René van den Berg

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

IMPORTANCE Intra-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. OBJECTIVE To evaluate the influence of time from stroke onset to the start of treatment and from stroke onset to reperfusion on the effect of IAT. DESIGN, SETTING, AND PARTICIPANTS The 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. MAIN OUTCOMES AND MEASURES Main 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. RESULTS Among 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 = .04) existed, but not between TOG and treatment (P = .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. CONCLUSION AND RELEVANCE For 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. TRIAL REGISTRATION trialregister.nl Identifier: NTR1804.

Automated segmentation of cerebral vasculature with aneurysms in 3DRA and TOF-MRA using geodesic active regions: an evaluation study.

PURPOSE To evaluate the suitability of an improved version of an automatic segmentation method based on geodesic active regions (GAR) for segmenting cerebral vasculature with aneurysms from 3D x-ray reconstruction angiography (3DRA) and time of flight magnetic resonance angiography (TOF-MRA) images available in the clinical routine. METHODS Three aspects of the GAR method have been improved: execution time, robustness to variability in imaging protocols, and robustness to variability in image spatial resolutions. The improved GAR was retrospectively evaluated on images from patients containing intracranial aneurysms in the area of the Circle of Willis and imaged with two modalities: 3DRA and TOF-MRA. Images were obtained from two clinical centers, each using different imaging equipment. Evaluation included qualitative and quantitative analyses of the segmentation results on 20 images from 10 patients. The gold standard was built from 660 cross-sections (33 per image) of vessels and aneurysms, manually measured by interventional neuroradiologists. GAR has also been compared to an interactive segmentation method: isointensity surface extraction (ISE). In addition, since patients had been imaged with the two modalities, we performed an intermodality agreement analysis with respect to both the manual measurements and each of the two segmentation methods. RESULTS Both GAR and ISE differed from the gold standard within acceptable limits compared to the imaging resolution. GAR (ISE) had an average accuracy of 0.20 (0.24) mm for 3DRA and 0.27 (0.30) mm for TOF-MRA, and had a repeatability of 0.05 (0.20) mm. Compared to ISE, GAR had a lower qualitative error in the vessel region and a lower quantitative error in the aneurysm region. The repeatability of GAR was superior to manual measurements and ISE. The intermodality agreement was similar between GAR and the manual measurements. CONCLUSIONS The improved GAR method outperformed ISE qualitatively as well as quantitatively and is suitable for segmenting 3DRA and TOF-MRA images from clinical routine.

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.

Late Reopening of Adequately Coiled Intracranial Aneurysms Frequency and Risk Factors in 400 Patients With 440 Aneurysms

Background and Purpose— In aneurysms that are adequately occluded 6 months after coiling, the risk of late reopening is largely unknown. We assessed the occurrence of late aneurysm reopening and possible risk factors. Methods— From January 1995 to June 2005, 1808 intracranial aneurysms were coiled in 1675 patients at 7 medical centers. At 6 months, 1066 aneurysms in 971 patients were adequately occluded. At mean 6.0 years after coiling, of the 971 patients, 400 patients with 440 aneurysms underwent 3 Tesla magnetic resonance angiography to assess occlusion status of the aneurysms. Proportions and corresponding 95% CI of aneurysm reopening and retreatment were calculated. Risk factors for late reopening were assessed by univariate and multivariate logistic regression analysis, and included patient sex, rupture status of aneurysms, aneurysm size ≥10 mm, and aneurysm location. Results— In 11 of 400 patients (2.8%; 95% CI, 1.4–4.9%) with 440 aneurysms (2.5%; 95% CI, 1.0–4.0%), late reopening had occurred; 3 reopened aneurysms were retreated (0.7%; 95% CI, 0.2–1.5%). Independent predictors for late reopening were aneurysm size ≥10 mm (OR 4.7; 95% CI, 1.3–16.3) and location on basilar tip (OR 3.9; 95% CI, 1.1–14.6). There were no late reopenings in the 143 anterior cerebral artery aneurysms. Conclusions— For the vast majority of adequately occluded intracranial aneurysms 6 months after coiling (those <10 mm and not located on basilar tip), prolonged imaging follow-up within the first 5 to 10 years after coiling does not seem beneficial in terms of detecting reopened aneurysms that need retreatment. Whether patients might benefit from screening beyond the 5- to 10-year interval is not yet clear.

De Novo Aneurysm Formation and Growth of Untreated Aneurysms A 5-Year MRA Follow-Up in a Large Cohort of Patients With Coiled Aneurysms and Review of the Literature

Background and Purpose— Rates of development of de novo intracranial aneurysms and of growth of untreated additional aneurysms are largely unknown. We performed MRA in a large patient cohort with coiled aneurysms at 5-year follow-up. Methods— In 276 patients with coiled intracranial aneurysms and 5±0.5 years of follow-up MRA (totaling 1332 follow-up patient-years), additional aneurysms were classified as unchanged, grown, de novo, or incomparable with previous imaging. We calculated 5-year cumulative incidence of de novo aneurysm formation and growth of untreated aneurysms. We searched PubMed and EMBASE databases for studies assessing aneurysm development, and growth. Results— In 50 of 276 patients (18%), 75 additional aneurysms were present at follow-up MRA. Of these 75, 2 were de novo (both 3 mm), 58 were unchanged, 5 had grown from 1 to 3 mm (7.9% of 63 known additional aneurysms; 95% CI, 1.3%-14.6%), and 10 were incomparable. Five-year cumulative incidence for a de novo aneurysm developing was 0.75%. Four additional aneurysms in 3 patients were treated. Ten previous studies reported annual incidences of growth of additional aneurysms ranging from 1.51% to 22.7%, and 5 studies reported annual incidences of de novo aneurysm formation ranging from 0.3 to 1.8%. Conclusions— MRA screening of patients with coiled aneurysms within the first 5 years after treatment has a low rate of de novo aneurysm development and growth of additional aneurysms, and an even lower treatment rate.

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

OBJECTIVE Differentiation 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. METHODS In 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. RESULTS We 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). CONCLUSION CTA 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.

Predictors of outcome in World Federation of Neurologic Surgeons grade V aneurysmal subarachnoid hemorrhage patients

Background:Only a small percentage of World Federation of Neurologic Surgeons grade V aneurysmal subarachnoid hemorrhage patients have a favorable outcome. The influence of clinical parameters on outcome was assessed. Methods:Retrospective evaluation of consecutive patients admitted from 2000–2007 with grade V subarachnoid hemorrhage at two institutions by evaluating, over time, the motor value of the Glasgow Coma Scale, effects of external ventricular drainage and rebleeding on outcome. Six-month outcome was assessed with the extended Glasgow Outcome Scale; favorable outcome was defined as good recovery or moderately disabled. Findings:Of 126 patients, 28 had absent brainstem reflexes, without improvement after external ventricular drainage. Rebleeding occurred in 26 patients, resulting in treatment withdrawal in 14. Only one patient had a favorable outcome after rebleeding. Of the 84 remaining patients, 61 improved at day 2 after subarachnoid hemorrhage to Glasgow Coma Scale motor value ≥4; 24 of these (39%) had a favorable outcome. All 23 patients with a Glasgow Coma Scale motor value ≤3 had an unfavorable outcome or died. Patients younger than 65 yrs of age had a better outcome (p < .03). Hydrocephalus was present in 71 of 84 patients. Favorable outcome was similar for patients with a positive external ventricular drainage response (8 of 28) as compared to no response to external ventricular drainage (12 of 43). Interpretation:The high rebleeding rate and subsequent poor outcome in World Federation of Neurologic Surgeons grade V patients warrants early treatment to secure the ruptured aneurysm. Favorable outcome was seen in 39% of patients with a Glasgow Coma Scale motor value ≥4 at day 2. In this study, patients with Glasgow Coma Scale motor value ≤3 at day 2 all had a very poor prognosis.

Small juxtacortical hemorrhages in cerebral venous thrombosis

Intracerebral hemorrhages (ICHs) are common in patients with cerebral venous thrombosis (CVT). We examined whether small juxtacortical hemorrhages (JCHs) are characteristic for CVT and studied their radiological and pathological properties.

Prevalence of Brain Arteriovenous Malformations in First-Degree Relatives of Patients With a Brain Arteriovenous Malformation

Background and Purpose— It is uncertain whether familial occurrence of brain arteriovenous malformations (BAVMs) represents coincidental aggregation or a shared familial risk factor. We aimed to compare the prevalence of BAVMs in first-degree relatives (FDRs) of patients with BAVM and the prevalence in the general population. Methods— We sent a postal questionnaire to 682 patients diagnosed with a BAVM in 1 of 4 university hospitals to retrieve information about the occurrence of BAVMs among their FDRs. We calculated a prevalence ratio using the BAVM prevalence among FDRs and the prevalence from a Scottish population-based study (93 per 628 788 adults). A prevalence ratio of ≥9 with a lower limit of the 95% confidence interval of 3 was considered indicative of a shared familial risk factor. Results— Informed consent was given by 460 (67%) patients, who had 2992 FDRs. We identified 3 patients with a FDR with a BAVM, yielding a prevalence ratio of 6.8 (95% CI, 2.2–21). Conclusions— The prevalence of BAVMs in FDRs of patients with a BAVM was increased but did not meet our prespecified criterion for a shared familial risk factor. In combination with the low absolute risk of a BAVM in FDRs, our results do not support screening of FDRs for BAVMs.