Functional impairments for outcomes in a randomized trial of unruptured brain AVMs.

OBJECTIVE: To investigate the effects of medical vs interventional management on functional outcome in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA). METHODS: We used the initial results of a nonblinded, randomized, controlled, parallel-group trial involving adults ≥18 years of age with an unruptured brain arteriovenous malformation (AVM) to compare the effects of medical management (MM) with or without interventional therapy (IT) on functional impairment, defined by a primary outcome of death or symptomatic stroke causing modified Rankin Scale (mRS) score ≥2. ARUBA closed recruitment on April 15, 2013. RESULTS: After a median of 33.3 months of follow-up (interquartile range 16.3-49.8 months), of the 223 enrolled in the trial, those in the MM arm were less likely to experience primary outcomes with an mRS score ≥2 than those who underwent IT. The results applied for both those as randomized (MM n = 109 vs IT n = 114) (hazard ratio [HR] 0.25, 95% confidence interval [CI] 0.11-0.57, p = 0.001) and as treated (MM n = 125 vs IT n = 98) (HR 0.10, 95% CI 0.04-0.28, p < 0.001). Functional impairment for the outcomes showed no significant difference by Spetzler-Martin grade for MM but was more frequent with increasing grades for IT (p < 0.001). CONCLUSION: Death or stroke with functional impairment in ARUBA after a median follow-up of 33 months was significantly lower for those in the MM arm both as randomized and as treated compared with those with IT. Functional severity of outcomes was lower in the MM arm, regardless of Spetzler-Martin grades. CLINICALTRIALSGOV IDENTIFIER: NCT00389181. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for adults with unruptured brain AVMs, interventional management compared to MM increases the risk of disability and death over ≈3 years.

Collateral state and the effect of endovascular reperfusion therapy on clinical outcome in ischemic stroke patients.

PURPOSE: Clinically successful endovascular therapy (EVT) in ischemic stroke requires reliable noninvasive pretherapeutic selection criteria. We investigated the association of imaging parameters including CT angiographic collaterals and degree of reperfusion with clinical outcome after EVT. METHODS: In our database, we identified 93 patients with large vessel occlusion in the anterior circulation treated with EVT. Besides clinical data, we assessed the baseline Alberta Stroke Program Early CT score (ASPECTS) on noncontrast CT (NCCT) and CT angiography (CTA) source images, collaterals (CT-CS) and clot burden score (CBS) on CTA and the degree of reperfusion after EVT on angiography. Three readers, blinded to clinical information, evaluated the images in consensus. Data-driven multivariable ordinal regression analysis identified predictors of good outcome after 90 days as measured with the modified Rankin Scale. RESULTS: Successful angiographic reperfusion (OR 26.50; 95%-CI 9.33-83.61) and good collaterals (OR 9.69; 95%-CI 2.28-59.27) were independent predictors of favorable outcome along with female sex (OR 0.35; 95%-CI 0.14-0.85), younger age (OR 0.88; 95%-CI 0.83-0.92) and higher NCCT ASPECTS (OR 2.54; 95%-CI 1.01-6.63). Outcome was best in patients with good collaterals and successful reperfusion, but there was no statistical interaction between collaterals and reperfusion. CONCLUSIONS: CTA-collateral status was the strongest pretherapeutic predictor of favorable outcome in ischemic stroke patients treated with EVT. CTA-collaterals are thus well suited for patient selection in EVT. However, the independent effect of reperfusion on outcome tended to be stronger than that of CTA-collaterals.

Endovascular treatment of ischaemic stroke patients - new evidence and old challenges.

An overwhelming benefit from endovascular treatment of ischaemic stroke could be shown in recent clinical trials, making it the new evidence-based standard of care for ischaemic stroke due to large vessel occlusion. To provide all eligible stroke patients with this therapy at any time, stroke networks and hospitals should streamline their workflow to rapidly image, select, and treat stroke patients. Interdisciplinary cooperation is vital for effective emergency endovascular stroke treatment, which is one of the most complex multidisciplinary functions a hospital can undertake.

Telemedical Brain Computed Tomography Misinterpretation by Stroke Neurologists Is Not Associated with Thrombolysis-Related Intracranial Hemorrhage.

BACKGROUND: The Stroke Eastern Saxony Network (SOS-NET) provides telecare for acute stroke patients. Stroke neurologists recommend intravenous thrombolysis based on clinical assessment and cerebral computed tomography (CT) evaluation using Alberta Stroke Program Early CT score (ASPECTS). We sought to assess whether ASPECTS misinterpretation by stroke neurologists was associated with thrombolysis-related symptomatic intracranial hemorrhage (sICH). METHODS: We retrospectively analyzed consecutive SOS-NET patients treated with thrombolytics from July 2007 to July 2012. Experienced neuroradiologists re-evaluated CT scans blinded to clinical information providing reference standard. We defined ASPECTS underestimation as ASPECTS stroke neurologist--ASPECTS neuroradiologist more than 1 point. Primary outcome was sICH by European Cooperative Acute Stroke Study II criteria. Secondary outcome was unfavorable outcome at discharge defined as modified Rankin Scale scores 3 or more. RESULTS: Of 1659 patients with acute ischemic stroke, thrombolysis was performed in 657 patients. Complete primary outcome and imaging data were available for 432 patients (median age, 75; interquartile range [IQR], 12 years; National Institutes of Health Stroke Scale score, 12 [IQR, 11]; 52.8% women). Nineteen patients (4.4%) had sICH, and 259 patients (60.0%) had an unfavorable outcome at discharge. Interobserver agreement between ASPECTS assessment was fair (κ = .51). ASPECTS underestimation was neither associated with sICH (adjusted odds ratio (OR), 1.32; 95% confidence interval (CI), .36-4.83, P = .68) nor unfavorable outcome (adjusted OR, 1.10; 95% CI, .47-2.54; P = .83). CONCLUSIONS: Despite fair interrater agreement between stroke neurologists and expert neuroradiologists, underestimation of ASPECTS by the former was not associated with thrombolysis-related sICH in our telestroke network.

Endovascular revascularization results in IMS III: intracranial ICA and M1 occlusions.

BACKGROUND: Interventional Management of Stroke III did not show that combining IV recombinant tissue plasminogen activator (rt-PA) with endovascular therapies (EVTs) is better than IV rt-PA alone. OBJECTIVE: To report efficacy and safety results for EVT of intracranial internal carotid artery (ICA) and middle cerebral artery trunk (M1) occlusion. METHODS: Five revascularization methods for persistent occlusions after IV rt-PA treatment were evaluated for prespecified primary and secondary endpoints, after accounting for differences in key baselines variables using propensity scores. Revascularization was scored using the arterial occlusive lesion (AOL) and the modified Thrombolysis in Cerebral Ischemia (mTICI) scores. RESULTS: EVT of 200 subjects with intracranial ICA or M1 occlusion resulted in 81.5% AOL 2-3 recanalization, in addition to 76% mTICI 2-3 and 42.5% mTICI 2b-3 reperfusion. Adverse events included symptomatic intracranial hemorrhage (SICH) (8.0%), vessel perforations (1.5%), and new emboli (14.9%). EVT techniques used were standard microcatheter n=51; EKOS n=14; Merci n=77; Penumbra n=39; Solitaire n=4; multiple n=15. Good clinical outcome was associated with both TICI 2-3 and TICI 2b-3 reperfusion. Neither modified Rankin scale (mRS) 0-2 (28.5%), nor 90-day mortality (28.5%), nor asymptomatic ICH (36.0%) differed among revascularization methods after propensity score adjustment for subjects with intracranial ICA or M1 occlusion. CONCLUSIONS: Good clinical outcome was associated with good reperfusion for ICA and M1 occlusion. No significant differences in efficacy or safety among revascularization methods were demonstrated after adjustment. Lack of high-quality reperfusion, adverse events, and prolonged time to treatment contributed to lower-than-expected mRS 0-2 outcomes and study futility compared with IV rt-PA. TRIAL REGISTRATION NUMBER: NCT00359424.

Diagnostic and Prognostic Impact of pc-ASPECTS Applied to Perfusion CT in the Basilar Artery International Cooperation Study.

BACKGROUND AND PURPOSE: The posterior circulation Acute Stroke Prognosis Early CT Score (pc-APECTS) applied to CT angiography source images (CTA-SI) predicts the functional outcome of patients in the Basilar Artery International Cooperation Study (BASICS). We assessed the diagnostic and prognostic impact of pc-ASPECTS applied to perfusion CT (CTP) in the BASICS registry population. METHODS: We applied pc-ASPECTS to CTA-SI and cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) parameter maps of BASICS patients with CTA and CTP studies performed. Hypoattenuation on CTA-SI, relative reduction in CBV or CBF, or relative increase in MTT were rated as abnormal. RESULTS: CTA and CTP were available in 27/592 BASICS patients (4.6%). The proportion of patients with any perfusion abnormality was highest for MTT (93%; 95% confidence interval [CI], 76%-99%), compared with 78% (58%-91%) for CTA-SI and CBF, and 46% (27%-67%) for CBV (P < .001). All 3 patients with a CBV pc-ASPECTS < 8 compared to 6/23 patients with a CBV pc-ASPECTS ≥ 8 had died at 1 month (RR 3.8; 95% CI, 1.9-7.6). CONCLUSION: CTP was performed in a minority of the BASICS registry population. Perfusion disturbances in the posterior circulation were most pronounced on MTT parameter maps. CBV pc-ASPECTS < 8 may indicate patients with high case fatality.

Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials.

BACKGROUND: Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase. METHODS: We did a pre-specified meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control. We included all completed randomised phase 3 trials of intravenous alteplase for treatment of acute ischaemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. We defined a good stroke outcome as no significant disability at 3-6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality. FINDINGS: Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3·0 h resulted in a good outcome for 259 (32·9%) of 787 patients who received alteplase versus 176 (23·1%) of 762 who received control (OR 1·75, 95% CI 1·35-2·27); delay of greater than 3·0 h, up to 4·5 h, resulted in good outcome for 485 (35·3%) of 1375 versus 432 (30·1%) of 1437 (OR 1·26, 95% CI 1·05-1·51); and delay of more than 4·5 h resulted in good outcome for 401 (32·6%) of 1229 versus 357 (30·6%) of 1166 (OR 1·15, 95% CI 0·95-1·40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage definition 231 [6·8%] of 3391 vs 44 [1·3%] of 3365, OR 5·55, 95% CI 4·01-7·70, p<0·0001; SITS-MOST definition 124 [3·7%] vs 19 [0·6%], OR 6·67, 95% CI 4·11-10·84, p<0·0001) and of fatal intracranial haemorrhage within 7 days (91 [2·7%] vs 13 [0·4%]; OR 7·14, 95% CI 3·98-12·79, p<0·0001). The relative increase in fatal intracranial haemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17·9%) in the alteplase group versus 556 (16·5%) in the control group (hazard ratio 1·11, 95% CI 0·99-1·25, p=0·07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial haemorrhage of about 2%, by 3-6 months this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3·0 h and about 5% for patients treated after 3·0 h, up to 4·5 h. INTERPRETATION: Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of stroke onset, with earlier treatment associated with bigger proportional benefits. FUNDING: UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.

Collaterals at angiography and outcomes in the Interventional Management of Stroke (IMS) III trial.

BACKGROUND AND PURPOSE: Endovascular strategies provide unique opportunity to correlate angiographic measures of collateral circulation at the time of endovascular therapy. We conducted systematic analyses of collaterals at conventional angiography on recanalization, reperfusion, and clinical outcomes in the endovascular treatment arm of the Interventional Management of Stroke (IMS) III trial. METHODS: Prospective evaluation of angiographic collaterals was conducted via central review of subjects treated with endovascular therapy in IMS III (n=331). Collateral grade before endovascular therapy was assessed with the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology scale, blinded to all other data. Statistical analyses investigated the association between collaterals with baseline clinical variables, angiographic measures of recanalization, reperfusion and clinical outcomes. RESULTS: Adequate views of collateral circulation to the ischemic territory were available in 276 of 331 (83%) subjects. Collateral grade was strongly related to both recanalization of the occluded arterial segment (P=0.0016) and downstream reperfusion (P<0.0001). Multivariable analyses confirmed that robust angiographic collateral grade was a significant predictor of good clinical outcome (modified Rankin Scale score≤2) at 90 days (P=0.0353), adjusted for age, history of diabetes mellitus, National Institutes of Health Stroke Scale strata, and Alberta Stroke Program Early CT Score. The relationship between collateral flow and clinical outcome may depend on the degree of reperfusion. CONCLUSIONS: More robust collateral grade was associated with better recanalization, reperfusion, and subsequent better clinical outcomes. These data, from the largest endovascular trial to date, suggest that collaterals are an important consideration in future trial design. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424.

Emergency transfer of acute stroke patients within the East Saxony telemedicine stroke network: a descriptive analysis.

BACKGROUND: Telemedicine may facilitate the selection of stroke patients who require emergency transfer to a comprehensive stroke center to receive additional therapies other than intravenous tissue plasminogen activator. AIMS AND/OR HYPOTHESIS: We sought to analyze frequency, patient characteristics, and specific therapies among emergently transferred patients within the telemedical Stroke East Saxony Network. METHODS: We reviewed consecutive patients who were transferred emergently from remote spoke sites to hub sites. Certified stroke neurologists performed teleconsultations 24/7, with access to high-speed videoconferencing and transfer of brain images. Emergent transfers were initiated when considered necessary by the stroke neurologist. RESULTS: In 2009 and 2010, we conducted 1413 teleconsultations and subsequently recommended transfer in 339 (24%) patients [mean age 64 ± 14 years, 54% males, median National Institutes of Health Stroke Scale score 5 (interquartile range, IQR 12). The mean teleconsultation-to-arrival time was 1·7 ± 0·8 h (median 1·6 h). Sixty-eight (20%) transferred patients had a nonstroke diagnosis. The remaining 271 (80%) patients had stroke diagnoses [ischemic stroke, 114 (34%); transient ischemic attack, 8 (2%); and intracranial haemorrhage, 149 (44%)]. Forty (35%) ischemic stroke patients received tissue plasminogen activator at spoke sites ('drip and ship'). Of the 240 stroke patients emergently transferred to the main hub site, 119 (49·6%) received at least one specific stroke therapy. CONCLUSIONS: A remarkable number of stroke patients can be transferred within a telemedical network to enable the delivery of specific stroke therapies that require advanced multispecialty expertise. Whether associated logistic efforts and costs have an impact on patients' clinical outcomes needs to be evaluated.

Association of sleep apnea with clinically silent microvascular brain tissue changes in acute cerebral ischemia.

The aim of this study was to determine the importance of sleep apnea in relation to clinically silent microvascular brain tissue changes in patients with acute cerebral ischemia. Patients with acute cerebral ischemia prospectively underwent nocturnal respiratory polygraphy within 5 days from symptom-onset. Sleep apnea was defined as apnea-hypopnea-index (AHI) ≥5/h. Experienced readers blinded to clinical and sleep-related data reviewed brain computed tomography and magnetic resonance imaging scans for leukoaraiosis and chronic lacunar infarctions. Ischemic lesions were considered clinically silent when patients did not recall associated stroke-like symptoms. Functional outcome was assessed with modified Rankin Scale at discharge, 6 and 12 months. Fifty-one of 56 (91 %) patients had sleep apnea of any degree. Patients with moderate-to-severe leukoaraiosis (Wahlund score ≥5) were found to have higher mean AHI than those with none or mild leukoaraiosis (34.4 vs. 12.8/h, p < 0.001). Moderate-to-severe sleep apnea (AHI ≥15/h) was found to be an independent predictor of moderate-to-severe leukoaraiosis (adjusted OR 6.03, 95 % CI 1.76-20.6, p = 0.0042) and of moderate-to-severe leukoaraiosis associated with clinically silent chronic lacunar infarctions (adjusted OR 10.5, 95 % CI 2.19-50.6, p = 0.003). The higher the Wahlund score and the AHI, the more likely unfavorable functional outcome resulted over time (p = 0.0373). In acute cerebral ischemia, sleep apnea is associated with clinically silent microvascular brain tissue changes and may negatively influence functional outcome. Routine sleep apnea screening and further investigation of possible long-term effects of non-invasive ventilatory treatment of sleep apnea appear warranted in this at-risk population.

Reliability of brain CT evaluation by stroke neurologists in telemedicine.

OBJECTIVE: To determine the reliability and therapeutic impact of standardized cerebral CT evaluation and quantification of early ischemic changes (EIC) with the Alberta Stroke Program Early CT Score (ASPECTS) by stroke neurologists in the Stroke Eastern Saxony Network (SOS-NET), which provides telemedical consultations for patients with acute ischemic stroke. METHODS: Two neuroradiologists re-evaluated all CT scans of consecutive SOS-NET patients in 2009 blinded to clinical information providing reference standard. We defined discrepant CT findings as all false-positive or false-negative EIC and brain pathology findings and ASPECTS deviations >1 point. We subsequently discussed the clinical impact of discrepant CT findings unblinded to clinical information. Weighted kappa (κ(w)) statistic was used to determine the interobserver agreement for ASPECTS. RESULTS: Of 582 patients, complete imaging data were available for 536 patients (351 cerebral ischemic events, 105 primary intracranial hemorrhages, and 80 stroke mimics). The neuroradiologists detected discrepant CT findings in 43 patients (8.0%) that were rated as clinically relevant in 9 patients (1.7%). Stroke neurologists recommended IV thrombolysis in 8 patients despite extensive EIC (ASPECTS ≤5). One of these patients had symptomatic intracranial hemorrhage. In 1 nonthrombolyzed patient, the stroke neurologist missed subdural hematoma. The interobserver agreement on ASPECTS between stroke neurologists and expert readers was substantial (κ(w) = 0.62; 95% confidence interval 0.54-0.71). CONCLUSIONS: Clinically relevant misinterpretation of the CT scans was rare in our acute telestroke service. ASPECTS is a reliable tool to assess the extent of EIC by stroke neurologists in telemedicine in real time.

Extent of hypoattenuation on CT angiography source images in basilar artery occlusion: prognostic value in the Basilar Artery International Cooperation Study.

BACKGROUND AND PURPOSE: The posterior circulation Acute Stroke Prognosis Early CT Score (pc-ASPECTS) quantifies the extent of early ischemic changes in the posterior circulation with a 10-point grading system. We hypothesized that pc-ASPECTS applied to CT angiography source images predicts functional outcome of patients in the Basilar Artery International Cooperation Study (BASICS). METHODS: BASICS was a prospective, observational registry of consecutive patients with acute symptomatic basilar artery occlusion. Functional outcome was assessed at 1 month. We applied pc-ASPECTS to CT angiography source images of patients with CT angiography for confirmation of basilar artery occlusion. We calculated unadjusted and adjusted risk ratios (RRs) of pc-ASPECTS dichotomized at ≥8 versus <8. Primary outcome measure was favorable outcome (modified Rankin Scale scores 0-3). Secondary outcome measures were mortality and functional independence (modified Rankin Scale scores 0-2). RESULTS: Of 158 patients included, 78 patients had a CT angiography source images pc-ASPECTS≥8. Patients with a pc-ASPECTS≥8 more often had a favorable outcome than patients with a pc-ASPECTS<8 (crude RR, 1.7; 95% CI, 0.98-3.0). After adjustment for age, baseline National Institutes of Health Stroke Scale score, and thrombolysis, pc-ASPECTS≥8 was not related to favorable outcome (RR, 1.3; 95% CI, 0.8-2.2), but it was related to reduced mortality (RR, 0.7; 95% CI, 0.5-0.98) and functional independence (RR, 2.0; 95% CI, 1.1-3.8). In post hoc analysis, pc-ASPECTS dichotomized at ≥6 versus <6 predicted a favorable outcome (adjusted RR, 3.1; 95% CI, 1.2-7.5). CONCLUSIONS: pc-ASPECTS on CT angiography source images independently predicted death and functional independence at 1 month in the CT angiography subgroup of patients in the BASICS registry.

Extent of hypoattenuation on CT angiography source images predicts functional outcome in patients with basilar artery occlusion.

BACKGROUND AND PURPOSE: Quantification of early ischemic changes (EIC) may predict functional outcome in patients with basilar artery occlusion (BAO). We tested the validity of a novel CT score, the posterior circulation Acute Stroke Prognosis Early CT score (pc-ASPECTS). METHODS: Pc-ASPECTS allots the posterior circulation 10 points. Two points each are subtracted for EIC in midbrain or pons and 1 point each for EIC in left or right thalamus, cerebellum or PCA-territory, respectively. We studied 2 different populations: (1) patients with suspected vertebrobasilar ischemia and (2) patients with BAO. We applied pc-ASPECTS to noncontrast CT (NCCT), CT angiography source images (CTASI), and follow-up image by 3-reader consensus. We calculated sensitivity for ischemic changes and analyzed the predictivity of pc-ASPECTS for independent (modified Rankin Scale [mRS] score /=8 but only 4% (1/23) with a score <8 had favorable functional outcome (RR 12.1; 95% CI, 1.7 to 84.9). This difference was consistent in 21 patients with angiographic recanalization (RR 7.7; 95% CI, 1.1 to 52.1). CONCLUSIONS: The CTASI pc-ASPECTS score may identify BAO patients unlikely to have a favorable outcome despite recanalization.

Reduced olfactory bulb volume in post-traumatic and post-infectious olfactory dysfunction.

The olfactory bulb is a highly plastic structure the volume of which partly reflects the degree of afferent neural activity. In this study, 22 patients with post-infectious olfactory deficit, nine participants with post-traumatic olfactory deficit, and 17 healthy controls underwent magnetic resonance volumetry of the olfactory bulb. Patients presented with significantly smaller olfactory bulb volumes than controls; significant correlations between olfactory function and bulb volume were observed. Patients with parosmia exhibited smaller olfactory bulb volumes than those without parosmia. Findings indicate that smell deficits leading to a reduced sensory input to the olfactory bulb result in structural changes at the level of the bulb. Reduced olfactory bulb volumes may also be considered to be characteristic of parosmia.