Joachim Berkefeld

Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial.

BACKGROUND The clinical benefit of preventive eradication of unruptured brain arteriovenous malformations remains uncertain. A Randomised trial of Unruptured Brain Arteriovenous malformations (ARUBA) aims to compare the risk of death and symptomatic stroke in patients with an unruptured brain arteriovenous malformation who are allocated to either medical management alone or medical management with interventional therapy. METHODS Adult patients (≥18 years) with an unruptured brain arteriovenous malformation were enrolled into this trial at 39 clinical sites in nine countries. Patients were randomised (by web-based system, in a 1:1 ratio, with random permuted block design [block size 2, 4, or 6], stratified by clinical site) to medical management with interventional therapy (ie, neurosurgery, embolisation, or stereotactic radiotherapy, alone or in combination) or medical management alone (ie, pharmacological therapy for neurological symptoms as needed). Patients, clinicians, and investigators are aware of treatment assignment. The primary outcome is time to the composite endpoint of death or symptomatic stroke; the primary analysis is by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389181. FINDINGS Randomisation was started on April 4, 2007, and was stopped on April 15, 2013, when a data and safety monitoring board appointed by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health recommended halting randomisation because of superiority of the medical management group (log-rank Z statistic of 4·10, exceeding the prespecified stopping boundary value of 2·87). At this point, outcome data were available for 223 patients (mean follow-up 33·3 months [SD 19·7]), 114 assigned to interventional therapy and 109 to medical management. The primary endpoint had been reached by 11 (10·1%) patients in the medical management group compared with 35 (30·7%) in the interventional therapy group. The risk of death or stroke was significantly lower in the medical management group than in the interventional therapy group (hazard ratio 0·27, 95% CI 0·14-0·54). No harms were identified, other than a higher number of strokes (45 vs 12, p<0·0001) and neurological deficits unrelated to stroke (14 vs 1, p=0·0008) in patients allocated to interventional therapy compared with medical management. INTERPRETATION The ARUBA trial showed that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with unruptured brain arteriovenous malformations followed up for 33 months. The trial is continuing its observational phase to establish whether the disparities will persist over an additional 5 years of follow-up. FUNDING National Institutes of Health, National Institute of Neurological Disorders and Stroke.

Leukoaraiosis Is a Risk Factor for Symptomatic Intracerebral Hemorrhage After Thrombolysis for Acute Stroke

Background and Purpose— The aim of the study was to evaluate whether leukoaraiosis (LA) is a risk factor for symptomatic intracerebral hemorrhage (sICH) in patients treated with thrombolysis for acute stroke. Methods— In this retrospective, multicenter analysis, we evaluated data from acute anterior circulation stroke patients (n=449; <6 hours after symptom onset) treated with thrombolysis. All patients had received standard magnetic resonance imaging evaluation before thrombolysis, including a high-quality T2-weighted sequence. For the analysis, LA in the deep white matter was dichotomized into absent or mild versus moderate or severe (corresponding to Fazekas scores of 0 to 1 versus 2 to 3). Results— The rate of sICH was significantly more frequent in patients with moderate to severe LA of the deep white matter (n=12 of 114; 10.5%) than in patients without relevant LA (n=13 of 335; 3.8%), corresponding to an odds ratio of 2.9 (95% CI, 1.29 to 6.59; P=0.015). In a logistic-regression analysis (including age, National Institutes of Health Stroke Scale score at presentation, and type of thrombolytic treatment), LA remained a significant independent risk factor (odds ratio, 2.9; P=0.03). Conclusions— LA of the deep white matter is an independent risk factor for sICH after thrombolytic treatment for acute stroke.

Serum S100B Predicts a Malignant Course of Infarction in Patients With Acute Middle Cerebral Artery Occlusion

Background and Purpose— Early predictors of infarct volume may improve therapeutic decisions in patients with acute cerebral ischemia. We investigated whether measurements of serum astroglial protein S100B can predict a malignant course of infarction in acute middle cerebral artery (MCA) occlusion. Methods— We included 51 patients (24 women, mean age 69.1±12.4 years) admitted within 6 hours after stroke symptom onset caused by proximal MCA occlusion, as shown by magnetic resonance angiography (n=39), intra-arterial angiography (n=4), or transcranial duplex sonography (n=8). Blood samples were drawn at hospital admission and 8, 12, 16, 20, and 24 hours after symptom onset. Serum S100B concentrations were determined using a fully automated immunoluminometric assay. A malignant course of infarction was defined as the occurrence of clinical signs of cerebral herniation within the first 7 days of treatment or the clinical decision to perform decompressive hemicraniectomy caused by critical space-occupying swelling as detected by repeated neuroimaging. Results— Sixteen patients developed malignant infarction (31%). Beginning with the 12-hour value, mean S100B serum concentrations were significantly higher in patients with a malignant course compared with those without (12 hours 1.23±1.24 versus 0.29±0.45 μg/L; 16 hours 1.80±1.65 versus 0.38±0.53 μg/L; 20 hours 1.90±1.53 versus 0.44±0.48 μg/L; and 24 hours 2.41±1.59 versus 0.57±0.66 μg/L; all P <0.001). A 12-hour S100B value >0.35 μg/L predicted malignant infarction with 0.75 sensitivity and 0.80 specificity. A 24-hour value >1.03 μg/L provided 0.94 sensitivity and 0.83 specificity. Conclusions— The serum marker S100B can predict a malignant course of infarction in proximal MCA occlusion. This finding may improve the identification and monitoring of patients at particularly high risk for herniation.

Serum glial fibrillary acidic protein as a biomarker for intracerebral haemorrhage in patients with acute stroke

Background: Biomarkers of stroke are an evolving field of clinical research. A serum marker which can differentiate between haemorrhagic and ischaemic stroke in the very early phase would help to optimise acute stroke management. Objective: To examine whether serum glial fibrillary acidic protein (GFAP) identifies intracerebral haemorrhage (ICH) in acute stroke patients. Methods: A pilot study assessing 135 stroke patients admitted within six hours after symptom onset. Diagnosis of ICH (n = 42) or ischaemic stroke (n = 93) was based on brain imaging. GFAP was determined from venous blood samples obtained immediately after admission, using a research immunoassay. Results: GFAP was detectable in the serum of 39 patients (34 of 42 (81%) with ICH, and five of 93 (5%) with ischaemic stroke). Serum GFAP was substantially raised in patients with ICH (median 11 ng/l, range 0 to 3096 ng/l) compared with patients with ischaemic stroke (median 0 ng/l, range 0 to 14 ng/l, p<0.001). Using receiver operating characteristic curve analysis, a cut off point of 2.9 ng/l provided a sensitivity of 0.79 and a specificity of 0.98 for the identification of ICH in acute stroke (positive predictive value 0.94, negative predictive value 0.91; p<0.001). Conclusions: Serum GFAP can reliably detect ICH in the acute phase of stroke. Further evaluation of the usefulness of GFAP as an early diagnostic marker of ICH is now required, with the aim of optimising cause specific emergency management.

Mechanical recanalization in basilar artery occlusion: The ENDOSTROKE study

A study was undertaken to evaluate clinical and procedural factors associated with outcome and recanalization in endovascular stroke treatment (EVT) of basilar artery (BA) occlusion.

Sentinel Headache and the Risk of Rebleeding After Aneurysmal Subarachnoid Hemorrhage

Background and Purpose— The clinical significance of sentinel headaches in patients with subarachnoid hemorrhage (SAH) is still unknown. We investigated whether patients with a sentinel headache (SH) have a higher rate of rebleeding after SAH. Methods— An SH was defined as a sudden, severe, unknown headache lasting >1 hour with or without accompanying symptoms, not leading to a diagnosis of SAH in the 4 weeks before the index SAH. Age, sex, smoking status, clinical grade, computed tomography (CT) findings, angiographic findings, placement of an external ventricular drain, and time to aneurysm obliteration were prospectively recorded. All rebleeding events were confirmed by CT. Outcome was assessed at 6 months according to the modified Rankin Scale. Results— Of 237 consecutive patients with SAH, 41 (17.3%) had an SH. Rebleeding occurred in 23 (9.7%) of all patients. Patients with an SH had a 10-fold increased odds of rebleeding compared with patients without SH. Aneurysm size and the total number of aneurysms were also significantly associated with rebleeding. There were no differences in age, sex, smoking, CT or angiographic findings, external ventricular drain placement, or time to aneurysm obliteration between groups. Patients with rebeeding had a significantly worse outcome. Logistic regression revealed the presence of an SH as an independent risk factor for rebleeding. Conclusions— In our study, patients with SAH who had an SH constituted a special group of patients with a 10-fold odds for early rebleeding. The presence of an SH may select candidates for ultraearly aneurysm obliteration or drug treatment.

Risk Assessment of Symptomatic Intracerebral Hemorrhage After Thrombolysis Using DWI-ASPECTS

Background and Purpose— Pretreatment lesion size on diffusion-weighted imaging (DWI) is a risk factor for symptomatic intracerebral hemorrhage (sICH) associated with thrombolytic treatment. Here, we investigated whether the Alberta Stroke Programme Early CT Score (ASPECTS) applied to DWI images (DWI-ASPECTS) predicts sICH risk accurately. Methods— In this retrospective multicenter study, prospectively collected data of 217 patients with anterior circulation stroke treated with intravenous or intraarterial thrombolysis within 6 hours after symptom onset were analyzed. Pretreatment DWI-ASPECTS scores were assessed by 2 independent investigators. For bleeding risk analysis, DWI-ASPECTS scores were either categorized into 0 to 7 (n=105) or 8 to 10 (n=112) or in 3 groups of similar sample size (DWI-ASPECTS 0 to 5 [n=69], 6 to 7 [n=70], and 8 to 10 [n=78]). Results— DWI-ASPECTS scores correlated well with the DWI lesion volume (r=0.77, P<0.001, Spearman Rank test). Interobserver reliability for the assessment of DWI-ASPECTS was moderate (weighted kappa 0.441 [95% CI 0.373 to 0.509]). Twenty-three (10.6%) patients developed sICH. The sICH rate was significantly higher in patients with DWI-ASPECTS scores 0 to 7 (n=21, 15.1%) as compared to patients with DWI-ASPECTS scores 8 to 10 (n=2, 2.6%, P=0.004). sICH risk was 20.3%, 10%, and 2.6% in the 0 to 5, 6 to 7, and 8 to 10 DWI-ASPECTS groups, respectively. DWI-ASPECTS remained an independent prognostic factor for sICH after adjustment for clinical baseline variables (age, NIHSS, time to thrombolysis). Conclusions— DWI-ASPECTS predicts sICH risk after thrombolysis and may be helpful to contributing to quick sICH risk assessment before thrombolytic therapy.

Difference in configuration of ruptured and unruptured intracranial aneurysms determined by biplanar digital subtraction angiography

Summary¶Summary There is an ongoing discussion about the risk of bleeding from unruptured intracranial aneurysms. Management guidelines were developed recently and some of the recommendations for decision making are based on the anatomical configuration of the aneurysm. The common assumption is that the presence of multiple lobes or a daughter sac indicates a higher risk of rupture. We have investigated the anatomical configuration of ruptured and unruptured intracranial aneurysms using biplanar digital subtraction angiography (DSA). The objective was to determine, whether there was a difference between ruptured and unruptured aneurysms regarding lobulation, the presence of a daughter sac or the shape as measured by the height/neck ratio.Biplanar DSA images of 124 patients were retrospectively analyzed. A total of 53 unruptured and 94 ruptured aneurysms were found (=147 aneurysms in total). Aneurysms of less than 10 mm diameter accounted for 82% of all aneurysms. Overall, 10% of unruptured aneurysm showed a multilobular appearance on DSA compared with 20% of ruptured aneurysms (Fisher’s exact test, p=0.10). In the 5–9 mm aneurysm group, multiple lobes were found significantly more frequent in ruptured aneurysms (26% vs. 4%, Fisher’s exact test, p<0.05). A height/neck ratio of less than 1.5 was not found in unruptured aneurysms (0/26) but in 21% (12/57) of ruptured aneurysms (p<0.05).Our data provide scientific support for using morphological features for the decision making process in the management of unruptured intracranial aneurysms. An irregular multilobar appearance was significantly more common in aneurysms of 5–9 mm size that ruptured.

Treatment related morbidity of unruptured intracranial aneurysms: results of a prospective single centre series with an interdisciplinary approach over a 6 year period (1999–2005)

Objectives: To review the angiographic and clinical outcome of patients with unruptured intracranial aneurysm(s) (UIA) with regard to complications and successful obliteration by surgical clipping or endovascular coiling. Methods: Data were derived from a prospective database of intracranial aneurysms from June 1999 to May 2005. All patients were followed-up for 6 months using the modified Rankin Scale (mRS). Favourable outcome was classified as mRS 0–2. From a total of 691 patients included in the database, 173 harboured 206 UIA of whom 118 patients (133 UIA) were treated. Results: Primary treatment assignment was surgical repair in 91 UIA and endovascular treatment in 42. In 3 UIA (7.1%), endovascular treatment was not feasible and had to be abandoned. Definite treatment was surgery in 94 UIA (81 patients) and endovascular obliteration in 39 UIA (37 patients). There were no deaths related to any treatment. Immediately after treatment, 6.4% of the surgical and 7.7% of the endovascular patients showed new neurological deficits, mainly related to cerebral ischaemia. After 6 months, 3 (2.3%) patients had a treatment related unfavourable outcome, defined as mRS >2, 2 patients after surgical and 1 patient after endovascular aneurysm repair (not statistically different, p = 0.3; Fisher’s exact test). This led to an overall satisfactory outcome in 97.9% of surgically and 97.4% of endovasculary treated UIA. After surgical clipping, complete occlusion of the aneurysm was achieved in 88 (93.6%) and near complete (small residual neck) in 4 (4.3%) of 94 UIA. Two small posterior communicating artery aneurysms with a fetal type posterior communicating artery were wrapped. After endovascular treatment, obliteration was complete in 26 (66.7%). Small residual neck was seen in 13 (33.3%), but none of the UIA showed residual aneurysm filling. Five patients in the endovascular group (13.9%) underwent repeated endovascular treatment after aneurysm recanalisation. Conclusions: If patients are carefully selected and individually assigned to their optimum treatment modality, UIA can be obliterated by surgery or endovascular treatment in the majority of patients, with a low percentage of unfavourable outcomes. In this series, the outcome was not dependent on treatment. However, the rate of recanalisation of UIA is higher after endovascular obliteration. After diagnosis of an UIA, an individual interdisciplinary decision is essential for each patient to provide the optimum management.

Endovascular Treatment of Symptomatic Carotid Stenosis Using Stent Placement Long-Term Follow-Up of Patients With a Balanced Surgical Risk/Benefit Ratio

Background and Purpose— Carotid endarterectomy (CEA) is not necessarily beneficial in all patients with symptomatic high-grade (≥70%) internal carotid artery (ICA) stenosis. Independent risk factors modulate both the individual stroke risk under medical treatment and the combined stroke and death risk after CEA. Endovascular stenting of symptomatic ICA stenosis may be an alternative to CEA in patients with a balanced surgical risk/benefit ratio. Methods— We included 43 patients (71% men; median age, 67 years) with a recently symptomatic ICA stenosis with ≥70% luminal narrowing in whom the individual sum of medical and surgical risk factors suggested a balanced surgical risk/benefit ratio (risk-modeling appraisal derived from the European Carotid Surgery Trial). After stenting of the stenosed ICA with distal balloon protection, the mean±SD follow-up, including clinical and ultrasonographic examinations, was 20±11.8 months, with a median number of examinations of 5 per patient. Results— Recanalization of ICA stenoses was technically successful in 40 of 43 procedures (93%). Within the 30-day postinterventional period 1 death occurred (2.5%), and the combined stroke and death rate within follow-up was 5%. Except for 1 asymptomatic ICA occlusion, no restenosis ≥70% occurred during follow-up. Conclusions— ICA stenting in symptomatic patients with a balanced surgical risk/benefit ratio is technically feasible, with a low periprocedural risk of stroke or death. Furthermore, the risk of future stroke and rate of significant restenosis during long-term follow-up appears to be low, suggesting that ICA stenting may be useful in carotid revascularization and stroke prevention.