RESUMO
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.
Assuntos
Hemangioma Cavernoso do Sistema Nervoso Central , Humanos , Animais , Camundongos , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/metabolismo , Células Endoteliais/metabolismo , Proteínas Reguladoras de Apoptose/genética , Tromboinflamação , Fator de von Willebrand/metabolismo , Hipóxia/metabolismoRESUMO
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.
Assuntos
Armadilhas Extracelulares , Hemangioma Cavernoso do Sistema Nervoso Central , Animais , Proteínas Reguladoras de Apoptose/genética , Células Endoteliais/metabolismo , Armadilhas Extracelulares/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Humanos , Inflamação/patologia , Proteínas de Membrana/metabolismo , CamundongosRESUMO
BACKGROUND: Previously thought to be congenital, AVMs have shown evidence of de-novo formation and continued growth, thus shifting thoughts on their pathophysiology. Pediatric AVM patients have been reported to be more prone to develop AVM recurrence after a seemingly complete cure. Therefore, we assessed the risk of AVM treated in childhood to recur in adulthood after a long-term follow-up in our own cohort. METHODS: Control DS-angiography was arranged during 2021-2022 as part of a new protocol for all AVM patients who were under 21 years of age at the time of their treatment and in whom the treatment had occurred at least five years earlier. Angiography was offered only to patients under 50 years of age at the time of the new protocol. The complete eradication of AVM after the primary treatment had been originally confirmed with DSA in every patient. RESULTS: A total of 42 patients participated in the late DSA control, and 41 of them were included in this analysis after excluding the patient diagnosed with HHT. The median age at the time of admission for AVM treatment was 14.6 (IQR 12-19, range 7-21 years) years. The median age at the time of the late follow-up DSA was 33.8 years (IQR 29.8-38.6, range 19.4-47.9 years). Two recurrent sporadic AVMs and one recurrent AVM in a patient with hereditary hemorrhagic telangiectasia (HHT) were detected. The recurrence rate was 4.9% for sporadic AVMs and 7.1% if HHT-AVM was included. All the recurrent AVMs had originally bled and been treated microsurgically. The patients with sporadic AVM recurrence had been smoking their whole adult lives. CONCLUSIONS: Pediatric and adolescent patients are prone to develop recurrent AVMs, even after complete AVM obliteration verified by angiography. Therefore, imaging follow-up is recommended.
Assuntos
Malformações Arteriovenosas Intracranianas , Radiocirurgia , Telangiectasia Hemorrágica Hereditária , Adulto , Adolescente , Humanos , Criança , Adulto Jovem , Pessoa de Meia-Idade , Seguimentos , Malformações Arteriovenosas Intracranianas/diagnóstico por imagem , Malformações Arteriovenosas Intracranianas/epidemiologia , Malformações Arteriovenosas Intracranianas/terapia , Encéfalo , Angiografia , Resultado do Tratamento , Estudos Retrospectivos , Radiocirurgia/métodosRESUMO
BACKGROUND: It is estimated that significant (3.2%) of population carries intracranial aneurysm (IA). An increasing number of imaging studies have caused that the chance of finding an incidental aneurysm is becoming more common. Since IA rupture causes subarachnoidal hemorrhage (SAH) and have significant mortality and morbidity prophylactic treatment should be considered when IA is detected. The benefit and risk of treatment of IA is based on epidemiological estimate which takes account patient and aneurysm characteristics. However we know that aneurysm rupture is biological process where inflammation of aneurysm wall is actively leading to degeneration of aneurysm wall and finally weakens it until it bursts. Until now, there have not been imaging method to detect inflammatory process of aneurysm wall METHODS: We created targeting immunoliposome for use in the imaging of aneurysm. Immunoliposome comprises antibodies against at least one vascular inflammatory marker associated with aneurysm inflammation and a label and/or a contrast agent. RESULTS: Histological analysis of IAs where immunoliposome comprises antibodies against vascular inflammation with a label shows promising results for selectively detecting aneurysms inflammation. In magnetic resonance imaging (MRI) we were able to detect immunoliposomes carrying gadolinium. CONCLUSION: Our work opens a new avenue for using contrast labeled immunoliposomes for detecting rupture-prone aneurysms. Immunoliposomes can cary gadolinium and selectively bind to inflammatory section of aneurysm that can be detected with MRI. Further research is needed to develop immunoliposomes to be used with MRI in humans to target treatment to those patients who benefit from it the most.
Assuntos
Aneurisma Roto , Aneurisma Intracraniano , Hemorragia Subaracnóidea , Humanos , Aneurisma Intracraniano/epidemiologia , Gadolínio , Inflamação/complicações , Inflamação/patologia , Fatores de Risco , Imageamento por Ressonância Magnética/efeitos adversos , Aneurisma Roto/diagnóstico por imagem , Aneurisma Roto/epidemiologia , Hemorragia Subaracnóidea/complicaçõesRESUMO
BACKGROUND: Spontaneous angiogram-negative subarachnoid hemorrhage (SAH) is considered a benign illness with little of the aneurysmal SAH-related complications. We describe the clinical course, SAH-related complications, and outcome of patients with angiogram-negative SAH. METHODS: We retrospectively reviewed all adult patients admitted to a neurosurgical intensive care unit during 2004-2018 due to spontaneous angiogram-negative SAH. Our primary outcome was a dichotomized Glasgow Outcome Scale (GOS) at 3 months. We assessed factors that associated with outcome using multivariable logistic regression analysis. RESULTS: Of the 108 patients included, 84% had a favorable outcome (GOS 4-5), and mortality was 5% within 1 year. The median age was 58 years, 51% were female, and 93% had a low-grade SAH (World Federation of Neurosurgical Societies grading I-III). The median number of angiograms performed per patient was two. Thirty percent of patients showed radiological signs of acute hydrocephalus, 28% were acutely treated with an external ventricular drain, 13% received active vasospasm treatment and 17% received a permanent shunt. In the multivariable logistic regression model, only acute hydrocephalus associated with unfavorable outcome (odds ratio = 4.05, 95% confidence interval = 1.05-15.73). Two patients had a new bleeding episode. CONCLUSION: SAH-related complications such as hydrocephalus and vasospasm are common after angiogram-negative SAH. Still, most patients had a favorable outcome. Only acute hydrocephalus was associated with unfavorable outcome. The high rate of SAH-related complications highlights the need for neurosurgical care in these patients.
Assuntos
Hidrocefalia , Hemorragia Subaracnóidea , Adulto , Angiografia , Estudos de Coortes , Feminino , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/etiologia , Hidrocefalia/cirurgia , Pessoa de Meia-Idade , Estudos Retrospectivos , Hemorragia Subaracnóidea/diagnóstico por imagem , Hemorragia Subaracnóidea/cirurgiaRESUMO
BACKGROUND: We wanted to understand how patients with different modified Rankin Scale (mRS) grades differ regarding their health-related quality of life (HRQoL) and how this affects the interpretation and dichotomization of the grade. METHODS: In 2016, all adult patients in our brain arteriovenous malformation (AVM) database (n = 432) were asked to fill in mailed letters including a questionnaire about self-sufficiency and lifestyle and the 15D HRQoL questionnaire. The follow-up mRS was defined in 2016 using the electronic patient registry and the questionnaire data. The 15D profiles of each mRS grade were compared to those of the general population and to each other, using ANCOVA with age and sex standardization. RESULTS: Patients in mRS 0 (mean 15D score = 0.954 ± 0.060) had significantly better HRQoL than the general population (mean = 0.927 ± 0.028), p < 0.0001, whereas patients in mRS 1-4 had worse HRQoL than the general population, p < 0.0001. Patients in mRS 1 (mean = 0.844 ± 0.100) and mRS 2 (mean = 0.838 ± 0.107) had a similar HRQoL. In the recently published AVM research, the most commonly used cut points for mRS dichotomization were between mRS 1 and 2 and between mRS 2 and 3. CONCLUSIONS: Using 15D, we were able to find significant differences in the HRQoL between mRS 0 and mRS 1 AVM patients, against the recent findings on stroke patients using EQ-5D in their analyses. Although the dichotomization cut point is commonly set between mRS 1 and 2, patients in these grades had a similar HRQoL and a decreased ability to continue their premorbid lifestyle, in contrast to patients in mRS 0.
Assuntos
Malformações Arteriovenosas , Encéfalo , Feminino , Humanos , Malformações Arteriovenosas Intracranianas , Controle da População , Qualidade de Vida , Acidente Vascular CerebralRESUMO
BACKGROUND: A major barrier to effective treatment of glioblastoma (GBM) is the large intertumoral heterogeneity at the genetic and cellular level. In early phase clinical trials, patient heterogeneity in response to therapy is commonly observed; however, how tumor heterogeneity is reflected in individual drug sensitivities in the treatment-naïve glioblastoma stem cells (GSC) is unclear. METHODS: We cultured 12 patient-derived primary GBMs as tumorspheres and validated tumor stem cell properties by functional assays. Using automated high-throughput screening (HTS), we evaluated sensitivity to 461 anticancer drugs in a collection covering most FDA-approved anticancer drugs and investigational compounds with a broad range of molecular targets. Statistical analyses were performed using one-way ANOVA and Spearman correlation. RESULTS: Although tumor stem cell properties were confirmed in GSC cultures, their in vitro and in vivo morphology and behavior displayed considerable tumor-to-tumor variability. Drug screening revealed significant differences in the sensitivity to anticancer drugs (p < 0.0001). The patient-specific vulnerabilities to anticancer drugs displayed a heterogeneous pattern. They represented a variety of mechanistic drug classes, including apoptotic modulators, conventional chemotherapies, and inhibitors of histone deacetylases, heat shock proteins, proteasomes and different kinases. However, the individual GSC cultures displayed high biological consistency in drug sensitivity patterns within a class of drugs. An independent laboratory confirmed individual drug responses. CONCLUSIONS: This study demonstrates that patient-derived and treatment-naïve GSC cultures maintain patient-specific traits and display intertumoral heterogeneity in drug sensitivity to anticancer drugs. The heterogeneity in patient-specific drug responses highlights the difficulty in applying targeted treatment strategies at the population level to GBM patients. However, HTS can be applied to uncover patient-specific drug sensitivities for functional precision medicine.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Ensaios de Triagem em Larga Escala , Células-Tronco Neoplásicas/efeitos dos fármacos , Esferoides Celulares/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Camundongos SCID , Transplante de Neoplasias , Células-Tronco Neoplásicas/patologia , Esferoides Celulares/patologia , Células Tumorais Cultivadas/patologiaRESUMO
OBJECTIVE: We reviewed retrospectively the perioperative treatment of microsurgically resected brain arteriovenous malformations (bAVMs) at the neurosurgical department of Helsinki University Hospital between the years 2006 and 2014. We examined the performance of the treatment protocol and the incidence of delayed postoperative hemorrhage (DPH). METHODS: The Helsinki protocol for postoperative treatment of bAVMs was used for the whole patient cohort of 121. The patients who had subsequent DPH were reviewed in more detail. RESULTS: Five out of 121 (4.1%) patients had DPH. These patients had a higher Spetzler-Martin grade (SMG) (p = 0.043) and a more complex venous drainage pattern (p = 0.003) as compared to those who had no postoperative bleed. Patients with DPH had 43% larger intravenous fluid intake in the neurosurgical intensive care unit (p = 0.052); they were all male (p = 0.040) and had longer stay in the intensive care unit (p = 0.022). CONCLUSIONS: The Helsinki protocol for postoperative treatment of bAVMs was found to produce comparable results to a more complex treatment algorithm. DPH was associated with high SMG, complex venous drainage pattern, male gender and high intravenous fluid intake. Our findings support the use of SMG in defining patient's postoperative treatment as the DPHs in our study occurred in patients with grade 2-5.
Assuntos
Malformações Arteriovenosas Intracranianas/cirurgia , Microcirurgia , Procedimentos Neurocirúrgicos , Assistência Perioperatória/métodos , Hemorragia Pós-Operatória/epidemiologia , Adolescente , Adulto , Protocolos Clínicos , Feminino , Hidratação/estatística & dados numéricos , Humanos , Incidência , Tempo de Internação/estatística & dados numéricos , Masculino , Estudos Retrospectivos , Fatores Sexuais , Adulto JovemRESUMO
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.
Assuntos
Estudo de Associação Genômica Ampla , Aneurisma Intracraniano/genética , Acidente Vascular Cerebral/genética , Hemorragia Subaracnóidea/genética , Cromossomos Humanos Par 2/genética , Europa (Continente) , Finlândia , Frequência do Gene , Predisposição Genética para Doença , Variação Genética , Genética Populacional , Humanos , Aneurisma Intracraniano/patologia , Fatores de Risco , Acidente Vascular Cerebral/patologia , Hemorragia Subaracnóidea/patologiaAssuntos
Hospitais , Neurocirurgia , Departamentos Hospitalares , Humanos , Procedimentos NeurocirúrgicosRESUMO
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.
Assuntos
Fístula Arteriovenosa/cirurgia , Malformações Arteriovenosas Intracranianas/cirurgia , Microcirurgia/métodos , Procedimentos Neurocirúrgicos/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Tempo para o Tratamento , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Navigated transcranial magnetic stimulation (nTMS) is increasingly used for preoperative mapping of motor function, and clinical evidence for its benefit for brain tumor patients is accumulating. In respect to language mapping with repetitive nTMS, literature reports have yielded variable results, and it is currently not routinely performed for presurgical language localization. The aim of this project is to define a common protocol for nTMS motor and language mapping to standardize its neurosurgical application and increase its clinical value. METHODS: The nTMS workshop group, consisting of highly experienced nTMS users with experience of more than 1500 preoperative nTMS examinations, met in Helsinki in January 2016 for thorough discussions of current evidence and personal experiences with the goal to recommend a standardized protocol for neurosurgical applications. RESULTS: nTMS motor mapping is a reliable and clinically validated tool to identify functional areas belonging to both normal and lesioned primary motor cortex. In contrast, this is less clear for language-eloquent cortical areas identified by nTMS. The user group agreed on a core protocol, which enables comparison of results between centers and has an excellent safety profile. Recommendations for nTMS motor and language mapping protocols and their optimal clinical integration are presented here. CONCLUSION: At present, the expert panel recommends nTMS motor mapping in routine neurosurgical practice, as it has a sufficient level of evidence supporting its reliability. The panel recommends that nTMS language mapping be used in the framework of clinical studies to continue refinement of its protocol and increase reliability.
Assuntos
Mapeamento Encefálico/métodos , Idioma , Córtex Motor/fisiologia , Neuronavegação/métodos , Estimulação Magnética Transcraniana/métodos , Humanos , Córtex Motor/diagnóstico por imagem , Córtex Motor/cirurgiaRESUMO
Navigated transcranial magnetic stimulation (nTMS) is employed in eloquent brain area localization prior to intraoperative direct cortical electrical stimulations and neurosurgery. No commercial archiving or file transfer protocol existed for these studies. The aim of our project was to establish a standardized protocol for the transfer of nTMS results and medical assessments to the end users in pursuance of improving data security and facilitating presurgical planning. The existing infrastructure of the hospital's Radiology Department was used. Hospital information systems and networks were configured to allow communications and archiving of the study results, and in-house software was written for file manipulations and transfers. Graphical user interface with description suggestions and user-defined text legends enabled an easy and straightforward workflow for annotations and archiving of the results. The software and configurations were implemented and have been applied in studies of ten patients. The creation of the study protocol required the involvement of various professionals and interdepartmental cooperation. The introduction of the protocol has ended previously recurrent involvement of staff in the file transfer phase and improved cost-effectiveness.
Assuntos
Mapeamento Encefálico , Neoplasias Encefálicas/cirurgia , Sistemas de Informação em Radiologia , Estimulação Magnética Transcraniana , Humanos , Cuidados Pré-Operatórios , SoftwareRESUMO
BACKGROUND AND PURPOSE: Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. METHODS: Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. RESULTS: Genome-wide evidence of association was detected in the discovery sample on chromosome 9 (CDKN2BAS; rs10733376: P<1.0×10(-11)), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9, was associated with IA (rs10230207; P=4.14×10(-8)). This association replicated in the Dutch sample (P=0.01) but failed to show association in the Finnish sample (P=0.25). Meta-analysis results of the 3 cohorts reached statistical significant (P=9.91×10(-10)). CONCLUSIONS: We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9), suggesting a possible genetic link between this stroke subtype and IA.
Assuntos
Cromossomos Humanos Par 7/genética , Estudo de Associação Genômica Ampla/métodos , Aneurisma Intracraniano/genética , Polimorfismo de Nucleotídeo Único/genética , População Branca/genética , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Aneurisma Intracraniano/diagnóstico , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Visual field defects (VFDs) negatively affect activities of daily living and rehabilitation following aneurysmal subarachnoid haemorrhage (aSAH). The aim here was to assess VFDs in patients with aSAH and their associations with age, gender, aSAH severity, and clinical outcome. METHODS: Patients admitted to Helsinki University Central Hospital and treated during 2011 were participants in this prospective study. Findings obtained with the Octopus 900 perimeter (Haag-Streit Inc, Koenic, Switzerland), the Goldmann perimeter (Haag-Streit Inc, Bern, Switzerland), or the confrontation visual field test on admission and 3 days, 14 days, 2 to 4 months, and 6 months postoperatively were assigned to 16 classes. Associations between post-chiasmal VFDs and relevant clinical, radiological, and demographic data were analysed with uni- and multivariate logistic regression. RESULTS: Of 105 survivors at 6 months, 20 (19 %) had VFDs occurring for aneurysm- or operation-related reasons; homonymous hemianopias or quadrantanopias were the most common finding, occurring in 16 patients (15 %). Posterior ischaemic optic neuropathy presented in two patients (2 %). Ten survivors (10 %) no longer fulfilled visual field requirements for driving licences. Significant associations emerged between VFDs at 6 months and the Hunt and Hess (H&H), World Federation of Neurosurgical Societies (WFNS), and Fisher grades on admission, presence of intracerebral haemorrhage (ICH), hydrocephalus, or postoperative infarction, and higher modified Rankin Scale scores at 6 months. Multivariate logistic regression showed the H&H grade and presence of ICH to independently predict VFDs. CONCLUSIONS: Assessing VFDs is advisable, especially among patients with poor-grade aSAH (H&H grade IV or V) and ICH.
Assuntos
Aneurisma Roto/cirurgia , Aneurisma Intracraniano/cirurgia , Procedimentos Neurocirúrgicos , Transtornos da Visão/epidemiologia , Transtornos da Visão/fisiopatologia , Campos Visuais/fisiologia , Adulto , Fatores Etários , Idoso , Feminino , Seguimentos , Hemianopsia/epidemiologia , Hemianopsia/fisiopatologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neuropatia Óptica Isquêmica/epidemiologia , Neuropatia Óptica Isquêmica/fisiopatologia , Estudos Prospectivos , Fatores Sexuais , Fatores de Tempo , Testes de Campo VisualRESUMO
UNLABELLED: BACKGOUND/OBJECTIVE: To determine the level of association between uptake of the amyloid positron emission tomography (PET) imaging agent [(18)F]flutemetamol and the level of amyloid-ß measured by immunohistochemical and histochemical staining in a frontal cortical region biopsy site. METHODS: Seventeen patients with probable normal pressure hydrocephalus (NPH) underwent prospective [(18)F]flutemetamol PET and subsequent frontal cortical brain biopsy during ventriculoperitoneal shunting. Tissue amyloid-ß was evaluated using the monoclonal antibody 4G8, thioflavin S and Bielschowsky silver stain. RESULTS: Four of the 17 patients (23.5%) had amyloid-ß pathology based on the overall pathology read and also showed increased [(18)F]flutemetamol uptake. [(18)F]Flutemetamol standardized uptake values from the biopsy site were significantly associated with biopsy specimen amyloid-ß levels (Pearson's r = 0.67; p = 0.006). There was also good correlation between the biopsy specimen amyloid-ß level and uptake of [(18)F]flutemetamol in the region contralateral to the biopsy site (r = 0.67; p = 0.006), as well as with composite cortical [(18)F]flutemetamol uptake (r = 0.65; p = 0.008). The blinded visual read showed a high level of agreement between all readers (κ = 0.88). Two of 3 readers were in full agreement on all images; 1 reader disagreed on 1 of the 17 NPH cases. Blinded visual assessments of PET images by 1 reader were associated with 100% sensitivity to the overall pathology read, and assessments by the 2 others were associated with 75% sensitivity (overall sensitivity by majority read was 75%); specificity of all readers was 100%. CONCLUSIONS: [(18)F]Flutemetamol detects brain amyloid-ß in vivo and shows promise as a valuable tool to study and possibly facilitate diagnosis of Alzheimer's disease both in patients with suspected NPH and among the wider population.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/análise , Compostos de Anilina , Benzotiazóis , Hidrocefalia de Pressão Normal/diagnóstico por imagem , Idoso , Doença de Alzheimer/patologia , Feminino , Humanos , Hidrocefalia de Pressão Normal/patologia , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Estudos ProspectivosRESUMO
BACKGROUND: The association between intracranial hemangioblastomas and arteriovenous malformations has been documented in very few cases in literature since 1965 and might present in three modalities: "intermixed, adjacent and separated (spatially and temporally)". Often, the pattern of presentation is "intermixed". According to our systematic review, we propose an adjustment of the previous classification, specifically for these entities. We describe the first case of a truly "spatially separated" association between these two lesions. METHODS: Our study encompassed all adult patients diagnosed with both intracranial hemangioblastoma and AVM who were evaluated in the last 20-year period, from 2003 to 2023 at Helsinki University Hospital. Cases of this coexistence were retrospectively identified and collected from clinical records. For the systematic review, studies reporting the coexistence of hemangioblastoma and AVM in adult patients (>18 years old) were selected. Given the rarity of this pattern, case reports were also included. RESULTS: The combined analysis of our systematic review and institutional retrospective study revealed a total of only seven identified cases. We applied the classification of neoplasms and AVM by Yano, modifying and adapting it into our screened patient series. We systematically reclassified "adjacent" and genuinely "spatially separated" patterns based on the vascular axis supplying both lesions. CONCLUSIONS: Hemangioblastomas and AVMs rarely coexist in the same patient. Our study reports the first instance of a truly "spatially separated" sporadic association between these vascular lesions. The rarity of such coexistence underscores the need for a nuanced and systematic classification to guide the management of these infrequent cases.
Assuntos
Hemangioblastoma , Malformações Arteriovenosas Intracranianas , Hemangioblastoma/cirurgia , Humanos , Malformações Arteriovenosas Intracranianas/complicações , Malformações Arteriovenosas Intracranianas/cirurgia , Adulto , Estudos Retrospectivos , Neoplasias Cerebelares/cirurgia , Feminino , Masculino , Pessoa de Meia-Idade , Neoplasias EncefálicasRESUMO
BACKGROUND AND OBJECTIVES: The knowledge about the management of patients with brain arteriovenous malformations (AVM) during pregnancy is limited, owing partly to insufficient evidence about the outcomes of newborns. This study aims to explore symptomatic AVMs and their outcomes during pregnancy, delivery, and the postpartum period. METHODS: We conducted a retrospective analysis by combining patients with symptomatic AVM from a nationwide population-based cohort of all women with a pregnancy resulting in delivery during 1987 to 2016 (n = 1 773 728 deliveries) and our AVM database (n = 805, 1942-2014). Cerebrovascular events during pregnancy were identified through International Classification of Diseases-9, International Classification of Diseases-10, or surgical procedure codes from the Hospital Discharge and Medical Birth Registers. Our analysis focused on treatment characteristics and outcomes of patients with AVM hemorrhage or symptomatic AVM during pregnancy, delivery, or puerperium. RESULTS: A total of 28 women with symptomatic AVMs during pregnancy, delivery, or postpartum period were followed for an average of 12.8 years (SD = 15.5) after admission. Among them, 21 (75%) experienced AVM hemorrhages during pregnancy, puerperium, or delivery. The mean age of patients was 28.9 years (SD = 5.5). Hemorrhages occurred predominantly during the second (n = 9, 43% of all ruptures) or the third trimester (n = 5, 24%). Two AVM ruptures occurred during labor. Treatment for AVM took place during pregnancy (n = 7, 25%) or puerperium (n = 3, 14%) in 10 patients (35.7%). Only 5 mothers (17.8%) had not been previously pregnant. There was no significant difference in mean Apgar scores between those with AVM hemorrhage (8.3) and those without (8.4). CONCLUSION: Most mothers in the study had prior pregnancies, suggesting a potentially weaker association between AVM rupture and pregnancy compared to previous reports. Notably, 2 AVM ruptures occurred during spontaneous vaginal deliveries. Outcomes were generally favorable in both mothers and infants. More research is needed to refine our understanding of the optimal timing for invasive treatment during pregnancy.
RESUMO
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.