The first association between the clinical course of CCM disease and circulating systematic compounds reported a hierarchical cluster of 5 plasma inflammatory cytokines, including IL-2, IFN-γ, TNF-α, IL-1β, and IL-6, defining CCM patients with a “high” inflammatory state, which was associated with seizures and more than one prior SH during a patient’s lifetime [89]. This evidence concerns the gene TNF and cerebral cavernous malformation.