Wouter J. Schonewille

Endovascular Therapy after Intravenous t-PA versus t-PA Alone for Stroke

BACKGROUND Endovascular therapy is increasingly used after the administration of intravenous tissue plasminogen activator (t-PA) for patients with moderate-to-severe acute ischemic stroke, but whether a combined approach is more effective than intravenous t-PA alone is uncertain. METHODS We randomly assigned eligible patients who had received intravenous t-PA within 3 hours after symptom onset to receive additional endovascular therapy or intravenous t-PA alone, in a 2:1 ratio. The primary outcome measure was a modified Rankin scale score of 2 or less (indicating functional independence) at 90 days (scores range from 0 to 6, with higher scores indicating greater disability). RESULTS The study was stopped early because of futility after 656 participants had undergone randomization (434 patients to endovascular therapy and 222 to intravenous t-PA alone). The proportion of participants with a modified Rankin score of 2 or less at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with intravenous t-PA; absolute adjusted difference, 1.5 percentage points; 95% confidence interval [CI], -6.1 to 9.1, with adjustment for the National Institutes of Health Stroke Scale [NIHSS] score [8-19, indicating moderately severe stroke, or ≥20, indicating severe stroke]), nor were there significant differences for the predefined subgroups of patients with an NIHSS score of 20 or higher (6.8 percentage points; 95% CI, -4.4 to 18.1) and those with a score of 19 or lower (-1.0 percentage point; 95% CI, -10.8 to 8.8). Findings in the endovascular-therapy and intravenous t-PA groups were similar for mortality at 90 days (19.1% and 21.6%, respectively; P=0.52) and the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P=0.83). CONCLUSIONS The trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA, as compared with intravenous t-PA alone. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00359424.).

Treatment and outcomes of acute basilar artery occlusion in the Basilar Artery International Cooperation Study (BASICS): a prospective registry study.

BACKGROUND Treatment strategies for acute basilar artery occlusion (BAO) are based on case series and data that have been extrapolated from stroke intervention trials in other cerebrovascular territories, and information on the efficacy of different treatments in unselected patients with BAO is scarce. We therefore assessed outcomes and differences in treatment response after BAO. METHODS The Basilar Artery International Cooperation Study (BASICS) is a prospective, observational registry of consecutive patients who presented with an acute symptomatic and radiologically confirmed BAO between November 1, 2002, and October 1, 2007. Stroke severity at time of treatment was dichotomised as severe (coma, locked-in state, or tetraplegia) or mild to moderate (any deficit that was less than severe). Outcome was assessed at 1 month. Poor outcome was defined as a modified Rankin scale score of 4 or 5, or death. Patients were divided into three groups according to the treatment they received: antithrombotic treatment only (AT), which comprised antiplatelet drugs or systemic anticoagulation; primary intravenous thrombolysis (IVT), including subsequent intra-arterial thrombolysis; or intra-arterial therapy (IAT), which comprised thrombolysis, mechanical thrombectomy, stenting, or a combination of these approaches. Risk ratios (RR) for treatment effects were adjusted for age, the severity of neurological deficits at the time of treatment, time to treatment, prodromal minor stroke, location of the occlusion, and diabetes. FINDINGS 619 patients were entered in the registry. 27 patients were excluded from the analyses because they did not receive AT, IVT, or IAT, and all had a poor outcome. Of the 592 patients who were analysed, 183 were treated with only AT, 121 with IVT, and 288 with IAT. Overall, 402 (68%) of the analysed patients had a poor outcome. No statistically significant superiority was found for any treatment strategy. Compared with outcome after AT, patients with a mild-to-moderate deficit (n=245) had about the same risk of poor outcome after IVT (adjusted RR 0.94, 95% CI 0.60-1.45) or after IAT (adjusted RR 1.29, 0.97-1.72) but had a worse outcome after IAT compared with IVT (adjusted RR 1.49, 1.00-2.23). Compared with AT, patients with a severe deficit (n=347) had a lower risk of poor outcome after IVT (adjusted RR 0.88, 0.76-1.01) or IAT (adjusted RR 0.94, 0.86-1.02), whereas outcomes were similar after treatment with IAT or IVT (adjusted RR 1.06, 0.91-1.22). INTERPRETATION Most patients in the BASICS registry received IAT. Our results do not support unequivocal superiority of IAT over IVT, and the efficacy of IAT versus IVT in patients with an acute BAO needs to be assessed in a randomised controlled trial. FUNDING Department of Neurology, University Medical Center Utrecht.

Basilar artery occlusion

The clinical presentation of basilar artery occlusion (BAO) ranges from mild transient symptoms to devastating strokes with high fatality and morbidity. Often, non-specific prodromal symptoms such as vertigo or headaches are indicative of BAO, and are followed by the hallmarks of BAO, including decreased consciousness, quadriparesis, pupillary and oculomotor abnormalities, dysarthria, and dysphagia. When clinical findings suggest an acute brainstem disorder, BAO has to be confirmed or ruled out as a matter of urgency. If BAO is recognised early and confirmed with multimodal CT or MRI, intravenous thrombolysis or endovascular treatment can be undertaken. The goal of thrombolysis is to restore blood flow in the occluded artery and salvage brain tissue; however, the best treatment approach to improve clinical outcome still needs to be ascertained.

Outcome in patients with basilar artery occlusion treated conventionally

Background: Most data on the outcome of basilar artery occlusion are from recent case series of patients treated with intra-arterial thrombolysis. The limited knowledge on the outcome after a conventional treatment approach comes from a few small case series of highly selected patients. Objective: To provide more data on the outcome of conventional treatment. Methods: Data were analysed on patients from three centres with symptomatic basilar artery occlusion treated conventionally. Conventional therapy was defined as treatment with antiplatelets, anticoagulation, or both. Results: Data were available on 82 patients. The case fatality was 40%. Among survivors, 65% remained dependent (Rankin score 4–5). Patients younger than 60 years (odds ratio = 3.1 (95% confidence interval, 1.0 to 9.5)) and those with a minor stroke (OR = 3.1 (1.0 to 9.6)) were more likely to have a good outcome (Rankin score 0–3). Patients with a progressive stroke were less likely to have a good outcome (OR = 0.3 (0.08 to 1.2)) than patients with a maximum deficit at onset or fluctuating symptoms at presentation. Conclusions: Conventional treatment of symptomatic basilar artery occlusion is associated with a poor outcome in almost 80% of patients, which emphasises the importance of the search for a more effective treatment approach.

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.

Type of Anesthesia and Differences in Clinical Outcome After Intra-Arterial Treatment for Ischemic Stroke

Background and Purpose— Intra-arterial treatment (IAT) in patients with acute ischemic stroke (AIS) can be performed with or without general anesthesia (GA). Previous studies suggested that IAT without the use of GA (non-GA) is associated with better clinical outcome. Nevertheless, no consensus exists about the anesthetic management during IAT of AIS patients. This study investigates the association between type of anesthesia and clinical outcome in a large cohort of patients with AIS treated with IAT. Methods— All consecutive patients with AIS of the anterior circulation who received IAT between 2002 and 2013 in 16 Dutch hospitals were included in the study. Primary outcome was functional outcome on the modified Rankin Scale at discharge. Difference in primary outcome between GA and non-GA was estimated using multiple ordinal regression analysis, adjusting for age, stroke severity, occlusion of the internal carotid artery terminus, previous stroke, atrial fibrillation, and diabetes mellitus. Results— Three hundred forty-eight patients were included in the analysis; 70 patients received GA and 278 patients did not receive GA. Non-GA was significantly associated with good clinical outcome (odds ratio 2.1, 95% confidence interval 1.02–4.31). After adjusting for prespecified prognostic factors, the point estimate remained similar; statistical significance, however, was lost (odds ratio 1.9, 95% confidence interval 0.89–4.24). Conclusions— Our study suggests that patients with AIS of the anterior circulation undergoing IAT without GA have a higher probability of good clinical outcome compared with patients treated with general anesthesia.

Time is Brain(stem) in Basilar Artery Occlusion

Background and Purpose— The frequent use of a longer time window for recanalization therapy in patients with basilar artery occlusion (BAO) in daily practice is not supported by any scientific evidence. We investigated the relationship between time to recanalization therapy and functional outcome in BAO with data from the Basilar Artery International Cooperation Study (BASICS). Methods— BASICS is a prospective multicenter registry of patients (n=619) with radiologically confirmed BAO. We analyzed patients receiving intravenous thrombolysis or intra-arterial treatment. Patients were divided into 4 groups based on the interval between estimated time of BAO and start of recanalization therapy: ⩽3 hours (n=134), >3 to ⩽6 hours (n=151), >6 to ⩽9 hours (n=56), and >9 hours (n=68). Primary outcome measure was poor functional outcome (modified Rankin scale score 4–6) after 1 month. We calculated adjusted risk ratios with 95% CIs using Poisson regression analyses with the ⩽3 hours group as the reference group. Results— Patients had an increased risk of poor functional outcome as time to recanalization therapy became longer (⩽3 hours: 62%; >3 to ⩽6 hours: 67% [adjusted risk ratio, 1.06; 0.91–1.25]; >6 to ⩽9 hours: 77% [adjusted risk ratio, 1.26; 1.06–1.51]; >9 hours: 85% [adjusted risk ratio, 1.47; 1.26–1.72]). Conclusions— Early recanalization therapy in patients with BAO is associated with a more favorable outcome with a significant increased chance of a poor outcome when recanalization therapy is started >6 hours after estimated time of BAO.

Embolization of pulmonary arteriovenous malformations and decrease in prevalence of migraine

Objective: To determine if embolization of pulmonary arteriovenous malformations (PAVMs) decreases the occurrence of migraine. Methods: All 105 patients with hereditary hemorrhagic telangiectasia (HHT), minimum age 16 years, who underwent an embolization of PAVM in our hospital between June 1995 and April 2004, were included in this study. A structured headache questionnaire was sent to all patients and focused on two periods: 1 year before and at least 6 months after embolization. Two independent neurologists diagnosed migraine according to the International Headache Society criteria. Results: Eighty-four patients (80%) sent back the questionnaire (mean age 47.8 ± 15.1 years, 51 female). Median follow-up time was 48 months (first quartile: 23 months; third quartile: 66 months). The overall prevalence of migraine decreased from 45.2% before to 34.5% after embolization (p = 0.01). The prevalence of migraine with aura decreased from 33.3% before to 19.0% after embolization (p = 0.002). The severity of headache attacks decreased in patients who still had migraine (p = 0.15) or migraine with aura after embolization (p = 0.11). Conclusion: Embolization of pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia seems to be related to a decrease in prevalence of migraine, suggesting that the presence of a right-to-left shunt rather than the localization of this shunt plays a causative role in the pathogenesis of migraine.

Diffusion-Weighted MRI in Acute Lacunar Syndromes A Clinical-Radiological Correlation Study

BACKGROUND AND PURPOSE Clinical-radiological correlation studies in lacunar syndromes have been handicapped by the low sensitivity of CT and standard MRI for acute small-vessel infarction and their difficulty in differentiating between acute and chronic lesions. METHODS We prospectively studied 43 patients presenting with a classic lacunar syndrome using diffusion-weighted MRI, a technique with a high sensitivity and specificity for acute small-vessel infarction. RESULTS All patients were scanned within 6 days of stroke onset. An acute infarction was identified in all patients. Pure motor stroke was associated with lesions in the posterior limb of the internal capsule (PLIC), pons, corona radiata, and medial medulla; ataxic hemipareses with lesions in the PLIC, corona radiata, pons, and insular cortex; sensorimotor stroke with lesions in the PLIC and lateral medulla; dysarthria-clumsy hand syndrome with lesions in the PLIC and caudate nucleus; and pure sensory stroke with a lesion in the thalamus. Supratentorial lesions extended into neighboring anatomic structures in 48% of the patients. CONCLUSIONS Lacunar syndromes can be caused by lesions in a variety of locations, and specific locations can cause a variety of lacunar syndromes. Extension of lesions into neighboring structures in patients with lacunar syndromes appears to be more frequent than previously described in studies using CT and standard MRI.

Histopathologic Composition of Cerebral Thrombi of Acute Stroke Patients Is Correlated with Stroke Subtype and Thrombus Attenuation

Introduction We related composition of cerebral thrombi to stroke subtype and attenuation on non-contrast CT (NCCT) to gain more insight in etiopathogenesis and to validate thrombus attenuation as a new imaging biomarker for acute stroke. Methods We histopathologically investigated 22 thrombi retrieved after mechanical thrombectomy in acute stroke patients. First, thrombi were classified as fresh, lytic or organized. Second, percentages of red blood cells (RBCs), platelets and fibrin and number of red, white (respectively RBCs or platelets outnumbering other components with ≥15%) or mixed thrombi were compared between large artery atherosclerosis (LAA), cardioembolism, dissection and unknown subtype. Third, correlation between attenuation and RBCs, platelets and fibrin was calculated using Pearsons correlation coefficients (r). Results Thrombi were fresh in 73% (n = 16), lytic in 18% (n = 4) and organized in 9% (n = 2). The stroke cause was LAA in eight (36%), cardioembolism in six (27%), dissection in three (14%), and unknown in five (23%) patients. LAA thrombi showed the highest percentage RBCs (median 50 (range 35–90)), followed by dissection (35 (20–40), p = 0.05), cardioembolism (35 (5–45), p = 0.013) and unknown subtype (25 (2–40), p = 0.006). No differences in platelets (p = 0.16) and fibrin (p = 0.52) between subtypes were found. LAA thrombi were classified as red or mixed (both n = 4), cardioembolisms as mixed (n = 5) or white (n = 1) and dissection as mixed (n = 3). There was a moderate positive correlation between attenuation and RBCs (r = 0.401, p = 0.049), and weak negative correlations with platelets (r = −0.368, p = 0.09) and fibrin (r = −0.073, p = 0.75). Conclusions The majority of cerebral thrombi is fresh. There are no differences in age of thrombi between subtypes. LAA thrombi have highest percentages RBCs, cardioembolism and unknown subtype lowest. No relationship exists between subtype and platelets or fibrin percentages. We found a correlation between the RBC-component and thrombus attenuation, which improves validation of thrombus attenuation on NCCT as an imaging biomarker for stroke management.