Marieke J.H. Wermer

Risk of Rupture of Unruptured Intracranial Aneurysms in Relation to Patient and Aneurysm Characteristics An Updated Meta-Analysis

Background and Purpose— We updated our previous review from 1996 on the risk of rupture of unruptured intracranial aneurysms, aiming to include the newly published articles. Methods— We reviewed all studies from our former meta-analysis and performed a Medline search for new studies published after 1996. We calculated overall risks of rupture for studies with a mean follow-up time of <5, 5 to 10, and >10 years. Relative risks (RR) were calculated by comparing the risk of rupture in patients with and without potential risk factors. We aimed to perform multivariable analyses of the different risk factors with meta-regression analysis. Results— We included 19 studies (10 new) with 4705 patients and 6556 unruptured aneurysms (follow-up 26 122 patient-years). The overall rupture risks were 1.2% (follow-up <5 years), 0.6% (follow-up 5 to 10 years), and 1.3% (follow-up >10 years). In the univariable analysis, statistically significant risk factors for rupture were age >60 years (RR 2.0; 95% confidence interval [CI], 1.1 to 3.7), female gender (RR 1.6; 95% CI, 1.1 to 2.4), Japanese or Finnish descent (RR 3.4; 95% CI, 2.6 to 4.4), size >5 mm (RR 2.3; 95% CI, 1.0 to 5.2), posterior circulation aneurysm (RR 2.5; 95% CI, 1.6 to 4.1), and symptomatic aneurysm (RR 4.4; 95% CI, 2.8 to 6.8). Meta-regression analysis yielded implausible results. Conclusions— Age, gender, population, size, site, and type of aneurysm should be considered in the decision whether to treat an unruptured aneurysm. Pooled multivariable analyses of individual data are needed to identify independent risk factors and to provide more reliable risk estimates for individual patients.

Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies

BACKGROUND The decision of whether to treat incidental intracranial saccular aneurysms is complicated by limitations in current knowledge of their natural history. We combined individual patient data from prospective cohort studies to determine predictors of aneurysm rupture and to construct a risk prediction chart to estimate 5-year aneurysm rupture risk by risk factor status. METHODS We did a systematic review and pooled analysis of individual patient data from 8382 participants in six prospective cohort studies with subarachnoid haemorrhage as outcome. We analysed cumulative rupture rates with Kaplan-Meier curves and assessed predictors with Cox proportional-hazard regression analysis. FINDINGS Rupture occurred in 230 patients during 29,166 person-years of follow-up. The mean observed 1-year risk of aneurysm rupture was 1·4% (95% CI 1·1-1·6) and the 5-year risk was 3·4% (2·9-4·0). Predictors were age, hypertension, history of subarachnoid haemorrhage, aneurysm size, aneurysm location, and geographical region. In study populations from North America and European countries other than Finland, the estimated 5-year absolute risk of aneurysm rupture ranged from 0·25% in individuals younger than 70 years without vascular risk factors with a small-sized (<7 mm) internal carotid artery aneurysm, to more than 15% in patients aged 70 years or older with hypertension, a history of subarachnoid haemorrhage, and a giant-sized (>20 mm) posterior circulation aneurysm. By comparison with populations from North America and European countries other than Finland, Finnish people had a 3·6-times increased risk of aneurysm rupture and Japanese people a 2·8-times increased risk. INTERPRETATION The PHASES score is an easily applicable aid for prediction of the risk of rupture of incidental intracranial aneurysms. FUNDING Netherlands Organisation for Health Research and Development.

Incidence of Recurrent Subarachnoid Hemorrhage After Clipping for Ruptured Intracranial Aneurysms

Background and Purpose— Because intracranial aneurysms develop during life, patients with subarachnoid hemorrhage (SAH) and successfully occluded aneurysms are at risk for a recurrence. We studied the incidence of and risk factors for recurrent SAH in patients who regained independence after SAH and in whom all aneurysms were occluded by means of clipping. Methods— From a cohort of patients with SAH admitted between 1985 and 2001, we included those patients who were discharged home or to a rehabilitation facility. We interviewed these patients about new episodes of SAH. We retrieved all medical records and radiographs in case of reported recurrences. If patients had died, we retrieved the cause of death. We analyzed the incidence of and risk factors for recurrent SAH by Kaplan-Meier curves and Cox regression analysis. Results— Of 752 patients with 6016 follow-up years (mean follow up 8.0 years), 18 had a recurrence. In the first 10 years after the initial SAH, the cumulative incidence of recurrent SAH was 3.2% (95% confidence interval [CI], 1.5% to 4.9%) and the incidence rate 286 of 100 000 patient-years (95% CI, 160 to 472 per 100 000). Risk factors were smoking (hazard ratio [HR], 6.5; 95% CI, 1.7 to 24.0), age (HR, 0.5 per 10 years; 95% CI, 0.3 to 0.8) and multiple aneurysms at the time of the initial SAH (HR, 5.5; 95% CI, 2.2 to 14.1). Conclusions— After SAH, the incidence of a recurrence within the first 10 years is 22 (12 to 38) times higher than expected in populations with comparable age and sex. Whether this increased risk justifies screening for recurrent aneurysms in patients with a history of SAH requires further study.

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.

Subarachnoid hemorrhage treated with clipping: long-term effects on employment, relationships, personality, and mood.

OBJECTIVEOnly one-third of patients regain functional independence after aneurysmal subarachnoid hemorrhage (SAH). Despite this recovery, many of these patients experience psychosocial problems. We assessed the long-term effects of SAH on employment, relationships, personality, and mood. METHODSWe included patients who had been treated by clipping after SAH between 1985 and 2001 and who resumed independent living. Patients underwent structured interviews regarding employment, relationships, and personality before and after the SAH. Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale, and scores were compared between the study group and a control population. RESULTSSix hundred and ten patients were interviewed (mean follow-up after SAH, 8.9 yr). Of the employed patients, 26% stopped working and 24% worked shorter hours or had a position with less responsibility. On average, patients returned to work 9.4 months after discharge (range, 0–96 mo). Seven percent of patients were divorced because of SAH-related problems. Fifty-nine percent of the patients reported changes in personality, with the most commonly noted changes being increased irritability (37%) or emotionality (29%). Patients with SAH had a statistically significant higher mean depression score than the control population. Approximately 10% of the patients had a Hospital Anxiety and Depression Scale score in the range of a probable depressive or anxious state. Only 25% reported a complete recovery without psychosocial or neurological problems. CONCLUSIONThe long-term psychosocial effects of SAH are considerable, even in patients who regain functional independence. Treating physicians should be aware of these long-term effects of SAH when discussing prognosis and reintegration to work after initial recovery with patients and family.

The unruptured intracranial aneurysm treatment score A multidisciplinary consensus

Objective: We endeavored to develop an unruptured intracranial aneurysm (UIA) treatment score (UIATS) model that includes and quantifies key factors involved in clinical decision-making in the management of UIAs and to assess agreement for this model among specialists in UIA management and research. Methods: An international multidisciplinary (neurosurgery, neuroradiology, neurology, clinical epidemiology) group of 69 specialists was convened to develop and validate the UIATS model using a Delphi consensus. For internal (39 panel members involved in identification of relevant features) and external validation (30 independent external reviewers), 30 selected UIA cases were used to analyze agreement with UIATS management recommendations based on a 5-point Likert scale (5 indicating strong agreement). Interrater agreement (IRA) was assessed with standardized coefficients of dispersion (vr*) (vr* = 0 indicating excellent agreement and vr* = 1 indicating poor agreement). Results: The UIATS accounts for 29 key factors in UIA management. Agreement with UIATS (mean Likert scores) was 4.2 (95% confidence interval [CI] 4.1–4.3) per reviewer for both reviewer cohorts; agreement per case was 4.3 (95% CI 4.1–4.4) for panel members and 4.5 (95% CI 4.3–4.6) for external reviewers (p = 0.017). Mean Likert scores were 4.2 (95% CI 4.1–4.3) for interventional reviewers (n = 56) and 4.1 (95% CI 3.9–4.4) for noninterventional reviewers (n = 12) (p = 0.290). Overall IRA (vr*) for both cohorts was 0.026 (95% CI 0.019–0.033). Conclusions: This novel UIA decision guidance study captures an excellent consensus among highly informed individuals on UIA management, irrespective of their underlying specialty. Clinicians can use the UIATS as a comprehensive mechanism for indicating how a large group of specialists might manage an individual patient with a UIA.

CT after subarachnoid hemorrhage Relation of cerebral perfusion to delayed cerebral ischemia

Background: Delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) is difficult to predict. The authors studied the relation between several parameters of brain perfusion at admission and development of DCI. Methods: The authors analyzed the admission CT perfusion (CTP) scans of 46 patients scanned within 72 hours after SAH. They assessed cerebral blood volume (CBV) and flow (CBF), mean transit time (MTT), and time to peak (TTP) for eight predefined regions of interest. For patients with and without DCI, the authors compared perfusion quantitatively and semiquantitatively. With receiver-operator characteristic (ROC) curves, the authors assessed the relationship between DCI and perfusion parameters. To assess the potential prognostic value, they calculated sensitivity and specificity of optimal threshold values for the semiquantitative data. Results: DCI was not significantly related with quantitative perfusion values. For the semiquantitative data, patients with DCI had significantly more asymmetry in perfusion, and ROC curves indicated a good relation (0.75 to 0.81). Optimal threshold values distinguishing between patients with and without DCI were 0.77 for CBV and 0.72 for CBF ratios, and 0.87 seconds for MTT and 1.0 second for TTP differences. The corresponding sensitivity was 0.75 for all parameters; the specificity was 0.70 for CBV, 0.93 for CBF, 0.70 for MTT, and 0.90 for TTP. Conclusions: Delayed cerebral ischemia (DCI) is related to perfusion asymmetry on admission CT perfusion (CTP). The cerebral blood flow ratio (comparing contralateral regions of interest) seems the best prognosticator for development of DCI. Further studies are needed to investigate the additional value of CTP to other prognosticators for DCI and to validate the chosen threshold values.

Growth rates of intracranial aneurysms: exploring constancy

OBJECT The annual rate of rupture of intracranial aneurysms is often assumed to be constant, but it is unknown whether this assumption is true. Recent case reports have suggested that aneurysms grow fast in a short period of time. The authors of the present report investigated the plausibility of a constant growth rate for intracranial aneurysms. METHODS Assuming a constant aneurysm growth rate within an individual and varying rates between individuals, a hypothetical cohort was simulated. Individuals with high growth rates will display aneurysm formation and rupture at a young age; such persons disappear early from the hypothetical cohort. As a result the mean lesion growth rate varies over time. In hypothetical cohorts with different initial mean growth rates, the authors calculated age-specific incidence rates (per 100,000 person-years) of subarachnoid hemorrhage and compared these rates with population-based data on the incidence of subarachnoid hemorrhage (per 100,000 person-years). RESULTS A hypothetical cohort with a mean initial growth rate of 0.18 mm/year reproduced most closely the incidence rates observed in the population. However, even for this most plausible hypothetical cohort, age-specific incidence rates in the model differed substantially and statistically significantly from those observed in the population. CONCLUSIONS Based on the results of this study, it is unlikely that intracranial aneurysms in general grow at a constant time-independent rate. The authors hypothesized that the actual growth process is irregular and discontinuous, which results in periods with and without aneurysm growth and with high and low risks of rupture.

New Detected Aneurysms on Follow-Up Screening in Patients With Previously Clipped Intracranial Aneurysms Comparison With DSA or CTA at the Time of SAH

Background and Purpose— Patients with a history of aneurysmal subarachnoid hemorrhage may have aneurysms on screening several years after the hemorrhage. For determining the benefits of follow-up screening, it is important to know whether these aneurysms have developed after the hemorrhage or are visible in retrospect, and if so, whether the size has increased. Methods— Aneurysms were categorized into de novo aneurysms and aneurysms visible in retrospect (already present) with increased or stable size. We studied aneurysm characteristics for these 3 categories: the relation between aneurysm development or enlargement and duration of follow up and the relation between enlargement and initial size of the aneurysm. Results— In 87 of 495 patients (17.6%), aneurysms were detected; for 51 of these patients with 62 aneurysms, the original catheter or computed tomographic angiogram was available for comparison. Of the 62 aneurysms, 19 were de novo and 43 were visible in retrospect, 10 with increased size and 33 with stable size. De novo aneurysms were mainly ≤5 mm (95%) and located at the middle cerebral artery (63%). For aneurysms visible in retrospect, the most frequent location was the posterior communicating artery (21%). There was no relation between the development of de novo aneurysms or enlargement and the duration of follow-up or between enlargement and the initial size of the aneurysm. Conclusions— Of aneurysms detected at screening, one third were de novo and two thirds were missed at the time of the initial hemorrhage. One quarter of initially small aneurysms had enlarged during follow-up.

Optimal screening strategy for familial intracranial aneurysms: A cost-effectiveness analysis

Objective: Individuals with a family history of subarachnoid hemorrhage (SAH), defined as 2 or more affected first-degree relatives, have an increased risk of aneurysm formation and rupture. Screening such individuals for intracranial aneurysms is advocated, but its effectiveness and cost-effectiveness are unknown, as are the optimal age ranges and interval for screening. Methods: With a Markov model and Monte Carlo simulations we compared screening with no screening in individuals with a family history of SAH. We varied age ranges (starting screening at 20, 30, or 40 years old, ending screening at 60, 70, or 80 years old) and screening intervals (2-, 3-, 5-, 7-, 10-, and 15-year interval), and analyzed the impact in costs and quality-adjusted life years (QALY). Results: Screening individuals with a family history of SAH is cost-effective. The strategy with the lowest costs per QALY was to screen only twice, at 40 and 55 years old. Sequentially lengthening the screening period and decreasing the screening interval yielded additional health benefits at acceptable costs up to screening from age 20 to 80 every 7 years. More frequent screening within this age range still provided extra QALYs, with an incremental cost-effectiveness ratio more favorable than 26,308/QALY (