Management of Cerebral Cavernous Malformations: Molecular Insight and Clinical Considerations

Abstract

Introduction: Cavernous malformations (cavernomas) occur in 0.4% - 0.9% of the population. Clinical symptoms are mainly caused by recurrent hemorrhages and/or their progressive growth. The neurological deficit depends on their exact localization. Most common symptoms are epileptic seizures. Particularly, in deep seated lesions (brain stem, basal ganglia, etc.) a well elaborated preoperative imaging is critical in ordert to select the most favorable approach for every patient. Usually, cavernomas occur as single lesions, but in some individuals (10-20%) more than one cavernoma might be diagnosed. Particularly in these patients a treatment strategy is critically dependant on the understanding of the biology of multiple (and familial?) lesions. Aim: Therefore, our recent research aimed at (1) unshadowing the biological activity and ageressivenes of cavernomas (2) understanding their human genetics and (3) increasing the imaging quality of cavernomas and associated venous malfomations. Material and Methods: Endothelial cells were isolated and purified from the fresh operative specimens of sporadic CCMs with single lesions (CCM-ECs). The expression profile of VEGF and its receptors as well as CCM1-3 genes were detected by real-time PCR. Endothelial proliferation, migration, sprouting and tube formation were compared in the absence and the presence of angiogenic stimuli and after CCM1-3 siRNA in CCM-ECs and in different types of healthy endothelial cells. Furthermore, a strong correlation with VEGF related neoangiogenesis as well as the influence of a PTEN deficiency was studied. Patients with multiple lesions were evalutated for germ line mutations of the CCM1-3 genes. By using susceptibility weighted imaging (SWI) at 7T high field strength MRI both patients with single and multiple lesions were evaluated for cavernomas and associated venous malformations (VM). Results: A highly activated VEGF system was revealed in CCM-ECs. Accordingly, CCM-ECs exhibited marked growth potential under normal culture conditions and a significantly high proliferation activity in response to various angiogenic stimuli including hypoxia, fetal calf serum and VEGF treatment. Furthermore, a significantly higher mobility, spontaneous growth of sprouts and extensively branched tubes were exclusively detected in CCM-ECs. In comparison to healthy endothelia, CCM-ECs resisted apoptotic stimuli and showed distinct responses toward to activating angiogenesis after CCM1 silencing. Endothelila proliferation was conducted by the VEGF related pathways. PTEN deficiency in endothelial cavernoma cells seems to play a role particularly in patients suffering from multiple cavernomas. Tyrosin-kinase receptor inhibitors suppresses neoangiogenetic activity in CCM1 deficient endothelial cells in an animal model. In patients with multiple cavernomas, a germ line mutation of the CCM1-3 genes can be found in up to 80%. Patients with CCM1 mutations might additionally display a cutaneous nevus. In the patients harbouring single cavernomas, a solitary or multiple venous drainage was found in all lesions using susceptibility weighted imaging (SWI) at 7T high field strength MRI. A typical so called developmental anomaly (DVA) was found in 30% of the lesions. In the other cases, associated VM were depicted as well, although showing a different phenotype when compared with DVAs. Conclusion: Cavernomas are growing and active lesions similar to benign tumors with also similar underlying molecular growth mechanisms. The highly activated VEGF system and the distinct angiogenic characteristics of CCM-ECs may serve as an endothelia-pathomechanism synergistically acting together with genetic and other factors for the development of vascular lesions in the human brain. Particularly, the surgical resection of lesions with a CCM1-3 gene defects (familial cavernomas) should be evaluated very carefully. Ultra-high-field magnetic resonance imaging at 7T improves the detection of cavernomas. The improved depiction of small cavernomas might possibly help to clarify cryptogenic seizures, which represent 30% of all seizures. We believe, that the additional information gained will have an impact on treatment plans for deep seated lesions in the future. Furthermore, our data support previous assumptions of CCMs being notoriously associated with local venous malformation (VM and DVA) involving larger outflow vessels.