Miikka Korja

Saccular intracranial aneurysm: pathology and mechanisms

Saccular intracranial aneurysms (sIA) are pouch-like pathological dilatations of intracranial arteries that develop when the cerebral artery wall becomes too weak to resist hemodynamic pressure and distends. Some sIAs remain stable over time, but in others mural cells die, the matrix degenerates, and eventually the wall ruptures, causing life-threatening hemorrhage. The wall of unruptured sIAs is characterized by myointimal hyperplasia and organizing thrombus, whereas that of ruptured sIAs is characterized by a decellularized, degenerated matrix and a poorly organized luminal thrombus. Cell-mediated and humoral inflammatory reaction is seen in both, but inflammation is clearly associated with degenerated and ruptured walls. Inflammation, however, seems to be a reaction to the ongoing degenerative processes, rather than the cause. Current data suggest that the loss of mural cells and wall degeneration are related to impaired endothelial function and high oxidative stress, caused in part by luminal thrombosis. The aberrant flow conditions caused by sIA geometry are the likely cause of the endothelial dysfunction, which results in accumulation of cytotoxic and pro-inflammatory substances into the sIA wall, as well as thrombus formation. This may start the processes that eventually can lead to the decellularized and degenerated sIA wall that is prone to rupture.

Lifelong Rupture Risk of Intracranial Aneurysms Depends on Risk Factors A Prospective Finnish Cohort Study

Background and Purpose— Our aim was to define for the first time the lifelong natural course of unruptured intracranial aneurysms (UIAs) and identify high-risk and low-risk patients for the rupture. Methods— One hundred and eighteen patients (61 women) with UIAs were diagnosed between 1956 and 1978 and followed up until death or subarachnoid hemorrhage (SAH). The median age at the diagnosis was 43.5 years (range, 22.6–60.7 years). The median size of the UIA at the diagnosis was 4 mm (range, 2–25 mm). Analyzed risk factors for a rupture included sex, age, cigarette smoking, systolic blood pressure values, diagnosed hypertension, UIA size, and number of UIAs. Results— Thirty four (29%) out of 118 people had SAH during the lifelong follow-up. The median age at SAH was 51.3 years (range, 30.1–71.8 years). The annual rupture rate per patient was 1.6%. Female sex, current smoking, and aneurysm size of ≥7 mm in diameter were risk factors for a lifetime SAH. Depending on the risk factor burden, the lifetime risk of an aneurysmal SAH varied from 0% to 100%, and the annual rupture rate from 0% to 6.5%. Of the 96 patients with small (<7 mm) UIAs, 24 (25%) had an aneurysmal SAH during the follow-up. Conclusions— Almost 30% of all UIAs in people of working age ruptured during a lifelong follow-up. The risk varied substantially on the basis of risk factor burden. Because even small UIAs ruptured, treatment decisions of UIAs should perhaps be based on the risk factor status.

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.

Cause-specific mortality of 1-year survivors of subarachnoid hemorrhage

Objective: To assess long-term, cause-specific mortality rates and rate ratios of the patients alive at 1 year after subarachnoid hemorrhage (SAH). Methods: The population-based, prospective, cohort study with a nested case-control design consisted of 64,349 persons (aged 25–74 years at enrollment) who participated in the National FINRISK Study between 1972 and 2007. Four hundred thirty-seven SAH cases, 233 one-year SAH survivors, and their matched intrinsic controls were identified and followed up until the end of 2009 through the nationwide Finnish Causes of Death Register. All-cause mortality rates and rate ratios of the 1-year SAH survivors and controls were the main outcome measures. Results: Eighty-eight (37.8%) of 233 one-year SAH survivors died during the total follow-up time of 2,487 person-years (median 8.6 years, range 0.1–35.8 years). The 1-year SAH survivors had a hazard ratio of 1.96 (95% confidence interval 1.57–2.47) for death compared with the matched general population with 10 controls for each SAH survivor. One-year SAH survivors had up to 31 additional deaths per 1,000 person-years compared with controls with minimal cerebrovascular risk factors. The higher long-term risk of death among SAH survivors was attributed solely to cerebrovascular diseases, and most important modifiable risk factors for death were smoking, high systolic blood pressure (≥159 mm Hg), and high cholesterol levels (≥7.07 mmol/L). Conclusion: One-year SAH survivors have excess mortality, which is attributed to an exceptional risk of deadly cerebrovascular events. Aggressive post-SAH cerebrovascular risk factor intervention strategies are highly warranted.

Genetic Epidemiology of Spontaneous Subarachnoid Hemorrhage Nordic Twin Study

Background and Purpose— It would be essential to clinicians, familial aneurysm study groups, and aneurysm families to understand the genetic basis of subarachnoid hemorrhage (SAH), but there are no large population-based heritability estimates assessing the relative contribution of genetic and environmental factors to SAH. Methods— We constructed the largest twin cohort to date, the population-based Nordic Twin Cohort, which comprised 79 644 complete twin pairs of Danish, Finnish, and Swedish origin. The Nordic Twin Cohort was followed up for 6.01 million person-years using nationwide cause-of-death and hospitalization registries. Results— One hundred eighty-eight fatal and 321 nonfatal SAH cases were recorded in the Nordic Twin Cohort. Thus, SAH incidence was 8.47 cases per 100 000 follow-up years. Data for pairwise analyses were available for a total of 504 SAH cases, of which 6 were concordant (5 monozygotic and 1 opposite sex) and 492 discordant twin pairs for SAH. The concordance for SAH in monozygotic twins was 3.1% compared with 0.27% in dizygotic twins, suggesting at most a modest role for genetic factors in the etiology of SAH. The population-based probability estimate for SAH in dizygotic siblings of a patient with SAH is 0.54%, and only 1 of 185 full siblings experience familial SAH. The corresponding risk of SAH in monozygotic twins is 5.9%. Model-fitting, which was based on the comparison of the few monozygotic and dizygotic pairs, suggested that the estimated heritability of SAH is 41%. Conclusions— SAH appears to be mainly of nongenetic origin, and familial SAHs can mostly be attributed to environmental risk factors.

Risk Factors and Their Combined Effects on the Incidence Rate of Subarachnoid Hemorrhage – A Population-Based Cohort Study

Background Prospective studies on the risk factors for subarachnoid hemorrhage (SAH) are limited. Moreover, the effect of risk factors on the incidence rates of SAH is not well known about. Aims In this study, we aimed to identify risk factors for SAH and characterize subgroups in a population with a high incidence of SAH. Methods After recording multiple potential risk factors for SAH at the time of enrolment, first ever SAH events between 1972 and 2009 were recorded through the nationwide Causes of Death Register and Hospital Discharge Register for the population-based cohort of 64 349 participants, who participated in the National FINRISK Study between 1972 and 2007 in Finland. Results During the follow-up time of 1.26 million person-years (median 17.9 years, range 0 to 37.9 years), 437 persons experienced fatal or non-fatal SAH. Crude SAH incidence was 34.8 (95% confidence interval: 31.7–38.2) per 100 000 person-years among ≥25-year-old persons. Female sex, high blood pressure values and current smoking were confirmed as risk factors for SAH. Previous myocardial infarction, history of premature stroke (any kind) in mother and elevated cholesterol levels in men were identified as new risk factors for SAH. Depending on the combination of risk factors, SAH incidence varied between 8 and 171 per 100 000 person-years. Conclusions New and previously reported risk factors appear to have a much stronger association with the incidence of SAH than is ordinarily seen in cardiovascular diseases. Risk factor assessments may facilitate the identification of high-risk persons who should be the focus of preventive interventions.

The tumour-associated carbonic anhydrases CA II, CA IX and CA XII in a group of medulloblastomas and supratentorial primitive neuroectodermal tumours: an association of CA IX with poor prognosis

BackgroundMedulloblastomas (MBs) and supratentorial primitive neuroectodermal tumours (PNETs) are the most common highly aggressive paediatric brain tumours. In spite of extensive research on these tumours, there are only few known biomarkers or therapeutic target proteins, and the prognosis of patients with these tumours remains poor. Our aim was to investigate whether carbonic anhydrases (CAs), enzymes commonly overexpressed in various tumours including glioblastomas and oligodendrogliomas, are present in MBs and PNETs, and whether their expression can be correlated with patient prognosis.MethodsWe determined the expression of the tumour-associated carbonic anhydrases CA II, CA IX and CA XII in a series of MB/PNET specimens (n = 39) using immunohistochemistry.ResultsEndothelial CA II, cytoplasmic CA II, CA IX and CA XII were expressed in 49%, 73%, 23% and 11% of the tumours, respectively. CA II was detected in the neovessel endothelium and the tumour cell cytoplasm. CA IX was mainly expressed in the tumour cells located in perinecrotic areas. CA XII showed the most homogenous distribution within the tumours. Importantly, CA IX expression predicted poor prognosis in both univariate (p = 0.041) and multivariate analyses (p = 0.016).ConclusionsWe suggest that CA IX should be considered a potential prognostic and therapeutic target in MBs and PNETs.

Controversies in epidemiology of intracranial aneurysms and SAH

Rupture of an intracranial aneurysm is the most common cause of subarachnoid haemorrhage (SAH), which is a life-threatening acute cerebrovascular event that typically affects working-age people. The exact prevalence of unruptured intracranial aneurysms (UIAs) is unknown, but at least one in 20 to 30 adults is likely to carry an asymptomatic UIA. Approximately one quarter of these UIAs rupture in a lifetime. Complex methodological challenges in conducting studies of epidemiology and risk factors for UIAs and SAH might have led to conclusions being drawn on the basis of epidemiological data of variable quality. We believe that, as a result, misconceptions about UIAs and SAH may have arisen. In this Perspectives article, we discuss three possible misconceptions about the epidemiology of UIAs and SAH, and suggest how the quality of future research could be improved.

Role of Surgery in the Management of Brain Arteriovenous Malformations Prospective Cohort Study

Background and Purpose— Management of brain arteriovenous malformation (bAVM) is controversial. We have analyzed the largest surgical bAVM cohort for outcome. Methods— Both operated and nonoperated cases were included for analysis. A total of 779 patients with bAVMs were consecutively enrolled between 1989 and 2014. Initial management recommendations were recorded before commencement of treatment. Surgical outcome was prospectively recorded and outcomes assigned at the last follow-up visit using modified Rankin Scale. First, a sensitivity analyses was performed to select a subset of the entire cohort for which the results of surgery could be generalized. Second, from this subset, variables were analyzed for risk of deficit or near miss (intraoperative hemorrhage requiring blood transfusion of ≥2.5 L, hemorrhage in resection bed requiring reoperation, and hemorrhage associated with either digital subtraction angiography or embolization). Results— A total of 7.7% of patients with Spetzler–Ponce classes A and B bAVM had an adverse outcome from surgery leading to a modified Rankin Scale >1. Sensitivity analyses that demonstrated outcome results were not subject to selection bias for Spetzler–Ponce classes A and B bAVMs. Risk factors for adverse outcomes from surgery for these bAVMs include size, presence of deep venous drainage, and eloquent location. Preoperative embolization did not affect the risk of perioperative hemorrhage. Conclusions— Most of the ruptured and unruptured low and middle-grade bAVMs (Spetzler–Ponce A and B) can be surgically treated with a low risk of permanent morbidity and a high likelihood of preventing future hemorrhage. Our results do not apply to Spetzler–Ponce C bAVMs.

Incidence of subarachnoid hemorrhage is decreasing together with decreasing smoking rates

Objective: To determine the nationwide incidence of subarachnoid hemorrhage (SAH) and report nationwide changes in smoking rates between 1998 and 2012 in Finland. Methods: In this register-based study, we utilized the nationwide Causes of Death Register and Hospital Discharge Register in identifying SAH events between 1998 and 2012. Population statistics in Finland, which were obtained through a database of Statistics Finland, were used to calculate crude annual incidence rates of SAH. For the direct age standardization of crude incidence rates, we used the European Standard Population (ESP) 2013. Data on changes in nationwide smoking rates between 1998 and 2012 were extracted from a database of the National Institute for Health and Welfare. Results: For the total of 79,083,579 cumulative person-years, we identified 6,885 people with SAH. Sudden deaths from SAH away from hospitals or in emergency rooms accounted for 1,771 (26%) of the events. Crude nationwide annual incidence rates varied between 6.2 and 10.0 per 100,000 persons, and increased by age particularly in women. Among 70- to 75-year-old women, the incidence of SAH was highest (22.5 per 100,000 persons). The 3-year average of ESP standardized incidence decreased 24% from 11.7 in 1998–2000 to 8.9 per 100,000 persons in 2010–2012. Daily smoking decreased 30% between 1998 and 2012. Conclusions: The incidence of SAH seems to be decreasing. This tendency may be coupled with changes in smoking rates. The incidence of SAH in Finland is similar to other Nordic countries.