Focal and diffuse NPSLE differ in their pathophysiology. In the former, there is a great association with thrombotic events frequently in the context of antiphospholipid (aPL) antibodies positivity with very occasional contribution of leukostasis and vasculitis. In the latter, a more complex picture arises: systemic production of antibodies that can induce neuronal damage either directly or through induction of blood–brain barrier (BBB) dysfunction which allows passive diffusion of antibodies to the cerebrospinal fluid (CSF); activation cascade; and the development of a complex in situ pro-inflammatory milieu including activation of interferon α cascade. Final neurotoxicity may be mediated by induction of apoptosis, antibody-mediated damage, or excitotoxicity by receptor-agonistic binding (anti-NMDA).

Abs, antibodies; anti-P rib, anti-P ribosomal antibodies; anti-Sm, anti-Smith antibodies; aEC, anti-endothelial cells antibodies; BBB, blood–brain barrier; CSF, cerebrospinal fluid.