Ultrastructural and immunocytochemical evidence that an incompetent blood-brain barrier is related to the pathophysiology of cavernous malformations

Objectives - Cerebral cavernous malformations are linked to mutations of the KRIT1 gene at the CCM1 locus and to mutations at two other loci, CCM2 and CCM3, for which genes are not yet identified. There is little information regarding the function of KRIT1. Histological and immunocytochemical analysis of cavernous malformations have not shed much light on their pathophysiology. Methods - Morphological analysis of cavernous malformations was extended to the ultrastructural level by examining lesions from two patients by immunocytochemistry and electron microscopy. Results - The lesions consisted of endothelial lined vascular sinusoids embedded in a collagen matrix. Nuclei belonging to cells distinct from endothelial cells were rare. The basal lamina of the endothelial cells consisted focally of multiple layers. No tight junctions at endothelial cell interfaces were found; however, several examined endothelial cell interfaces demonstrated apparent gaps between endothelial cell processes where basal lamina was exposed directly to the lumen of the sinusoids. Heavy hemosiderin deposits were found underlying the vascular channels within microns of the basal lamina without evidence of disrupted vessels. No astrocytic foot processes were seen within lesions. Glial fibrillary acidic protein immunocytochemistry confirmed that astrocyte processes stopped at the border of the lesions. Conclusions - The absence of blood-brain barrier components may lead to leakage of red blood cells into these lesions and the surrounding brain in the absence of major haemorrhage, thus accounting for the propensity of cavernous malformations to cause seizures. These data also raise the possibility that KRIT1 plays a part in the formation of endothelial cell junctions and expression of a mature vascular phenotype.