Catharina J.M. Klijn

Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis

BACKGROUND Since the early 1980s, imaging techniques have enabled population-based studies of intracerebral haemorrhage. We aimed to assess the incidence, case fatality, and functional outcome of intracerebral haemorrhage in relation to age, sex, ethnic origin, and time period in studies published since 1980. METHODS From PubMed and Embase searches with predefined inclusion criteria, we identified population-based studies published between January, 1980, and November, 2008. We calculated incidence and case fatality. Incidences for multiple studies were pooled in a random-effects binomial meta-analysis. Time trends of case fatality were assessed with weighted linear-regression analysis. FINDINGS 36 eligible studies described 44 time periods (mid-year range 1983-2006). These studies included 8145 patients with intracerebral haemorrhage. Incidence did not decrease between 1980 and 2008. Overall incidence was 24.6 per 100 000 person-years (95% CI 19.7-30.7). Incidence was not significantly lower in women than in men (overall incidence ratio 0.85, 95% CI 0.61-1.18). Using the age group 45-54 years as reference, incidence ratios increased from 0.10 (95% CI 0.06-0.14) for people aged less than 45 years to 9.6 (6.6-13.9) for people older than 85 years. Median case fatality at 1 month was 40.4% (range 13.1-61.0) and did not decrease over time, and was lower in Japan (16.7%, 95% CI 15.0-18.5) than elsewhere (42.3%, 40.9-43.6). Six studies reported functional outcome, with independency rates of between 12% and 39%. Incidence of intracerebral haemorrhage per 100 000 person-years was 24.2 (95% CI 20.9-28.0) in white people, 22.9 (14.8-35.6) in black people, 19.6 (15.7-24.5) in Hispanic people, and 51.8 (38.8-69.3) in Asian people. INTERPRETATION Incidence of intracerebral haemorrhage increases with age and has not decreased between 1980 and 2006. Case fatality is lower in Japan than elsewhere, increases with age, and has not decreased over time. More data on functional outcome are needed. FUNDING Netherlands Heart Foundation.

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.

Symptomatic carotid artery occlusion. A reappraisal of hemodynamic factors.

BACKGROUND Over the last several years evidence has accumulated that in addition to embolism, a compromised cerebral blood flow may play an important role in causing transient ischemic attacks and ischemic stroke in patients with occlusion of the internal carotid artery. This evidence is found in both clinical features and ancillary investigations, particularly measurements of cerebral blood flow. SUMMARY OF REVIEW On the basis of 20 follow-up studies in patients with transient ischemic attacks or minor ischemic stroke associated with an occluded carotid artery, the annual risk of stroke was 5.5% (95% confidence interval [CI], 5.0% to 6.0%), and that of ipsilateral stroke (distinguished in 11 of the 20 studies) was 2.1% (95% CI, 1.6% to 2.8%). Patients with a compromised cerebral blood flow as measured by positron emission tomography, single-photon emission CT, transcranial Doppler, or stable xenon CT (six studies) have an even higher annual risk of stroke (all strokes: 12.5%; 95% CI, 8.9% to 17.6%; ipsilateral stroke: 9.5%; 95% CI, 6.4% to 14.0%). CONCLUSIONS Because a compromised cerebral blood flow may be an important causal factor in patients with symptomatic carotid artery occlusion, medical and surgical options for treatment are reviewed in this light.

European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage

Background Intracerebral hemorrhage (ICH) accounted for 9% to 27% of all strokes worldwide in the last decade, with high early case fatality and poor functional outcome. In view of recent randomized controlled trials (RCTs) of the management of ICH, the European Stroke Organisation (ESO) has updated its evidence-based guidelines for the management of ICH. Method A multidisciplinary writing committee of 24 researchers from 11 European countries identified 20 questions relating to ICH management and created recommendations based on the evidence in RCTs using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results We found moderate- to high-quality evidence to support strong recommendations for managing patients with acute ICH on an acute stroke unit, avoiding hemostatic therapy for acute ICH not associated with antithrombotic drug use, avoiding graduated compression stockings, using intermittent pneumatic compression in immobile patients, and using blood pressure lowering for secondary prevention. We found moderate-quality evidence to support weak recommendations for intensive lowering of systolic blood pressure to <140 mmHg within six-hours of ICH onset, early surgery for patients with a Glasgow Coma Scale score 9–12, and avoidance of corticosteroids. Conclusion These guidelines inform the management of ICH based on evidence for the effects of treatments in RCTs. Outcome after ICH remains poor, prioritizing further RCTs of interventions to improve outcome.

Treatment of Brain Arteriovenous Malformations: A Systematic Review and Meta-analysis

CONTEXT Outcomes following treatment of brain arteriovenous malformations (AVMs) with microsurgery, embolization, stereotactic radiosurgery (SRS), or combinations vary greatly between studies. OBJECTIVES To assess rates of case fatality, long-term risk of hemorrhage, complications, and successful obliteration of brain AVMs after interventional treatment and to assess determinants of these outcomes. DATA SOURCES We searched PubMed and EMBASE to March 1, 2011, and hand-searched 6 journals from January 2000 until March 2011. STUDY SELECTION AND DATA EXTRACTION We identified studies fulfilling predefined inclusion criteria. We used Poisson regression analyses to explore associations of patient and study characteristics with case fatality, complications, long-term risk of hemorrhage, and successful brain AVM obliteration. DATA SYNTHESIS We identified 137 observational studies including 142 cohorts, totaling 13,698 patients and 46,314 patient-years of follow-up. Case fatality was 0.68 (95% CI, 0.61-0.76) per 100 person-years overall, 1.1 (95% CI, 0.87-1.3; n = 2549) after microsurgery, 0.50 (95% CI, 0.43-0.58; n = 9436) after SRS, and 0.96 (95% CI, 0.67-1.4; n = 1019) after embolization. Intracranial hemorrhage rates were 1.4 (95% CI, 1.3-1.5) per 100 person-years overall, 0.18 (95% CI, 0.10-0.30) after microsurgery, 1.7 (95% CI, 1.5-1.8) after SRS, and 1.7 (95% CI, 1.3-2.3) after embolization. More recent studies were associated with lower case-fatality rates (rate ratio [RR], 0.972; 95% CI, 0.955-0.989) but increased rates of hemorrhage (RR, 1.02; 95% CI, 1.00-1.03). Male sex (RR, 0.964; 95% CI, 0.945-0.984), small brain AVMs (RR, 0.988; 95% CI, 0.981-0.995), and those with strictly deep venous drainage (RR, 0.975; 95% CI, 0.960-0.990) were associated with lower case fatality. Lower hemorrhage rates were associated with male sex (RR, 0.976, 95% CI, 0.964-0.988), small brain AVMs (RR, 0.988, 95% CI, 0.980-0.996), and brain AVMs with deep venous drainage (0.982, 95% CI, 0.969-0.996). Complications leading to permanent neurological deficits or death occurred in a median 7.4% (range, 0%-40%) of patients after microsurgery, 5.1% (range, 0%-21%) after SRS, and 6.6% (range, 0%-28%) after embolization. Successful brain AVM obliteration was achieved in 96% (range, 0%-100%) of patients after microsurgery, 38% (range, 0%-75%) after SRS, and 13% (range, 0%-94%) after embolization. CONCLUSIONS Although case fatality after treatment has decreased over time, treatment of brain AVM remains associated with considerable risks and incomplete efficacy. Randomized controlled trials comparing different treatment modalities appear justified.

Outcome after spontaneous and arteriovenous malformation-related intracerebral haemorrhage: population-based studies

Spontaneous (non-traumatic) intracerebral haemorrhage (ICH) has a high case-fatality and leaves many survivors disabled. Clinical characteristics and outcome seem to vary according to the cause of ICH, but population-based comparisons are scarce. We studied two prospective, population-based cohorts to determine differences in outcome [case-fatality and modified Rankin Scale (mRS)] after incident ICH due to brain arteriovenous malformations (AVM) [Scottish Intracranial Vascular Malformation Study (SIVMS), n = 90] and spontaneous ICH [Oxford Vascular Study (OXVASC), n = 60]. Patients with AVM-ICH were younger, had lower pre-stroke and admission blood pressure (BP), higher admission Glasgow Coma Scale (GCS) and were more likely to have an ICH in a lobar location than patients with spontaneous ICH (sICH). Case fatality throughout 2-year follow-up was greater following sICH than AVM-ICH [34/56 (61%) versus 11/90 (12%) at 1 year, odds ratio (OR) 11 (95% Confidence Interval (CI) 5-25)], as was death or dependence (mRS >or= 3) [40/48 (83%) versus 26/65 (40%) at 1 year, OR 8 (3-19)]. Differences in outcome persisted following stratification by age and sensitivity analyses. In multivariable analyses of 1 year outcome, independent predictors of death were sICH (OR 21, 4-104) and increasing ICH volume (OR 1.03, 1.01-1.05), and independent predictors of death or dependence were sICH (OR 11, 2-62) and GCS on admission (OR 0.79, 0.67-0.93). Outcome after AVM-ICH is better than after sICH, independent of patient age and other known predictors of ICH outcome.

Comparison of Telephone and Face-to-Face Assessment of the Modified Rankin Scale

Background: A structured interview improves the reliability of the modified Rankin Scale (mRS), a commonly used functional outcome scale in stroke trials. Telephone interview is a fast and convenient way to assess the mRS grade, but its validity is unknown. We assessed the validity of a telephone interview in patients who had had an aneurysmal subarachnoid haemorrhage (SAH) by comparing it with a face-to-face assessment. Methods: Eighty-three SAH patients were interviewed twice, once face-to-face and once by telephone, by 2 of 5 observers who used a structured interview to assess the mRS grade. Intermodality agreement was measured using weighted kappa statistics. To check for systematic differences between face-to-face and telephone assessment the Wilcoxon test for matched pairs was used. Results: Agreement between telephone and face-to-face assessment was perfect in 47 (57%) patients. A difference of 1 level occurred in 31 (37%) patients and this was almost equally distributed over the grades of the mRS. Weighted kappa was 0.71 (95% CI 0.59–0.82). Telephone assessment did not result in a consistently more or less favourable grade than face-to-face assessment (Wilcoxon test for matched pairs, p = 0.33). Conclusions: Telephone assessment of the mRS with a structured interview has a good agreement with face-to-face assessment and can thus be used reliably in the setting of a clinical trial.

Arterial spin labeling perfusion MRI at multiple delay times: a correlative study with H215O positron emission tomography in patients with symptomatic carotid artery occlusion

Arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) with image acquisition at multiple inversion times is a noninvasive ASL technique able to compensate for spatial heterogeneities in transit times caused by collateral blood flow in patients with severe stenosis of the cerebropetal blood vessels. Our aim was to compare ASL-MRI and H215O positron emission tomography (PET), the gold standard for cerebral blood flow (CBF) assessment, in patients with a symptomatic internal carotid artery (ICA) occlusion. Fourteen patients (63±14 years) with a symptomatic ICA occlusion underwent both ASL-MRI and H215O PET. The ASL-MRI was performed using a pulsed STAR labeling technique at multiple inversion times within 7 days of the PET. The CBF was measured in the gray-matter of the anterior, middle and posterior cerebral artery, and white-matter. Both PET and ASL-MRI showed a significantly decreased CBF in the gray-matter of the middle cerebral artery in the hemisphere ipsilateral to the ICA occlusion. The average gray-matter CBF measured with ASL-MRI (71.8±4.3 mL/min/100 g) was higher (P<0.01) than measured with H215O PET (43.1±1.0 mL/min/100 g). In conclusion, ASL-MRI at multiple TIs is capable of depicting areas of regions with low CBF in patients with an occlusion of the ICA, although a systematic overestimation of CBF relative to H215O PET was noted.

Recurrent ischemia in symptomatic carotid occlusion Prognostic value of hemodynamic factors

Objective: To identify hemodynamic factors that predict recurrence of ipsilateral cerebral ischemic events in patients with symptomatic carotid artery occlusion (CAO). Patients and Methods: The authors studied 117 consecutive patients with CAO and corresponding recent (≤6 months) ischemic symptoms of the brain or eye that were transient or at most mildly disabling. They determined, using Cox proportional hazards analysis, the prognostic value for recurrence of ipsilateral cerebral ischemic events of 1) clinical features believed to indicate hemodynamic compromise, 2) collateral blood flow pattern, and 3) transcranial Doppler CO2-reactivity. Results: None of the 24 patients with symptoms of retinal ischemia alone had a recurrent cerebral ischemic event. In the 93 patients with cerebral ischemic symptoms on entry, recurrence of these symptoms was independently predicted by 1) the nature of the initial symptoms being of purported hemodynamic origin (limb-shaking, precipitation of symptoms by rising, exercise or low blood pressure, retinal claudication) (hazard ratio [HR] 3.8, 95% CI 1.5 to 9.5), 2) continuing symptoms after the CAO had been documented, but before inclusion in the study (HR 5.9, 95% CI 2.2 to 16.1), and 3) the presence of collateral blood flow via leptomeningeal vessels (HR 4.1, 95% CI 1.3 to 13.1). CO2-reactivity did not predict recurrence of cerebral ischemic events. Conclusions: Having cerebral in contrast to retinal ischemia, clinical features suggestive of hemodynamic compromise, continuing symptoms after demonstration of the CAO, and presence of leptomeningeal collaterals may help to identify patients with symptomatic CAO at high risk of future cerebral ischemia.

Cognitive disorders in patients with occlusive disease of the carotid artery: a systematic review of the literature

Abstract We present a systematic review of the literature on the prevalence, nature, severity, course, and causes of cognitive deficits in patients with occlusive disease of the carotid artery prior to surgery (if surgery was under discussion). Searches were carried out on Medline and Psychlit from 1980 to 1999 using neurovascular and psychological index terms, and papers and books were checked for further references. Studies describing neuropsychological assessment of groups of patients with carotid obstruction were included. Eighteen studies were found. We extracted from the papers data on study design, demographic characteristics of patients, clinical diagnosis, carotid obstruction, cerebral imaging, time interval between ischemic episode and neuropsychological assessment, neuropsychological asessment procedures, integration and interpretation of test performances, and conclusions of authors. Fourteen studies concluded that there are cognitive deficits both in patients with symptomatic and in those with asymptomatic carotid obstruction; four studies denied cognitive impairment. There were no differences in patient characteristics, study design, or neuropsychological assessment procedures between the 14 studies that found deficits and the 4 that did not. There are indications for a mild, diffuse, detrimental effect of carotid occlusive disease on cognitive functioning. However, methodological problems prevent a definitive conclusion. Further research is needed to confirm these findings and to ascertain the neurovascular risk factors for and the natural course of cognitive impairment in patients with carotid occlusive disease.