Therefore, complement activation in the connective tissue spaces and parenchyma can stimulate the production of TNFα and other pleiotropic cytokines, which can be directly cytotoxic (and differentially expressed in cases characterised by leptomeningeal inflammation and more extensive cortical demyelination) (Magliozzi et al., 2019b; Picon et al., 2021), whilst cytokine release by activated glia can further drive the transcription of genes encoding early complement proteins. This evidence concerns the gene VTN and Peripheral demyelination.