RESUMEN
Brain arteriovenous malformations (bAVMs) are complex, and rare arteriovenous shunts that present with a wide range of signs and symptoms, with intracerebral hemorrhage being the most severe. Despite prior societal position statements, there is no consensus on the management of these lesions. ARISE (Aneurysm/bAVM/cSDH Roundtable Discussion With Industry and Stroke Experts) was convened to discuss evidence-based approaches and enhance our understanding of these complex lesions. ARISE identified the need to develop scales to predict the risk of rupture of bAVMs, and the use of common data elements to perform prospective registries and clinical studies. Additionally, the group underscored the need for comprehensive patient management with specialized centers with expertise in cranial and spinal microsurgery, neurological endovascular surgery, and stereotactic radiosurgery. The collection of prospective multicenter data and gross specimens was deemed essential for improving bAVM characterization, genetic evaluation, and phenotyping. Finally, bAVMs should be managed within a multidisciplinary framework, with clinical studies and research conducted collaboratively across multiple centers, harnessing the collective expertise and centralization of resources.
Asunto(s)
Malformaciones Arteriovenosas Intracraneales , Humanos , Hemorragia Cerebral/terapia , Procedimientos Endovasculares/métodos , Malformaciones Arteriovenosas Intracraneales/terapia , Radiocirugia/métodosRESUMEN
PURPOSE: Although infundibular dilatations (IDs) have been thought to be benign anatomical variants, case reports suggest that they can grow and rupture. The aim of this study was to determine whether IDs have a tendency to grow or rupture. METHODS: The study population was collected from the Tampere University Hospital (TAUH) Aneurysm Database. The presence of IDs was screened from the medical records and imaging studies of 356 intracranial aneurysm patients left to follow-up from 2005 to 2020. The imaging studies were reviewed to confirm the IDs, and their clinical course. Finally, we performed a systematic review of published cases of ID leading to aneurysmatic rupture from PubMed. RESULTS: We found 97 typical IDs in 83 patients and 9 preaneurysmal lesions resembling ID in 9 patients. Out of the typical cone-shaped IDs, none grew or ruptured in a total follow-up of 409 patient-years. One preaneurysmal lesion ruptured during a follow-up: this lesion had components of both infundibular dilatation and aneurysm at the beginning of follow-up. In the systematic literature search, we found 20 cases of aneurysmatic SAHs originating from an ID. Of those, only 7 had imaging available prerupture. All 7 IDs were typically cone-shaped, but a branching vessel originating from the apex of ID was only seen in 4/7. CONCLUSION: Typical infundibular dilatations seem to be benign anatomical variants that are stable and, thus, do not need prophylactic treatment or imaging follow-up. Likely, the SAHs reported from IDs were actually caused by misdiagnosed preaneurysmal lesions.
Asunto(s)
Aneurisma Roto , Aneurisma Intracraneal , Humanos , Aneurisma Roto/complicaciones , Angiografía Cerebral , Dilatación/efectos adversos , Dilatación Patológica/diagnóstico por imagen , Dilatación Patológica/complicaciones , Estudios de Seguimiento , Aneurisma Intracraneal/diagnóstico , Revisiones Sistemáticas como AsuntoRESUMEN
BACKGROUND: Several neurovascular procedures require temporary occlusion of cerebral arteries, leading to ischemia of unpredictable length, occasionally causing brain infarction. Experimental models of cerebral ischemia-reperfusion injury have established that platelet adhesion and coagulation play detrimental roles in reperfusion injury following transient cerebral ischemia. Therefore, in a model of cerebral ischemia-reperfusion injury (IRI), we investigated the therapeutic potential of a dual antiplatelet and anticoagulant (APAC) heparin proteoglycan mimetic which is able to bind to vascular injury sites. METHODS: Brain ischemia was induced in mice by transient occlusion of the right middle cerebral artery for 60 min. APAC, unfractionated heparin (UFH) (both at heparin equivalent doses of 0.5 mg/kg), or vehicle was intravenously administered 10 min before or 60 min after the start of ischemia. At 24 h later, mice were scored for their neurological and motor behavior, and brain damage was quantified. RESULTS: Both APAC and UFH administered before the onset of ischemia reduced brain injury. APAC and UFH pretreated mice had better neurological and motor functions (p < 0.05 and p < 0.01, respectively) and had significantly reduced cerebral infarct sizes (p < 0.01 and p < 0.001, respectively) at 24 h after transient occlusion compared with vehicle-treated mice. Importantly, no macroscopic bleeding complications were observed in either APAC- or UFH-treated animals. However, when APAC or UFH was administered 60 min after the start of ischemia, the therapeutic effect was lost, but without hemorrhaging either. CONCLUSIONS: Pretreatment with APAC or UFH was safe and effective in reducing brain injury in a model of cerebral ischemia induced by transient middle cerebral artery occlusion. Further studies on the use of APAC to limit ischemic injury during temporary occlusion in neurovascular procedures are indicated.
Asunto(s)
Lesiones Encefálicas , Isquemia Encefálica , Daño por Reperfusión , Ratones , Animales , Anticoagulantes/farmacología , Anticoagulantes/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Encéfalo/metabolismo , Heparina/farmacología , Heparina/uso terapéutico , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Daño por Reperfusión/tratamiento farmacológicoRESUMEN
Treatment for arteriovenous malformations of the brain (bAVMs) aims to achieve complete removal or occlusion of the lesion in order to eradicate the risk of rupture and subsequent morbidity associated with these lesions. Despite initially successful treatment, bAVMs may carry a risk of recurrence especially in younger patients. We studied the rate of recurrence of surgically treated bAVMs at Kuopio University Hospital (KUH) in 1981-2021. The study population was collected retrospectively from KUH databases and presented a cohort of 135 surgically treated bAVMs with complete occlusion of the lesion. We also performed a systematic literature review on this topic. In our series, 6 out of 135 (4.4%) patients with angiographically confirmed removal of the lesion later developed a recurrent bAVM with a median time to diagnosis of recurrence of 7.46 years. In pediatric patients, the rate was 5 out of 17 (29.4%). bAVM recurrence was associated with age (p = 0.001) and initial hemorrhagic presentation (p = 0.039). Median age of the study population was 37 years (min 0, max 70), and 51/135 (37.8%) of the patients were female. Seventeen (12.6%) of the 135 bAVM patients were considered pediatric (18 years old or younger) at the time of the operation. In the literature review, 79 of 1739 (4.5%) of surgically treated patients later developed a recurrence with a mean delay of 3.1 years until diagnosis of recurrence. Young surgically treated bAVM patients with a hemorrhagic presentation at initial diagnosis are at a relatively high risk of bAVM recurrence. Follow-up imaging should be arranged for these patients in order to prevent rupture from a recurrent bAVM and subsequent morbidity.
Asunto(s)
Encéfalo , Malformaciones Arteriovenosas Intracraneales , Enfermedades Vasculares , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Hospitales , Malformaciones Arteriovenosas Intracraneales/complicaciones , Estudios Retrospectivos , Enfermedades Vasculares/complicacionesRESUMEN
PURPOSE: Periodontal diseases and caries are common oral diseases that predispose to tooth loss if untreated. In this study, we investigated whether loss of teeth or caries associate with intracranial aneurysm (IA) pathology similar to periodontal diseases. METHODS: A total of 166 patients with either IA or aneurysmal subarachnoid hemorrhage (aSAH) underwent oral examination in Kuopio University Hospital and Tampere University Hospital. Findings were compared to geographically matched controls acquired from cross-sectional Health2000 survey. This study consisted of three sequential steps. First, we compared the number of missing teeth and prevalence of caries in IA and aSAH patients and geographically matched control population, second step was a multivariate analysis including other risk factors, and third step was a 13-year follow-up of the Health2000 survey participants with missing teeth or caries at baseline. RESULTS: Loss of teeth did not significantly differ between IA patients and controls. In logistic regression model adjusted for known risk factors and demographic data, 1-4 caries lesions (OR: 0.40 95%Cl 0.2-0.9, p = 0.031) was associated with lack of IAs, while age (OR: 1.03 95%Cl 1.01.1 p = 0.024), current smoking (OR: 2.7 95%Cl 1.4-5.1, p = 0.003), and severe periodontitis (OR: 5.99 95%Cl 2.6-13.8, p < 0.001) associated to IA formation. In the cox-regression, severe periodontitis at baseline increased the risk of aSAH (HR: 14.3, 95%Cl 1.5-135.9, p = 0.020) during a 13-year follow-up, while caries or missing teeth did not. CONCLUSION: Unlike severe periodontitis, caries does not increase the risk of IAs and aSAHs. However, cariogenic bacteria may participate to IA pathology by disseminating to circulation via inflamed gingival tissue.
Asunto(s)
Aneurisma Intracraneal , Enfermedades Periodontales , Periodontitis , Hemorragia Subaracnoidea , Humanos , Hemorragia Subaracnoidea/complicaciones , Aneurisma Intracraneal/complicaciones , Aneurisma Intracraneal/epidemiología , Estudios Transversales , Susceptibilidad a Caries Dentarias , Periodontitis/complicaciones , Periodontitis/epidemiología , Enfermedades Periodontales/complicacionesRESUMEN
BACKGROUND: Non-aneurysmal subarachnoid hemorrhages (SAHs) are thought to have a benign clinical course compared to aneurysmal SAHs. The aim of this study is to report the clinical course and outcomes of non-aneurysmal SAHs in a large single-center study. METHODS: The patients with non-aneurysmal SAHs were screened from Tampere University Hospital from 2005 to 2020. The clinical data were collected from the patient's medical records and from the imaging studies. The primary interest was the neurological outcome assessed by dichotomized GOS at 2 months. Multivariable logistic regression was used to study the factors associated with unfavorable outcome. RESULTS: We found 216 non-aneurysmal SAHs in 214 patients (2 patients with > 1 bleed). Ninety-seven percent of patients with a typical perimesencephalic bleeding pattern SAH (PSAH) (75/77) had a favorable outcome, while 86% of patients with non-perimesencephalic SAH (NPSAH) had a favorable outcome (84/98). In a multivariable logistic regression analysis, loss of consciousness (LOC) (aOR 214.67, 95% CI 17.62-2615.89) and Fisher grade 4 bleeding pattern (aOR 23.32, 95% CI 1.40-387.98) were associated with increased risk for unfavorable outcome (GOS 1-3). Vasospasm was seen in 20% of non-aneurysmal SAH patients, hydrocephalus in 17%, and 13% needed ventriculostomy. CONCLUSIONS: Non-aneurysmal SAH seems to have a good prognosis for majority of patients, especially for patients with a PSAH. Non-aneurysmal SAH patients are however affected by vasospasm and hydrocephalus and have similar risk factors for poor outcome as patients with aneurysmal SAH. This suggests that it is the severity of the bleed rather than the etiology that associates with poor outcome.
Asunto(s)
Hidrocefalia , Hemorragia Subaracnoidea , Vasoespasmo Intracraneal , Humanos , Hemorragia Subaracnoidea/diagnóstico por imagen , Hemorragia Subaracnoidea/cirugía , Hemorragia Subaracnoidea/complicaciones , Estudios Retrospectivos , Vasoespasmo Intracraneal/etiología , Hidrocefalia/cirugía , Hidrocefalia/complicaciones , Progresión de la EnfermedadRESUMEN
BACKGROUND AND PURPOSE: Hypertension is a risk factor for subarachnoid hemorrhage and is also considered a risk factor for saccular intracranial aneurysm (sIA) formation. However, there is little direct evidence that antihypertensive medication will reduce sIA formation. METHODS: The impact of antihypertensive medication on de novo sIA formation was studied in an angiographically followed cohort of 1419 patients. Patients were identified from our population-based Kuopio Intracranial Aneurysm Database, and data on the purchases of antihypertensive medication were obtained from a national registry. Univariate and multivariate analyses were used to investigate the risk factors. RESULTS: Of the 966 sIA patients who were prescribed with antihypertensive medication, 841 patients used the medication regularly; 20 of them had de novo sIA. One hundred and twenty-five patients used the medication irregularly and 12 of them developed de novo sIAs. Four hundred and fifty-three patients did not use antihypertensive medication even though 27 of them had a diagnosis of hypertension, and 10 of them developed de novo sIAs. In the multivariate analysis antihypertensive medication did not significantly reduce de novo sIA formation (hazard ratio [HR] 1.60, 95% confidence interval [CI] 0.84-3.06). Age at primary diagnosis (HR: 0.95, 95%: CI 0.93-0.98) and smoking history (HR: 5.53, 95% CI: 2.77-11.05) were significant risk factors for de novo sIA formation. Also, irregular usage of antihypertensive medication was a significant risk factor (HR: 3.84, 95% CI: 1.59-9.29) for de novo sIA formation. CONCLUSIONS: Antihypertensive agents were not associated with a reduction of de novo sIA formation, but irregular use of antihypertensive agents was associated with an increased risk of de novo sIA formation.
Asunto(s)
Aneurisma Roto , Hipertensión , Aneurisma Intracraneal , Hemorragia Subaracnoidea , Aneurisma Roto/complicaciones , Antihipertensivos/uso terapéutico , Estudios de Cohortes , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Aneurisma Intracraneal/complicaciones , Aneurisma Intracraneal/tratamiento farmacológico , Aneurisma Intracraneal/epidemiología , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/epidemiologíaRESUMEN
BACKGROUND AND PURPOSE: Pathophysiological studies of saccular intracranial aneurysm (sIA) disease have shown that inflammation plays a crucial role in sIA development. Pharmaceutical inhibition of COX-2-PGE2-NF-κB signaling (COX-2, cyclooxygenase-2; PGE2, prostaglandin E2; NF-κB, nuclear factor κB) has been shown in animal models to inhibit sIA formation and progression suggesting that use of medication inhibiting COX-2 could reduce intracranial aneurysm formation also in patients. METHODS: The impact of COX-2 inhibition on de novo sIA formation was studied in two cohorts: in a previously described angiographically followed cohort of 1419 sIA patients and in a cohort of 117 sIA patients treated with stenting or stent-assisted embolization. Patients were identified from our population-based Kuopio Intracranial Aneurysm Database. Data on the use of anti-inflammatory medications and hospital diagnoses were obtained from national registries. Risk factors were identified by univariate and multivariate analyses. RESULTS: De novo sIA patients were younger and more often smokers. Use of COX-2 selective inhibitors or nonsteroidal anti-inflammatory drugs did not significantly reduce de novo sIA formation, but the percentage of patients with de novo sIA formation was smaller in patients with prescribed regular acetylsalicylic acid medication (1.1% vs. 3.6%). In the multivariate analysis, however, neither acetylsalicylic acid use nor other type of pharmaceutical inhibition of COX-2 reduced the formation of de novo sIAs. The risk was mostly affected by age, smoking history and irregular usage of antihypertensive medication regardless of used COX-2 inhibition level. CONCLUSION: For the prevention of de novo sIA formation, risk factor management with focus on cessation of smoking and treating hypertension adequately seems more important than pharmaceutical COX-2 inhibition.
Asunto(s)
Antiinflamatorios no Esteroideos , Inhibidores de la Ciclooxigenasa 2 , Aneurisma Intracraneal , Antiinflamatorios no Esteroideos/uso terapéutico , Aspirina/uso terapéutico , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Dinoprostona , Humanos , Hipertensión/complicaciones , Aneurisma Intracraneal/etiología , Aneurisma Intracraneal/prevención & control , FN-kappa B , Factores de Riesgo , Fumar/efectos adversosRESUMEN
BACKGROUND: Sporadic arteriovenous malformations of the brain, which are morphologically abnormal connections between arteries and veins in the brain vasculature, are a leading cause of hemorrhagic stroke in young adults and children. The genetic cause of this rare focal disorder is unknown. METHODS: We analyzed tissue and blood samples from patients with arteriovenous malformations of the brain to detect somatic mutations. We performed exome DNA sequencing of tissue samples of arteriovenous malformations of the brain from 26 patients in the main study group and of paired blood samples from 17 of those patients. To confirm our findings, we performed droplet digital polymerase-chain-reaction (PCR) analysis of tissue samples from 39 patients in the main study group (21 with matching blood samples) and from 33 patients in an independent validation group. We interrogated the downstream signaling pathways, changes in gene expression, and cellular phenotype that were induced by activating KRAS mutations, which we had discovered in tissue samples. RESULTS: We detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from arteriovenous malformations of the brain, we detected KRAS mutations and observed that expression of mutant KRAS (KRASG12V) in endothelial cells in vitro induced increased ERK (extracellular signal-regulated kinase) activity, increased expression of genes related to angiogenesis and Notch signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK (mitogen-activated protein kinase)-ERK signaling. CONCLUSIONS: We identified activating KRAS mutations in the majority of tissue samples of arteriovenous malformations of the brain that we analyzed. We propose that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain endothelial cells. (Funded by the Swiss Cancer League and others.).
Asunto(s)
Malformaciones Arteriovenosas Intracraneales/genética , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Adulto , Células Cultivadas , Análisis Mutacional de ADN , Exoma , Expresión Génica , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Malformaciones Arteriovenosas Intracraneales/etiología , Malformaciones Arteriovenosas Intracraneales/patología , Quinasas Quinasa Quinasa PAM/metabolismo , Sistema de Señalización de MAP Quinasas , Fosforilación , Proteínas Proto-Oncogénicas p21(ras)/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Periodontal infections are associated with the formation and rupture of intracranial aneurysms (IAs). This study investigated the role of two key periodontal pathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. METHODS: Immunoglobulin A (IgA) and IgG antibodies against P. gingivalis and A. actinomycetemcomitans were measured with enzyme immune assay from the serum of 227 IA patients, of whom 64 also underwent clinical oral examination. As a control group, 1096 participants in a cross-sectional health survey, Health 2000, underwent serological studies and oral examination. Logistic regression was used for multivariate analysis. Immunohistochemistry was performed to demonstrate bacteria-derived epitopes in the IA wall. RESULTS: Widespread gingivitis and severe periodontitis were more common in IA patients than in controls (2× and 1.5×, respectively). IgA antibodies against P. gingivalis and A. actinomycetemcomitans were 1.5× and 3-3.4× higher, respectively, in both unruptured and ruptured IA patients compared to controls (p ≤ 0.003). IgG antibodies against P. gingivalis were 1.8× lower in unruptured IA patients (p < 0.001). In multivariate analysis, high IgA, but low IgG, antibody levels against P. gingivalis (odds ratio [OR] = 1.4, 95% confidence interval [Cl] = 1.1-1.8 and OR = 1.5, 95% Cl = 1.1-1.9; OR = 0.6, 95% Cl = 0.4-0.7 and OR = 0.5, 95% Cl = 0.4-0.7) and against A. actinomycetemcomitans (OR = 2.3, 95% Cl = 1.7-3.1 and OR = 2.1, 95% Cl = 1.5-2.9; OR = 0.6, 95% Cl = 0.4-0.8 and OR = 0.6, 95% Cl = 0.5-0.9) were associated with the risk of IA formation and rupture. Immunohistochemistry showed P. gingivalis epitopes in the IA wall. CONCLUSIONS: Exposure to the periodontal pathogens P. gingivalis and A. actinomycetemcomitans and dysfunctional acquired immune response against them may increase the risk of IA formation and IA rupture.
Asunto(s)
Aggregatibacter actinomycetemcomitans , Aneurisma Intracraneal , Anticuerpos Antibacterianos , Estudios Transversales , Humanos , Inmunidad , Porphyromonas gingivalisRESUMEN
Degeneration of intracranial aneurysm wall is under active research and recent studies indicate an increased risk of rupture of intracranial aneurysm among patients with periodontal diseases. In addition, oral bacterial DNA has been identified from wall samples of ruptured and unruptured aneurysms. These novel findings led us to evaluate if oral diseases could predispose to pathological changes seen on intracranial aneurysm walls eventually leading to subarachnoid hemorrhage. The aim of this review is to consider mechanisms on the relationship between periodontitis and aneurysm rupture, focusing on recent evidence.
Asunto(s)
Aneurisma Intracraneal/etiología , Aneurisma Intracraneal/microbiología , Boca/microbiología , Enfermedades Periodontales/complicaciones , Enfermedades Periodontales/microbiología , Aneurisma Roto/etiología , Aneurisma Roto/microbiología , Humanos , Hemorragia Subaracnoidea/etiología , Hemorragia Subaracnoidea/microbiologíaRESUMEN
BACKGROUND: Brain arteriovenous malformations (bAVM) may rupture causing disability or death. BAVM vessels are characterized by abnormally high flow that in general triggers expansive vessel remodeling mediated by cyclo-oxygenase-2 (COX2), the target of non-steroidal anti-inflammatory drugs. We investigated whether COX2 is expressed in bAVMs and whether it associates with inflammation and haemorrhage in these lesions. METHODS: Tissue was obtained from surgery of 139 bAVMs and 21 normal Circle of Willis samples. The samples were studied with immunohistochemistry and real-time quantitative polymerase chain reaction (RT-PCR). Clinical data was collected from patient records. RESULTS: COX2 expression was found in 78% (109/139) of the bAVMs and localized to the vessels' lumen or medial layer in 70% (95/135) of the bAVMs. Receptors for prostaglandin E2, a COX2-derived mediator of vascular remodeling, were found in the endothelial and smooth muscle cells and perivascular inflammatory cells of bAVMs. COX2 was expressed by infiltrating inflammatory cells and correlated with the extent of inflammation (r = .231, p = .007, Spearman rank correlation). COX2 expression did not associate with haemorrhage. CONCLUSION: COX2 is induced in bAVMs, and possibly participates in the regulation of vessel wall remodelling and ongoing inflammation. Role of COX2 signalling in the pathobiology and clinical course of bAVMs merits further studies.
Asunto(s)
Encéfalo/metabolismo , Ciclooxigenasa 2 , Malformaciones Arteriovenosas Intracraneales , Remodelación Vascular , Encéfalo/patología , Ciclooxigenasa 2/genética , Humanos , Inflamación , Malformaciones Arteriovenosas Intracraneales/metabolismoRESUMEN
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.
Asunto(s)
Aneurisma Roto/patología , Aterosclerosis/patología , Calcinosis/patología , Procesamiento de Imagen Asistido por Computador/métodos , Aneurisma Intracraneal/patología , Microtomografía por Rayos X/métodos , Anciano , Análisis de Varianza , Aterosclerosis/diagnóstico por imagen , Calcinosis/diagnóstico por imagen , Calcinosis/epidemiología , Humanos , Aneurisma Intracraneal/cirugía , Persona de Mediana Edad , Prevalencia , Medición de Riesgo , Muestreo , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Recolección de Tejidos y ÓrganosRESUMEN
Oral bacteria DNA has been found in intracranial aneurysms (IA) and a high prevalence of periodontitis was reported in IA patients. We investigated whether periodontitis associates with IA formation and aneurysmal subarachnoid hemorrhage (aSAH). First, we compared in a case-control setting the prevalence of periodontal disease in IA patients (42 unruptured IA, 34 ruptured IA) and in age- and gender-matched controls (n = 70) from the same geographical area (Health 2000 Survey, BRIF8901). Next, we investigated whether periodontitis at baseline associated with aSAH in a 13-year follow-up study of 5170 Health 2000 Survey participants. Follow-up data was obtained from national hospital discharge and cause of death registries. Univariate analysis, logistic regression, and Cox-regression were used. Periodontitis (≥ 4mm gingival pocket) and severe periodontitis (≥ 6mm gingival pocket) were found in 92% and 49% of IA patients respectively and associated with IAs (OR 5.3, 95%CI 1.1-25.9, p < 0.000 and OR 6.3, 95%CI 1.3-31.4, p < 0.001, respectively). Gingival bleeding had an even stronger association, especially if detected in 4-6 teeth sextants (OR 34.4, 95%CI 4.2-281.3). Severe periodontitis in ≥ 3 teeth or gingival bleeding in 4-6 teeth sextants at baseline increased the risk of aSAH during follow-up (HR 22.5, 95%CI 3.6-139.5, p = 0.001 and HR 8.3, 95%CI 1.5-46.1, p = 0.015, respectively). Association of periodontitis and gingival bleeding with risk of IA development and aSAH was independent of gender, smoking status, hypertension, or alcohol abuse. Periodontitis and gingival bleeding associate with increased risk for IA formation and eventual aSAH. Further epidemiological and mechanistic studies are indicated.
Asunto(s)
Aneurisma Roto/complicaciones , Hemorragia Gingival/epidemiología , Aneurisma Intracraneal/complicaciones , Periodontitis/epidemiología , Hemorragia Subaracnoidea/complicaciones , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Prevalencia , Sistema de Registros , Factores de Riesgo , Fumar , Adulto JovenRESUMEN
BACKGROUND: Arteriovenous malformations of the brain (bAVM) may rupture from aneurysms or ectasias of the feeding, draining, or nidal vessels. Moreover, they may rupture from the immature, fragile nidal vessels that are characteristic to bAVMs. How the histopathological changes of the nidal vessels associate with clinical presentation and hemorrhage of the lesion is not well known. MATERIALS AND METHODS: We investigated tissue samples from surgically treated bAVMs (n = 85) using standard histological and immunohistochemical stainings. Histological features were compared with the clinical presentation of the patient. RESULTS: Microhemorrhages from nidal vessels were found both in bAVMs with a history of clinically evident rupture and in bAVMs considered unruptured. These microhemorrhages were associated with presence of immature, pathological nidal vessels (p = 0.010) and perivascular inflammation of these vessels (p = 0.001), especially with adhesion of neutrophils (p < 0.001). In multivariate analysis, perivascular inflammation (OR = 19, 95% CI 1.6 to 230), neutrophil infiltration of the vessel wall (OR = 13, 95% CI 1.9 to 94), and rupture status (OR = 0.13, 95% CI 0.017 to 0.92) were significantly associated with microhemorrhages. CONCLUSIONS: Clinically silent microhemorrhages from nidal vessels seem to be very common in bAVMs, and associate with perivascular inflammation and neutrophil infiltration. Further studies on the role of perivascular inflammation in the clinical course of bAVMs are indicated.
Asunto(s)
Vasos Sanguíneos/patología , Hemorragia/etiología , Malformaciones Arteriovenosas Intracraneales/patología , Adulto , Encéfalo/irrigación sanguínea , Encéfalo/patología , Femenino , Hemorragia/patología , Humanos , Malformaciones Arteriovenosas Intracraneales/complicaciones , Malformaciones Arteriovenosas Intracraneales/cirugía , MasculinoRESUMEN
BACKGROUND: Hemorrhage from an arteriovenous malformation of the brain (bAVM) has been associated with focal inflammation of the bAVM. Intrigued by the possibility of anti-inflammatory drug therapy to stabilize bAVMs and prevent hemorrhage, we investigated the association of bAVM inflammation with other histological features and clinical presentation. MATERIALS AND METHODS: Tissue samples from 85 surgically treated bAVMs were studied with histology and CD45 immunostainings. The histological data was compared with the clinical history of the patient. Univariate analysis and logistic regression were performed. RESULTS: Inflammation was found in all studied bAVMs and did not associate with rupture (p = 0.442). While multiple types of inflammatory cells were present, macrophages were clearly the dominant inflammatory cell type, especially in samples with strong inflammation (87% of the samples). Of those bAVMs that had strong inflammation, only 56% had presented with clinically evident rupture. However, hemosiderin which is a sign of prior hemorrhage was detected in 78.4% (58/74) of samples with strong inflammation and was associated with it (p = 0.003). Inflammation in the nidus and parenchyma was associated with perivascular inflammation (p < 0.001). Multivariate analysis did not reveal any independent histological or clinical risk factor for inflammation. CONCLUSIONS: Since strong inflammation is present in both unruptured and ruptured bAVMs, it is not just a reaction to rupture. Our observations suggest that inflammation of the bAVM may indeed predispose to fragility and hemorrhage of the nidal vessels. Further studies in the role of inflammation in the untreated clinical course of bAVMs are indicated.
Asunto(s)
Malformaciones Arteriovenosas Intracraneales/patología , Adulto , Vasos Sanguíneos/patología , Encéfalo/irrigación sanguínea , Encéfalo/patología , Femenino , Humanos , Inflamación , MasculinoRESUMEN
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.
Asunto(s)
Aneurisma Intracraneal/etiología , Aneurisma Intracraneal/patología , Embolización Terapéutica , Procedimientos Endovasculares , Humanos , Aneurisma Intracraneal/cirugía , Recurrencia , Trombosis , Resultado del Tratamiento , Cicatrización de HeridasRESUMEN
OBJECTIVE: Unruptured intracranial aneurysms (UIAs) are relatively common lesions that may cause devastating intracranial hemorrhage, thus producing considerable suffering and anxiety in those affected by the disease or an increased likelihood of developing it. Advances in the knowledge of the pathobiology behind intracranial aneurysm (IA) formation, progression, and rupture have led to preclinical testing of drug therapies that would prevent IA formation or progression. In parallel, novel biologically based diagnostic tools to estimate rupture risk are approaching clinical use. Arterial wall remodeling, triggered by flow and intramural stresses and mediated by inflammation, is relevant to both. METHODS: This review discusses the basis of flow-driven vessel remodeling and translates that knowledge to the observations made on the mechanisms of IA initiation and progression on studies using animal models of induced IA formation, study of human IA tissue samples, and study of patient-derived computational fluid dynamics models. RESULTS: Blood flow conditions leading to high wall shear stress (WSS) activate proinflammatory signaling in endothelial cells that recruits macrophages to the site exposed to high WSS, especially through macrophage chemoattractant protein 1 (MCP1). This macrophage infiltration leads to protease expression, which disrupts the internal elastic lamina and collagen matrix, leading to focal outward bulging of the wall and IA initiation. For the IA to grow, collagen remodeling and smooth muscle cell (SMC) proliferation are essential, because the fact that collagen does not distend much prevents the passive dilation of a focal weakness to a sizable IA. Chronic macrophage infiltration of the IA wall promotes this SMC-mediated growth and is a potential target for drug therapy. Once the IA wall grows, it is subjected to changes in wall tension and flow conditions as a result of the change in geometry and has to remodel accordingly to avoid rupture. Flow affects this remodeling process. CONCLUSIONS: Flow triggers an inflammatory reaction that predisposes the arterial wall to IA initiation and growth and affects the associated remodeling of the UIA wall. This chronic inflammation is a putative target for drug therapy that would stabilize UIAs or prevent UIA formation. Moreover, once this coupling between IA wall remodeling and flow is understood, data from patient-specific flow models can be gathered as part of the diagnostic workup and utilized to improve risk assessment for UIA initiation, progression, and eventual rupture.
Asunto(s)
Arterias Cerebrales/patología , Circulación Cerebrovascular , Inflamación/patología , Aneurisma Intracraneal/patología , Humanos , Hidrodinámica , Inflamación/complicaciones , Aneurisma Intracraneal/etiología , Modelos Biológicos , Estrés FisiológicoRESUMEN
OBJECTIVE: Incidental aneurysms pose a challenge for physicians, who need to weigh the rupture risk against the risks associated with treatment and its complications. A statistical model could potentially support such treatment decisions. A recently developed aneurysm rupture probability model performed well in the US data used for model training and in data from two European cohorts for external validation. Because Japanese and Finnish patients are known to have a higher aneurysm rupture risk, the authors' goals in the present study were to evaluate this model using data from Japanese and Finnish patients and to compare it with new models trained with Finnish and Japanese data. METHODS: Patient and image data on 2129 aneurysms in 1472 patients were used. Of these aneurysm cases, 1631 had been collected mainly from US hospitals, 249 from European (other than Finnish) hospitals, 147 from Japanese hospitals, and 102 from Finnish hospitals. Computational fluid dynamics simulations and shape analyses were conducted to quantitatively characterize each aneurysm's shape and hemodynamics. Next, the previously developed model's discrimination was evaluated using the Finnish and Japanese data in terms of the area under the receiver operating characteristic curve (AUC). Models with and without interaction terms between patient population and aneurysm characteristics were trained and evaluated including data from all four cohorts obtained by repeatedly randomly splitting the data into training and test data. RESULTS: The US model's AUC was reduced to 0.70 and 0.72, respectively, in the Finnish and Japanese data compared to 0.82 and 0.86 in the European and US data. When training the model with Japanese and Finnish data, the average AUC increased only slightly for the Finnish sample (to 0.76 ± 0.16) and Finnish and Japanese cases combined (from 0.74 to 0.75 ± 0.14) and decreased for the Japanese data (to 0.66 ± 0.33). In models including interaction terms, the AUC in the Finnish and Japanese data combined increased significantly to 0.83 ± 0.10. CONCLUSIONS: Developing an aneurysm rupture prediction model that applies to Japanese and Finnish aneurysms requires including data from these two cohorts for model training, as well as interaction terms between patient population and the other variables in the model. When including this information, the performance of such a model with Japanese and Finnish data is close to its performance with US or European data. These results suggest that population-specific differences determine how hemodynamics and shape associate with rupture risk in intracranial aneurysms.