Diss. Stockholm : Karol. inst.

Cerebral Cavernous Malformations (CCM) and Intracranial Aneurysms (IA) are cerebrovascular disorders that can lead to a hemorrhagic stroke and other neurological problems. CCMs are characterized by abnormally enlarged capillary cavities while IAs are saccular outpouchings of intracranial arteries. CCM is found in approximately 0.4% to 0.9% of the population, while IA is more common (3-6%). / This dissertation aimed to add to the body of research for CCM and IA and was divided into two parts. Initial work focused on the characterization and identification of the genes involved in CCM; the second phase focused on the identification of a susceptibility gene for IA. / In the first phase, the CCM1, CCM2 and CCM3 genes were characterized in families and in sporadic cases of CCM. In both cohorts, a causative mutation was identified in 71% of the cases. Subsequent MLPA analysis of subjects with no CCM mutations revealed that large genomic deletions and duplications are a common cause of CCM. In addition, investigation of CCM1 point mutations revealed that these were not simple missense mutations but that they rather activated cryptic splice-donor sites and caused aberrant splicing. Furthermore, the genetic predisposition to CCM in sporadic cases with a single lesion was determined to be different from sporadic cases with multiple malformations. Investigation into the loss of heterozygosity demonstrated a plausible mechanism for CCM pathogenesis involving a second somatic hit at the site of the lesion, suggesting that CCM may be caused by a complete loss of CCM protein function. / In the second phase, a genome-wide scan of a large family and subsequent linkage analysis using a monogenic approach identified a susceptibility locus for IA (ANIB4). / As a result of this research, we have greatly contributed to the field of CCM, most specifically to its clinical diagnosis. A greater understanding of the genetics involved in CCM will facilitate and permit better management care for patients. Furthermore, the possibility of identification of a gene with a major effect for IA will give us more insight into which pathways are involved in IA formation.

No description available.

According to the literature, MRI has been applied to characterize the atherosclerosis in coronary and extracranial internal carotid artery. The cross-sections of MCA were scanned by Magnetic Resonance Imaging (MRI) to assess the accuracy of MRI in identifying MCA stenosis with histopathology as a golden standard, which was performed in the same post-mortem brains as in the second part. The sensitivity and specificity of MRI in detecting more than 30% MCA stenosis were 38.6% and 92.2%, with a positive predictive value of 87.2% and negative predictive value of 52.2%, and the corresponding values of MRI in identifying more than 50% MCA stenosis were 57.1%, 90.8%, 50% and 83.0%, respectively. Stenotic lesions >30% and >50% identified by MRI were found to be associated with infarctions in corresponding MCA territory. / After verification of potential relationship between ischemic stroke and intracranial artery calcification, the incidence of intracranial artery calcification was assessed in the ischemic stroke. One hundred and seventy-five ischemic stroke patients and 182 controls were enrolled. There was a higher prevalence of intracranial artery calcification in ischemic stroke patients than in controls. Hypertension, diabetes, smoking, intracranial artery calcification, hyperlipidemia, and atrial fibrillation were found to be independently associated with ischemic stroke. / Atherosclerotic stenosis is a heterogeneous disorder. The studies performed in extracranial carotid artery and coronary artery showed that the genes associated with lipoprotein metabolism may be associated with atherosclerosis. Thus, we speculated that the genes concerned with lipid metabolism may also be risk factors for MCA atherosclerotic stenosis. In the part of genetic analysis, clinical parameters and the genotypes of polymorphisms in the apolipoprotein E (ApoE), lipoprotein lipase (LPL), and paraoxonase (PON1) genes were compared in patients with and without MCA stenosis. Two hundred and ninety-four ischemic stroke patients were recruited, 136 cases with and 158 without MCA stenosis. Systolic blood pressure (SBP), rather than ApoE, LPL, and PON1 polymorphism was found to be a risk factor of MCA stenosis. / Calcification of intracranial artery, as a common complication of atherosclerosis, was investigated by multi-detector-row computed tomography (MDCT). By this advanced technique, the prevalence and location of calcification in intracranial arteries were determined, and its potential risk factors were also investigated. Four hundred and ninety patients were recruited. The incidence of intracranial artery calcification was 69.4%. The highest prevalence of intracranial artery calcification was seen in internal carotid artery (60%), followed by vertebral artery (20%), middle cerebral artery (5%) and basilar artery (5%). Age, a history of ischemic stroke, and white blood cell count were shown to be independently associated with intracranial artery calcification. / In the present study, genetic, pathological, imaging characterizations and prognosis of MCA stenosis were investigated. The effect of candidate genes has not been confirmed in the present study, but SBP and hypertension appears to contribute a lot to the occurrence of MCA stenosis among Chinese populations. As for the pathology of MCA atherosclerotic plaques, luminal stenosis and also the morphology of atherosclerotic plaque seem to play a cooperative role in leading to ischemic stroke. Imaging studies demonstrated the agreement between ex vivo MRI and histopathology in identifying MCA stenosis, and the correlation between the MCA stenosis identified by MRI and ischemic events. Calcification of intracranial artery, as a common complication of atherosclerosis, may be associated with age, history of ischemic stroke. High incidence of ischemic stroke has been demonstrated in Chinese type 2 diabetes patients. The presence of asymptomatic MCA stenosis plays an important role in the occurrence of ischemic stroke. / Lastly, using a cohort-study, we aimed to investigate stroke incidence of asymptomatic MCA stenosis and its risk factors in Chinese type II diabetic population. Transcranial Doppler was performed to define MCA stenosis. Incident strokes between 1996 and 2006 were ascertained by the database of Clinical Management System of the Hong Kong Hospital Authority. Anthropometric parameters (waist circumference and body mass index), blood pressure, and baseline plasma biochemical profile (lipid and glucose) were recorded to find the risk factors of ischemic stroke in asymptomatic MCA stenosis patients. Totally, 2,197 type II diabetic patients without symptoms of cerebrovascular disease were recruited. The evidence of MCA stenosis was identified in 272 subjects (12.4%), including 146 (53.7%) subjects with single-vessel involvement. Ischemic stroke occurred in one hundred and eighty-four (8.4%, 184/2197) patients. History of ischemic heart disease, MCA stenosis, the presence of retinopathy, lipid total cholesterol and age were independently associated with ischemic stroke. / Secondly, the pathological features of MCA stenosis and their relationship with cerebral infarcts were investigated in a series of post-mortem adults aged 45 years or above. The morphological features of the MCA atherosclerotic plaques were described in detail. The results demonstrated that the degree of luminal stenosis, the percentage of the plaques containing more than 40% lipid area, the values of cap-lipid, cap-lipid-stenosis, and the prevalence of intraplaque hemorrhage, neovasculature and thrombus were higher in the group of plaques associated with infarction. And the mean index of both CD45RO and CD68 were higher in the group of plaques associated with infarction. Binary logistic regression showed that stenosis, lipid area and presence of neovasculature were independent risk factors of MCA infarcts. / Stroke is one of the leading causes of death, disability, and dementia throughout the world. The stenosis of the intracranial large artery, especially the middle cerebral artery (MCA), is common in Chinese, Hispanic, and African populations. But MCA stenosis has been understudied due to its infrequency in the white population and its relative inaccessibility and invasiveness involved in its investigations. The purpose of the study was to investigate the genetic, pathological, imaging characteristics and prognosis of MCA atherosclerotic stenosis in Chinese population. / Chen Xiang-yan. / "September 2006." / Adviser: MH Ng. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1460. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 193-212). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Hypofractionated conformal stereotactic radiotherapy (HCSRT) has been used for the treatment of AVMs at the Umeå University Hospital since 1986. From this year and onwards an increasing number of patients with single or oligo brain metastases have also been treated using this technique. In paper I we have retrospectively evaluated our treatment results of AVMs in terms of obliteration and complications. The rates of obliteration and complications seem to be comparable with SRS even if the AVM volumes in our series were larger than in most series with SRS. In paper II we have retrospectively evaluated the results in terms of local control, survival and complications in two groups of patients with single or oligo brain metastases. One group was treated with HCSRT alone and the other group was treated with whole brain radiotherapy in combination with a stereotactic boost. Controversy still exists concerning the benefit of additional use of WBRT in combination with stereotactic irradiation. The survival times were equal in the two groups and no significant difference in local control was observed. The omission of WBRT seems to carry a higher risk for development new brain metastases distant from the irradiated area. In paper III we report the treatment results in a subgroup of AVMs treated with a combination of embolisation and HCSRT. We also focus on the reduction of vascular density within the nidus of an AVM and propose a method to digitally compare images and more objectively assess a reduction in vascular density following embolisation. Obliteration rates seem comparable with other series using a combination of SRS and embolisation even if our rate of complications was higher than what is usually reported. Using luminescence as measure of vascular density all AVMs seemed to be less dense after embolisation. Treatment accuracy in terms of reproducibility of the isocenter in consecutive treatment sessions is crucial in fractionated radiotherapy. In paper IV we have radiologically evaluated the reproducibility of the isocenter in successive treatment sessions using the non invasive relocatable Fixster frame. There was a high degree of reproducibility and only small errors that most likely is of no clinical importance. A reliable dose plan is equally important as a tool to predict the dose delivered inside and outside the target volume. In paper V we have evaluated the reliability of treatment plans in HCSRT for targets of different geometry and size. A liquid ion chamber and gel dosimeter was used for assessment of dose distribution and absorbed dose. The doseplanning system proved to be accurate in predicting the absorbed dose and dose distribution for the different targets.

Object Rupture of intracranial arteriovenous malformations is a leading cause of stroke in children and young adults. Treatment options include surgery and highly focused radiation (stereotactic radiosurgery). For large and deep seated lesions, the risks of surgery may be prohibitively high, while radiosurgery has a disappointingly low efficacy and long latency. Radiosurgery carries the most promise for significant advances, however the process by which radiosurgery achieves obliteration is incompletely understood. Inflammation and thrombosis are likely to be important in the radiation response and may be amenable to pharmacological manipulation to improve radiosurgical efficacy. Materials and methods Immunohistochemistry and electron microscopy were used to study normal cerebral vessels, cavernous malformations and AVMs, some of which had previously been irradiated. An attempt was made to culture AVM endothelial cells to study the immediate response of AVM endothelium to radiosurgery. The effects of radiosurgery in a rat model of AVM were studied using immunohistochemistry and the results used to determine the choice of a pharmacological strategy to enhance the thrombotic effects of radiosurgery. Results Vascular malformations have a different endothelial inflammatory phenotype than normal cerebral vessels. Radiosurgery may cause long term changes in inflammatory molecule expression and leads to endothelial loss with exposure of pro-thrombotic molecules. Ultrastructural effects of irradiation include widespread cell loss, smooth muscle cell (SMC) proliferation and thrombosis. Endothelial culture from AVMs proved difficult due to SMC predominance in initial cultures. Radiosurgery upregulated several endothelial inflammatory molecules in the animal model and may induce pro-thrombotic cell membrane alterations. The administration of lipopolysaccharide and soluble tissue factor to rats following radiosurgery led to selective thrombosis of irradiated vessels. Conclusions Inflammation and thrombosis are important in the radiosurgical response of AVMs. Lumen obliteration appears to be mediated by proliferation of cells within the vessel wall and thrombosis. Upregulation of inflammatory molecules and perhaps disruption of the normal phospholipid asymmetry of the endothelial and SMC membranes are some of the earliest responses to radiosurgery. The alterations induced by radiation may be harnessed to selectively initiate thrombus formation. Stimulation of thrombosis may improve the efficacy of radiosurgery, increasing treatable lesion size and reducing latency.

CONTENT 1. INTRODUCTION 7 2. PATIENTS AND METHODS 8 2.1. Patients 8 2.2. Control Group 8 2.3. Study Methods 9 2.4. Treatment of Patients 9 2.5. Outcome State 10 2.6. Statistical Data Analysis 10 3. RESULTS 10 3.1. Clinical Manifestations of Cerebral Arteriovenous Malformations 10 3.2. Consciousness according to Glasgow Coma Scale 10 3.3. Distribution of Patients According to Spetzler-Martin Classification 11 3.4. Localization of Cerebral Arteriovenous Malformations 11 3.5. The Localization of Intracranial Haemorrhages after the Rupture of Cerebral Arteriovenous Malformations 11 3.6. Distribution of Patients with Intracerebral Haemorrhages after the Ruptures of Cerebral Arteriovenous Malformations and without Haemorrhages according to Spetzler-Martin classification 12 3.7. The Relationships between Haemorrhagic Manifestation and Size of Cerebral Arteriovenous Malformations 13 3.8. Transcranial Doppler Sonography Sensitivity and Specificity in Patients with Cerebral Arteriovenous Malformations 13 3.9. Cerebral Haemodynamics in Patients with Cerebral Arteriovenous Malformations and Healthy Controls 15 3.10. Cerebral Haemodynamics Changes in Patients with Cerebral Arteriovenous Malformations before and after the Surgery 16 3.11. Transcranial Doppler evaluation of Different Localizations Cerebral Arteriovenous Malformations 18 3.12. Cerebral Haemodynamics in Patients with Intracerebral Haematomas after Ruptures of Cerebral Arteriovenous Malformations 19 3.13. Cerebral... [to full text]

Durante la pandemia COVID-19 se ha incrementado el uso de la telemedicina y de plataformas virtuales en el campo de la medicina, por ello en nuestra institución contamos con un sistema multicámara que permite la visualización en vivo de procedimientos endovasculares. Se realizaron once casos de aneurismas, malformaciones arteriovenosas y hematomas subdurales crónicos que fueron tratados y transmitidos en vivo sin problemas técnicos a través de la plataforma Zoom®. El tiempo promedio de transmisión y del número de participantes fue de 2.5 horas y 6 participantes, respectivamente. En todos los casos se discutió la técnica empleada y las complicaciones ocurridas. El aprendizaje remoto con plataformas en línea es hoy en día una herramienta importante, pero no un sustituto del aprendizaje práctico para procedimientos endovasculares. Recomendamos su implementación durante la pandemia de COVID-19 como un sustituto temporal, especialmente para los médicos en entrenamiento que no tienen acceso a intervenciones endovasculares avanzadas.

Introdução: As malformações arteriovenosas são lesões congênitas caracterizadas por uma rede capilar malformada (nidus) que comunica o sistema arterial e venoso em um mecanismo de shunt arteriovenoso não irrigando tecido normal. Devido ao shunt arteriovenoso as MAVs apresentam alto fluxo sanguíneo, podem ser assintomáticas ou sintomáticas dependendo de sua localização. O tratamento das MAV busca a exclusão circulatória completa do nidus o que pode ser alcançado por meio de ressecção cirúrgica, radiocirurgia ou embolização endovascular. Objetivo: descrição técnica de uma série de dois casos de MAVs de localização periférica (fora do sistema nervoso central), que foram tratadas através da embolização com uso de cateter-balão de duplo lúmen. Materiais e métodos: Trata-se de estudo retrospectivo que avaliou os pacientes submetidos a embolização com cateter-balão de duplo lúmen para o tratamento das MAVs periféricas pelo Setor de Radiologia Intervencionista do HCFMRP-USP. Resultados: Os achados encontrados foram consistentes com a literatura atual demonstrando altas taxas de sucesso técnico e clínico, sem complicações inerentes ao procedimento. Conclusão: O uso destes dispositivos se mostrou mais eficaz em obliterar completamente o nidus deste tipo de lesão, além de reduzir o tempo de procedimento, a exposição à fluoroscopia. Neste estudo foi obtida a exclusão angiográfica completa das MAV em uma única sessão de embolização e não foram descritas complicações relacionadas ao tratamento. / Introduction: Arteriovenous malformations are congenital lesions characterized by a malformed capillary network (nidus) that communicates the arterial and venous system in an arteriovenous shunt mechanism and does not irrigate normal tissue. Due to the arteriovenous shunt AVMs present high blood flow, they may be asymptomatic or symptomatic depending on their location. The AVM treatment seeks the complete circulatory exclusion of the nidus which can be achieved by means of surgical resection, radiosurgery or endovascular embolization. Objectives: A technical description of a series of two cases of peripheral AVMs that were treated through embolization using a dual-lumen balloon catheter. Materials and methods: This is a retrospective study that evaluated patients undergoing embolization with a double-lumen balloon catheter for the treatment of peripheral AVMs by the Interventional Radiology Sector of HCFMRP-USP. Results: The findings were consistent with the current literature demonstrating high rates of technical and clinical success, without complications inherent to the procedure. Conclusion: The use of these devices has been shown to be more effective in completely obliterating the nidus of this type of lesion, in addition to reducing the procedure time, exposure to fluoroscopy. In this study complete angiographic exclusion of AVM was obtained in a single embolization session and no complications related to treatment were described.

Introdução: O risco do tratamento das malformações arteriovenosas encefálicas (MAVEs) é proporcional à sua graduação. O processo de seleção da técnica empregada depende, além da natureza e localização das MAVEs, das condições clínicas e idade dos doentes e da disponibilidade de profissionais treinados e de equipamentos apropriados no ambiente onde o doente é tratado. Objetivo: Avaliar a eficácia da radiocirurgia e da embolização prévia ao tratamento radiocirúrgico das MAVEs classificadas como graus 3A, 3B, 4 ou 5. Métodos e Resultados: O trabalho baseou-se na observação retrospectiva de prontuários clínicos e de arquivos de imagens de 90 doentes com diagnóstico de MAVEs classificadas como graus 3A, 3B, 4 ou 5 submetidos a tratamento com radiocirurgia precedida ou não de embolização no Departamento de Radioterapia e Radioterapia Estereotáctica, Neuroradiologia Intervencionista e Neurocirugia da Real e Benemérita Associação Portuguesa de Beneficência de São Paulo, de outubro de 1993 a outubro de 2008. As idades dos doentes variaram de sete a 60 anos (média de 30,6 anos ± 11,59 anos, mediana de 28 anos). Eram do sexo feminino 46 (51,1%) doentes. Todos foram submetidos a três exames de ressonância magnética (RM) ou tomografia computadorizada (TC) no primeiro ano de acompanhamento e a um exame de RM ou TC do encéfalo no segundo e terceiro anos. Quando um dos exames sugeriu oclusão da MAVE ou o período de acompanhamento foi maior que três anos, os doentes foram submetidos à angiografia digital do encéfalo. Em 51 (56,7%) dos 90 doentes tratados ocorreu oclusão completa da MAVE após a primeira radiocirurgia (1ª Rc), em 21 (23,3%) foram evidenciadas complicações clínica em 36 (40,0%), foram visibilizadas anormalidades no exame de RM. Em 30 (33,3%) doentes evidenciou-se hipersinal no encéfalo em T2 na RM xvi e, em seis (6,7%), radionecrose. Trinta e dois(82,0%) dos 39 doentes que não apresentaram oclusão completa da MAVE após a 1ª Rc foram submetidos à segunda radiocirurgia (2ª Rc). Ocorreu oclusão completa em 12 (37,5%) destes doentes, instalaram-se complicações clínicas em cinco (15,6%) e, anormalidades no exame de RM em oito (25,0%), ou seja, hipersinal em T2 na RM em três (9,5%) e radionecrose em cinco (15,6%). Conclusão: Concluiu-se que a radiocirurgia foi eficaz no tratamento das MAVEs graus 3A, 3B, 4 e 5, que as MAVEs classificadas como grau 3B devem tratadas, preferencialmente, apenas com radiocirurgia e que as MAVEs classificadas como 3A, 4 e 5 devem ser submetidas à embolização previamente à radiocirugia para reduzir-se sua graduação e seu fluxo sanguíneo / Introduction: The risk of treatment of the cerebral arteriovenous malformations (AVM) is proportional to their grade and is affected by the method used. The selection of the AVM therapeutic method depends of the vascular pattern and anatomical site, clinical condition and age of the patient, experience of the treating team and of the equipment available. Objectives: This study aimed the evaluation of the efficacy of the radiosurgical treatment of Grade 3A, 3B, 4 and 5 cerebral AVMs in patients previosly treated or not with embolization. Methods and Results: The data of the clinical notes and the computed tomography (CT) and magnetic ressonance (RM) images of the brain of 90 patients with Grade 3A, 3B, 4 or 5 cerebral embolised or not AVMs treated with radiosurgery at the Department of Radiotherapy, Stereotactic Radiotherapy, Interventional Neuroradiology and Neurosurgery at Real e Benemerita Associação Portuguesa de Beneficência de São Paulo were retrospectively reviewed. The ages of the patients ranged from 7 to 60 years of (average = 30.6 ± 11.59 years; median = 28 years) and 46 (51.1%) were female. During the first year after treatment three MR or CT scans of the brain were evaluated and one at the end of the 2nd and 3rd years after the treatment one MR or CT scan were re-evaluated respectively. When the brain scans suggest AVM occlusion, cerebral angiography was performed. In 51 of the 90 patients (56.7%) there was complete occlusion of the AVM after one radiosurgical treatment; 21 of the patients (23.3%) had clinical complications. In 36 patients (40.0%) new abnormalities of the MR became evident. Thirty (33.3%) presented T2 hypersignal and six (6.7%), had radionecrosis. From the 39 patients who did not had complete occlusion of the AVM, 32 (82.0%) had a second radiosurgical course of treatment; in 12 xviii (37.5%) the AVM became completely occluded but five (15.6%) had clinical complications. Eight (25.0%) of these patients presented new abnormalities at the MR scan of the brain; three (9.5%) had T2 hypersignal and five (15.6%) radionecrosis. Conclusions: Radiosurgery was effective in the treatment of Grade 3A, 3B, 4 and 5 cerebral AVMs , Grade 3B cerebral AVM should be treated only with radiosurgery without previous embolization, and Grade 3A, 4 and 5 AVMs should be treated with embolization to reduce their AVM grade and blood flow prior to radiosurgery