Association of tumor necrosis factor-alpha-238GA and apolipoprotein E2 polymorphisms with intracranial hemorrhage after brain arteriovenous malformation treatment

Patients with brain arteriovenous malformations (BAVM) are at life-threatening risk of intracranial hemorrhage (ICH) (25). Obliteration or resection of the lesion to prevent future ICH is the primary motivation behind invasive therapy. Effective clinical management requires accurate estimates of natural history risks balanced against the hazards of invasive therapy. Clinical presentation of BAVM with ICH is the most widely demonstrated predictor of future ICH in the natural course of untreated BAVM (11, 12); predictors of future ICH risk in patients with nonhemorrhagic presentations are lacking (34). The absence of hemorrhagic presentation has recently been reported as an underappreciated risk factor predicting morbidity after microsurgical arteriovenous malformation resection (21), despite the fact that it is not part of major surgical risk prediction tools such as the Spetzler-Martin grading scale (32). Nonhemorrhagic presentation carries a similar risk magnitude for adverse outcome after microsurgical resection as the components of the Spetzler-Martin grade (21), underscoring weaknesses in current risk grading assessments and the need for additional predictors of future morbidity after treatment, particularly in patients with BAVMs with unruptured lesions. Identification of single nucleotide polymorphisms (SNPs) associated with increased risk of new ICH could facilitate risk stratification and therapeutic decision-making (28). We previously demonstrated that genetic variation might influence the natural course of BAVM. We reported an association between the −238G>A promoter polymorphism of the inflammatory cytokine tumor necrosis factor-alpha (TNF-α) (1) and the epsilon2 (e2) allele of the Apolipoprotein (ApoE) gene (27), and risk of new ICH in the untreated course of the disease. In the present study, we sought to determine whether or not these genotypes would independently predict posttreatment ICH risks in the clinical course after the initiation of BAVM treatment. Whereas previous reports focused on new ICH in longitudinal follow-up after initial presentation but before any intervening treatment, the present study focused on an entirely different period of observation, i.e., any new ICH in longitudinal follow-up after the initiation of treatment, using similar multivariate analysis with additional adjustment for any risks carried over from natural course events.