This is the first study to identify an association between RNF213 genotypes and FCH after revascularization surgery for MMD. Our findings showed that mutation in RNF213 was significantly correlated with prolonged FCH in adult patients. The present study also demonstrated that FCH is observed quite frequently in both pediatric and adult patients undergoing combined revascularization surgery. The high incidence of FCH strongly suggests an intrinsic pathological background for MMD.
The mechanisms underlying the development of FCH after revascularization surgery for MMD are unclear, but we speculate that vasogenic edema is involved in this intrinsic phenomenon. The absence of DWI-high intensity in the corresponding area of FCH supports this hypothesis [20]. Takemoto et al. demonstrated that the postoperative cerebral blood volume increase was correlated with the occurrence of FCH; they considered that the underlying mechanism of FCH was vasogenic edema, which is associated with impairment of the blood–brain barrier (BBB) and leakage of fluid into the brain parenchyma [16]. Previous studies have shown that patients with MMD intrinsically have vascular vulnerability associated with BBB impairment. First, serum and plasma cytokine analysis revealed that patients with MMD showed significantly higher expression of vascular endothelial growth factor and matrix metalloproteinase 9, which have potential roles in increasing the permeability of the BBB, than healthy subjects [14, 21]. Second, histological analysis of surgically collected MCA specimens from MMD patients showed significantly thinner media than control specimens, implying anatomical fragility in the intracranial arteries [22]. Third, intraoperative videoangiography using sodium fluorescein extravasation demonstrated that MMD patients had BBB impairment [13]. These findings suggest that the intrinsic vascular vulnerability in MMD may contribute to the formation of vasogenic edema or FCH after revascularization surgery.
Although the molecular functions of RNF213 and its effect on postoperative vasogenic edema need to be elucidated, RNF213 is known to play a vital role in endothelial cells and vascular smooth muscle cells, contributing to the functional maintenance of these vascular cells through controlling inflammation cascades [18, 23]. Therefore, mutation in RNF213 can make these vascular cells vulnerable to secondary insults. In fact, Tashiro et al. demonstrated a correlation between RNF213 mutations and prolonged/delayed CHP after direct revascularization surgery for MMD, strongly suggesting that RNF213 mutations affect vascular integrity in the postoperative pathophysiology [10]. Similarly, in the present study, prolonged FCH in adult patients with RNF213 mutations also suggests an additional RNF213-related vascular vulnerability to postoperative hemodynamic changes.
Furthermore, the present study identified that the occurrence of CHP is significantly associated with extensive FCH in adult patients. In contrast, an association between CHP and FCH was not observed in pediatric patients. Several studies have analyzed the relationship between FCH and postoperative CBF increase. Takemoto et al. and Hamano et al. reported that a postoperative CBF increase was not related to the extension of FCH [15, 16]. One reason for this discrepancy would be that pediatric and adult patients were analyzed together in these studies; the patterns of postoperative cerebral hemodynamic changes and the frequency of CHP are quite different between pediatric and adult patients [7]. Therefore, the present study evaluated pediatric and adult patients separately, which suggested involvement of some age-related vascular factors in adult patients because pediatric patients showed improvement of FCH regardless of the RNF213 genotype. Further study is warranted to elucidate the precise mechanism of the difference in postoperative cerebral hemodynamics between pediatric and adult patients.
The present study has several limitations. First, the FCH scores were determined by the agreement of two neurosurgeons, who were blinded to genetic analyses and clinical outcomes, and accurate inter-observer variability was not evaluated; variability could have been obtained if the judgments had been performed independently. Second, the present study did not indicate which postoperative managements should be conducted against FCH or whether there were any long-term effects of FCH on patients’ clinical outcomes, such as cognitive function. However, postoperative managements against CHP, such as precise hemodynamic examinations and adequate control of blood pressure, are important [24] because the present study suggests that CHP and FCH share common pathophysiology.