Kevin M. Cockroft

Tumor necrosis factor is a brain damaging cytokine in cerebral ischemia.

Two contrasting roles, one beneficial and the injurious, have been proposed for tumor necrosis factor (TNF) in the pathogenesis of cerebral ischemia. Reported here are results obtained in a standard model of permanent focal cortical ischemia in rats, in which the volume of cerebral infarction is measured after permanent occlusion of the middle cerebral artery. Administration of neutralizing anti-rat TNF antibodies (PI14) into the brain cortex significantly reduced ischemic brain damage (85% reduced infarct volume as compared with preimmune-treated controls). Similar results were achieved by systemic administration of CNI-1493, a recently described tetravalent guanylhydrazone compound, which effectively inhibited endogenous brain TNF synthesis and conferred significant protection against the development of cerebral infarction (80% reduced infarct volume as compared with vehicle controls treated 1 h postischemia with 10 mg/kg). PI14 anti-TNF and CNI-1493 were each cerebroprotective when given within a clinically relevant time window for up to 2 h after the onset of ischemia. These findings establish an important, pathophysiological role of TNF in mediating the progression of ischemic brain damage, and suggest that inhibiting TNF with CNI-1493 may be beneficial in the future treatment of stroke.

Guidelines for the Management of Patients With Unruptured Intracranial Aneurysms A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association

Purpose— The aim of this updated statement is to provide comprehensive and evidence-based recommendations for management of patients with unruptured intracranial aneurysms. Methods— Writing group members used systematic literature reviews from January 1977 up to June 2014. They also reviewed contemporary published evidence-based guidelines, personal files, and published expert opinion to summarize existing evidence, indicate gaps in current knowledge, and when appropriate, formulated recommendations using standard American Heart Association criteria. The guideline underwent extensive peer review, including review by the Stroke Council Leadership and Stroke Scientific Statement Oversight Committees, before consideration and approval by the American Heart Association Science Advisory and Coordinating Committee. Results— Evidence-based guidelines are presented for the care of patients presenting with unruptured intracranial aneurysms. The guidelines address presentation, natural history, epidemiology, risk factors, screening, diagnosis, imaging and outcomes from surgical and endovascular treatment.

Recanalization and Clinical Outcome of Occlusion Sites at Baseline CT Angiography in the Interventional Management of Stroke III Trial

PURPOSE To use baseline computed tomographic (CT) angiography to analyze imaging and clinical end points in an Interventional Management of Stroke III cohort to identify patients who would benefit from endovascular stroke therapy. MATERIALS AND METHODS The primary clinical end point was 90-day dichotomized modified Rankin Scale (mRS) score. Secondary end points were 90-day mRS score distribution and 24-hour recanalization. Prespecified subgroup was baseline proximal occlusions (internal carotid, M1, or basilar arteries). Exploratory analyses were subsets with any occlusion and specific sites of occlusion (two-sided α = .01). RESULTS Of 656 subjects, 306 (47%) underwent baseline CT angiography or magnetic resonance angiography. Of 306, 282 (92%) had arterial occlusions. At baseline CT angiography, proximal occlusions (n = 220) demonstrated no difference in primary outcome (41.3% [62 of 150] endovascular vs 38% [27 of 70] intravenous [IV] tissue-plasminogen activator [tPA]; relative risk, 1.07 [99% confidence interval: 0.67, 1.70]; P = .70); however, 24-hour recanalization rate was higher for endovascular treatment (n = 167; 84.3% [97 of 115] endovascular vs 56% [29 of 52] IV tPA; P < .001). Exploratory subgroup analysis for any occlusion at baseline CT angiography did not demonstrate significant differences between endovascular and IV tPA arms for primary outcome (44.7% [85 of 190] vs 38% [35 of 92], P = .29), although ordinal shift analysis of full mRS distribution demonstrated a trend toward more favorable outcome (P = .011). Carotid T- or L-type occlusion (terminal internal carotid artery [ICA] with M1 middle cerebral artery and/or A1 anterior cerebral artery involvement) or tandem (extracranial or intracranial) ICA and M1 occlusion subgroup also showed a trend favoring endovascular treatment over IV tPA alone for primary outcome (26% [12 of 46] vs 4% [one of 23], P = .047). CONCLUSION Significant differences were identified between treatment arms for 24-hour recanalization in proximal occlusions; carotid T- or L-type and tandem ICA and M1 occlusions showed greater recanalization and a trend toward better outcome with endovascular treatment. Vascular imaging should be mandated in future endovascular trials to identify such occlusions. Online supplemental material is available for this article.

Cerebroprotective Effects of Aminoguanidine in a Rodent Model of Stroke

BACKGROUND AND PURPOSE During a cerebral infarction, a complex cascade of cytotoxic events ultimately determines the volume of brain cell loss. The studies presented here demonstrate that aminoguanidine, an experimental therapeutic currently in clinical trials to prevent diabetic complications, is cerebroprotective in focal cerebral infarction. METHODS Adult Lewis rats (n = 6 to 12 per group) were anesthetized with ketamine and subjected to focal cerebral infarction by tandem permanent occlusion of the right middle cerebral artery and ipsilateral common carotid artery (CCA), followed by temporary occlusion of the contralateral CCA. Infarct volume (cortical) was assessed 24 hours after the onset of ischemia by planimetric analysis of coronal brain slices stained with tetrazolium. RESULTS Aminoguanidine (320 mg/kg IP) administered 15 minutes after the onset of ischemia resulted in a significant reduction of infarct volume (7.6 +/- 2.6% of hemisphere in controls versus 1.3 +/- 0.2% of hemisphere in aminoguanidine-treated rats; P < .05). Administration of aminoguanidine conferred significant cerebroprotection even when administered 1 or 2 hours after the onset of ischemia (88% and 85% reduction from control, respectively; P < .05). Cerebroprotection by aminoguanidine was independent of systemic physiological variables known to influence stroke size (eg, temperature, mean arterial blood pressure, blood glucose, and arterial pH, PCO2, and PO2). CONCLUSIONS These results indicate that the stroke-reducing properties of aminoguanidine are dose and time dependent, with substantial cerebroprotection persisting even with drug delivery up to 2 hours after the onset of ischemia. It is now plausible to pursue development of aminoguanidine as an experimental therapeutic in stroke, and possible mechanisms of these cerebroprotective effects are under consideration.

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 …

Feasibility and limitations of endovascular coil embolization of anterior communicating artery aneurysms: morphological considerations.

OBJECTIVE The purpose of this study is to analyze anterior communicating artery (AComA) aneurysm morphology and its relationship to the limitations and feasibility of endovascular coil embolization. METHODS One hundred twenty-three patients were treated with endovascular coil embolization for AComA aneurysms. Aneurysm morphology was classified into six categories according to the projection of the aneurysm (anterior, posterior/superior, or inferior) and neck size (< 4 mm or >or= 4 mm). The following categories were used: Class A1, anterior projection and neck of aneurysm less than 4 mm; Class A2, anterior projection and neck of aneurysm 4 mm or more; Class B1, posterior (superior) projection and neck of aneurysm less than 4 mm; Class B2, posterior (superior) projection and neck of aneurysm 4 mm or more; Class C1, inferior projection and neck of aneurysm less than 4 mm; and Class C2, inferior projection and neck of aneurysm 4 mm or more. Endovascular procedures were categorized as either successful or unsuccessful according to specific criteria. In addition, patients were followed for recanalization. Clinical follow-up data was obtained at discharge and after 6 months and was classified according to the Glasgow Outcome Scale. RESULTS Complete or near complete aneurysm occlusion was observed in 108 (88%) patients, partial embolization was performed in three (2.4%) patients, and embolization was attempted in 12 (9.7%) patients. Successful embolization for AComA aneurysms was performed in 86 out of 123 (70%) patients or 77.5% (86 out of 111 patients) of those patients in whom embolization was possible. Statistical analysis demonstrated that anterior projecting aneurysms were more likely to be successfully coiled than either inferior or posterior/superior directed AComA aneurysms. In addition, inferiorly projecting AComA aneurysms and wide-neck aneurysms had a significantly higher rate of recanalization. CONCLUSION Endovascular coil embolization of AComA aneurysms shows good outcome in our study. Despite advanced modern techniques, there are limitations in the endovascular approach to AComA aneurysms. Consideration of aneurysm morphology may be used to guide approaches in the treatment of AComA aneurysms.

A novel inhibitor of inflammatory cytokine production (CNI-1493) reduces rodent post-hemorrhagic vasospasm

IntroductionCerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) is a devastating complication, yet despite multiple lines of investigation an effective treatment remains lacking. Cytokine-mediated inflammation has been implicated as a causative factor in the development of posthemorrhagic vasospasm. In previous experiments using the rat femoral artery model of vasospasm, we demonstrated that elevated levels of the proinflammatory cytokine interleukin (IL)-6 are present after hemorrhage and that a polyclonal antibody against IL-6 is capable of attenuating experimental vasospasm.MethodsIn the present study, we tested the ability of a novel selective proinflammatory cytokine inhibitor (CNI-1493) to protect against the occurrence of experimental vasospasm in the same rat femoral artery model. CNI-1493 was administered by injection directly into the blood-filled femoral pouches of animals at the time of their initial surgery (hemorrhage). Control animals received an equal volume of vehicle alone. Animals were killed at 8 days posthemorrhage and degree of vasospasm was assessed by image analysis of artery cross-sectional area. In a separate series of experiments, enzyme-linked immunosorbent assay (ELISA) was used to assess levels of the proinflammatory cytokine IL-6 and the prototypical antiinflammatory cytokine transforming growth factor (TGF)-#x03B2;1 after treatment with CNI-1493.ResultsPretreatment with CNI-1493 provided dose-dependent attenuation of posthemorrhagic vasospasm, with the highest dose (200 μg in 8 μL dH2O) causing complete reversal of vasospasm (vessel cross-sectional area ratio 1.06±0.04 versus 0.87±0.06, p<0.05, one-way analysis of variance). Assessment of cytokine levels by ELISA confirmed the selectivity of CNI-1493 by demonstrating significant reductions in IL-6 levels, but no suppression TGF-β1 levels.ConclusionsThese findings support the conclusion that inflammatory cytokines, in particular IL-6, play an important role in development of vasospasm in the rat femoral artery model. Furthermore, these results suggest that the inhibition of inflammatory cytokines may be an appropriate strategy for the treatment of vasospasm after SAH.

Delayed epistaxis resulting from external carotid artery injury requiring embolization: a rare complication of transsphenoidal surgery: case report.

OBJECTIVE AND IMPORTANCE Delayed epistaxis resulting from trauma to branches of the external carotid artery is an infrequent but potentially serious complication of transsphenoidal surgery. We report two cases of severe, delayed epistaxis in patients who had undergone transsphenoidal surgery. In both cases, noninvasive treatment failed, necessitating endovascular intervention. CLINICAL PRESENTATION The first patient, a 52-year-old woman with a prolactinoma, underwent a second transsphenoidal resection 18 months after the first surgery. She was readmitted on postoperative Day 15 with massive epistaxis. The second patient, a 40-year-old woman, had undergone two transsphenoidal surgeries, 14 years apart, for an adrenocorticotropic hormone-secreting adenoma. She was readmitted with massive epistaxis on postoperative Day 17. INTERVENTION Both patients were initially treated with nasal balloon packing but experienced recurrent hemorrhage when the balloon was deflated, necessitating referral to the interventional radiology department for embolization. At arteriography, the first patient was found to have a pseudoaneurysm of the medial branch of the left internal maxillary artery, which was subsequently embolized. Arteriography in the second patient revealed an abnormally dilated midline branch of the right internal maxillary artery in the nasal septum; this vessel was occluded at arteriography. CONCLUSION Delayed massive epistaxis is a rare but significant complication of transsphenoidal surgery. Injury to branches of the external carotid artery, along with injury to the internal carotid artery, should be suspected in patients who present with delayed epistaxis after transsphenoidal surgery. Angiography performed in patients with refractory bleeding should include selective external carotid injections. Epistaxis that is refractory to anterior and posterior nasal packing may be effectively treated with endovascular embolization.

Impact of General Anesthesia on Safety and Outcomes in the Endovascular Arm of Interventional Management of Stroke (IMS) III Trial

Background and Purpose— General anesthesia (GA) for endovascular therapy (EVT) of acute ischemic stroke may be associated with worse outcomes. Methods— The Interventional Management of Stroke III trial randomized patients within 3 hours of acute ischemic stroke onset to intravenous tissue-type plasminogen activator±EVT. GA use within 7 hours of stroke onset was recorded per protocol. Good outcome was defined as 90-day modified Rankin Scale ⩽2. A multivariable analysis adjusting for dichotomized National Institutes of Health Stroke Scale (NIHSS; 8–19 versus ≥20), age, and time from onset to groin puncture was performed. Results— Four hundred thirty-four patients were randomized to EVT, 269 (62%) were treated under local anesthesia and 147 (33.9%) under GA; 18 (4%) were undetermined. The 2 groups were comparable except for median baseline NIHSS (16 local anesthesia versus 18 GA; P<0.0001). The GA group was less likely to achieve a good outcome (adjusted relative risk, 0.68; confidence interval, 0.52–0.90; P=0.0056) and had increased in-hospital mortality (adjusted relative risk, 2.84; confidence interval, 1.65–4.91; P=0.0002). Those with medically indicated GA had worse outcomes (adjusted relative risk, 0.49; confidence interval, 0.30–0.81; P=0.005) and increased mortality (relative risk, 3.93; confidence interval, 2.18–7.10; P<0.0001) with a trend for higher mortality with routine GA. There was no significant difference in the adjusted risks of subarachnoid hemorrhage (P=0.32) or symptomatic intracerebral hemorrhage (P=0.37). Conclusions— GA was associated with worse neurological outcomes and increased mortality in the EVT arm; this was primarily true among patients with medical indications for GA. Relative risk estimates, though not statistically significant, suggest reduced risk for subarachnoid hemorrhage and symptomatic intracerebral hemorrhage under local anesthesia. Although the reasons for these associations are not clear, these data support the use of local anesthesia when possible during EVT. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424.

Neutralizing Antibody against Interleukin-6 Attenuates Posthemorrhagic Vasospasm in the Rat Femoral Artery Model

OBJECTIVEThe degree to which inflammation contributes to the development of posthemorrhagic vasospasm is controversial. In the present study, we investigated the relationship between various inflammatory cytokines (tumor necrosis factor-&agr;, interleukin [IL]-1&agr;, IL-1&bgr;, and IL-6) and the development of experimental vasospasm. METHODSPosthemorrhagic vasospasm was produced in the rat femoral artery model. A latex pouch was placed around each femoral artery, and one pouch was injected with autologous blood and the other with saline as an internal control. Animals were killed at various time points (1 h to 16 d) after surgery (blood exposure), and the degree of vasospasm was assessed by image analysis of artery cross sectional area. Levels of inflammatory cytokines were determined by enzyme-linked immunosorbent assay, and the ability of a polyclonal antibody against rat IL-6 to inhibit vasospasm was tested. RESULTSThe rat femoral artery model produced a biphasic vasospasm response, with maximal chronic delayed vasospasm occurring at 8 days after hemorrhage. Enzyme-linked immunosorbent assay revealed a significant increase in IL-6 concentrations in blood-exposed arteries relative to saline-exposed arteries at multiple time points (6, 12, 24, and 48 h) after hemorrhage (P < 0.0001). A relative increase in IL-1&agr; levels was noted at 24 hours (P < 0.01). IL-1&bgr; levels were similarly elevated in both blood- and saline-exposed arteries, and tumor necrosis factor-&agr; levels were not detectable. Administration of a neutralizing polyclonal antibody against rat IL-6 directly into the blood-exposed periarterial pouch at the time of initial surgery resulted in a dose-dependent reduction in the degree of vasospasm compared with vehicle-treated controls at 8 days after hemorrhage (P < 0.05). CONCLUSIONSThese results indicate that cytokine-mediated inflammation is active in the setting of posthemorrhagic vasospasm produced by the rat femoral artery model. In particular, the profound increase in IL-6 levels after exposure to hemorrhage and the ability of a polyclonal antibody against IL-6 to reduce vasospasm suggest that IL-6 may play a prominent role in the development of vasospasm in this model.