Surgical treatment of symptomatic pineal cysts without hydrocephalus-meta-analysis of the published literature.

BACKGROUND: To examine published data and assess evidence relating to safety and efficacy of surgical management of symptomatic pineal cysts without hydrocephalus (nhSPC), we performed a systematic review of the literature and meta-analysis. METHODS: Following the PRISMA guidelines, we searched Pubmed and SCOPUS for all reports with the query 'Pineal Cyst' AND 'Surgery' as of March 2021, without constraints on study design, publication year or status (PROSPERO_CRD:42,021,242,517). Assessment of 1537 hits identified 26 reports that met inclusion and exclusion criteria. RESULTS: All 26 input studies were either case reports or single-centre retrospective cohorts. The majority of outcome data were derived from routine physician-recorded notes. A total of 294 patients with surgically managed nhSPC were identified. Demographics: Mean age was 29 (range: 4-63) with 77% females. Mean cyst size was 15 mm (5-35). Supracerebellar-infratentorial approach was adopted in 90% of cases, occipital-transtentorial in 9%, and was not reported in 1%. Most patients were managed by cyst resection (96%), and the remainder by fenestration. Mean post-operative follow-up was 35 months (0-228). PRESENTATION: Headache was the commonest symptom (87%), followed by visual (54%), nausea/vomit (34%) and vertigo/dizziness (31%). Other symptoms included focal neurology (25%), sleep disturbance (17%), cognitive impairment (16%), loss of consciousness (11%), gait disturbance (11%), fatigue (10%), 'psychiatric' (2%) and seizures (1%). Mean number of symptoms reported at presentation was 3 (0-9). OUTCOMES: Improvement rate was 93% (to minimise reporting bias only consecutive cases from cohort studies were considered, N = 280) and was independent of presentation. Predictors of better outcomes were large cyst size (OR = 5.76; 95% CI: 1.74-19.02) and resection over fenestration (OR = 12.64; 3.07-52.01). Age predicted worse outcomes (OR = 0.95; 0.91-0.99). Overall complication rate was 17% and this was independent of any patient characteristics. Complications with long-term consequences occurred in 10 cases (3.6%): visual disturbance (3), chronic incisional pain (2), sensory disturbance (1), fatigue (1), cervicalgia (1), cerebellar stroke (1) and mortality due to myocardial infarction (1). CONCLUSIONS: Although the results support the role of surgery in the management of nhSPCs, they have to be interpreted with a great deal of caution as the current evidence is limited, consisting only of case reports and retrospective surgical series. Inherent to such studies are inhomogeneity and incompleteness of data, selection bias and bias related to assessment of outcome carried out by the treating surgeon in the majority of cases. Prospective studies with patient-reported and objective outcome assessment are needed to provide higher level of evidence.

Shedding the Light on the Natural History of Intracranial Aneurysms: An Updated Overview.

The exact molecular pathways underlying the multifactorial natural history of intracranial aneurysms (IAs) are still largely unknown, to the point that their understanding represents an imperative challenge in neurovascular research. Wall shear stress (WSS) promotes the genesis of IAs through an endothelial dysfunction causing an inflammatory cascade, vessel remodeling, phenotypic switching of the smooth muscle cells, and myointimal hyperplasia. Aneurysm growth is supported by endothelial oxidative stress and inflammatory mediators, whereas low and high WSS determine the rupture in sidewall and endwall IAs, respectively. Angioarchitecture, age older than 60 years, female gender, hypertension, cigarette smoking, alcohol abuse, and hypercholesterolemia also contribute to growth and rupture. The improvements of aneurysm wall imaging techniques and the implementation of target therapies targeted against inflammatory cascade may contribute to significantly modify the natural history of IAs. This narrative review strives to summarize the recent advances in the comprehension of the mechanisms underlying the genesis, growth, and rupture of IAs.

Microsurgical Clipping of Carotid-Ophthalmic Tandem Aneurysms: Case Report and Surgical Nuances.

Tandem intracranial aneurysms (TandIAs) are rare but inherently complex, and special technical considerations are required for their surgical management. The present case highlights the key surgical aspects of two carotid-ophthalmic TandIAs incidentally found in a 60-year-old female. Both the aneurysms were superiorly projecting, regular in size, and involved the left ophthalmic segment of the internal carotid artery (ICA). The minimum distance between the necks was 3 mm. The patient underwent microsurgery because of the reported major complications rate of the endovascular treatment in the case of a very short minimum distance between the TandIAs. After cervical ICA exposure, both the aneurysms were excluded through a pterional approach. Intradural anterior clinoidectomy and unroofing of the optic canal allowed the mobilization of the left optic nerve. The more distal aneurysm was clipped before the opening of the distal dural ring of the ICA. The proximal aneurysm was clipped with two straight clips stacked perpendicular to the ICA. A small remnant was intentionally left to avoid the stenosis of the ophthalmic artery. Postoperative angiography showed the exclusion of both the aneurysms with a small dog-ear of the more proximal one. The patient was discharged neurologically intact and, after one year, the remnant remained stable. Microsurgical clipping is a definitive and durable treatment for carotid-ophthalmic TandIAs. In the case of a very short minimum distance between the aneurysms, the distal one should be clipped first to make the anterior clinoidectomy, opening of the distal dural ring of the ICA, and clipping of the more proximal aneurysm easier.

Long-term survival outcomes of pineal region gliomas.

PURPOSE: Surgical series of pineal region gliomas are rarely available. Whereas it is a general assumption that the extent of surgical resection correlates with survival outcomes of intracranial gliomas; the impact of the microsurgical resection on the long-term outcomes of pineal gliomas has been questioned. We present a surgical series of pineal region gliomas with focus on the survival outcome analysis. METHODS: 17 histologically confirmed pineal region glioma patients classified as diffuse and non-diffuse gliomas were retrospectively analyzed. A detailed description of the series was followed by regression models to identify predictors of clinical outcomes. Uni- a multivariate survival analysis was performed to determine independent predictors of mortality. RESULTS: Although the number of treated patients was small, only WHO grade histopathology remained significant (p = 0.02) after multivariate survival analysis with extent of resection, age, tumor volume, and preoperative functional status. The extent of the surgical resection did not correlate with the disease survival rates of non-diffuse (p = 1), diffuse (p = 0.2), nor all gliomas (p = 0.6). 15 of 17 patients underwent gross total (nine patients) or subtotal resection. The preoperative functional status of the patients showed overall improvement on the immediate (p < 0.001) and long-term (p = 0.03) follow-up after 106 (3 - 324) months. CONCLUSION: The extent of the surgical resection does not seem to significantly impact on the survival outcomes of pineal region gliomas. Thus, genotype and molecular features may essentially affect the outcome. Further research on the field is required.

Systematic review of pineal cysts surgery in pediatric patients.

INTRODUCTION: We present a consecutive case series and a systematic review of surgically treated pediatric PCs. We hypothesized that the symptomatic PC is a progressive disease with hydrocephalus at its last stage. We also propose that PC microsurgery is associated with better postoperative outcomes compared to other treatments. METHODS: The systematic review was conducted in PubMed and Scopus. No clinical study on pediatric PC patients was available. We performed a comprehensive evaluation of the available individual patient data of 43 (22 case reports and 21 observational series) articles. RESULTS: The review included 109 patients (72% females). Ten-year-old or younger patients harbored smaller PC sizes compared to older patients (p < 0.01). The pediatric PCs operated on appeared to represent a progressive disease, which started with unspecific symptoms with a mean cyst diameter of 14.5 mm, and progressed to visual impairment with a mean cyst diameter of 17.8 mm, and hydrocephalus with a mean cyst diameter of 23.5 mm in the final stages of disease (p < 0.001). Additionally, 96% of patients saw an improvement in their symptoms or became asymptomatic after surgery. PC microsurgery linked with superior gross total resection compared to endoscopic and stereotactic procedures (p < 0.001). CONCLUSIONS: Surgically treated pediatric PCs appear to behave as a progressive disease, which starts with cyst diameters of approximately 15 mm and develops with acute or progressive hydrocephalus at the final stage. PC microneurosurgery appears to be associated with a more complete surgical resection compared to other procedures.

Pineal Gland Tumor Microenvironment.

A wide and heterogeneous variety of tumors develop from the pineal gland. Pineal parenchymal tumors, germ cell tumors, and glial tumors represent most of them. The molecular profiles and tumor microenvironment play a key role in the development and progression of pineal gland tumors. Consequently, they represent important factors that may determine the efficacy of the different treatment modalities and the clinical outcome. Current literature is scarce regarding the microenvironment research of pineal gland tumors. Here, we review the cellular and molecular profile of the pineal gland tumor microenvironment.

Recurrence of endovascularly and microsurgically treated intracranial aneurysms-review of the putative role of aneurysm wall biology.

Although endovascular therapy has been proven safe and has become in many centers the primary method of treatment for intracranial aneurysms, the long-term durability of endovascular embolization remains a concern; at least for some aneurysms despite initial good result. While healing after clipping relies on mechanical occlusion, restoration after endovascular occlusion mainly requires the induction of a biological response. Healing after embolization depends on the growth of new tissue over the thrombus formed by the embolization material, or alternatively, on the organization of thrombus into fibrous tissue. This review highlights the fundamental importance of aneurysm wall biology on the healing process and long-term occlusion after intracranial aneurysm (IA) treatment. It seems likely that the effect of luminal thrombus on the IA wall, as well as the IA wall condition at the time of thrombosis, determine if thrombus organizes into scar tissue (neointima formation by infiltration of cells originating from the IA wall) or if the wall undergoes continuous remodeling, which is primarily destructive (loss of mural cells). In the latter, intraluminal thrombus organization fails and the impaired healing increases the chance of recurrence. Mechanisms underlying IA reopening, the influence of intraluminal thrombosis on the IA wall, and clinical implications of the IA wall condition are discussed in detail, along with how knowledge of IA wall biology can offer new solutions for IA treatment and affect the patient selection for and follow-up after endovascular treatment.

Outcome and rational management of civilian gunshot injuries to the brain-retrospective analysis of patients treated at the Helsinki University Hospital from 2000 to 2012.

BACKGROUND: Treatment of gunshot wounds of the brain (GSWB) remains controversial and there is high variation in reported survival rates (from < 10 to > 90%) depending on the etiology and country. We retrospectively analyzed the outcome of a series of consecutive GSWB patients admitted alive to a level 1 trauma center in a safe high-income welfare country with a low rate of homicidal gun violence. METHODS: Patients admitted due to a GSWB to the HUS Helsinki University Hospital during 2000-2012 were identified from hospital discharge registry and log books of the emergency room and ICU. CT scans and medical records of these patients were reviewed. Univariate analysis and backward logistic regression were performed, and their results compared with that of a systematic literature review of factors related to the outcome of GSWB patients. RESULTS: Sixty-four patients admitted alive after GSWB were identified. Eighty percent had self-inflicted GSWB, 81% were contact shots, and 70% were caused by handguns. In-hospital mortality was 72%. Factors associated with mortality in our series were low GCS (≤ 8) at admission, transventricular bullet trajectory, and associated damage to deep brain structures, as reported before in the literature. Of the 64 patients admitted alive, 42% (27/64) were admitted to ICU, 34% (22/64) underwent surgery, and in 25% (16/64), craniotomy and hematoma evacuation was performed. Mortality in the surgically treated group was 32% but near 100% without surgery and ICU treatment. Median GOS in the surgically treated patients was 3 (range 1-5). CONCLUSIONS: GSWB caused by contact shot from handguns has a high mortality rate, but can be survived with reasonable outcome if limited to lobar injury without significant damage to deep brain structures or brain stem. In such GSWB patients, initial aggressive resuscitation, ICU admission, and surgery seem indicated.

The focus of temperature monitoring with zero-heat-flux technology (3M Bair-Hugger): a clinical study with patients undergoing craniotomy.

In the noninvasive zero-heat-flux (ZHF) method, deep body temperature is brought to the skin surface when an insulated temperature probe with servo-controlled heating on the skin creates a region of ZHF from the core to the skin. The sensor of the commercial Bair-Hugger ZHF device is placed on the forehead. According to the manufacturer, the sensor reaches a depth of 1-2 cm below the skin. In this observational study, the anatomical focus of the Bair-Hugger ZHF sensor was assessed in pre- and postoperative CT or MRI images of 29 patients undergoing elective craniotomy. Assuming the 2-cm depth from the forehead skin surface, the temperature measurement point preoperatively reached the brain cortex in all except one patient. Assuming the 1-cm depth, the preoperative temperature measurement point did not reach the brain parenchyma in any of the patients and was at the cortical surface in two patients. Corresponding results were obtained postoperatively, although either sub-arachnoid fluid or air was observed in all CT/MRI images. Craniotomy did not have a detectable effect on the course of the ZHF temperatures. In Bland-Altman analysis, the agreement of ZHF temperature with the nasopharyngeal temperature was 0.11 (95% confidence interval - 0.54 to 0.75) °C and with the bladder temperature - 0.14 (- 0.81 to 0.52) °C. As conclusions, within the reported range of the Bair-Hugger ZHF measurement depth, the anatomical focus of the sensor cannot be determined. Craniotomy did not have a detectable effect on the course of the ZHF temperatures that showed good agreement with the nasopharyngeal and bladder temperatures.

Molecular alterations in pediatric brainstem gliomas.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis. Previously, diagnosis was based on a typical clinical presentation and magnetic resonance imaging findings. After the start of the era of biopsies, DIPGs bearing H3 K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27-mutated diffuse midline gliomas, and whether rare long-term survivors also belong to this group. METHODS: We studied tumor samples obtained at diagnosis or upon autopsy from 23 children, including two long-term survivors. Based on clinical, radiological, and histological findings, all tumors were previously diagnosed as DIPGs. All samples were analyzed for genetic alterations by next-generation sequencing (NGS) and for protein expression by immunohistochemistry (IHC). RESULTS: H3 K27 was mutated in NGS or IHC in 20 patients, excluding both long-term survivors. One of these long-term survivors harbored a mutation in IDH1, formerly considered to be an alteration absent in pediatric diffuse brainstem gliomas. Other altered genes in NGS included TP53 (10 patients), MET and PDGFRA (3 patients each), VEGFR and SMARCA4 (2 patients each), and PPARγ, PTEN and EGFR in 1 patient, respectively. IHC revealed cMYC expression in 15 of 24 (63%) of all samples, exclusively in the biopsies. CONCLUSIONS: Eighty-seven percent of the tumors formerly diagnosed as DIPGs could be reclassified as H3 K27-mutated diffuse midline gliomas. Both long-term survivors lacked this alteration. Contrary to former conceptions, IDH1 mutations may occur also in pediatric brainstem gliomas.

High risk population isolate reveals low frequency variants predisposing to intracranial aneurysms.

3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a sporadic and a familial form. Subarachnoid hemorrhage from sIA (sIA-SAH) is a devastating form of stroke. Certain rare genetic variants are enriched in the Finns, a population isolate with a small founder population and bottleneck events. As the sIA-SAH incidence in Finland is >2× increased, such variants may associate with sIA in the Finnish population. We tested 9.4 million variants for association in 760 Finnish sIA patients (enriched for familial sIA), and in 2,513 matched controls with case-control status and with the number of sIAs. The most promising loci (p<5E-6) were replicated in 858 Finnish sIA patients and 4,048 controls. The frequencies and effect sizes of the replicated variants were compared to a continental European population using 717 Dutch cases and 3,004 controls. We discovered four new high-risk loci with low frequency lead variants. Three were associated with the case-control status: 2q23.3 (MAF 2.1%, OR 1.89, p 1.42×10-9); 5q31.3 (MAF 2.7%, OR 1.66, p 3.17×10-8); 6q24.2 (MAF 2.6%, OR 1.87, p 1.87×10-11) and one with the number of sIAs: 7p22.1 (MAF 3.3%, RR 1.59, p 6.08×-9). Two of the associations (5q31.3, 6q24.2) replicated in the Dutch sample. The 7p22.1 locus was strongly differentiated; the lead variant was more frequent in Finland (4.6%) than in the Netherlands (0.3%). Additionally, we replicated a previously inconclusive locus on 2q33.1 in all samples tested (OR 1.27, p 1.87×10-12). The five loci explain 2.1% of the sIA heritability in Finland, and may relate to, but not explain, the increased incidence of sIA-SAH in Finland. This study illustrates the utility of population isolates, familial enrichment, dense genotype imputation and alternate phenotyping in search for variants associated with complex diseases.

Timing of surgery for ruptured supratentorial arteriovenous malformations.

BACKGROUND: There are conflicting opinions regarding the optimal waiting time to perform surgery after rupture of supratentorial arteriovenous malformations (AVMs) to achieve the best possible outcome. OBJECTIVE: To analyze factors influencing outcomes for ruptured supratentorial AVMs after surgery, paying particular attention to the timing of the surgery. METHODS: We retrospectively investigated 59 patients admitted to our center between 2000 and 2014 for surgical treatment of ruptured supratentorial AVMs. We evaluated the effect of timing of surgery and other variables on the outcome at 2-4 months (early outcome), at 12 months (intermediate outcome) after surgery, and at final follow-up at the end of 2016 (late outcome). RESULTS: Age over 40 years (OR 18.4; 95% CI 1.9-172.1; p = 0.011), high Hunt and Hess grade (4 or 5) before surgery (OR 13.5; 95% CI 2.1-89.2; p = 0.007), hydrocephalus on admission (OR 12.9; 95% CI 1.8-94.4; p = 0.011), and over 400 cm3 bleeding during surgery (OR 11.5; 95% CI 1.5-86.6; p = 0.017) were associated with an unfavorable early outcome. Age over 40 years (OR 62.8; 95% CI 2.6-1524.9; p = 0.011), associated aneurysms (OR 34.7; 95% CI 1.4-829.9; p = 0.029), high Hunt and Hess grade before surgery (OR 29.2; 95% CI 2.6-332.6; p = 0.007), and over 400 cm3 bleeding during surgery (OR 35.3; 95% CI 1.7-748.7; p = 0.022) were associated with an unfavorable intermediate outcome. Associated aneurysms (OR 8.2; 95% CI 1.2-55.7; p = 0.031), high Hunt and Hess grade before surgery (OR 5.7; 95% CI 1.3-24.3; p = 0.019), and over 400 cm3 bleeding during surgery (OR 5.8; 95% CI 1.2-27.3; p = 0.027) were associated with an unfavorable outcome at last follow-up. Elapsed time between rupture and surgery did not affect early or final outcome. CONCLUSIONS: Early surgery in patients with ruptured supratentorial arteriovenous malformation is feasible strategy, with late results comparable to those achieved with delayed surgery. Many other factors than timing of surgery play significant roles in long-term outcomes for surgically treated ruptured supratentorial AVMs.

"Dirty coagulation" technique as an alternative to microclips for control of bleeding from deep feeders during brain arteriovenous malformation surgery.

BACKGROUND: Meticulous haemostasis is one of the most important factors during microneurosurgical resection of brain arteriovenous malformation (AVM). Controlling major arterial feeders and draining veins with clips and bipolar coagulation are well-established techniques, while managing with bleeding from deep tiny vessels still proves to be challenging. This technical note describes a technique used by the senior author in AVM surgery for last 20 years in dealing with the issue highlighted. METHOD: "Dirty coagulation" is a technique of bipolar coagulation of small feeders carried out together with a thin layer of brain tissue that surrounds these fragile vessels. The senior author uses this technique for achieving permanent haemostasis predominantly in large and/or deep-seated AVMs. To illustrate the efficacy of this technique, we retrospectively reviewed the outcome of Spetzler-Martin (SM) grade III-V AVMs resected by the senior author over the last 5 years (2010-2015). RESULTS: Thirty-five cases of AVM surgeries (14 SM grade III, 15 SM grade IV and 6 SM grade V) in this 5-year period were analysed. No postoperative intracranial haemorrhage was encountered as a result of bleeding from the deep feeders. Postoperative angiograms showed complete resection of all AVMs, except in two cases (SM grade V and grade III). CONCLUSIONS: "Dirty coagulation" provides an effective way to secure haemostasis from deep tiny feeders. This cost-effective method could be successfully used for achieving permanent haemostasis and thereby decreasing postoperative haemorrhage in AVM surgery.

Risk of Shunting After Aneurysmal Subarachnoid Hemorrhage: A Collaborative Study and Initiation of a Consortium.

BACKGROUND AND PURPOSE: Shunt dependent hydrocephalus after aneurysmal subarachnoid hemorrhage (aSAH) is a common sequela that may lead to poor neurological outcome and predisposes to various interventions, admissions, and complications. We reviewed post-aSAH shunt dependency in a population-based sample and tested the feasibility of a clinical risk score to identify subgroups of aSAH patients with increasing risk of shunting for hydrocephalus. METHODS: A total of 1533 aSAH patients from the population-based Eastern Finland Saccular Intracranial Aneurysm Database (Kuopio, Finland) were used in a recursive partitioning analysis to identify risk factors for shunting after aSAH. The risk model was built and internally validated in random split cohorts. External validation was conducted on 946 aSAH patients from the Southwestern Tertiary Aneurysm Registry (Dallas, TX) and tested using receiver-operating characteristic curves. RESULTS: Of all patients alive ≥14 days, 17.7% required permanent cerebrospinal fluid diversion. The recursive partitioning analysis defined 6 groups with successively increased risk for shunting. These groups also successively risk stratified functional outcome at 12 months, shunt complications, and time-to-shunt rates. The area under the curve-receiver-operating characteristic curve for the exploratory sample and internal validation sample was 0.82 and 0.78, respectively, with an external validation of 0.68. CONCLUSIONS: Shunt dependency after aSAH is associated with higher morbidity and mortality, and prediction modeling of shunt dependency is feasible with clinically useful yields. It is important to identify and understand the factors that increase risk for shunting and to eliminate or mitigate the reversible factors. The aSAH-PARAS Consortium (Aneurysmal Subarachnoid Hemorrhage Patients' Risk Assessment for Shunting) has been initiated to pool the collective insights and resources to address key questions in post-aSAH shunt dependency to inform future aSAH treatment guidelines.

Long-Term Excess Mortality After Aneurysmal Subarachnoid Hemorrhage: Patients With Multiple Aneurysms at Risk.

BACKGROUND AND PURPOSE: There is high case-fatality rate and loss of productive life-years related to aneurysmal subarachnoid hemorrhage (aSAH) but data on long-term survival of patients with aSAH are scarce. We aim to evaluate long-term excess mortality and related risk factors after an aSAH event. METHODS: Survivors (n=3078) of aSAH who had survived for ≥1 year were reviewed for this retrospective follow-up study, which was conducted in the Department of Neurosurgery in Helsinki between 1980 and 2007. Follow-up started 1 year after the aSAH and continued until death or the end of 2012 (48 918 patient-years). Mortality and relative survival ratios were derived using a matched general population. RESULTS: Survivors of aSAH after 20 years showed 17% excess mortality compared with the general population. Even young patients and patients with good recovery showed excess mortality. The highest excess mortality was among patients with multiple aneurysms, old age, poor preoperative clinical condition, conservative aneurysm treatment, and unfavorable clinical outcome at 1 year. CONCLUSIONS: Even after initially favorable recovery from an aSAH, survivors experience excess mortality in the long run in comparison to a matched general population. Cardiovascular disease at younger age and cerebrovascular events were overrepresented as causes of death, which indicates the importance of treatment of vascular risk factors. Young patients and patients with multiple aneurysms who are recovering from an aSAH should be followed-up and treated most actively.

Comparison of vascular growth factors in the murine brain reveals placenta growth factor as prime candidate for CNS revascularization.

Vascular bypass procedures in the central nervous system (CNS) remain technically challenging, hindered by complications and often failing to prevent adverse outcome such as stroke. Thus, there is an unmet clinical need for a safe and effective CNS revascularization. Vascular endothelial growth factors (VEGFs) are promising candidates for revascularization; however, their effects appear to be tissue-specific and their potential in the CNS has not been fully explored. To test growth factors for angiogenesis in the CNS, we characterized the effects of endothelium-specific growth factors on the brain vasculature and parenchyma. Recombinant adeno-associated virus (AAV) vectors encoding the growth factors were injected transcranially to the frontoparietal cerebrum of mice. Angiogenesis, mural cell investment, leukocyte recruitment, vascular permeability, reactive gliosis and neuronal patterning were evaluated by 3-dimensional immunofluorescence, electron microscopy, optical projection tomography, and magnetic resonance imaging. Placenta growth factor (PlGF) stimulated robust angiogenesis and arteriogenesis without significant side effects, whereas VEGF and VEGF-C incited growth of aberrant vessels, severe edema, and inflammation. VEGF-B, angiopoietin-1, angiopoietin-2, and a VEGF/angiopoietin-1 chimera had minimal effects on the brain vessels or parenchyma. Of the growth factors tested, PlGF emerged as the most efficient and safe angiogenic factor, hence making it a candidate for therapeutic CNS revascularization.

Intracranial aneurysm risk locus 5q23.2 is associated with elevated systolic blood pressure.

Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, the pathomechanisms of most remain elusive. Studying the genetics of risk factors predisposing to disease is an attractive approach to identify targets for functional studies. Intracranial aneurysms (IA) are rupture-prone pouches at cerebral artery branching sites. IA is a complex disease for which GWAS have identified five loci with strong association and a further 14 loci with suggestive association. To decipher potential underlying disease mechanisms, we tested whether there are IA loci that convey their effect through elevating blood pressure (BP), a strong risk factor of IA. We performed a meta-analysis of four population-based Finnish cohorts (n(FIN)  =  11 266) not selected for IA, to assess the association of previously identified IA candidate loci (n  =  19) with BP. We defined systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure as quantitative outcome variables. The most significant result was further tested for association in the ICBP-GWAS cohort of 200 000 individuals. We found that the suggestive IA locus at 5q23.2 in PRDM6 was significantly associated with SBP in individuals of European descent (p(FIN)  =  3.01E-05, p(ICBP-GWAS)  =  0.0007, p(ALL)  =  8.13E-07). The risk allele of IA was associated with higher SBP. PRDM6 encodes a protein predominantly expressed in vascular smooth muscle cells. Our study connects a complex disease (IA) locus with a common risk factor for the disease (SBP). We hypothesize that common variants in PRDM6 can contribute to altered vascular wall structure, hence increasing SBP and predisposing to IA. True positive associations often fail to reach genome-wide significance in GWAS. Our findings show that analysis of traditional risk factors as intermediate phenotypes is an effective tool for deciphering hidden heritability. Further, we demonstrate that common disease loci identified in a population isolate may bear wider significance.

Experiences with TachoSil® in microneurosurgery.

BACKGROUND: We analyze our experience of using TachoSil® (Takeda Austria GmbH: Linz, Austria) in microneurosurgical procedures as a hemostat and also as a sealant to patch dural defects. MATERIALS AND METHODS: Beginning on January 1, 2012, we prospectively analyzed 100 consecutive surgeries where TachoSil was used. The patient group included 58 women (58 %) and 42 men (42 %); the mean age was 52 years (range, 3-85 years). Indications for surgery included removal of the tumor (53 cases; 53 %), clipping of the cerebral arterial aneurysm (31 cases; 31 %), and treatment of other pathologies, including AVM (four cases; 4 %), cavernomas (four cases; 4 %), spinal tumor, and traumatic subdural hematoma. Patients received postoperative care according to local neurosurgical department protocol, including a postoperative CT scan after each craniotomy. Primary assessment of the wound took place during the hospital stay as well as at discharge or transfer to a rehabilitation unit. Mean follow-up time was 4 months (range, 1-12 months). RESULTS: None of the patients developed postoperative hematoma after craniotomy or spinal procedure. At primary assessment during hospital stay, 93 patients (93 %) had had no wound-related problems over the normal course of healing. No case registered any liquor leak from the wound, and none of the patients showed any signs of allergic response related to TachoSil usage. At the last follow-up, 96 patients (96 %) experienced uneventful wound healing, and in four patients (4 %), superficial wound infection was successfully treated with oral antibiotics. CONCLUSIONS: Our results indicate that TachoSil can serve in neurosurgical practice at no additional risks. TachoSil proved to be an effective hemostat, sealant, and adhesive in either cranial or spinal procedures.

Intraluminal cell transplantation prevents growth and rupture in a model of rupture-prone saccular aneurysms.

BACKGROUND AND PURPOSE: Aneurysm occlusion by intraluminal thrombus formation is the desired effect of all endovascular treatments. Intraluminal thrombus may, however, recanalize and be absorbed, unless it is infiltrated by cells that turn it into fibrous tissue (neointima). Because ruptured aneurysm walls are characterized by loss of smooth muscle cells, we assessed the impact of mural cell loss on wall remodeling of thrombosed aneurysms and investigated whether neointima formation could be enhanced by direct transplantation of cells into the thrombus. METHODS: Sidewall aneurysms were microsurgically created in rats (n=81). Certain aneurysms were decellularized. Thrombosis was induced using direct injection of a fibrin polymer into the aneurysm. CM-Dil-labeled smooth muscle cells were injected into 25 of 46 fibrin embolized aneurysms. Recanalization and aneurysm growth were monitored with magnetic resonance angiography. Endoscopy, optical projection tomography, histology, and immunohistochemistry were used to study the fate of transplanted cells, thrombus organization, and neointima formation. RESULTS: Decellularized embolized aneurysms demonstrated higher angiographic recurrence compared with decellularized embolized aneurysms with transplanted cells (P=0.037). Local cell replacement at the time of thrombosis resulted in better histological neointima formation than both nondecellularized embolized aneurysms (P<0.001) and decellularized embolized aneurysms (P=0.002). Aneurysm growth and rupture were observed exclusively in decellularized embolized aneurysms. CONCLUSIONS: Lack of smooth muscle cells in the aneurysm wall promotes wall degradation, aneurysm growth and rupture, even if the aneurysm is occluded by luminal thrombus. Transplantation of smooth muscle cells into the luminal thrombus can reduce this degenerative remodeling.

Loss of mural cells leads to wall degeneration, aneurysm growth, and eventual rupture in a rat aneurysm model.

BACKGROUND AND PURPOSE: The biological mechanisms predisposing intracranial saccular aneurysms to growth and rupture are not yet fully understood. Mural cell loss is a histological hallmark of ruptured cerebral aneurysms. It remains unclear whether mural cell loss predisposes to aneurysm growth and eventual rupture. METHODS: Sodium dodecyl sulfate decellularized and nondecellularized saccular aneurysm from syngeneic thoracic aortas were transplanted to the abdominal aorta of Wistar rats. Aneurysm patency and growth was followed up for 1 month with contrast-enhanced serial magnetic resonance angiographies. Endoscopy and histology of the aneurysms were used to assess the role of periadventitial environment, aneurysm wall, and thrombus remodeling. RESULTS: Nondecellularized aneurysms (n=12) showed a linear course of thrombosis and remained stable. Decellularized aneurysms (n=12) exhibited a heterogeneous pattern of thrombosis, thrombus recanalization, and growth. Three of the growing aneurysms (n=5) ruptured during the observation period. Growing and ruptured aneurysms demonstrated marked adventitial fibrosis and inflammation, complete wall disruption, and increased neutrophil accumulation in unorganized intraluminal thrombus. CONCLUSIONS: In the presented experimental setting, complete loss of mural cells acts as a driving force for aneurysm growth and rupture. The findings suggest that aneurysms missing mural cells are incapable to organize a luminal thrombus, leading to recanalization, increased inflammatory reaction, severe wall degeneration, and eventual rupture.