Seppo Juvela

Definition of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage as an Outcome Event in Clinical Trials and Observational Studies Proposal of a Multidisciplinary Research Group

Background and Purpose— In clinical trials and observational studies there is considerable inconsistency in the use of definitions to describe delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. A major cause for this inconsistency is the combining of radiographic evidence of vasospasm with clinical features of cerebral ischemia, although multiple factors may contribute to DCI. The second issue is the variability and overlap of terms used to describe each phenomenon. This makes comparisons among studies difficult. Methods— An international ad hoc panel of experts involved in subarachnoid hemorrhage research developed and proposed a definition of DCI to be used as an outcome measure in clinical trials and observational studies. We used a consensus-building approach. Results— It is proposed that in observational studies and clinical trials aiming to investigate strategies to prevent DCI, the 2 main outcome measures should be: (1) cerebral infarction identified on CT or MRI or proven at autopsy, after exclusion of procedure-related infarctions; and (2) functional outcome. Secondary outcome measure should be clinical deterioration caused by DCI, after exclusion of other potential causes of clinical deterioration. Vasospasm on angiography or transcranial Doppler can also be used as an outcome measure to investigate proof of concept but should be interpreted in conjunction with DCI or functional outcome. Conclusion— The proposed measures reflect the most relevant morphological and clinical features of DCI without regard to pathogenesis to be used as an outcome measure in clinical trials and observational studies.

Factors Affecting Formation and Growth of Intracranial Aneurysms A Long-Term Follow-Up Study

Background and Purpose — We sought to investigate factors determining growth rate of unruptured intracranial aneurysms as well as formation of new (de novo) aneurysms in patients from a time period when unruptured aneurysms were not treated surgically. Methods — Eighty-seven patients (79 had ruptured aneurysms clipped at start of follow-up) with 111 unruptured aneurysms as well as an additional 7 patients (2 with and 5 without unruptured aneurysms) who developed new aneurysms were followed from the 1950s to the 1970s until death or subarachnoid hemorrhage or until the last contact. Patients’ cerebral arteries were examined later either with conventional (control) angiography (n=38) and/or, for those alive during 1996–1998, with 3-dimensional CT angiography (n=57). In addition, 10 patients were studied at neuropathological autopsy. Results — Mean±SD duration of follow-up was 18.9±9.4 years (range, 1.2 to 38.9 years). Unruptured aneurysms increased in size ≥1 mm in 39 of the 87 patients (45%) and ≥3 mm in 31 (36%). New aneurysms were found in 15 of the 89 patients and in 5 without an unruptured aneurysm at the beginning of follow-up. Aneurysm rupture was associated very significantly (P <0.001) with aneurysm growth during follow-up. Of several potential risk factors tested, only cigarette smoking (odds ratio [OR], 3.92; 95% CI, 1.29 to 11.93) and female sex (OR, 3.36; 95% CI, 1.11 to 10.22) were, after adjustment for age, significant (P <0.05) independent risk factors for occurrence of aneurysm growth of ≥1 mm. Only cigarette smoking (OR, 3.48; 95% CI, 1.14 to 10.64;P <0.05) was associated with growth of ≥3 mm. Age- and hypertension-adjusted risk factors for aneurysm formation were female sex (OR, 4.73; 95% CI, 1.16 to 19.38) and cigarette smoking (OR, 4.07; 95% CI, 1.09 to 15.15). Conclusions — Women and cigarette smokers are at increased risk for intracranial aneurysm formation and growth. Cigarette smoking in particular hastens aneurysm growth. Cessation of smoking is important for patients with unruptured aneurysms and possibly also for those with a prior subarachnoid hemorrhage.

European Stroke Organization Guidelines for the Management of Intracranial Aneurysms and Subarachnoid Haemorrhage

Background: Intracranial aneurysm with and without subarachnoid haemorrhage (SAH) is a relevant health problem: The overall incidence is about 9 per 100,000 with a wide range, in some countries up to 20 per 100,000. Mortality rate with conservative treatment within the first months is 50–60%. About one third of patients left with an untreated aneurysm will die from recurrent bleeding within 6 months after recovering from the first bleeding. The prognosis is further influenced by vasospasm, hydrocephalus, delayed ischaemic deficit and other complications. The aim of these guidelines is to provide comprehensive recommendations on the management of SAH with and without aneurysm as well as on unruptured intracranial aneurysm. Methods: We performed an extensive literature search from 1960 to 2011 using Medline and Embase. Members of the writing group met in person and by teleconferences to discuss recommendations. Search results were graded according to the criteria of the European Federation of Neurological Societies. Members of the Guidelines Committee of the European Stroke Organization reviewed the guidelines. Results: These guidelines provide evidence-based information on epidemiology, risk factors and prognosis of SAH and recommendations on diagnostic and therapeutic methods of both ruptured and unruptured intracranial aneurysms. Several risk factors of aneurysm growth and rupture have been identified. We provide recommendations on diagnostic work up, monitoring and general management (blood pressure, blood glucose, temperature, thromboprophylaxis, antiepileptic treatment, use of steroids). Specific therapeutic interventions consider timing of procedures, clipping and coiling. Complications such as hydrocephalus, vasospasm and delayed ischaemic deficit were covered. We also thought to add recommendations on SAH without aneurysm and on unruptured aneurysms. Conclusion: Ruptured intracranial aneurysm with a high rate of subsequent complications is a serious disease needing prompt treatment in centres having high quality of experience of treatment for these patients. These guidelines provide practical, evidence-based advice for the management of patients with intracranial aneurysm with or without rupture. Applying these measures can improve the prognosis of SAH.

Natural history of brain arteriovenous malformations: a long-term follow-up study of risk of hemorrhage in 238 patients.

OBJECTIVELong-term follow-up studies in patients with brain arteriovenous malformations (AVM) have yielded contradictory results regarding both risk factors for rupture and annual rupture rate. We performed a long-term follow-up study in an unselected, consecutive patient population with AVMs admitted to the Department of Neurosurgery at Helsinki University Central Hospital between 1942 and 2005. METHODSPatients with untreated AVMs were followed from admission until death, occurrence of AVM rupture, initiation of treatment, or until the end of 2005. Patients with at least 1 month of follow-up were included in further analysis. Annual and cumulative incidence rates of AVM rupture as well as several potential risk factors for rupture were analyzed using Kaplan-Meier life table analyses and Cox proportional hazards regression models. RESULTSWe identified 238 patients with a mean follow-up period of 13.5 years (range, 1 month–53.1 years). The average annual risk of hemorrhage from AVMs was 2.4%. The risk was highest during the first 5 years after diagnosis, decreasing thereafter. Risk factors predicting subsequent AVM hemorrhage in univariate analysis were young age, previous rupture, deep and infratentorial locations, and exclusively deep venous drainage. Previous rupture, large AVM size, and infratentorial and deep locations were independent risk factors according to multivariate models. CONCLUSIONAccording to this long-term follow-up study, AVMs with previous rupture and large size, as well as with infratentorial and deep locations have the highest risk of subsequent hemorrhage. This risk is highest during the first few years after diagnosis but remains significant for decades.

Cigarette smoking and alcohol consumption as risk factors for aneurysmal subarachnoid hemorrhage.

Background and Purpose Aneurysmal subarachnoid hemorrhage is a serious disease despite recent improvements in medical and surgical treatment. Hence, identification of modifiable risk factors for subarachnoid hemorrhage is important. Methods We compared the smoking and drinking habits of 278 consecutive patients with aneurysmal subarachnoid hemorrhage, aged 15–60 years (145 men and 133 women) with those of 314 hospitalized control patients (164 men and 150 women) who did not differ in regard to age, day of onset of symptoms, and acuteness of disease onset. Results Multiple logistic regression analysis showed that recent alcohol intake and smoking, but not hypertension, were significant independent risk factors for hemorrhage. After adjustment for age, hypertension, and smoking status, men who had consumed 1–40, 41–120, or >120 g of alcohol within the 24 hours preceding the onset of illness had a relative risk of hemorrhage of 0.3 (95% confidence interval [CI], 0.1–0.8), 2.5 (95% CI, 1.1–5.5), and 4.5 (95% CI, 1.5–12.9), respectively, compared with men who had consumed 0 g. Women who had consumed 1–40 or >40 g of alcohol had a risk of hemorrhage of 0.4 (95% CI, 0.2–0.8) and 6.4 (95% CI, 2.3–17.9), respectively, compared with women without use of alcohol. Heavily smoking (>20 cigarettes per day) men and currently smoking women had adjusted relative risks of hemorrhage of 7.3 (95% CI, 3.8–14.3) and 2.1 (95% CI, 1.2–3.6), respectively, compared with men who had never smoked and with women who were not current smokers. Higher levels of erythrocyte mean corpuscular volume in patients with subarachnoid hemorrhage than in control subjects supported the notion of different smoking and drinking habits. Conclusions Recent heavy alcohol intake and current smoking seem to be independent risk factors for aneurysmal subarachnoid hemorrhage.

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.

Recommendations for the management of intracranial haemorrhage - part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee.

This article represents the recommendations for the management of spontaneous intracerebral haemorrhage of the European Stroke Initiative (EUSI). These recommendations are endorsed by the 3 European societies which are represented in the EUSI: the European Stroke Council, the European Neurological Society and the European Federation of Neurological Societies.This article represents the recommendations for the management of spontaneous intracerebral haemorrhage of the European Stroke Initiative (EUSI). These recommendations are endorsed by the 3 European s

Recommendations for the management of intracranial haemorrhage - Part I: Spontaneous intracerebral haemorrhage

This article represents the recommendations for the management of spontaneous intracerebral haemorrhage of the European Stroke Initiative (EUSI). These recommendations are endorsed by the 3 European societies which are represented in the EUSI: the European Stroke Council, the European Neurological Society and the European Federation of Neurological Societies.This article represents the recommendations for the management of spontaneous intracerebral haemorrhage of the European Stroke Initiative (EUSI). These recommendations are endorsed by the 3 European s

Risk Factors for Spontaneous Intracerebral Hemorrhage

BACKGROUND AND PURPOSE Spontaneous intracerebral hemorrhage has remained a serious disease despite recent improvements in medical treatment. This study was designed to identify modifiable risk factors for intracerebral hemorrhage. METHODS Health habits, previous diseases, and medication of 156 consecutive patients with intracerebral hemorrhage aged 16 to 60 years (96 men and 60 women) were compared with those of 332 hospitalized control patients (192 men and 140 women) who did not differ from case subjects in respect to age, day of onset of symptoms, or acuteness of disease onset. RESULTS After adjustment for sex, age, hypertension, body mass index, smoking status, and alcohol consumption during the last week, patients who had consumed 1 to 40, 41 to 120, or > 120 g of alcohol within the 24 hours preceding the onset of illness had a relative risk (95% confidence interval) of hemorrhage of 0.3 (0.2 to 0.7), 4.6 (2.2 to 9.4), and 11.3 (3.0 to 42.8), respectively, compared with those who had consumed 0 g. In addition, alcohol intake within 1 week before the onset of illness, excluding use within the last 24 hours, increased the risk of hemorrhage; adjusted risks were 2.0 (1.1 to 3.5) for 1 to 150 g, 4.3 (1.6 to 11.7) for 151 to 300 g, and 6.5 (2.4 to 17.7) for > 300 g compared with 0 g. The adjusted risk of hypertension for hemorrhage was 6.6 (3.9 to 11.3). Previous heavy alcohol consumption and current cigarette smoking were not independent risk factors for hemorrhage, but anticoagulant treatment was (P < .01). Erythrocyte mean corpuscular volume and gamma-glutamyl transferase values were also higher in patients with intracerebral hemorrhage than in control subjects. CONCLUSIONS Recent moderate and heavy alcohol intake as well as hypertension and likely also anticoagulant treatment seem to be independent risk factors for intracerebral hemorrhage.

Risk Factors for Multiple Intracranial Aneurysms

BACKGROUND AND PURPOSE The presence of multiple intracranial aneurysms may be a sign of significant risk factors for aneurysm formation that differ from those factors that increase risk for aneurysm rupture. Only 2 studies concern independent risk factors for multiple aneurysms, and the results are in part controversial. This study was designed to identify independent risk factors for multiple intracranial aneurysms in patients with subarachnoid hemorrhage. METHODS Of 266 patients with aneurysmal subarachnoid hemorrhage (139 men and 127 women, aged 15 to 60 years), 80 (30%) had multiple intracranial aneurysms. The prevalence of several health-related habits, previous diseases, and medications of these patients were compared by multiple logistic regression between those with single and those with multiple aneurysms. RESULTS On the basis of multivariate statistics, only regular cigarette smoking at any time was a significant risk factor for the presence of multiple aneurysms. The odds ratio (OR) of smoking for multiple aneurysms was 2.10 (95% CI, 1.06 to 4.13) after adjustment for age and sex. After additional adjustment for hypertension, the risk was 2.06 (95% CI, 1. 04 to 4.07). Of other variables, only age (OR, 1.02 per year; 95% CI, 1.00 to 1.05; P=0.09) and female sex (OR, 1.60; 95% CI, 0.90 to 2. 85; P=0.11) showed a tendency to increase the risk for multiple aneurysms after adjustment for smoking. On the other hand, patients with hypertension had significantly (P=0.029) more aneurysms (1. 61+/-1.04) than did those without (1.37+/-0.68), although they did not more frequently have multiple aneurysms. CONCLUSIONS Cigarette smoking and possibly also age and female sex seem to be risk factors for multiple intracranial aneurysms in patients of working age who have suffered a subarachnoid hemorrhage. Patients with hypertension seem to have more aneurysms than those without.