Challenges of decision making regarding futility in a randomized trial: the Interventional Management of Stroke III experience.

BACKGROUND AND PURPOSE: Interventional Management of Stroke (IMS) III is a randomized, parallel arm trial comparing the approach of intravenous tissue-type plasminogen activator followed by endovascular treatment with intravenous tissue-type plasminogen activator alone in patients with acute ischemic stroke presenting <3 hours of symptom onset. The trial intended to enroll 900 subjects to ensure adequate statistical power to detect an absolute 10% difference in the percentage of subjects with good outcome, defined as modified Rankin Scale score of 0 to 2 at 3 months. In April 2012, after 656 subjects were randomized, further enrollment was terminated by the National Institute of Neurological Disorders and Stroke based on the prespecified criterion for futility using conditional power<20%. METHODS: Conditional power was defined as the likelihood of finding statistical significance at the end of the study, given the accumulated data to date and with the assumption that a minimum hypothesized difference of 10% truly exists between the 2 groups. The evolution of study data leading to futility determination is described, including the interaction between the unblinded study statisticians and the Data and Safety Monitoring Board in the complex deliberation of analysis results. RESULTS: The futility boundary was crossed at the trial's fourth interim analysis. At this point, based on the conditional power criteria, the Data and Safety Monitoring Board recommended termination of the trial. CONCLUSIONS: Even in spite of prespecified interim analysis boundaries, interim looks at data pose challenges in interpretation and decision making, underscoring the importance of objective stopping criteria. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424.

Sodium time course using 23Na MRI in reversible focal brain ischemia in the monkey.

PURPOSE: To demonstrate the use of sodium MRI for measuring the time course of tissue sodium concentration (TSC) in a nonhuman primate model of reversible focal brain ischemia. MATERIALS AND METHODS: Reversible endovascular focal brain ischemia was induced in nonhuman primates (n = 4), and sodium MRI was performed on a 3 Tesla scanner for monitoring changes in TSC during both the middle cerebral artery (MCA) occlusion and MCA reperfusion portions of the experiment. RESULTS: The TSC increased linearly in the ischemic tissue during MCA occlusion (ranging from a mean TSC increase of 5.44%/h to 7.15%/h across the four subjects), and then there was a statistically significant change from a positive TSC slope during MCA occlusion to a TSC slope after MCA reperfusion that was not statistically different from zero. The linear increase in sodium MRI during brain ischemia was used to estimate the stroke onset time to within 0.45 h in each of the four subjects (with a maximum 95% confidence interval of +/- 1.147 h). CONCLUSION: The data indicate that sodium MRI increases linearly during brain ischemia, and that this increase is stopped by tissue reperfusion within 5.4 h after stroke onset.

MAP2 immunostaining in thick sections for early ischemic stroke infarct volume in non-human primate brain.

The delineation of early infarction in large gyrencephalic brain cannot be accomplished with triphenyl-tetrazolium chloride (TTC) due to its limitations in the early phase, nor can it be identified with microtubule-associated protein 2 (MAP2) immunohistochemistry, due to the fragility of large thin sections. We hypothesize that MAP2 immunostaining of thick brain sections can accurately identify early ischemia in the entire monkey brain. Using ischemic brains of one rat and three monkeys, a thick-section MAP2 immunostaining protocol was developed to outline the infarct region over the entire non-human primate brain. Comparison of adjacent thick and thin sections in a rat brain indicated complete correspondence between ischemic regions (100.4mm(3)+/-1.2%, n=7, p=0.44). Thick sections in monkey brain possessed the increased structural stability necessary for the extensive MAP2 immunostaining procedure permitting quantification of the ischemic region as a percent of total monkey brain, giving infarct volumes of 11.4, 16.3, and 19.0% of total brain. Stacked 2D images of the intact thick brain tissue sections provided a 3D representation for comparison to MRI images. The infarct volume of 16.1cm(3) from the MAP2 sections registered with MRI images agreed well with the volume calculated directly from the stained sections of 16.6 cm(3). Thick brain tissue section MAP2 immunostaining provides a new method for determining infarct volume over the entire brain at early time points in a non-human primate model of ischemic stroke.

Emergent stenting of extracranial internal carotid artery occlusion in acute stroke has a high revascularization rate.

BACKGROUND AND PURPOSE: Acute ischemic stroke attributable to extracranial internal carotid artery (ICA) occlusion is frequently associated with severe disability or death. In selected cases, revascularization with carotid artery stenting has been reported, but the safety, recanalization rate, and clinical outcomes in consecutive case series are not known. METHODS: We retrospectively reviewed all of the cases of ICA occlusions that underwent cerebral angiography with the intent to revascularize over a 38-month period. Two groups were identified: (1) patients who presented with an acute clinical presentation within 6 hours of symptom onset (n=15); and (2) patients who presented subacutely with neurologic fluctuations because of the ICA occlusion (n=10). RESULTS: Twenty-five patients with a mean age of 62+/-11 years and median National Institutes of Health Stroke Scale (NIHSS) of 14 were identified. Twenty-three of the 25 patients (92%) were successfully revascularized with carotid artery stenting. Patients in group 1 were younger and more likely to have a tandem occlusion and higher baseline NIHSS when compared with group 2. Patients in group 2 were more likely to show early clinical improvement defined as a reduction of their NIHSS by > or =4 points and a modified Rankin Score of < or =2 at 30-day follow-up. Two clinically insignificant adverse events were noted: 1 asymptomatic hemorrhage and 1 nonflow-limiting dissection. CONCLUSIONS: Endovascular treatment of acute ICA occlusion appears to have a high-recanalization rate and be relatively safe in our cohort of patients with acute ICA occlusion. Future prospective studies are necessary to determine which patients are most likely to benefit from this form of therapy.

Mechanical thrombolysis in acute ischemic stroke with endovascular photoacoustic recanalization.

BACKGROUND AND PURPOSE: We present the results of endovascular photoacoustic recanalization (EPAR) treatment for acute ischemic stroke from the Safety and Performance Study at 6 centers in Europe and North America. The objectives of mechanical thrombolysis are rapid vessel recanalization and minimal use of chemical thrombolysis. METHODS: This study was a prospective, nonrandomized study. The National Institutes of Health Stroke Scale (NIHSS) score and the modified Rankin Scale (mRS) score were recorded before treatment. The presence of recanalization was assessed by angiography. To measure outcome, follow-up examinations were performed at 24 hours, 7 days, and 30 days after stroke onset. RESULTS: Thirty-four patients (median NIHSS 19) were enrolled. Ten patients had internal carotid artery occlusion, 12 patients had middle cerebral artery occlusion, 11 patients had vertebrobasilar occlusion, and 1 patient had posterior cerebral artery occlusion. The overall recanalization rate was 41.1% (14/34). Complete EPAR treatment was possible in 18 patients (median NIHSS 18), with vessel recanalization in 11 patients (61.1%) after EPAR. The average lasing time was 9.65 minutes. Incomplete EPAR treatment (16/34, median NIHSS 19) was defined as intention to treat with EPAR and that the EPAR microcatheter entered the patient. Additional treatment with intraarterial application of rTPA occurred in 13 patients. An adverse event associated with use of the device occurred in 1 patient. Symptomatic hemorrhages occurred in 2 patients (5.9%). The mortality rate was 38.2%. CONCLUSIONS: This study demonstrates the safety and technical feasibility of EPAR. This new technique may provide another treatment option in the therapeutic armamentarium for patients with acute ischemic stroke.

Model of reversible cerebral ischemia in a monkey model.

We have developed a model of reversible cerebral ischemia in a high-level nonhuman primate. By using endovascular techniques, the posterior cerebral artery is permanently occluded with coils, and the ipsilateral middle cerebral artery is temporarily occluded with a balloon. The balloon can be deflated and/or removed to reestablish flow at precise time intervals. Functional imaging of the brain can be performed during occlusion and reperfusion, since the balloon can be deflated or removed in a scanner.

Symptomatic cavernous sinus aneurysms: management and outcome after carotid occlusion and selective cerebral revascularization.

BACKGROUND AND PURPOSE: Therapeutic internal carotid artery (ICA) occlusion for symptomatic intracavernous artery aneurysms can result in ischemic infarction despite normal clinical balloon test occlusion (BTO). We evaluated outcomes in patients with symptomatic cavernous sinus aneurysms in whom clinical BTO was normal, who underwent carotid occlusion with selective bypass surgery guided by physiologic BTO using quantitative cerebral blood flow (CBF) analysis by means of stable xenon-enhanced CT. METHODS: After a normal clinical BTO, 26 consecutive patients with symptomatic cavernous sinus aneurysms underwent a baseline xenon-enhanced CT CBF analysis followed by a second CBF analysis, during which repeat BTO was performed. Patients with a decrease in cortical CBF to below 30 mL/100 g/min were considered moderate risk and those with greater than 30 mL/100 g/min were low risk for developing postocclusion ischemic infarction. Moderate-risk patients underwent cerebral revascularization followed by proximal carotid occlusion. Low-risk patients underwent carotid occlusion alone. Patients were clinically followed up for at least 3 months after carotid occlusion. All patients underwent head CT at least 1 month after carotid occlusion. RESULTS: Eight patients were moderate risk and 18 low risk. Mean follow-up was 15.3 months. Mean CT follow-up was 10.2 months. No low-risk patient developed a postocclusion ischemic deficit by examination or infarct by CT. One patient in the moderate-risk group developed right hemiparesis and a left posterior middle cerebral artery infarction by CT 2 months after carotid occlusion. CONCLUSION: In this series, BTO combined with quantitative CBF analysis was a safe and reliable technique for identification of patients at risk for ischemic infarction after carotid occlusion, despite a normal clinical BTO.

Diffusion-weighted MRI in Creutzfeldt-Jakob disease: a better diagnostic marker than CSF protein 14-3-3?

Two middle-aged patients presented with rapidly progressive dementia and ataxia, nonspecific electroencephalography findings, and negative cerebrospinal fluid (CSF) protein 14-3-3. Both patients underwent brain magnetic resonance imaging (MRI) scans that demonstrated abnormalities on diffusion-weighted imaging (DWI) sequences, and both were later confirmed to have Creutzfeldt-Jakob disease. (CJD) by tissue examination. Because a recent position paper from the American Academy of Neurology characterized CSF protein 14-3-3 as a gold standard for clinically diagnosing CJD, the authors reviewed studies of CJD in which DWI-MRI imaging and CSF protein 14-3-3 studies were both performed. Among 19 reported cases of CJD with DWI-MRI lesions, CSF protein 14-3-3 was negative in 6 cases and positive in 2 others. The authors' findings suggest that multifocal cortical and subcortical hyperintensities confined to gray matter regions in DWI-MRI may be a more useful noninvasive diagnostic marker for CJD than CSF protein 14-3-3. These observations provide a compelling rationale for a prospective comparative study.

Delayed rupture of a previously coiled unruptured anterior communicating artery aneurysm: case report.

OBJECTIVE AND IMPORTANCE: We describe a case of an unruptured anterior communicating aneurysm that was treated successfully with Guglielmi detachable coils, which subsequently ruptured 23 months after initial therapy. This report discusses only the second published case of an unruptured lesion that was well embolized (>95% occlusion) and stable at 6-month angiographic follow-up that ruptured in a delayed fashion almost 2 years after the primary procedure. CLINICAL PRESENTATION: An 80-year-old man presented in Hunt and Hess Grade IV as a result of a ruptured anterior communicating artery aneurysm. The patient had undergone endovascular therapy 23 months earlier with documented nearly complete (1-mm residual neck) occlusion at 0 and 6 months. INTERVENTION: The patient underwent diagnostic catheter angiography at the time of admission, which revealed a 10-mm aneurysm adjacent to the previously embolized lesion. No further therapy was administered, and the patient died within 24 hours as a result of ictus. The request for an autopsy was denied. CONCLUSION: Aneurysm rupture after Guglielmi detachable coil embolization is a rare event. Most cases involve previously ruptured lesions. To the best of our knowledge, only one previous case of delayed rupture of an unruptured aneurysm that was managed endovascularly has been published in the English-language literature. This second case points to the need for vigilance in the follow-up of patients with coiled lesions.