Proteomics on human cerebral cavernous malformations reveals novel biomarkers in neurovascular dysfunction for the disease pathology.

BACKGROUND: Cerebral cavernous malformation (CCM) is a disease associated with an elevated risk of focal neurological deficits, seizures, and hemorrhagic stroke. The disease has an inflammatory profile and improved knowledge of CCM pathology mechanisms and exploration of candidate biomarkers will enable new non-invasive treatments. METHODS: We analyzed protein signatures in human CCM tissue samples by using a highly specific and sensitive multiplexing technique, proximity extension assay. FINDINGS: Data analysis revealed CCM specific proteins involved in endothelial dysfunction/inflammation/activation, leukocyte infiltration/chemotaxis, hemostasis, extracellular matrix dysfunction, astrocyte and microglial cell activation. Biomarker expression profiles matched bleeding status, especially with higher levels of inflammatory markers and activated astrocytes in ruptured than non-ruptured samples, some of these biomarkers are secreted into blood or urine. Furthermore, analysis was also done in a spatially resolving manner by separating the lesion area from the surrounding brain tissue. Our spatial studies revealed that although appearing histologically normal, the CCM border areas were pathological when compared to control brain tissues. Moreover, the functional relevance of CD93, ICAM-1 and MMP9, markers related to endothelial cell activation and extracellular matrix was validated by a murine pre-clinical CCM model. INTERPRETATION: Here we present a novel strategy for proteomics analysis on human CCMs, offering a possibility for high-throughput protein screening acquiring data on the local environment in the brain. Our data presented here describe CCM relevant brain proteins and specifically those which are secreted can serve the need of circulating CCM biomarkers to predict cavernoma's risk of bleeding.

Circulating biomarkers in familial cerebral cavernous malformation.

BACKGROUND: Cerebral Cavernous Malformation (CCM) is a rare cerebrovascular disease, characterized by the presence of multiple vascular malformations that may result in intracerebral hemorrhages (ICHs), seizure(s), or focal neurological deficits (FND). Familial CCM (fCCM) is due to loss of function mutations in one of the three independent genes KRIT1 (CCM1), Malcavernin (CCM2), or Programmed Cell death 10 (PDCD10/CCM3). The aim of this study was to identify plasma protein biomarkers of fCCM to assess the severity of the disease and predict its progression. METHODS: Here, we have investigated plasma samples derived from n = 71 symptomatic fCCM patients (40 female/31 male) and n = 17 healthy donors (HD) (9 female/8 male) of the Phase 1/2 Treat_CCM trial, using multiplexed protein profiling approaches. FINDINGS: Biomarkers as sCD14 (p = 0.00409), LBP (p = 0.02911), CXCL4 (p = 0.038), ICAM-1 (p = 0.02013), ANG2 (p = 0.026), CCL5 (p = 0.00403), THBS1 (p = 0.0043), CRP (p = 0.0092), and HDL (p = 0.027), were significantly different in fCCM compared to HDs. Of note, sENG (p = 0.011), THBS1 (p = 0.011) and CXCL4 (p = 0.011), were correlated to CCM genotype. sROBO4 (p = 0.014), TM (p = 0.026) and CRP (p = 0.040) were able to predict incident adverse clinical events, such as ICH, FND or seizure. GDF-15, FLT3L, CXCL9, FGF-21 and CDCP1, were identified as predictors of the formation of new MRI-detectable lesions over 2-year follow-up. Furthermore, the functional relevance of ang2, thbs1, robo4 and cdcp1 markers was validated by zebrafish pre-clinical model of fCCM. INTERPRETATION: Overall, our study identifies a set of biochemical parameters to predict CCM progression, suggesting biological interpretations and potential therapeutic approaches to CCM disease. FUNDING: Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro (AIRC), ERC, Leducq Transatlantic Network of Excellence, Swedish Research Council.

Natural history of intracavernous aneurysms: a consecutive single-center study of 250 patients with 276 aneurysms.

OBJECTIVE: The natural history of cavernous carotid aneurysms (CCAs) is not fully understood. For robust clinical decision-making, the behavior of CCAs needs to be fully understood. The objective of this paper was to calculate the mortality and morbidity rates of patients with diagnosed but untreated CCAs from a relatively large single-center cohort. METHODS: The authors identified 250 patients with 276 CCAs from August 1946 to August 2017 from an aneurysm database including 12,000 intracranial aneurysm patients. Patient and aneurysm characteristics were extracted for further analysis. RESULTS: The cumulative patient follow-up was 1560 years, with a mean of 6.3 years. For patients presenting with a cranial nerve deficit caused by a CCA, those with a ruptured CCA, and patients who received treatment for a CCA, the cumulative patient follow-up was 121 years, with a mean of 1.3 years. For patients with symptom-free or conservatively treated CCAs, the cumulative patient follow-up was 1093 years, with a mean of 7.2 years. Of the 276 aneurysms, 57 (21%) caused cranial nerve deficits and 18 (6.5%) other symptoms, while 201 (73%) remained symptom free. A total of 264 (96%) of the CCAs remained unruptured, and 2 were considered possibly ruptured. Ten (3.6%) ruptures of the CCAs were found. However, none of the ruptured aneurysms caused subarachnoid hemorrhage or death of the patient. Of the CCAs, 51 were multiple, and 131 patients had ≥ 1 intradural aneurysm. The CCAs were analyzed separately. CONCLUSIONS: The majority of the CCAs were asymptomatic during follow-up, and none caused the death of the patient. The incidence of symptoms increased with aneurysm size. Because CCAs have a benign natural course, treatment should be considered mainly if the CCA is symptomatic or grows during follow-up.

Anterior inferior cerebellar artery (AICA) aneurysms: a radiological study of 15 consecutive patients.

Introduction: The aneurysms of the anterior inferior cerebellar artery (AICA) are rare lesions of the posterior circulation and to treat them is challenging. We aim to present anatomical and morphological characteristics of AICA aneurysms in a series of 15 patients. Method: The DSA and CT angiography images of AICA aneurysms in 15 consecutive patients were analyzed retrospectively. Different anatomical characteristics were quantified, including morphology, location, width, neck width, length, bottleneck factor, and aspect ratio. Results: Eighty percent of the patients were females. The age was 52.4 ± 9.6 (mean ± SD) years. 11 patients were smokers. Ten patients had a saccular aneurysm and five patients had a fusiform aneurysm. Aneurysm in 10 patients were located in the proximal segment, in three patients in the meatal segment, and in two patients in the distal segment. Ten out of 15 patients presented with a ruptured aneurysm. The size of AICA aneurysms was 14.8 ± 18.9 mm (mean ± SD). The aspect ratio was 0.92 ± 0.47 (mean ± SD) and bottleneck factor was 1.66 ± 1.65 (mean ± SD). Conclusion: AICA aneurysms are rare lesions of posterior circulation predominantly found in females, present predominantly with subarachnoid hemorrhage, and are mostly large in size.

Slow-Closing Clip for the Treatment of Nonsaccular Vertebrobasilar Aneurysms: A Retrospective Case Series.

OBJECTIVE: Vertebrobasilar artery nonsaccular aneurysms (VBANSAs) are associated with a 13% annual mortality. Revascularization and flow diversion are life-saving options in select cases; technical failures and rapid hemodynamic changes may contribute to unwanted outcomes. We describe a technique and report clinical outcomes of patients treated with an experimental slow-closing clip (SCC). METHODS: An experimental SCC was created to gradually close the parent artery of aneurysms. Clinical, radiographic, and outcome data from patients with VBANSAs who underwent experimental treatment with the SCC were retrospectively analyzed. RESULTS: Among 10 patients (7 men; mean age, 49.5 years; range, 18-73 years), 6 presented with mass effect symptoms, 1 with ischemic stroke, 2 with subarachnoid hemorrhage, and 1 with hydrocephalus. Five patients underwent revascularization plus SCC application, and 5 were treated with SCC alone. The mean follow-up was 6.7 years. The expected mortality among patients with unruptured VBANSAs with previous treatment options in this period was 52.7%, whereas the observed rate was 20%. Four patients died within 12 months after treatment. Causes of death were brainstem ischemic stroke, poor-grade subarachnoid hemorrhage, poor clinical presentation, and unknown. Six patients were alive at last follow-up, with unchanged or improved modified Rankin Scale scores. Mortality was associated with posterior-projecting aneurysms and late-stage treatment. CONCLUSIONS: In this small case series, use of SCC overcame the natural history of VBANSAs when treatment timing and aneurysm anatomy were suitable. The SCC potentially favors aneurysm thrombosis and collateral reactivation. More studies are necessary to better develop the SCC.

"Dolichoectatic Vertebrobasilar Artery Aneurysms".

Intracranial dolichoectasia mainly affects the posterior circulation in aging populations. It may develop into an aneurysmatic formation without a clear neck to be closed from circulation. These vertebrobasilar dolichoectatic artery aneurysms may lead to thromboembolic complications and mass effects on the brainstem and surrounding cranial nerves. Treatment is highly risky, especially in older patients with large or giant aneurysmatic formations. Vascular plasticity and collateral formation might stabilize aneurysmatic formation. The etiology and natural history behind this anomaly are unknown as are the best treatment options in different stages of the disease.

Immunothrombosis and vascular heterogeneity in cerebral cavernous malformation.

Cerebral cavernous malformation (CCM) is a neurovascular disease that results in various neurological symptoms. Thrombi have been reported in surgically resected CCM patient biopsies, but the molecular signatures of these thrombi remain elusive. Here, we investigated the kinetics of thrombi formation in CCM and how thrombi affect the vasculature and contribute to cerebral hypoxia. We used RNA sequencing to investigate the transcriptome of mouse brain endothelial cells with an inducible endothelial-specific Ccm3 knock-out (Ccm3-iECKO). We found that Ccm3-deficient brain endothelial cells had a higher expression of genes related to the coagulation cascade and hypoxia when compared with wild-type brain endothelial cells. Immunofluorescent assays identified key molecular signatures of thrombi such as fibrin, von Willebrand factor, and activated platelets in Ccm3-iECKO mice and human CCM biopsies. Notably, we identified polyhedrocytes in Ccm3-iECKO mice and human CCM biopsies and report it for the first time. We also found that the parenchyma surrounding CCM lesions is hypoxic and that more thrombi correlate with higher levels of hypoxia. We created an in vitro model to study CCM pathology and found that human brain endothelial cells deficient for CCM3 expressed elevated levels of plasminogen activator inhibitor-1 and had a redistribution of von Willebrand factor. With transcriptomics, comprehensive imaging, and an in vitro CCM preclinical model, this study provides experimental evidence that genes and proteins related to the coagulation cascade affect the brain vasculature and promote neurological side effects such as hypoxia in CCMs. This study supports the concept that antithrombotic therapy may be beneficial for patients with CCM.

Inflammation and neutrophil extracellular traps in cerebral cavernous malformation.

Cerebral Cavernous Malformation (CCM) is a brain vascular disease with various neurological symptoms. In this study, we describe the inflammatory profile in CCM and show for the first time the formation of neutrophil extracellular traps (NETs) in rodents and humans with CCM. Through RNA-seq analysis of cerebellum endothelial cells from wild-type mice and mice with an endothelial cell-specific ablation of the Ccm3 gene (Ccm3iECKO), we show that endothelial cells from Ccm3iECKO mice have an increased expression of inflammation-related genes. These genes encode proinflammatory cytokines and chemokines, as well as adhesion molecules, which promote recruitment of inflammatory and immune cells. Similarly, immunoassays showed elevated levels of these cytokines and chemokines in the cerebellum of the Ccm3iECKO mice. Consistently, both flow cytometry and immunofluorescence analysis showed infiltration of different subsets of leukocytes into the CCM lesions. Neutrophils, which are known to fight against infection through different strategies, including the formation of NETs, represented the leukocyte subset within the most pronounced increase in CCM. Here, we detected elevated levels of NETs in the blood and the deposition of NETs in the cerebral cavernomas of Ccm3iECKO mice. Degradation of NETs by DNase I treatment improved the vascular barrier. The deposition of NETs in the cavernomas  of patients with CCM confirms the clinical relevance of NETs in CCM.

Anatomic Risk Factors for S1 Segment Superior Cerebellar Artery Aneurysm Rupture: A Radiologic Study on 81 Consecutive Patients.

BACKGROUND: Due to treatment associated risks, it is still debatable which unruptured aneurysm should be treated. Anatomic and morphologic characteristics may aid to predict the rupture risk of superior cerebellar artery (SCA) aneurysm and possibly support in decision- making during treatment. OBJECTIVES: To identify morphologic characteristics that could predict the rupture of SCA aneurysms. METHODS: A retrospective analysis of computed tomography angiography images of 81 consecutive patients harboring SCA aneurysm who were treated between 1980 to 2014 at Helsinki University Hospital was performed. RESULTS: Of the 81 analyzed SCA aneurysms, 30 (37%) were unruptured and remaining 51 (63%) presented with subarachnoid hemorrhage. The mean ± SD size of unruptured SCA aneurysms was 6.2 ± 6.3 mm; mean size of ruptured SCA aneurysms was 5.9 ± 5.4 mm. The mean ± SD aspect ratio was 0.9 ± 0.3 in unruptured and 1.14 ± 0.44 in ruptured SCA aneurysms. The mean ± SD degree angle between basilar artery and aneurysm was 74.7 ± 24.4 in unruptured and 65.9 ± 23 ruptured SCA aneurysms. Patients with ruptured SCA aneurysm showed significantly higher aspect ratio (Mann-Whitney U, P = 0.01) and smaller aneurysm to basilar artery angle (Mann-Whitney U, P = 0.039). Aspect ratio >1.1 had 2.3 times higher risk of rupture (odds ration [OR] 2.3, 95% confidence interval [CI] 0.84-6.34). An aneurysm to basilar angle <70 degrees had 2.8 times higher risk of rupture (OR 2.75, 95% CI 1.086-6.96). CONCLUSIONS: Ruptured SCA aneurysms are usually small in size. Higher aspect ratio and smaller angle between SCA aneurysm and basilar artery had significantly higher risk of SCA (S1 segment) aneurysm rupture.

Prediction of bleb formation in intracranial aneurysms using machine learning models based on aneurysm hemodynamics, geometry, location, and patient population.

BACKGROUND: Bleb presence in intracranial aneurysms (IAs) is a known indication of instability and vulnerability. OBJECTIVE: To develop and evaluate predictive models of bleb development in IAs based on hemodynamics, geometry, anatomical location, and patient population. METHODS: Cross-sectional data (one time point) of 2395 IAs were used for training bleb formation models using machine learning (random forest, support vector machine, logistic regression, k-nearest neighbor, and bagging). Aneurysm hemodynamics and geometry were characterized using image-based computational fluid dynamics. A separate dataset with 266 aneurysms was used for model evaluation. Model performance was quantified by the area under the receiving operating characteristic curve (AUC), true positive rate (TPR), false positive rate (FPR), precision, and balanced accuracy. RESULTS: The final model retained 18 variables, including hemodynamic, geometrical, location, multiplicity, and morphology parameters, and patient population. Generally, strong and concentrated inflow jets, high speed, complex and unstable flow patterns, and concentrated, oscillatory, and heterogeneous wall shear stress patterns together with larger, more elongated, and more distorted shapes were associated with bleb formation. The best performance on the validation set was achieved by the random forest model (AUC=0.82, TPR=91%, FPR=36%, misclassification error=27%). CONCLUSIONS: Based on the premise that aneurysm characteristics prior to bleb formation resemble those derived from vascular reconstructions with their blebs virtually removed, machine learning models can identify aneurysms prone to bleb development with good accuracy. Pending further validation with longitudinal data, these models may prove valuable for assessing the propensity of IAs to progress to vulnerable states and potentially rupturing.

Blebs in intracranial aneurysms: prevalence and general characteristics.

BACKGROUND: Blebs are rupture risk factors in intracranial aneurysms (IAs), but their prevalence, distribution, and associations with clinical factors as well as their causes and effects on aneurysm vulnerability remain unclear. METHODS: A total of 122 blebs in 270 IAs selected for surgery were studied using patient-specific vascular reconstructions from 3D angiographic images. Bleb geometry, location on the aneurysm, and frequency of occurrence in aneurysms at different locations were analyzed. Associations between gender, age, smoking, hypertension, hormone therapy, dental infection, and presence of blebs were investigated. RESULTS: Of all aneurysms with blebs, 77% had a single bleb and 23% had multiple blebs. Only 6% of blebs were at the neck, while 46% were in the body and 48% in the dome. Aneurysms with blebs were larger (p<0.0001), more elongated (p=0.0002), and with wider necks than aneurysms without blebs. Bleb presence was associated with dental infection (p=0.0426) and negatively associated with hormone therapy (p=0.0426) in women. Anterior and posterior communicating arteries had larger percentages of aneurysms with blebs than internal carotid arteries. Patients with a history of hypertension tended to have a larger percentage of aneurysms with blebs. However, these trends did not reach significance in this sample. CONCLUSIONS: Blebs are common in IAs, and most aneurysms harboring blebs have a single bleb. Blebs in the aneurysm neck are rare, but they are equally common in the body and dome. The presence of blebs in IAs was associated with dental infection, and negatively associated with hormone replacement therapy.

Hemodynamics in aneurysm blebs with different wall characteristics.

BACKGROUND: Blebs are important secondary structures of intracranial aneurysms associated with increased rupture risk and can affect local wall stress and hemodynamics. Mechanisms of bleb development and evolution are not clearly understood. We investigate the relationship between blebs with different wall characteristics and local hemodynamics and rupture sites. METHODS: Blebs with different wall appearances in intra-operative videos were analyzed with image-based computational fluid dynamics. Thin red blebs were compared against thick atherosclerotic/hyperplastic white/yellow blebs. Rupture points were identified in videos of ruptured aneurysms harboring blebs. RESULTS: Thin blebs tended to be closer to the inflow than atherosclerotic blebs of the same aneurysm (P=0.0234). Blebs near the inflow had higher velocity (P=0.0213), vorticity (P=0.0057), shear strain rate (P=0.0084), wall shear stress (WSS) (P=0.0085), and WSS gradient (P=0.0151) than blebs far from the inflow. In a subset of 12 ruptured aneurysms harboring blebs, rupture points were associated with thin blebs in 42% of aneurysms, atherosclerotic blebs in 25%, and were away from blebs in the remaining 33%. CONCLUSIONS: Not all blebs are equal; some have thin translucent walls while others have thick atherosclerotic walls. Thin blebs tend to be located closer to the inflow than atherosclerotic blebs. Blebs near the inflow are exposed to stronger flows with higher and spatially variable WSS than blebs far from the inflow which tend to have uniformly lower WSS. Aneurysms can rupture at thin blebs, atherosclerotic blebs, and even away from blebs. Further study of wall failure in aneurysms with different bleb types is needed.

Risk of stroke in hospitalized SARS-CoV-2 infected patients: A multinational study.

BACKGROUND: There is an increased attention to stroke following SARS-CoV-2. The goal of this study was to better depict the short-term risk of stroke and its associated factors among SARS-CoV-2 hospitalized patients. METHODS: This multicentre, multinational observational study includes hospitalized SARS-CoV-2 patients from North and South America (United States, Canada, and Brazil), Europe (Greece, Italy, Finland, and Turkey), Asia (Lebanon, Iran, and India), and Oceania (New Zealand). The outcome was the risk of subsequent stroke. Centres were included by non-probability sampling. The counts and clinical characteristics including laboratory findings and imaging of the patients with and without a subsequent stroke were recorded according to a predefined protocol. Quality, risk of bias, and heterogeneity assessments were conducted according to ROBINS-E and Cochrane Q-test. The risk of subsequent stroke was estimated through meta-analyses with random effect models. Bivariate logistic regression was used to determine the parameters with predictive outcome value. The study was reported according to the STROBE, MOOSE, and EQUATOR guidelines. FINDINGS: We received data from 26,175 hospitalized SARS-CoV-2 patients from 99 tertiary centres in 65 regions of 11 countries until May 1st, 2020. A total of 17,799 patients were included in meta-analyses. Among them, 156(0.9%) patients had a stroke-123(79%) ischaemic stroke, 27(17%) intracerebral/subarachnoid hemorrhage, and 6(4%) cerebral sinus thrombosis. Subsequent stroke risks calculated with meta-analyses, under low to moderate heterogeneity, were 0.5% among all centres in all countries, and 0.7% among countries with higher health expenditures. The need for mechanical ventilation (OR: 1.9, 95% CI:1.1-3.5, p = 0.03) and the presence of ischaemic heart disease (OR: 2.5, 95% CI:1.4-4.7, p = 0.006) were predictive of stroke. INTERPRETATION: The results of this multi-national study on hospitalized patients with SARS-CoV-2 infection indicated an overall stroke risk of 0.5%(pooled risk: 0.9%). The need for mechanical ventilation and the history of ischaemic heart disease are the independent predictors of stroke among SARS-CoV-2 patients. FUNDING: None.

Microsurgical removal of a misplaced intraspinal venous stent in a patient with inferior vena cava atresia.

Inferior vena cava atresia (IVCA) is a rare vascular condition that may be treated by venous stenting. The authors report on the microsurgical removal of an intraspinally misplaced stent causing nerve root compression and neurological deficits.A 42-year-old patient with IVCA and painful cutaneous collaterals had been scheduled for treatment by stenting of the iliocaval confluence and associated venous collaterals. Initial stenting of the right iliac vein was successful; however, during recanalization of the left paravertebral plexus, the stent entered the spinal canal via extraspinal-to-intraspinal venous collaterals. Because of the use of monoplanar angiography, the stent misplacement was not seen during the procedure. Postinterventionally, the patient experienced a foot elevation weakness (grade 1/5) as well as pain and hypesthesia corresponding to the L5 dermatome. Ultrasonography ruled out a lumbosacral plexus hematoma. CT angiography showed that a stent had entered the spinal canal through the left S1 neuroforamen causing nerve root compression. The intraspinal portion of the stent was removed piecemeal via a left-sided hemilaminectomy. Venous bleeding due to the patient's anticoagulation therapy, the stent's sharp mesh wire architecture, and the proximity to nerve roots complicated the surgery. Postoperatively, the foot elevation improved to grade 4/5.

Risks and Benefits of Glioblastoma Resection in Older Adults: A Retrospective Austrian Multicenter Study.

OBJECTIVE: To assess the prognostic profile, clinical outcome, treatment-associated morbidity, and treatment burden of elderly patients with glioblastoma (GBM) undergoing microsurgical tumor resection as part of contemporary treatment algorithms. METHODS: We retrospectively identified patients with GBM ≥65 years of age who were treated by resection at 2 neuro-oncology centers. Survival was assessed by Kaplan-Meier analyses; log-rank tests identified prognostic factors. RESULTS: The study population included 160 patients (mean age, 73.1 ± 5.1 years), and the median contrast-enhancing tumor volume was 31.0 cm3. Biomarker analyses revealed O(6)-methylguanine-DNA methyltransferase-promoter methylation in 62.7% and wild-type isocitrate dehydrogenase in 97.5% of tumors. The median extent of resection (EOR) was 92.3%, surgical complications were noted in 10.0% of patients, and the median postoperative hospitalization period was 8 days. Most patients (60.0%) received adjuvant radio-/chemotherapy. The overall treatment-associated morbidity was 30.6%. The median progression-free and overall survival were 5.4 months (95% confidence interval [CI], 4.6-6.4 months) and 10.0 months (95% CI, 7.9-11.7 months). The strongest predictors for favorable outcome were patient age ≤73.0 years (P = 0.0083), preoperative Karnofsky Performance Status Scale score ≥80% (P = 0.0179), postoperative modified Rankin Scale score ≤1 (P < 0.0001), adjuvant treatment (P < 0.0001), and no treatment-associated morbidity (P = 0.0478). Increased EOR did not correlate with survival (P = 0.5046), but correlated significantly with treatment-associated morbidity (P = 0.0031). CONCLUSIONS: Clinical outcome for elderly patients with GBM remains limited. Nonetheless, the observed treatment-associated morbidity and treatment burden were moderate in the patients, and patient age and performance status remained the strongest predictors for survival. The risks and benefits of tumor resection in the age of biomarker-adjusted treatment concepts require further prospective evaluation.

The microsurgical management of benign pineal cysts: Helsinki experience in 60 cases.

BACKGROUND: Microsurgical resection represents a well-accepted management option for symptomatic benign pineal cysts. Symptoms such as a headache, hydrocephalus, and visual deficiency are typically associated with pineal cysts. However, more recent studies reported over the past years have characterized additional symptoms as a part of the clinical manifestation of this disease and represent additional indications for intervention. METHODS: We present a retrospective review of patients with histologically confirmed benign pineal cysts that were operated on in our department between 1997 and 2015. A demographic analysis, evaluation of preoperative status, surgical treatment, as well as immediate and long-term clinical and radiological outcomes were conducted. RESULTS: A total of 60 patients with benign pineal cysts underwent surgery between 1997 and 2015. Gross total resection was achieved in 58 cases. All patients except one improved in their clinical status or had made a full recovery at the time of the last follow-up. The key steps for surgical resection of pineal cysts are reported, based on an analysis of representative surgical videos. CONCLUSIONS: We describe in this paper one of the largest series of microsurgically treated pineal cysts. In our opinion, judicious microsurgery remains the most suitable technique to effectively deal with this disease.

Association of Intracranial Aneurysms With Aortic Aneurysms in 125 Patients With Fusiform and 4253 Patients With Saccular Intracranial Aneurysms and Their Family Members and Population Controls.

Background Varying degrees of co-occurrence of intracranial aneurysms (IA) and aortic aneurysms (AA) have been reported. We sought to compare the risk for AA in fusiform intracranial aneurysms (fIA) and saccular intracranial aneurysms (sIA) disease and evaluate possible genetic connection between the fIA disease and AAs. Additionally, the characteristics and aneurysms of the fIA and sIA patients were compared. Methods and Results The Kuopio Intracranial Aneurysm Database includes all 4253 sIA and 125 fIA patients from its Eastern Finnish catchment population, and 13 009 matched population controls and 18 455 first-degree relatives to the IA patients were identified, and the Finnish national registers were used to identify the individuals with AA. A total of 33 fIA patients were studied using an exomic gene panel of 37 genes associated with AAs. Seventeen (14.4%) fIA patients and 48 (1.2%) sIA patients had a diagnosis of AA. Both fIA and sIA patients had AAs significantly more often than their controls (1.2% and 0.5%) or relatives (0.9% and 0.3%). In a competing risks Cox regression model, the presence of fIA was the strongest risk factor for AA (subdistribution hazard ratio 7.6, 95% CI 3.9-14.9, P<0.0005). One likely pathogenic variant in COL5A2 and 3 variants of unknown significance were identified in MYH11, COL11A1, and FBN1 in 4 fIA patients. Conclusions The prevalence of AAs is increased slightly in sIA patients and significantly in fIA patients. fIA patients are older and have more comorbid diseases than sIA patients but this alone does not explain their clinically significant AA risk.

Calcification in Human Intracranial Aneurysms Is Highly Prevalent and Displays Both Atherosclerotic and Nonatherosclerotic Types.

OBJECTIVE: Although the clinical and biological importance of calcification is well recognized for the extracerebral vasculature, its role in cerebral vascular disease, particularly, intracranial aneurysms (IAs), remains poorly understood. Extracerebrally, 2 distinct mechanisms drive calcification, a nonatherosclerotic, rapid mineralization in the media and a slower, inflammation driven, atherosclerotic mechanism in the intima. This study aims to determine the prevalence, distribution, and type (atherosclerotic, nonatherosclerotic) of calcification in IAs and assess differences in occurrence between ruptured and unruptured IAs. Approach and Results: Sixty-five 65 IA specimens (48 unruptured, 17 ruptured) were resected perioperatively. Calcification and lipid pools were analyzed nondestructively in intact samples using high resolution (0.35 µm) microcomputed tomography. Calcification is highly prevalent (78%) appearing as micro (<500 µm), meso (500 µm-1 mm), and macro (>1 mm) calcifications. Calcification manifests in IAs as both nonatherosclerotic (calcification distinct from lipid pools) and atherosclerotic (calcification in the presence of lipid pools) with 3 wall types: Type I-only calcification, no lipid pools (20/51, 39%), Type II-calcification and lipid pools, not colocalized (19/51, 37%), Type III-calcification colocalized with lipid pools (12/51, 24%). Ruptured IAs either had no calcifications or had nonatherosclerotic micro- or meso-calcifications (Type I or II), without macro-calcifications. CONCLUSIONS: Calcification in IAs is substantially more prevalent than previously reported and presents as both nonatherosclerotic and atherosclerotic types. Notably, ruptured aneurysms had only nonatherosclerotic calcification, had significantly lower calcification fraction, and did not contain macrocalcifications. Improved understanding of the role of calcification in IA pathology should lead to new therapeutic targets.