archives@tulane.edu / 1 / Angela Crist

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Les Malformations Artérioveineuses sont des lésions vasculaires évolutives. Elles peuvent avoir des conséquences neurologiques lourdes liées au risque hémorragique élevé qui est leur mode de révélation le plus fréquent. Le développement de meilleurs outils d’imagerie a beaucoup amélioré le diagnostic de ces lésions et a permis une meilleure compréhension de leur interaction avec le tissu cérébral. Néanmoins, Leur 4eme dimension et leur évolution restent encore obscures.Par ailleurs, les traitements actuels (embolisation, microchirurgie, chirurgie stéréotaxique) sont associés à des risques de morbidité et mortalité importants.Pour ces raisons, nous avons travaillé sur un traitement potentiel peu invasif: des agents antiangiogéniques. Un modèle porcin simplifié a été élaboré consistant en l’occlusion unilatérale de l’artère carotide primitive et externe par voie endovasculaire. Ce modèle a présenté des preuves d’angiogénèse et des modifications anatomopathologiques proches de celles des MAVc humaines. Le Bevacizumab, un anticorps monoclonal pour le VEGF, a été administré in situ sur ce modèle. Les résultats ont montré que l’agent antiangiogénique altère l’angiogénèse sur les specimens histologiques. L’épaisseur de la paroi des vaissaux a été stabilisée après l’injection de Bevacizumab mais le volume des retia est demeuré identique montrant que le volume dépend de l’angiogénèse mais probablement également du flux / Brain arteriovenous malformations are dynamic, evolving vascular lesions. They present high morbidity rates due to hemorrhagic presentation that is the most frequent symptom at onset and potentially high mortality rates .Up to date imaging techniques has greatly facilitated the diagnosis of these lesions and the better understanding of their relation to adjacent brain tissue. However, it remains still a challenge to define their four dimensional nature and its consequences, a fact that can actually optimize their treatment. Embolization, surgery and stereotactic radiosurgery that are currently used in the treatment of AVMs carry also significant morbi-mortality risks. For this reason, a potential minimally invasive treatment with antiangiogenic agents was tested. A swine model was firstly created using the animal’s rete mirabile and performing an endovascular occlusion of one common and external carotid artery. This simplified model presented evidence of angiogenesis and histologic findings that are also observed in human AVMs compared to a control group. Secondly, Bevacizumab that is a monoclonal antibody to vascular endothelial growth factor, was in situ administered on this model. The results showed that the antiangiogenic agent tampered angiogenesis on histologic samples by stabilizing the wall thickness of the arteries but it did not have any effect on volume that is probably depending on flow and not only on angiogenesis.

Aspectos morfológicos do nido e embolização parcial neoadjuvante sem intenção de cura de malformações arteriovenosas encefálicas, precedendo a radiocirurgia, podem ter influência no resultado final do tratamento. Métodos: série consecutiva de 47 pacientes submetidos à radiocirurgia (1 a 5 sessões), precedida ou não por embolização com cianoacrilato. Acompanhamento clínico e radiológico mínimo de 36 meses. Resultados: a apresentação hemorrágica ocorreu em 68,1% dos pacientes tratados; destes, 62,5% portavam fístula arteriovenosa dentro da malformação arteriovenosa; 83,3% ectasia venosa e 90% restrição à drenagem venosa. A taxa de oclusão de embolização seguida de radiocirurgia foi de 46,1% e da radiocirurgia isolada foi de 52,4% (p=0,671). Foram identificados como fatores favoráveis à oclusão: baixo volume nidal, ausência de fístula arteriovenosa intranidal, maior dose de radiação e baixo grau na classificação das malformações arteriovenosas encefálicas baseadas na radiocirurgia (RBAS). Conclusões: o menor volume nidal (p < 0,001), o menor grau na escala RBAS (p=0,047), a ausência de fístula arteriovenosa intranidal (p=0,001) e a maior dose prescrita (p=0,001) tiveram correlação com resultado favorável no tratamento. Embolização seguida de radiocirurgia não foi superior à radiocirurgia isolada (p=0,772). A eliminação de fístulas arteriovenosas intranidais pela embolização pode aumentar a eficácia da radiocirurgia / Partial nidal embolization preceding radiosurgery of brain arteriovenous malformations (AVM) and some morphological nidal features may be related to final results. Methods: Analysis of a longitudinal cohort of 47 consecutive patients who underwent radiosurgery preceded or not by embolization. Embolizations were performed exclusively with n-butyl cyanoacrylate. Radiosurgery was delivered either as a single or divided up to 5 equal fractions. Clinical and radiological follow up of at least 36 months was obtained. Results: Hemorrhagic presentation was seen in 68.1% of the cases; 62.5% harbored intranidal arteriovenous fistulas (AVF), 83.3% had venous ectasias and 90% had venous outflow stenosis. The occlusion rate of embolization plus radiosurgery was 46.1% and radiosurgery alone was 52.4% (p = 0.671). Variables significantly associated with obliteration were lower nidus volume, lack of intranidal arteriovenous fistula, higher radiosurgical dose and lower grades in radiosurgical-based AVM scale (RBAS). Conclusions: a small nidus (p < 0.001), a lower RBAS grade (p = 0.047), no intranidal AVF (p = 0.001) and greater radiosurgical dose (p = 0.001) were associated to better results. Embolization followed by radiosurgery was not superior to radiosurgery alone (p = 0.772). Endovascular elimination of intranidal AVF\'s may help to promote radiosurgical occlusion

Aspectos morfológicos do nido e embolização parcial neoadjuvante sem intenção de cura de malformações arteriovenosas encefálicas, precedendo a radiocirurgia, podem ter influência no resultado final do tratamento. Métodos: série consecutiva de 47 pacientes submetidos à radiocirurgia (1 a 5 sessões), precedida ou não por embolização com cianoacrilato. Acompanhamento clínico e radiológico mínimo de 36 meses. Resultados: a apresentação hemorrágica ocorreu em 68,1% dos pacientes tratados; destes, 62,5% portavam fístula arteriovenosa dentro da malformação arteriovenosa; 83,3% ectasia venosa e 90% restrição à drenagem venosa. A taxa de oclusão de embolização seguida de radiocirurgia foi de 46,1% e da radiocirurgia isolada foi de 52,4% (p=0,671). Foram identificados como fatores favoráveis à oclusão: baixo volume nidal, ausência de fístula arteriovenosa intranidal, maior dose de radiação e baixo grau na classificação das malformações arteriovenosas encefálicas baseadas na radiocirurgia (RBAS). Conclusões: o menor volume nidal (p < 0,001), o menor grau na escala RBAS (p=0,047), a ausência de fístula arteriovenosa intranidal (p=0,001) e a maior dose prescrita (p=0,001) tiveram correlação com resultado favorável no tratamento. Embolização seguida de radiocirurgia não foi superior à radiocirurgia isolada (p=0,772). A eliminação de fístulas arteriovenosas intranidais pela embolização pode aumentar a eficácia da radiocirurgia / Partial nidal embolization preceding radiosurgery of brain arteriovenous malformations (AVM) and some morphological nidal features may be related to final results. Methods: Analysis of a longitudinal cohort of 47 consecutive patients who underwent radiosurgery preceded or not by embolization. Embolizations were performed exclusively with n-butyl cyanoacrylate. Radiosurgery was delivered either as a single or divided up to 5 equal fractions. Clinical and radiological follow up of at least 36 months was obtained. Results: Hemorrhagic presentation was seen in 68.1% of the cases; 62.5% harbored intranidal arteriovenous fistulas (AVF), 83.3% had venous ectasias and 90% had venous outflow stenosis. The occlusion rate of embolization plus radiosurgery was 46.1% and radiosurgery alone was 52.4% (p = 0.671). Variables significantly associated with obliteration were lower nidus volume, lack of intranidal arteriovenous fistula, higher radiosurgical dose and lower grades in radiosurgical-based AVM scale (RBAS). Conclusions: a small nidus (p < 0.001), a lower RBAS grade (p = 0.047), no intranidal AVF (p = 0.001) and greater radiosurgical dose (p = 0.001) were associated to better results. Embolization followed by radiosurgery was not superior to radiosurgery alone (p = 0.772). Endovascular elimination of intranidal AVF\'s may help to promote radiosurgical occlusion

Les agents d'embolisation liquides utilisés dans le traitement endovasculaire ont de nombreuses limitations. Des polymères, tels que l’Onyx et les cyanoacrylates sont disponibles. L’alcool est un agent puissant, mais non radio-opaque. Les cyanoacrylates entrainent une réaction inflammatoire significative. Leur polymérisation rapide est responsable d’un comportement mal prévisible.Il existe une possibilité de traitement incomplet.L’Onyx est efficace pour le traitement des MAV.Une pénétration plus distale est obtenue avec l’alcool, mais associée à un risque de migration systémique. Nous avons évalué les propriétés d'un nouvel agent embolique (Alconyx) composé d'un mélange d'alcool et d'Onyx. Cet agent devrait cumuler les avantages respectifs de l'alcool et de l'onyx avec une visualisation adéquate sous fluoroscopie, une meilleure pénétration distale que l'Onyx seul et moins de toxicité systémique liée à la réduction de quantité d’alcool injecté. Divers mélanges ont été testés avec différentes concentrations d'Onyx 18 et d’alcool absolu. Alconyx 25 (75% Onyx 18; 25% d'éthanol) est la formulation la plus prometteuse. Nous avons démontré sa facilité d'injection in vivo, sa nature cohésive sans fragmentation ainsi que sa bonne visualisation sous fluoroscopie. En raison de sa moindre viscosité démontrée in vitro, Alconyx a été capable de pénétrer profondément dans le lit artériel.. L'occlusion proximale par Alconyx 25 devrait permettre d'améliorer le contact entre l'éthanol et la paroi vasculaire et donc augmenter son pouvoir sclérosant et limiter son passage systémique. Les propriétés occlusives d’Alconyx 25 sont similaires à celle de l’Onyx 18 sous haute pression in vitro. / Commercially available liquid embolization agents used in endovascular treatment have many limitations. Polymeric agents as Onyx and cyanoacrylate are available. Ethanol also is a potent sclero-embolic agent. Cyanoacrylates are effective liquid embolic agents, however, their rapid polymerization makes their behaviour unpredictable with possibility of incomplete treatment. These properties render their use challenging.Onyx is easy to use. However, in very small arterial niduses, Onyx, is unable to penetrate deeply. Deep penetration is obtained with ethanol, associated with risk of systemic migration.Poor visualization of ethanol under fluoroscopy is major drawback. Mixing Onyx with ethanol had never been described in the literature till now. In this work, various mixtures have been tested with different concentrations of Onyx 18 and absolute ethanol. Alconyx 25 (75% Onyx 18; 25% ethanol) seems to be a promising product. We proved its ease of injection in vivo and in vitro, its cohesive nature showing no fragmentation or interruption of the injected column as well as its good visualization under fluoroscopy. It was able to penetrate deeply in the arterial bed. The occlusive properties of Alconyx 25 were rated as good as Onyx 18 under high pressure in vitro. Further investigation is needed to better understand the behavior of ethanol in the suspension and its effect on tissues compared to Onyx diluted simply with an equivalent amount of DMSO. Studies on other commercially available concentrations of Onyx would certainly be interesting.