Juha E. Jääskeläinen

Remodeling of Saccular Cerebral Artery Aneurysm Wall Is Associated With Rupture: Histological Analysis of 24 Unruptured and 42 Ruptured Cases

Background and Purpose— The cellular mechanisms of degeneration and repair preceding rupture of the saccular cerebral artery aneurysm wall need to be elucidated for rational design of growth factor or drug-releasing endovascular devices. Methods— Patient records, preoperative vascular imaging studies, and the snap-frozen fundi resected after microsurgical clipping from 66 aneurysms were studied. Immunostainings for markers of smooth muscle cell (SMC) phenotype, proliferation, and inflammatory cell subtypes and TUNEL reaction were performed. Results— Unruptured (24) and ruptured (42) aneurysms had similar dimensions (median diameter in unruptured 6 mm; median in ruptured 7 mm; P=0.308). We identified 4 basic types of aneurysm wall that associated with rupture: (1) endothelialized wall with linearly organized SMCs (17/66; 42% ruptured), (2) thickened wall with disorganized SMCs (20/66; 55% ruptured), (3) hypocellular wall with either myointimal hyperplasia or organizing luminal thrombosis (14/66; 64% ruptured), and (4) an extremely thin thrombosis-lined hypocellular wall (15/66; 100% ruptured). Apoptosis, de-endothelialization, luminal thrombosis, SMC proliferation, and T-cell and macrophage infiltration associated with rupture. Furthermore, macrophage infiltration associated with SMC proliferation, and both were increased in ruptured aneurysms resected <12 hours from rupture, suggesting that these were not just reactive changes. Conclusions— Before rupture, the wall of saccular cerebral artery aneurysm undergoes morphological changes associated with remodeling of the aneurysm wall. Some of these changes, like SMC proliferation and macrophage infiltration, likely reflect ongoing repair attempts that could be enhanced with pharmacological therapy.

Population-based analysis of sporadic and type 2 neurofibromatosis-associated meningiomas and schwannomas

Objective: To estimate the incidence of meningiomatosis and schwannomatosis, and their familial occurrences and relation to type 2 neurofibromatosis (NF2) in a well-defined population. Methods: Patients with histologically verified intracranial, spinal, or peripheral schwannomas or meningiomas, who were residents of the Helsinki University Hospital catchment area (population, 1,713,000) from January 1, 1985, to December 31, 1995, were included in the study. The Population Register Center was used to identify relatives of all the patients, and their data were linked further to the Finnish Cancer Registry to find NF2-related tumors. Detailed pedigrees were constructed for the patients with NF2, schwannomatosis, meningiomatosis, patients with relatives with histologically verified schwannomas or meningiomas, and patients younger than 25 years of age at the time of diagnosis. Results: Approximately 3% (12 of 455) of the schwannoma patients had multiple schwannomas in association with NF2, and 2% (11 of 455) had schwannomatosis without NF2. Two of the patients with schwannomatosis (2 of 11) had familial schwannomatosis. Approximately 1% (7 of 823) of the patients with meningioma had multiple meningiomas in association with NF2, and 4% (29 of 823) had meningiomatosis without NF2. No families with meningiomatosis were found among the 823 patients with meningioma studied. The birth occurrence of NF2 was 1 in 87,410. Conclusions: The current diagnostic criteria of type 2 neurofibromatosis (NF2) seem valid because NF2 patients were differentiated rather easily from patients with sporadic schwannomatosis and meningiomatosis. Familial meningiomatosis, if it truly exists, is very rare, and familial schwannomatosis is uncommon.

Genome-wide association study of intracranial aneurysm identifies three new risk loci

Saccular intracranial aneurysms are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with ∼832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with intracranial aneurysms in the combined dataset, including intervals near RBBP8 on 18q11.2 (odds ratio (OR) = 1.22, P = 1.1 × 10−12), STARD13-KL on 13q13.1 (OR = 1.20, P = 2.5 × 10−9) and a gene-rich region on 10q24.32 (OR = 1.29, P = 1.2 × 10−9). We also confirmed prior associations near SOX17 (8q11.23–q12.1; OR = 1.28, P = 1.3 × 10−12) and CDKN2A-CDKN2B (9p21.3; OR = 1.31, P = 1.5 × 10−22). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting the proliferation and senescence of progenitor-cell populations that are responsible for vascular formation and repair.

Susceptibility loci for intracranial aneurysm in European and Japanese populations

Stroke is the worlds third leading cause of death. One cause of stroke, intracranial aneurysm, affects ∼2% of the population and accounts for 500,000 hemorrhagic strokes annually in mid-life (median age 50), most often resulting in death or severe neurological impairment. The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24–1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm. Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells, suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role. These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.

Assessment of β-Amyloid in a Frontal Cortical Brain Biopsy Specimen and by Positron Emission Tomography With Carbon 11–Labeled Pittsburgh Compound B

OBJECTIVE To compare carbon 11-labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET) findings in patients with and without Alzheimer disease lesions in frontal cortical biopsy specimens. DESIGN Cross-sectional study of [11C]PiB PET findings in patients with or without beta-amyloid (Abeta) aggregates in frontal cortical biopsy specimens. SETTING Two university hospitals in Finland. Patients Ten patients who had undergone intraventricular pressure monitoring with a frontal cortical biopsy (evaluated for Abeta aggregates and hyperphosphorylated tau) for suspected normal-pressure hydrocephalus. INTERVENTIONS [11C]PiB PET and evaluation for cognitive impairment using a battery of neuropsychological tests. MAIN OUTCOME MEASURES Immunohistochemical evaluation for Abeta aggregates and hyperphosphorylated tau in the frontal cortical biopsy specimen and [11C]PiB PET. RESULTS In patients with Abeta aggregates in the frontal cortical biopsy specimen, PET imaging revealed higher [11C]PiB uptake (P < .05) in the frontal, parietal, and lateral temporal cortices and in the striatum as compared with the patients without frontal Abeta deposits. CONCLUSIONS Our study supports the use of noninvasive [11C]PiB PET in the assessment of Abeta deposition in the brain. Large prospective studies are required to verify whether [11C]PiB PET will be a diagnostic aid, particularly in early Alzheimer disease.

Correlates of life satisfaction among psychiatric patients

The aim of this study was to examine the sociodemographic and clinical variables associated with life satisfaction in psychiatric patients. The study population consisted of out‐patients and in‐patients (n= 1204) treated at the Department of Psychiatry of Kuopio University Hospital in North Savo, Finland, during May 1993. Sociodemographic, psychosocial and clinical correlates of life satisfaction were examined by means of two different questionnaires, one directed at patients and the other directed at the staff. Life satisfaction was assessed by means of a separate scale based on four questions. Patients with schizophrenia were less dissatisfied than patients with other disorders. The strongest correlates of dissatisfaction were depression and poor social support. Other factors relating to dissatisfaction in multiple regression analysis were self‐rated health and poor financial circumstances. A psychosomatic reaction tendency or degree of psychosocial functioning at the time of the study was not independently related to life satisfaction. Psychiatric patients who are dissatisfied should be evaluated both for depression and for effectiveness of their social network.

COMPLEMENT ACTIVATION ASSOCIATES WITH SACCULARCEREBRAL ARTERY ANEURYSM WALL DEGENERATION AND RUPTURE

OBJECTIVE Saccular cerebral artery aneurysm (SCAA) wall degeneration and inflammatory cell infiltrations associate with aneurysm rupture and subarachnoid hemorrhage, resulting in a devastating form of stroke. The complement system is the key mediator of inflammation and household processing of injured tissue. We studied how complement activation associates with SCAA wall degeneration and rupture to better understand the pathobiology of SCAA wall rupture. METHODS Unruptured (n = 26) and ruptured (n = 32) SCAA fundi resected after microsurgical clipping were studied by immunostaining for complement activation (membrane attack complex [MAC]) and by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling reaction for related cell death. Complement activation was correlated with clinical and other histological parameters. Electromicroscopy and immunoelectron microscopy were used for locating MAC depositions at the ultrastructural level. RESULTS MAC localized consistently in a decellularized layer in the outer SCAA wall, and was found in all SCAA samples. The percentage of MAC-positive area relative to the total SCAA wall surface area (range, 5-77%) was greater in ruptured (n = 25; median, 39%) than in unruptured SCAAs (n = 18; median, 20%; P = 0.005). It also associated significantly with SCAA wall degeneration (P < 0.001), de-endothelialization(P < 0.001), and CD163+ macrophage (P = 0.023) and T-lymphocyte (P = 0.030) infiltrations. Apoptotic terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling-positive nuclei and MAC were located at the same wall areas in four out of 14 double-stained samples, but no double-positive cells were found. Electromicroscopy and immunoelectron microscopy of an unruptured SCAA showed cell death in the MAC-positive layers in the outer SCAA wall. CONCLUSION These data suggests that complement activation and MAC formation are involved in SCAA wall degeneration and rupture.

Microneurosurgical management of anterior communicating artery aneurysms

BACKGROUND Anterior communicating artery complex is the most frequent site of intracranial aneurysms in most reported series. Anterior communicating artery aneurysms are the most complex aneurysms of the anterior circulation due to the angioarchitecture and flow dynamics of the ACoA region, frequent anatomical variations, deep interhemispheric location, and danger of severing the perforators with ensuing neurologic deficits. The authors review the practical microsurgical anatomy, importance of preoperative imaging in surgical planning, and microneurosurgical steps in dissection and clipping of ACoAAs. METHODS This review, and the whole series on intracranial aneurysms, are mainly based on the personal microneurosurgical experience of the senior author (JH) in 2 Finnish centers (Helsinki and Kuopio), which serve, without patient selection, the catchment area in Southern and Eastern Finland. RESULTS These 2 centers have treated more than 10000 patients with aneurysm since 1951. In the Kuopio Cerebral Aneurysm Database of 3005 patients with 4253 aneurysms, 1145 patients (38%) had altogether 1179 ACA aneurysms; of them, 898 patients harbored 921 (78%) ACoAAs. In this series, 715 patients (80%) presented with ruptured ACoAAs with the median diameter of 7 mm. Giant ACoAAs were present in 15 (2%), whereas only 3 (0.3%) were classified as fusiform. CONCLUSIONS Anterior communicating artery aneurysms present frequently with SAH at small size. Furthermore, unruptured ACoAAs may have increased risk of rupture regardless of size, also as an associated aneurysm, and require treatment. The aim in microneurosurgical management of an ACoAA is total occlusion of the aneurysm sac with preservation of flow in all branching and perforating arteries. This demanding task necessitates perfect surgical strategy based on review of the 3D angioarchitecture and abnormalities of the patients ACoA complex with its ACoAA and to orientate accordingly during the microsurgical dissection. The surgical trajectory should provide optimal visualization of the ACoA complex without massive brain retraction. Precise dissection in the 3D anatomy of the ACoA complex and perforators requires not only experience and skill but patience to work the dome and base under repeated protection of temporary clips and pilot clips. This is particularly important with the complex, large, and giant aneurysms.

Incidence of gliomas by anatomic location

The anatomic location of a glioma influences prognosis and treatment options. The aim of our study was to describe the distribution of gliomas in different anatomic areas of the brain. A representative population-based sample of 331 adults with glioma was used for preliminary analyses. The anatomic locations for 89 patients from a single center were analyzed in more detail from radiologic imaging and recorded on a three-dimensional 1 x 1 x 1-cm grid. The age-standardized incidence rate of gliomas was 4.7 per 100,000 person-years. The most frequent subtypes were glioblastoma (47%) and grade II-III astrocytoma (23%), followed by oligodendroglioma and mixed glioma. The gliomas were located in the frontal lobe in 40% of the cases, temporal in 29%, parietal in 14%, and occipital lobe in 3%, with 14% in the deeper structures. The difference in distribution between lobes remained after adjustment for their tissue volume: the tumor:volume ratio was 4.5 for frontal, 4.8 for temporal, and 2.3 for parietal relative to the occipital lobe. The area with the densest occurrence was the anterior subcortical brain. Statistically significant spatial clustering was found in the three-dimensional analysis. No differences in location were found among glioblastoma, diffuse astrocytoma, and oligodendroglioma. Our results demonstrate considerable heterogeneity in the anatomic distribution of gliomas within the brain.

Magnetoencephalography in neurosurgery

OBJECTIVE:To present applications of magnetoencephalography (MEG) in studies of neurosurgical patients. METHODS:MEG maps magnetic fields generated by electric currents in the brain, and allows the localization of brain areas producing evoked sensory responses and spontaneous electromagnetic activity. The identified sources can be integrated with other imaging modalities, e.g., with magnetic resonance imaging scans of individual patients with brain tumors or intractable epilepsy, or with other types of brain imaging data. RESULTS:MEG measurements using modern whole-scalp instruments assist in tailoring individual therapies for neurosurgical patients by producing maps of functionally irretrievable cortical areas and by identifying cortical sources of interictal and ictal epileptiform activity. The excellent time resolution of MEG enables tracking of complex spaciotemporal source patterns, helping, for example, with the separation of the epileptic pacemaker from propagated activity. The combination of noninvasive mapping of subcortical pathways by magnetic resonance imaging diffusion tensor imaging with MEG source localization will, in the near future, provide even more accurate navigational tools for preoperative planning. Other possible future applications of MEG include the noninvasive estimation of language lateralization and the follow-up of brain plasticity elicited by central or peripheral neural lesions or during the treatment of chronic pain. CONCLUSION:MEG is a mature technique suitable for producing preoperative “road maps” of eloquent cortical areas and for localizing epileptiform activity.