrograde filling of the MCA branches to the level of the insula; (2) presence of border zone shift; (3) presence of delayed venous phase; and (4) measurement of posterior communicating artery size. Patients were divided into 2 groups based on the PET measurement of normal or increased OEF. Results —Seventeen of 47 patients had increased OEF distal to the occluded carotid artery. No significant relationship between increased OEF and any angiographic finding was found. Pial collateralization was present in only 2 patients, both with increased OEF ( P =0.105). Border zone shift was equally distributed between the 2 groups (12 of 30 with normal OEF and 6 of 15 with increased OEF). Delayed venous phase was present in 4 patients, 3 of whom had increased OEF ( P =0.073). The relationship between the size of the posterior communicating artery and OEF was not significant by linear regression analysis ( P =0.242). Conclusions —With the possible but infrequent exceptions of delayed venous phase and pial collateralization, anatomic findings made on routine angiographic studies of patients with carotid occlusion do not correlate with increased OEF.

Background and Purpose —The purpose of this experiment was to assess long-term cerebral hemodynamic and metabolic changes in patients with increased oxygen extraction fraction (OEF) in the hemisphere distal to an occluded carotid artery who remain free of stroke. Methods —Ten patients with increased OEF and no interval stroke underwent repeated positron emission tomography examinations 12 to 59 months after the initial examination. Quantitative regional measurements of cerebral blood flow, cerebral blood volume, cerebral rate of oxygen metabolism (CMRO 2 ), and OEF were obtained. Regional measurements of the cerebral rate of glucose metabolism (CMRGlc) were made on follow-up in 5 patients. Statistical significance ( P t tests and linear regression analysis. Results —The ipsilateral/contralateral OEF ratio declined from a mean of 1.16 to 1.08 ( P =0.022). Greater reductions were seen with longer duration of follow-up ( P =0.023, r =0.707). The cerebral blood flow ratio improved from 0.81 to 0.85 ( P =0.021). No change in cerebral blood volume or CMRO 2 was observed. CMRGlc was reduced in the ipsilateral hemisphere ( P =0.001 compared with normal), but the CMRO 2 /CMRGlc ratio was normal. Conclusions —Increased OEF improves in patients with carotid occlusion and no interval stroke. This improvement in OEF is due to an improvement in collateral blood flow.

To the Editor: We appreciate the opportunity to address several of the comments made by Nemoto and his colleagues1 regarding our prior work. First, and most importantly, we would like to emphasize that measurements of oxygen extraction fraction (OEF) remain the most rigorously validated method for identifying stroke risk in patients with carotid occlusion.2 We must disagree with statements by Nemoto et al that OEF is not predictive of stroke risk. This conclusion is not valid, as it is based on erroneous interpretation of our data. Increased OEF is predictive of stroke risk . The St. Louis Carotid Occlusion Study (STLCOS) was a blinded, prospective study of cerebral hemodynamics and stroke risk in patients with complete occlusion of a carotid artery.3 In this study, we prospectively set as a threshold the outer limits …

122 Background: Increased oxygen extraction fraction (OEF) suggesting reduced cerebral perfusion pressure below the autoregulatory limit has been reported in subacute hypertensive (HTN) ICH. We sought to confirm this finding in acute ICH. Methods: Nineteen HTN patients aged 63±15 years with spontaneous supratentorial ICH (.3–99 cc; median 12) were studied with PET 5–22 hours after onset. Five patients were re-studied after BP was lowered 23±9 mm Hg. Subsets of patients were age-matched to normal and HTN controls. Cerebral blood flow (CBF), metabolic rate (CMRO 2 ), and OEF for each hemisphere were derived from a 2-cm cortical rim. All measurements were corrected for partial volume effect. Results: Ipsilateral OEF was elevated and CBF and CMRO 2 reduced compared to normal controls, but not to levels sufficient to produce infarction. (Table.) OEF was no different from HTN controls, however. There was no correlation between OEF and size of clot or ventricles, suggesting that elevated OEF was not due to increased ICP or mass effect. Lowering of BP did not change CBF (-1.7±2.2 ml/100g/min); thus, there was no evidence for autoregulatory failure. Conclusions: Elevated hemispheric OEF in acute ICH may reflect the effects of chronic hypertension rather than increased ICP or other effects of the hematoma.

The relationships between cerebral blood volume (CBV), cerebral blood flow (CBF), and the cerebral vascular mean transit time (t v ) during acute changes in the Pa CO 2 over a range of 15 to 76 torr were investigated in vivo in rhesus monkeys by serially determining the mean transit time of a vascular tracer, 15 O-labeled carboxyhemoglobin, and the mean transit time of a diffusible tracer, 15 O-labeled water. Over this range of Pa CO 2 , a significant linear relationship of CBV = 0.041 Pa CO 2 + 2.0 was found. For each one torr change in Pa CO 2 , there is a change in CBV of 0.041 ml/100 gm of perfused tissue. At a normocarbic value of Pa CO 2 (37 torr), an average value of 3.5 ml/100 gm was found. A nonlinear relationship of CBV and CBF was found. This relationship is expressed in the equation, CBV = 0.80 CBF 0.38 . A significant linear relationship was found between CBF and Pa CO 2 . This was described by the equation, CBF = 1.8 Pa CO 2 - 16.75. For each one torr change in the PaCO 2 , there is a 1.8 ml/100 gm per minute change in the CBF. At a normocarbic value of Pa CO 2 (37 torr), an average value of CBF of 50 ml/100 gm per minute was found. The relationship of CBV and t v was nonlinear and was expressed in the equation, t C15O = 41 CBF -0.62 .

The effects of an iodinated contrast agent, Renografin-76® upon cerebral autoregulation was studied in rhesus monkeys. This was done by measuring the effects of an intravenous injection of Renografin-76 upon: (1) the response of baseline CBF as measured by the washout of a carotid bolus of H 2 15 O during and after the injection of Renografin-76, (2) the response of CBF monitored continuously by a Doppler flow probe technique to changes in the mean arterial blood pressure (MABP) before and after an injection of Renografin-76, and (3) the response of the regional cerebral blood volume (rCBV) as measured by stimulated x-ray fluorescence. An intravenous injection of Renografin-76 can disturb cerebral autoregulation in the rhesus monkey for as long as 15 minutes after the beginning of the injection. After the intravenous in jection of Renografin-76, transient rises in both CBF and MABP lasting from 2 to 12 minutes occurred on an average of 23% and 16%, respectively, over control values.

Cerebral blood flow (CBF) remains constant over a wide range of arterial blood pressure. This is thought to be accomplished by changes in the diameter, and therefore the volume, of the cerebral resistance vessels. To test this hypothesis, regional cerebral blood volume (rCBV) was measured in vivo in Rhesus monkeys over a range of mean arterial blood pressures (MABP) of 35 to 200 torr. Multiple measurements were made in each animal by the method of stimulated x-ray fluorescence. A significant linear relationship of rCBV = 6.26 (±0.47 SD) -0.015 (±0.004 SD) MABP was found. For each one torr change in the MABP, there is a change in rCBV of 0.015 cc/100 gm of brain tissue over a range of MABP of 35 to 200 torr. An additional observation of this investigation was that autoregulation of the cerebral blood flow (CBF) is perturbed for a period lasting up to 15 minutes after the intravenous injection of Renografin 76 R .