Mahesh V. Jayaraman

Identification of noninvasive imaging surrogates for brain tumor gene-expression modules

Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor in adults. We combined neuroimaging and DNA microarray analysis to create a multidimensional map of gene-expression patterns in GBM that provided clinically relevant insights into tumor biology. Tumor contrast enhancement and mass effect predicted activation of specific hypoxia and proliferation gene-expression programs, respectively. Overexpression of EGFR, a receptor tyrosine kinase and potential therapeutic target, was also directly inferred by neuroimaging and was validated in an independent set of tumors by immunohistochemistry. Furthermore, imaging provided insights into the intratumoral distribution of gene-expression patterns within GBM. Most notably, an “infiltrative” imaging phenotype was identified that predicted patient outcome. Patients with this imaging phenotype had a greater tendency toward having multiple tumor foci and demonstrated significantly shorter survival than their counterparts. Our findings provide an in vivo portrait of genome-wide gene expression in GBM and offer a potential strategy for noninvasively selecting patients who may be candidates for individualized therapies.

Angioplasty for Symptomatic Intracranial Stenosis: Clinical Outcome

Background and Purpose— Medical treatment of symptomatic intracranial stenosis carries a high risk of stroke. This study was done to evaluate the clinical and angiographic outcomes after intracranial angioplasty for this disease. Methods— A total of 120 patients with 124 intracranial stenoses were treated by primary angioplasty. All patients had neurologic symptoms (stroke or transient ischemic attack) attributable to intracranial stenoses ≥50%. Angiograms were evaluated before and after angioplasty for the degree of stenosis. Results— Pretreatment stenoses varied from 50% to 95% (mean 82.2±10.2). Post-treatment stenoses varied from 0% to 90% (mean 36.0±20.1). There were 3 strokes and 4 deaths (all neurological) within 30 days of the procedure, giving a combined periprocedural stroke and death rate of 5.8%. A total of 116 patients (96.7%) were available for a mean follow-up time of 42.3 months. There were 6 patients who had a stroke in the territory of treatment and 5 additional patients with stroke in other territories. Ten deaths occurred during the follow-up period, none of which were neurological. Including the periprocedural stroke and deaths, this yielded an annual stroke rate of 3.2% in the territory of treatment and a 4.4% annual rate for all strokes. Conclusion— Intracranial angioplasty can be performed with a high degree of technical success and a low risk of complications. Long-term clinical follow-up of intracranial angioplasty patients demonstrates a risk of future strokes that compares favorably to patients receiving medical therapy.

Neurologic Complications of Arteriovenous Malformation Embolization Using Liquid Embolic Agents

BACKGROUND AND PURPOSE: Embolization of arteriovenous malformations (AVMs) is commonly used to achieve nidal volume reduction before microsurgical resection or stereotactic radiosurgery. The purpose of this study was to examine the overall neurologic complication rate in patients undergoing AVM embolization and analyze the factors that may determine increased risk. MATERIALS AND METHODS: We performed a retrospective review of all patients with brain AVMs embolized at 1 center from 1995 through 2005. Demographics, including age, sex, presenting symptoms, and clinical condition, were recorded. Angiographic factors including maximal nidal size, presence of deep venous drainage, and involvement of eloquent cortex were also recorded. For each embolization session, the agent used, number of pedicles embolized, the percentage of nidal obliteration, and any complications were recorded. Complications were classified as the following: none, non-neurologic (mild), transient neurologic deficit, and permanent nondisabling and permanent disabling deficits. The permanent complications were also classified as ischemic or hemorrhagic. Modified Rankin Scale (mRS) scores were collected pre- and postembolization on all patients. Univariate regression analysis of factors associated with the development of any neurologic complication was performed. RESULTS: Four hundred eighty-nine embolization procedures were performed in 192 patients. There were 6 Spetzler-Martin grade I (3.1%), 26 grade II (13.5%), 71 grade III (37.0%), 57 grade IV (29.7%), and 32 grade V (16.7%) AVMs. Permanent nondisabling complications occurred in 5 patients (2.6%) and permanent disabling complications or deaths occurred in 3 (1.6%). In addition, there were non-neurologic complications in 4 patients (2.1%) and transient neurologic deficits in 22 (11.5%). Five of the 8 permanent complications (2.6% overall) were ischemic, and 3 of 8 (1.6% overall) were hemorrhagic. Of the 178 patients who were mRS 0–2 pre-embolization, 4 (2.3%) were dependent or dead (mRS >2) at follow-up. Univariate analysis of risk factors for permanent neurologic deficits following embolization showed that basal ganglia location was weakly associated with a new postembolization neurologic deficit. CONCLUSION: Embolization of brain AVMs can be performed with a high degree of technical success and a low rate of permanent neurologic complications.

A Perfect Storm How A Randomized Trial of Unruptured Brain Arteriovenous Malformations' (ARUBA's) Trial Design Challenges Notions of External Validity

The management of unruptured brain arteriovenous malformations (BAVMs) is controversial and uncertainties exist as to how best to care for these patients. The A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA)1 study attempts to shed light on some of these issues. However, the complexity of the disease process, the considerable variation in treatment options, and the trials actual design threaten its external validity making it unlikely that significant useful information will be obtained. The following comments are the opinion of the Society of Neuro-Interventional Surgery as well as the Cerebrovascular Section of the American Association of Neurological Surgeons and Congress of Neurological Surgeons. The authors have no financial interest in the ARUBA trial. As many who care for patients with BAVMs already know, the ARUBA trial seeks to determine whether or not the risks of treatment outweigh the risks of conservative management at 5 years for patients with unruptured BAVMs. Unfortunately, despite recent changes to the study, the trial remains significantly flawed. The trial continues to be plagued by concerns over inconsistent equipoise, overall structure, and selection bias. Additionally, the time horizon of the trial leads to a limited duration of follow-up, which is challenging for a disease with a lifelong threat of death and disability. All of these factors come together to create a trial whose final outcome will have limited external validity. Treatment of asymptomatic BAVMs clearly presents a significant clinical dilemma. The decision to treat a patient with an asymptomatic BAVM, and if so how to treat that patient, is necessarily based on a variety of considerations. The patients clinical situation and the natural history of the lesion are perhaps the most important considerations when deciding whether to treat. The exact method of treatment should be planned after a careful analysis of the BAVMs radiographic …

Hemorrhage Rate in Patients With Spetzler-Martin Grades IV and V Arteriovenous Malformations Is Treatment Justified?

Background and Purpose— We sought to examine the prospective annual risk of hemorrhage in patients harboring Spetzler-Martin grades IV and V arteriovenous malformations (AVMs) before and after initiation of treatment. Methods— Medical records of 61 consecutive patients presenting with Spetzler-Martin grades IV and V AVMs were retrospectively reviewed for demographics, angiographic features, presenting symptom(s), and time of all hemorrhage events, before or after treatment initiation. Pretreatment hemorrhage rates (excluding hemorrhages at presentation) and posttreatment rates were subsequently calculated. Modified Rankin Scale (mRS) scores before and after treatment were recorded. Results— The annual pretreatment hemorrhage rate for all patients was 10.4% per year (95% CI, 2.2 to 15.4%), 13.9% (95% CI, 3.5 to 22.1%) in patients with hemorrhagic presentation and 7.3% (2.6 to 14.3%) in patients with nonhemorrhagic presentation. Posttreatment hemorrhage rates were 6.1% per year (95% CI, 2.5 to 13.2%) for all patients, 5.6% (95% CI, 2.1 to 11.8%) for patients presenting with hemorrhage and 6.4% (95% CI, 1.6 to 10.1%) in patients with nonhemorrhagic presentation. A noninferiority test showed that the posttreatment hemorrhage rate was less than or equal to the pretreatment hemorrhage rate (P<0.0001), with some indication that the reduction was greatest in patients with hemorrhagic presentation. Of the 62 patients, 51 (82%) had an mRS score of 0 to 2 before treatment, and 47 (76%) had an mRS score of 0 to 2 at the last follow-up after treatment. Conclusions— The annual rate of hemorrhage in grades IV and V AVMs is higher in this series than reported for all AVMs, which may reflect some referral bias in this single-center study. Nevertheless, initiation of treatment does not appear to increase the rate of subsequent hemorrhage. Treatment for these lesions may be warranted, given their poor natural history.

Flow instability and wall shear stress variation in intracranial aneurysms

We investigate the flow dynamics and oscillatory behaviour of wall shear stress (WSS) vectors in intracranial aneurysms using high resolution numerical simulations. We analyse three representative patient-specific internal carotid arteries laden with aneurysms of different characteristics: (i) a wide-necked saccular aneurysm, (ii) a narrower-necked saccular aneurysm, and (iii) a case with two adjacent saccular aneurysms. Our simulations show that the pulsatile flow in aneurysms can be subject to a hydrodynamic instability during the decelerating systolic phase resulting in a high-frequency oscillation in the range of 20–50 Hz, even when the blood flow rate in the parent vessel is as low as 150 and 250 ml min−1 for cases (iii) and (i), respectively. The flow returns to its original laminar pulsatile state near the end of diastole. When the aneurysmal flow becomes unstable, both the magnitude and the directions of WSS vectors fluctuate at the aforementioned high frequencies. In particular, the WSS vectors around the flow impingement region exhibit significant spatio-temporal changes in direction as well as in magnitude.

Embolectomy for stroke with emergent large vessel occlusion (ELVO): report of the Standards and Guidelines Committee of the Society of NeuroInterventional Surgery

Stroke is the leading cause of adult disability in North America and is the fifth most common cause of death.1 ,2 The natural history of patients with acute ischemic stroke and occlusion of a major intracranial vessel such as the internal carotid artery (ICA), middle cerebral artery (MCA), or basilar artery is dismal, with high rates of mortality and low rates of disability-free survival.3 ,4 We introduce the term ‘Emergent Large Vessel Occlusion (ELVO)’ to describe this clinical scenario. Among acute ischemic stroke, ELVO accounts for the greatest proportion of patients with long-term disability. For the past two decades the use of endovascular therapy has been performed in many centers across the world. The therapies have spanned from infusion of thrombolytic agents5 ,6 to mechanical embolectomy with the introduction of first-generation devices,7 ,8 aspiration-based embolectomy techniques,9 ,10 and the use of stent-retriever based procedures.11 ,12 However, these embolectomy trials were single-arm trials demonstrating safety of the procedure and technique or superiority over another, without direct comparison with standard medical therapy alone. In the past 3 years, several major trials have been published comparing endovascular therapy with standard medical therapy alone. The purpose of this document is to summarize the results of these trials and synthesize the level of evidence supporting the use of embolectomy in patients with ELVO. This document was prepared by the Standards and Guidelines Committee of the Society of NeuroInterventional Surgery, a multidisciplinary society representing the leaders in the field of endovascular therapy for neurovascular disease. The strength of the evidence supporting each recommendation was summarized using a scale previously described by the American Heart Association. ### Role of intravenous thrombolysis In 1996 the FDA approved the use of recombinant tissue plasminogen activator (tPA) for the treatment of acute ischemic stroke …

Endovascular therapy of acute ischemic stroke: Report of the Standards of Practice Committee of the Society of NeuroInterventional Surgery

Objective To summarize and classify the evidence for the use of endovascular techniques in the treatment of patients with acute ischemic stroke. Methods Recommendations previously published by the American Heart Association (AHA) (Guidelines for the early management of adults with ischemic stroke (Circulation 2007) and Scientific statement indications for the performance of intracranial endovascular neurointerventional procedures (Circulation 2009)) were vetted and used as a foundation for the current process. Building on this foundation, a critical review of the literature was performed to evaluate evidence supporting the endovascular treatment of acute ischemic stroke. The assessment was based on guidelines for evidence based medicine proposed by the Stroke Council of the AHA and the University of Oxford, Centre for Evidence Based Medicine (CEBM). Procedural safety, technical efficacy and impact on patient outcomes were specifically examined.

Alberta Stroke Program Early Computed Tomographic Scoring Performance in a Series of Patients Undergoing Computed Tomography and MRI: Reader Agreement, Modality Agreement, and Outcome Prediction

Background and Purpose— In this study, we compare the performance of pretreatment Alberta Stroke Program Early Computed Tomographic scoring (ASPECTS) using noncontrast CT (NCCT) and MRI in a large endovascular therapy cohort. Methods— Prospectively enrolled patients underwent baseline NCCT and MRI and started endovascular therapy within 12 hours of stroke onset. Inclusion criteria for this analysis were evaluable pretreatment NCCT, diffusion-weighted MRI (DWI), and 90-day modified Rankin Scale scores. Two expert readers graded ischemic change on NCCT and DWI using the ASPECTS. ASPECTS scores were analyzed with the full scale or were trichotomized (0–4 versus 5–7 versus 8–10) or dichotomized (0–7 versus 8–10). Good functional outcome was defined as a 90-day modified Rankin Scale score of 0 to 2. Results— Seventy-four patients fulfilled our study criteria. The full-scale inter-rater agreement for CT-ASPECTS and DWI-ASPECTS was 0.579 and 0.867, respectively. DWI-ASPECTS correlated with functional outcome (P=0.004), whereas CT-ASPECTS did not (P=0.534). Both DWI-ASPECTS and CT-ASPECTS correlated with DWI volume. The receiver operating characteristic analysis revealed that DWI-ASPECTS outperformed both CT-ASPECTS and the time interval between symptom onset and start of the procedure for predicting good functional outcome (modified Rankin Scale score, ⩽2) and DWI volume ≥70 mL. Conclusion— Inter-rater agreement for DWI-ASPECTS was superior to that for CT-ASPECTS. DWI-ASPECTS outperformed NCCT ASPECTS for predicting functional outcome at 90 days.

Initial hospital management of patients with emergent large vessel occlusion (ELVO): report of the standards and guidelines committee of the Society of NeuroInterventional Surgery

Objective To summarize the current literature regarding the initial hospital management of patients with acute ischemic stroke (AIS) secondary to emergent large vessel occlusion (ELVO), and to offer recommendations designed to decrease the time to endovascular treatment (EVT) for appropriately selected patients with stroke. Methods Using guidelines for evidenced-based medicine proposed by the Stroke Council of the American Heart Association, a critical review of all available medical literature supporting best initial medical management of patients with AIS secondary to ELVO was performed. The purpose was to identify processes of care that most expeditiously determine the eligibility of a patient with an acute stroke for interventions including intravenous fibrinolysis with recombinant tissue plasminogen activator (IV tPA) and EVT using mechanical embolectomy. Results This review identifies four elements that are required to achieve timely revascularization in ELVO. (1) In addition to non-contrast CT (NCCT) brain scan, CT angiography should be performed in all patients who meet an institutional threshold for clinical stroke severity. The use of any advanced imaging beyond NCCT should not delay the administration of IV tPA in eligible patients. (2) Activation of the neurointerventional team should occur as soon as possible, based on either confirmation of large vessel occlusion or a prespecified clinical severity threshold. (3) Additional imaging techniques, particularly those intended to physiologically select patients for EVT (CT perfusion and diffusion–perfusion mismatch imaging), may provide additional value, but should not delay EVT. (4) Routine use of general anesthesia during EVT procedures, should be avoided if possible. These workflow recommendations apply to both primary and comprehensive stroke centers and should be tailored to meet the needs of individual institutions. Conclusions Patients with ELVO are at risk for severe neurologic morbidity and mortality. To achieve the best possible clinical outcomes stroke centers must optimize their triage strategies. Strategies that provide patients with ELVO with the fastest access to reperfusion depend upon detail-oriented process improvement.