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 C CM3, for which genes are not yet identified. There is little information re garding the function of KRIT1. Histological and immunocytochemical analysis of cavernous malformations have not shed much light on their pathophysiolo gy. Methods-Morphological analysis of cavernous malformations was extended to t he ultrastructural level by examining lesions from two patients by immunocy tochemistry and electron microscopy. Results-The lesions consisted of endothelial lined vascular sinusoids embed ded in a collagen matrix. Nuclei belonging to cells distinct from endotheli al cells were rare. The basal lamina of the endothelial cells consisted foc ally of multiple layers. No tight junctions at endothelial cell interfaces were found; however, several examined endothelial cell interfaces demonstra ted 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 la mina without evidence of disrupted vessels. No astrocytic foot processes we re 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 leaka ge of red blood cells into these lesions and the surrounding brain in the a bsence of major haemorrhage, thus accounting for the propensity of cavernou s malformations to cause seizures. These data also raise the possibility th at KRIT1 plays a part in the formation of endothelial cell junctions and ex pression of a mature vascular phenotype.