Geert J. Lycklama à Nijeholt

Time to Reperfusion and Treatment Effect for Acute Ischemic Stroke: A Randomized Clinical Trial

IMPORTANCEnIntra-arterial treatment (IAT) for acute ischemic stroke caused by intracranial arterial occlusion leads to improved functional outcome in patients treated within 6 hours after onset. The influence of treatment delay on treatment effect is not yet known.nnnOBJECTIVEnTo evaluate the influence of time from stroke onset to the start of treatment and from stroke onset to reperfusion on the effect of IAT.nnnDESIGN, SETTING, AND PARTICIPANTSnThe Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) was a multicenter, randomized clinical open-label trial of IAT vs no IAT in 500 patients. The time to the start of treatment was defined as the time from onset of symptoms to groin puncture (TOG). The time from onset of treatment to reperfusion (TOR) was defined as the time to reopening the vessel occlusion or the end of the procedure in cases for which reperfusion was not achieved. Data were collected from December 3, 2010, to June 3, 2014, and analyzed (intention to treat) from July 1, 2014, to September 19, 2015.nnnMAIN OUTCOMES AND MEASURESnMain outcome was the modified Rankin Scale (mRS) score for functional outcome (range, 0 [no symptoms] to 6 [death]). Multiple ordinal logistic regression analysis estimated the effect of treatment and tested for the interaction of time to randomization, TOG, and TOR with treatment. The effect of treatment as a risk difference on reaching independence (mRS score, 0-2) was computed as a function of TOG and TOR. Calculations were adjusted for age, National Institutes of Health Stroke Scale score, previous stroke, atrial fibrillation, diabetes mellitus, and intracranial arterial terminus occlusion.nnnRESULTSnAmong 500 patients (58% male; median age, 67 years), the median TOG was 260 (interquartile range [IQR], 210-311) minutes; median TOR, 340 (IQR, 274-395) minutes. An interaction between TOR and treatment (P =u2009.04) existed, but not between TOG and treatment (P =u2009.26). The adjusted risk difference (95% CI) was 25.9% (8.3%-44.4%) when reperfusion was reached at 3 hours, 18.8% (6.6%-32.6%) at 4 hours, and 6.7% (0.4%-14.5%) at 6 hours.nnnCONCLUSION AND RELEVANCEnFor every hour of reperfusion delay, the initially large benefit of IAT decreases; the absolute risk difference for a good outcome is reduced by 6% per hour of delay. Patients with acute ischemic stroke require immediate diagnostic workup and IAT in case of intracranial arterial vessel occlusion.nnnTRIAL REGISTRATIONntrialregister.nl Identifier: NTR1804.

Collateral Status on Baseline Computed Tomographic Angiography and Intra-Arterial Treatment Effect in Patients with Proximal Anterior Circulation Stroke

Background and Purpose— Recent randomized trials have proven the benefit of intra-arterial treatment (IAT) with retrievable stents in acute ischemic stroke. Patients with poor or absent collaterals (preexistent anastomoses to maintain blood flow in case of a primary vessel occlusion) may gain less clinical benefit from IAT. In this post hoc analysis, we aimed to assess whether the effect of IAT was modified by collateral status on baseline computed tomographic angiography in the Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN). Methods— MR CLEAN was a multicenter, randomized trial of IAT versus no IAT. Primary outcome was the modified Rankin Scale at 90 days. The primary effect parameter was the adjusted common odds ratio for a shift in direction of a better outcome on the modified Rankin Scale. Collaterals were graded from 0 (absent) to 3 (good). We used multivariable ordinal logistic regression analysis with interaction terms to estimate treatment effect modification by collateral status. Results— We found a significant modification of treatment effect by collaterals (P=0.038). The strongest benefit (adjusted common odds ratio 3.2 [95% confidence intervals 1.7–6.2]) was found in patients with good collaterals (grade 3). The adjusted common odds ratio was 1.6 [95% confidence intervals 1.0–2.7] for moderate collaterals (grade 2), 1.2 [95% confidence intervals 0.7–2.3] for poor collaterals (grade 1), and 1.0 [95% confidence intervals 0.1–8.7] for patients with absent collaterals (grade 0). Conclusions— In MR CLEAN, baseline computed tomographic angiography collateral status modified the treatment effect. The benefit of IAT was greatest in patients with good collaterals on baseline computed tomographic angiography. Treatment benefit appeared less and may be absent in patients with absent or poor collaterals. Clinical Trial Registration— URL: http://www.trialregister.nl and http://www.controlled-trials.com. Unique identifier: (NTR)1804 and ISRCTN10888758, respectively.

The effect of anesthetic management during intra-arterial therapy for acute stroke in MR CLEAN.

Background: The aim of the current study was to assess the influence of anesthetic management on the effect of treatment in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN). Methods: MR CLEAN was a multicenter, randomized, open-label trial of intra-arterial therapy (IAT) vs no IAT. The intended anesthetic management at the start of the procedure was used for this post hoc analysis. The primary effect parameter was the adjusted common odds ratio (acOR) for a shift in direction of a better outcome on the modified Rankin Scale (mRS) at 90 days, estimated with multivariable ordinal logistic regression analysis, which included a term for general anesthesia (GA). Results: GA was associated with significant (p = 0.011) effect modification, resulting in estimated decrease of 51% (95% confidence interval [CI] 31%–86%) in treatment effect compared to non-GA. We found a shift in the distribution on the mRS in favor of non-GA compared to control group (acOR 2.18 [95% CI 1.49–3.20]). The shift in distribution between GA and control group was in a similar direction (acOR 1.12 [95% CI 0.71–1.78]) with loss of statistical significance. Conclusions: In this post hoc analysis, we found that the type of anesthetic management influences outcome following IAT. Only treatment without general anesthesia was associated with a significant treatment benefit in MR CLEAN. Classification of evidence: This study provides Class II evidence that for patients with acute ischemic stroke undergoing IAT, mRS scores at 90 days improve only in patients treated without GA.

Carotid pseudo-occlusion on CTA in patients with acute ischemic stroke: A concerning observation

OBJECTIVEnDifferentiation between an occluded and a patent extracranial internal carotid artery (ICA) is crucial in the diagnostic workup of patients with acute ischemic stroke; particularly in patients eligible for endovascular treatment. We report neurological and radiological findings of cases in which CTA in the acute phase incorrectly revealed an occlusion of the ICA.nnnMETHODSnIn our image data base of 54 patients with acute ischemic stroke eligible for endovascular treatment, we searched for patients with an occluded extracranial ICA on CTA whereas DSA proved that this artery was patent. Of these patients, all available images were re-examined to investigate possible causes of these so-called pseudo-occlusions.nnnRESULTSnWe detected 6 patients (11%) with a pseudo-occlusion. The pseudo-occlusions on CTA were associated with reduced flow due to carotid T-occlusions (4 cases) or a combination of a high degree stenosis of the extracranial ICA and MCA occlusion (2 cases).nnnCONCLUSIONnCTA in the acute phase of ischemic stroke needs to be interpreted with severe caution, and in endovascular treatment decisions we should be aware that an extracranial ICA occlusion may be a false positive finding.

Acute Spinal-Cord Ischemia: Evolution of MRI Findings

Background and Purpose Magnetic resonance (MR) findings in acute spinal-cord ischemia can be summarized as focal cord enlargement and hyperintensities on T2-weighted images and gadolinium enhancement, especially of the central gray matter. However, in analogy with acute brain ischemia, it is to be expected that the findings of MR imaging (MRI) may be normal in the first hours after symptom onset. We evaluated the clinical and MRI findings in a series of patients with acute spinal-cord ischemia, and tested the hypothesis that the development and course of MR abnormalities are predictable. Methods Five patients with acute spinal-cord ischemia were admitted to our hospital over a 2-year period. Repeated MRI (1.5 T) was performed in all patients. Clinical data were retrieved from the patients charts. Results Four women and one man with a median age of 52 years (range, 31-75 years) were admitted. Three patients had anterior spinal artery infarction and two patients had transverse infarctions. All patients underwent spinal MRI within 24 hours; the findings were normal in four of the five patients. After 1-2 days, T2-weighted MRI generally exhibited focal cord enlargement and hyperintensity in all patients, while spinal-cord enhancement appeared after 2-11 days. Conclusions Acute spinal-cord ischemia may have a typical course on MRI. MRI findings are usually normal in the acute phase, but spinal cord swelling and T2 abnormality are expected after several days, while gadolinium enhancement appears even later after symptom onset. The sensitivity and specificity of MRI can be increased by repeated MRI in patients suspected of acute spinal-cord ischemia.

The Prognostic Value of CT Angiography and CT Perfusion in Acute Ischemic Stroke.

Background: CT angiography (CTA) and CT perfusion (CTP) are important diagnostic tools in acute ischemic stroke. We investigated the prognostic value of CTA and CTP for clinical outcome and determined whether they have additional prognostic value over patient characteristics and non-contrast CT (NCCT). Methods: We included 1,374 patients with suspected acute ischemic stroke in the prospective multicenter Dutch acute stroke study. Sixty percent of the cohort was used for deriving the predictors and the remaining 40% for validating them. We calculated the predictive values of CTA and CTP predictors for poor clinical outcome (modified Rankin Scale score 3-6). Associations between CTA and CTP predictors and poor clinical outcome were assessed with odds ratios (OR). Multivariable logistic regression models were developed based on patient characteristics and NCCT predictors, and subsequently CTA and CTP predictors were added. The increase in area under the curve (AUC) value was determined to assess the additional prognostic value of CTA and CTP. Model validation was performed by assessing discrimination and calibration. Results: Poor outcome occurred in 501 patients (36.5%). Each of the evaluated CTA measures strongly predicted outcome in univariable analyses: the positive predictive value (PPV) was 59% for Alberta Stroke Program Early CT Score (ASPECTS) ≤7 on CTA source images (OR 3.3; 95% CI 2.3-4.8), 63% for presence of a proximal intracranial occlusion (OR 5.1; 95% CI 3.7-7.1), 66% for poor leptomeningeal collaterals (OR 4.3; 95% CI 2.8-6.6), and 58% for a >70% carotid or vertebrobasilar stenosis/occlusion (OR 3.2; 95% CI 2.2-4.6). The same applied to the CTP measures, as the PPVs were 65% for ASPECTS ≤7 on cerebral blood volume maps (OR 5.1; 95% CI 3.7-7.2) and 53% for ASPECTS ≤7 on mean transit time maps (OR 3.9; 95% CI 2.9-5.3). The prognostic model based on patient characteristics and NCCT measures was highly predictive for poor clinical outcome (AUC 0.84; 95% CI 0.81-0.86). Adding CTA and CTP predictors to this model did not improve the predictive value (AUC 0.85; 95% CI 0.83-0.88). In the validation cohort, the AUC values were 0.78 (95% CI 0.73-0.82) and 0.79 (95% CI 0.75-0.83), respectively. Calibration of the models was satisfactory. Conclusions: In patients with suspected acute ischemic stroke, admission CTA and CTP parameters are strong predictors of poor outcome and can be used to predict long-term clinical outcome. In multivariable prediction models, however, their additional prognostic value over patient characteristics and NCCT is limited in an unselected stroke population.

Extensive White Matter Changes After Stereotactic Radiosurgery for Brain Arteriovenous Malformations: A Prognostic Sign for Obliteration?

OBJECTIVE Perinidal high-signal-intensity changes on T2-weighted magnetic resonance imaging can be seen surrounding radiosurgically treated brain arteriovenous malformations (AVM). Occasionally, these signal intensity changes develop far beyond the irradiated volume. A retrospective analysis of both the pre- and postradiosurgery magnetic resonance imaging and angiographic studies was performed to analyze the cause of these extensive perinidal white matter changes. METHODS The pre- and postradiosurgical magnetic resonance imaging and angiographic studies of 30 patients with T2 high-signal-intensity changes surrounding a brain AVM were analyzed retrospectively. Patients were divided into 2 groups on the basis of the extension of the signal intensity changes within or beyond the 10-Gy isodose area. The angiographic analysis was focused on the venous drainage pattern (deep versus superficial), venous stenosis, and the number of draining veins before and after radiosurgery. In addition, the obliteration rate was determined for the 2 subgroups. RESULTS Fourteen patients (47%) showed high-signal-intensity changes far beyond the 10-Gy isodose area. A single draining vein was more often present in these patients with extensive T2 hyperintensity signal changes than in the other group. Obliteration was achieved in 12 (88%) of 14 patients with extensive signal intensity changes, as opposed to 8 (50%) of 16 patients in the other group. CONCLUSION High-signal-intensity changes after radiosurgery for brain AVMs, far beyond the 10-Gy isodose area on T2-weighted images, are especially seen in brain AVMs draining through a single vein. The higher occlusion rate of brain AVMs under these circumstances is well appreciated.

Clot Burden Score on Baseline Computerized Tomographic Angiography and Intra-Arterial Treatment Effect in Acute Ischemic Stroke

Background and Purpose— A high clot burden score (CBS) is associated with favorable outcome after intravenous treatment for acute ischemic stroke. The added benefit of intra-arterial treatment might be less in these patients. The aim of this exploratory post hoc analysis was to assess the relation of CBS with neurological improvement and endovascular treatment effect. Methods— For 499 of 500 patients in the MR CLEAN study (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), the CBS was determined. Ordinal logistic regression models with and without main baseline prognostic variables were used to assess the association between CBS (continuous or dichotomized at CBS of 6) and a shift toward better outcome on the modified Rankin Scale. The model without main baseline prognostic variables only included treatment allocation and CBS. Models with and without a multiplicative interaction term of CBS and treatment were compared using the &khgr;2 test to assess treatment effect modification by CBS. Results— Higher CBS was associated with a shift toward better outcome on the modified Rankin Scale; adjusted common odds ratio per point CBS was 1.12 (95% confidence interval, 1.04–1.20]. Dichotomized CBS had an adjusted common odds ratio of 1.67 (95% confidence interval, 1.12–2.51). Both effect estimates were slightly attenuated by adding baseline prognostic variables. The addition of the interaction terms did not significantly improve the fit of the models. There was a small and insignificant increase of intra-arterial treatment efficacy in the high CBS group. Conclusions— A higher CBS is associated with improved outcome and may be used as a prognostic marker. We found no evidence that CBS modifies the effect of intra-arterial treatment. Clinical Trial Registration— URL: http://www.trialregister.nl. Unique identifier: NTR1804. URL: http://www.controlled-trials.com. Unique identifier: ISRCTN10888758.

The relationship between interventionists' experience and clinical and radiological outcome in intra-arterial treatment for acute ischemic stroke. A MR CLEAN pretrial survey

BACKGROUNDnIntra-arterial treatment in acute ischemic stroke is safe and effective as recently shown in several randomized clinical trials. The level of experience of the interventionist performing the IAT procedure has not been studied. The present study investigates effects of interventionists experience on technical aspects of the procedure and clinical outcome of the patient.nnnMETHODSnIn this study of 313 patients with a proximal intracranial arterial anterior circulation occlusion, treated in the Netherlands from 2002 until participation in the Multicenter Randomized Clinical trial of Endovascular treatment for acute ischemic stroke (MR CLEAN), data were collected retrospectively. The association of the senior interventionists experience with duration of the procedure, adverse events, recanalization, neurological outcome, and functional outcome at discharge was analyzed. Multiple regression models adjusted for age, sex, stroke severity, carotid terminus occlusion, use of a retrievable stent and onset to door time were used.nnnRESULTSnNo association between interventionists experience and recanalization, neurological outcome, or functional outcome was observed in a strict selection of patients. This strict selection include a start of intra-arterial treatment within 6h, no coagulation disturbances, systolic blood pressure<185mmHg and diastolic blood pressure<110mmHg), blood glucose level between 2.7 and 22.2mmol/L and the existence of a proximal intracranial occlusion. However, significant shorter procedure times were found with more experienced interventionists [adjusted beta coefficient -0.67, 95% CI: -1.24 to -0.11], when using less strict inclusion criteria.nnnCONCLUSIONnNo significant relation between the level of experience and either serious neurologic adverse events or poor outcomes was observed in this study of treatments by interventionists with experience of <50 previous procedures. We need further research to explore the relation of much higher levels of interventionists and team experience with procedure times, results and patient outcomes.