Karel G. terBrugge

Definition of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage as an Outcome Event in Clinical Trials and Observational Studies Proposal of a Multidisciplinary Research Group

Background and Purpose— In clinical trials and observational studies there is considerable inconsistency in the use of definitions to describe delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. A major cause for this inconsistency is the combining of radiographic evidence of vasospasm with clinical features of cerebral ischemia, although multiple factors may contribute to DCI. The second issue is the variability and overlap of terms used to describe each phenomenon. This makes comparisons among studies difficult. Methods— An international ad hoc panel of experts involved in subarachnoid hemorrhage research developed and proposed a definition of DCI to be used as an outcome measure in clinical trials and observational studies. We used a consensus-building approach. Results— It is proposed that in observational studies and clinical trials aiming to investigate strategies to prevent DCI, the 2 main outcome measures should be: (1) cerebral infarction identified on CT or MRI or proven at autopsy, after exclusion of procedure-related infarctions; and (2) functional outcome. Secondary outcome measure should be clinical deterioration caused by DCI, after exclusion of other potential causes of clinical deterioration. Vasospasm on angiography or transcranial Doppler can also be used as an outcome measure to investigate proof of concept but should be interpreted in conjunction with DCI or functional outcome. Conclusion— The proposed measures reflect the most relevant morphological and clinical features of DCI without regard to pathogenesis to be used as an outcome measure in clinical trials and observational studies.

Clinical Course of Cranial Dural Arteriovenous Fistulas With Long-Term Persistent Cortical Venous Reflux

Background and Purpose— The natural history of aggressive (Borden 2 and 3) cranial dural arteriovenous fistulas (DAVFs) is not well described. Reported annual mortality and hemorrhage rates vary widely and range up to 20% per year. A consecutive single-center cohort of 236 cases that presented with a cranial DAVF between June 1984 and May 2001 was reviewed for the consequences of long-term persistent cortical venous reflux (CVR). Methods— A group of 118 cranial DAVFs was selected for the presence of CVR. All patients were offered treatment aimed at the disconnection of the CVR. Patients who declined or had partial treatment with persistence of the CVR had long-term clinical and angiographic follow-up to study the disease course of this select group. Results— Treatment was instituted in 101 of the 118 patients (85.6%). Three patients were lost to follow-up. The remaining 14 nontreated patients (11.9%) and the partially treated patients (n=6) were assessed clinically and angiographically over time. The mean follow-up in this select group was 4.3 years (86.9 patient-years). During follow-up, 7 patients suffered an intracranial hemorrhage (35%). The incidence of nonhemorrhagic neurological deficit was 30%. Nine patients (45%) died: 6 patients expired after a hemorrhage, and 3 patients died of progressive neurological deterioration. Two patients demonstrated a spontaneous closure of the DAVF (10%). Conclusions— Persistence of the CVR in cranial DAVFs yields an annual mortality rate of 10.4%. Excluding events at presentation, in this series the annual risk for hemorrhage or nonhemorrhagic neurological deficit during follow-up was 8.1% and 6.9%, respectively, resulting in an annual event rate of 15.0%.

Idiopathic intracranial hypertension: The prevalence and morphology of sinovenous stenosis

Objective: To determine the prevalence and nature of sinovenous obstruction in idiopathic intracranial hypertension (IIH) using auto-triggered elliptic-centric-ordered three-dimensional gadolinium-enhanced MR venography (ATECO MRV). Methods: In a prospective controlled study, 29 patients with established IIH as well as 59 control patients underwent ATECO MRV. In a randomized blinded fashion, three readers evaluated the images. Using a novel scoring system, each reader graded the degree of stenosis seen in the transverse and sigmoid sinuses of each patient. Results: There was excellent agreement across the three readers for application of the grading system. Substantial bilateral sinovenous stenoses were seen in 27 of 29 patients with IIH and in only 4 of 59 control patients. Conclusion: Using ATECO MRV and a novel grading system for quantifying sinovenous stenoses, the authors can identify IIH patients with sensitivity and specificity of 93%.

Intracranial arterial wall imaging using high-resolution 3-tesla contrast-enhanced MRI

Background: Conventional arterial imaging focuses on the vessel lumen but lacks specificity because different pathologies produce similar luminal defects. Wall imaging can characterize extracranial arterial pathology, but imaging intracranial walls has been limited by resolution and signal constraints. Higher-field scanners may improve visualization of these smaller vessels. Methods: Three-tesla contrast-enhanced MRI was used to study the intracranial arteries from a consecutive series of patients at a tertiary stroke center. Results: Multiplanar T2-weighted fast spin echo and multiplanar T1 fluid-attenuated inversion recovery precontrast and postcontrast images were acquired in 37 patients with focal neurologic deficits. Clinical diagnoses included atherosclerotic disease (13), CNS inflammatory disease (3), dissections (3), aneurysms (3), moyamoya syndrome (2), cavernous angioma (1), extracranial source of stroke (5), and no definitive clinical diagnosis (7). Twelve of 13 with atherosclerotic disease had focal, eccentric vessel wall enhancement, 10 of whom had enhancement only in the vessel supplying the area of ischemic injury. Two of 3 with inflammatory diseases had diffuse, concentric vessel wall enhancement. Three of 3 with dissection showed bright signal on T1, and 2 had irregular wall enhancement with a flap and dual lumen. Conclusions: Three-tesla contrast-enhanced MRI can be used to study the wall of intracranial blood vessels. T2 and precontrast and postcontrast T1 fluid-attenuated inversion recovery images at 3 tesla may be able to differentiate enhancement patterns of intracranial atherosclerotic plaques (eccentric), inflammation (concentric), and other wall pathologies. Prospective studies are required to determine the sensitivity and specificity of arterial wall imaging for distinguishing the range of pathologic conditions affecting cerebral vasculature.

Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial

BACKGROUND Neuroprotection with NA-1 (Tat-NR2B9c), an inhibitor of postsynaptic density-95 protein, has been shown in a primate model of stroke. We assessed whether NA-1 could reduce ischaemic brain damage in human beings. METHODS For this double-blind, randomised, controlled study, we enrolled patients aged 18 years or older who had a ruptured or unruptured intracranial aneurysm amenable to endovascular repair from 14 hospitals in Canada and the USA. We used a computer-generated randomisation sequence to allocate patients to receive an intravenous infusion of either NA-1 or saline control at the end of their endovascular procedure (1:1; stratified by site, age, and aneurysm status). Both patients and investigators were masked to treatment allocation. The primary outcome was safety and primary clinical outcomes were the number and volume of new ischaemic strokes defined by MRI at 12-95 h after infusion. We used a modified intention-to-treat (mITT) analysis. This trial is registered with ClinicalTrials.gov, number NCT00728182. FINDINGS Between Sept 16, 2008, and March 30, 2011, we randomly allocated 197 patients to treatment-12 individuals did not receive treatment because they were found to be ineligible after randomisation, so the mITT population consisted of 185 individuals, 92 in the NA-1 group and 93 in the placebo group. Two minor adverse events were adjudged to be associated with NA-1; no serious adverse events were attributable to NA-1. We recorded no difference between groups in the volume of lesions by either diffusion-weighted MRI (adjusted p value=0·120) or fluid-attenuated inversion recovery MRI (adjusted p value=0·236). Patients in the NA-1 group sustained fewer ischaemic infarcts than did patients in the placebo group, as gauged by diffusion-weighted MRI (adjusted incidence rate ratio 0·53, 95% CI 0·38-0·74) and fluid-attenuated inversion recovery MRI (0·59, 0·42-0·83). INTERPRETATION Our findings suggest that neuroprotection in human ischaemic stroke is possible and that it should be investigated in larger trials. FUNDING NoNO Inc and Arbor Vita Corp.

Multidisciplinary management of spinal dural arteriovenous fistulas: Clinical presentation and long-term follow-up in 49 patients

Background and Purpose— In the early 1980s, it was demonstrated that surgical intradural division of the shunting vein to the medullary venous plexus cures a spinal dural arteriovenous fistula (DAVF) at low morbidity. There is, however, growing literature to support endovascular therapy. Methods— The clinical features of 49 consecutive patients with a spinal DAVF treated at a single institution between 1986 and 2001 were studied (mean age, 63 years; range, 28 to 78 years; 80% male). When possible, embolization was offered as the initial treatment. Endovascular treatment was considered adequate only if the proximal shunting vein could be occluded with liquid adhesive embolics. Motor and bladder function was evaluated with Aminoff scores an average of 32.3 months after treatment. Results— All but 1 patient presented with myelopathy. At a mean of 2.3 years after symptom onset, 48 DAVFs were angiographically demonstrated. Since 1999, gadolinium-enhanced MR angiography was additionally performed in 7 patients to point out the level of the DAVF. Endovascular embolization could be attempted in 44 of the 48 DAVFs and resulted in a cure in 11 (25%). Thirty-five DAVFs were surgically cured; 2 patients refused surgery after failed embolization. Angiographic confirmation of the treatment result was available in 97.7% of the patients. No permanent complications of either embolization or surgery were noted. Motor and bladder function scores were significantly improved in 35 patients who had long-term follow-up (both P <0.005). Conclusions— Endovascular treatment with liquid adhesive material provided a result equal to surgery in 25% of patients, overall resulting in a significant amelioration in the neurological status of patients with a spinal DAVF.

Embolization before radiosurgery reduces the obliteration rate of arteriovenous malformations.

OBJECTIVETo evaluate the arteriovenous malformation (AVM) obliteration rate and the clinical outcome after radiosurgery in patients with and without previous embolization. METHODSOf 244 patients who underwent linear accelerator radiosurgery for AVMs at the Sunnybrook Health Sciences Centre between 1989 and 2000, 61 patients had embolization before radiosurgery and complete follow-up for at least 3 years. For 47 of these 61 patients (Group A, embolization plus radiosurgery), we were able to find 47 matching patients without previous embolization (Group B, radiosurgery alone). This group of matching patients had the same AVM volume (after embolization in Group A), location, and marginal dose. The radiosurgery-based AVM score and the obliteration prediction index were calculated. RESULTSThe median follow-up period was 44 months. Nidus obliteration was achieved in 22 patients in Group A (47%) and 33 patients in Group B (70%, P = 0.036). Permanent deficit related to hemorrhage or radiation occurred in three patients (6%) in Group A and three patients (6%) in Group B. During the first 3 years after radiosurgery, two patients (4%) in Group A experienced hemorrhage; in Group B, five patients (11%) experienced hemorrhage (P = 0.2). In Group B, two patients (4%) died and two patients (4%) had their AVM surgically removed. Both deaths were related to hemorrhage during the latency period. The excellent outcome (obliteration plus no deficit) in Group A was 47% compared with 64% in Group B (P = 0.146). There was no difference in the obliteration prediction index and the radiosurgery-based AVM score between Groups A and B. The predicted rates of obliteration and excellent outcome were 55 and 62.5%, respectively, according to the obliteration prediction index and the radiosurgery-based AVM score. CONCLUSIONEmbolization before radiosurgery significantly decreases the obliteration rate, even in AVMs with the same volume, location, and marginal dose. Although an excellent outcome rate was higher in the group without embolization, this was not statistically significant.

Angioarchitectural Factors Present in Brain Arteriovenous Malformations Associated With Hemorrhagic Presentation

Background and Purpose— Associations between clinical presentation of brain arteriovenous malformations (AVMs) and their angioarchitecture have been described. This study aims to identify significant factors related to the initial hemorrhagic event through multivariate statistical methodology. Methods— The authors studied the initial clinical presentation of 390 consecutive patients with brain AVMs at the University of Toronto Vascular Malformation Study Group. Angiographic features present at that time, such as location, size, and blood supply, were recorded following a standard protocol and associated, through multivariate analysis techniques, with type of presentation. Results— Patients had hemorrhagic presentation in 146 cases (37.4%). Hemorrhage was the initial presentation in 59.5% of the deep-seated AVMs (odds ratio [OR]=3.26; 95% CI=1.15 to 9.2;P =0.03). A single draining vein was associated with bleeding at presentation in 57.6% AVMs (OR=1.78; 95% CI=1.12 to 2.82;P =0.01), and 72.8% of the patients with venous ectasia had bleeding as initial evidence (OR=3.9; 95% CI=1.63 to 9.28;P =0.002). Hemorrhage was the initial presentation in 47.6% (111/233) of AVMs <3 cm, 22.5% (32/142) in sizes between 3 and 6 cm, and 20% in malformations >6 cm (3/15), but these differences were not significant in multivariate analyses. Conclusions— For initial hemorrhagic presentation, a small number of draining veins, deep location, and the presence of venous ectasias were significant associated factors. In contrast with many previous reports, AVM size was not associated with hemorrhage at presentation in adjusted analyses.

Acute subarachnoid hemorrhage: using 64-slice multidetector CT angiography to "triage" patients' treatment.

IntroductionTo evaluate the clinical role of CT angiography (CTA) in patients with acute subarachnoid hemorrhage (SAH) for treatment decision-making.MethodsConsecutive patients with acute SAH had CTA using a 64-slice scanner for initial clinical decision-making. Image processing included multiplanar volume reformatted (MPVR) maximum intensity projections (MIP) and 3D volume-rendered reconstructions. CTAs were used for (1) evaluating the cause of SAH, and (2) triaging aneurysm-bearing patients to the more appropriate management, either surgical clipping or endovascular coiling. CTA findings were confirmed by neurosurgical exploration or catheter angiography (digital subtraction angiography, DSA). Successful coiling provided evidence that triaging to endovascular treatment was correct.ResultsIncluded in the study were 73 patients. CTA findings were confirmed by DSA or neurosurgical operation in 65 patients, and of these 65, 47 had aneurysmal SAH, 3 had vasculitis, 1 had arterial dissection and 14 had no underlying arterial abnormality. The cause of SAH was detected with CTA in 62 out of the 65 patients (95.4%, sensitivity 94%, specificity 100%). CTA revealed the aneurysm in 46 of 47 patients (98%, sensitivity 98%, specificity 100%, positive predictive value 100%, negative predictive value 82.3%), 1 of 3 vasculitides and 1 of 1 dissection. Of the 46 patients with aneurysm, 44 (95.7%) were referred for treatment based on CTA. In 2 patients (2 of 46, 4.4%) CTA was not informative enough to choose treatment requiring DSA. Of the 44 patients, 27 (61.4%) were referred to endovascular treatment and successful coiling was achieved in 25 (25 of 27, 92.6%).ConclusionCTA using a 64-slice scanner is an accurate tool for detecting and characterizing aneurysms in acute SAH. CTA is useful in the decision process whether to coil or clip an aneurysm.

Large and Deep Brain Arteriovenous Malformations Are Associated With Risk of Future Hemorrhage

Background and Purpose— The correlation between features present in brain arteriovenous malformations (AVMs) such as size, location, and angioarchitecture at presentation with subsequent risk of hemorrhage may be valuable in predicting the behavior of AVMs and therefore guiding management. Methods— We prospectively followed up 390 patients with brain AVMs at the University of Toronto Vascular Malformation Study Group. Location, size, angioarchitecture details, blood supply, and clinical presentation were recorded at baseline. Intracranial hemorrhages during follow-up were recorded. Significant factors from univariate analyses were used to construct a multivariate model relating the above features to the occurrence of hemorrhage. Results— Thirty-eight patients had bleeding caused by the AVM in a follow-up of 1205 patient-years (mean, 3.1 years per patient). In analyses adjusted for multiple AVM characteristics, large AVMs bled more frequently than small lesions (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.41 to 4.35;P <0.0001), and deep-seated AVMs had more bleeding in follow-up than those located at superficial sites (OR, 5.56; 95% CI, 2.63 to 12.5;P <0.0001). Conclusions— Deep-seated and large AVMs were significantly more prone to hemorrhage during prospective follow-up. The distinction between factors associated with hemorrhagic presentation and the natural history risk of hemorrhage will be emphasized.