Lupus and the central nervous system

Abstract

In about 60% of the cases, no causes for the NP symptoms can be found. Thus, one considers these symptoms to be caused by SLE that translates to ‘primary NPSLE’. In the other 40%, NP symptoms are the consequence of secondary insults that may be indirectly related to SLE such as infections, side effects of drugs or metabolic derangement because of damage to other organs. No specific routine tests or symptoms exist that discriminate reliably primary from secondary NPSLE. In primary NPSLE, the pathogenesis of diffuse NP syndromes has been unclear for a long time. The presence of antiphospholipid (APL) antibodies has been shown to correlate with focal syndromes such as stroke; in some studies, these antibodies are also more frequent in diffuse NP manifestations such as cognitive dysfunction. Besides APL antibodies causing cerebral infarcts, intracranial angiopathy, cytokine and autoantibody-mediated neuronal dysfunction have been suggested as underlying processes in NPSLE. 3,4 In the last years, convincing evidence in animals was presented that the integrity of the blood brain barrier (BBB) plays a critical role in facilitating antibodymediated CNS effects. Diamond et al. reported that a subset of antibodies to double stranded DNA (dsDNA) in patients with SLE cross-reacts with subunits of the NMDA receptor (anti-NMDAR antibodies) on neuronal cells and can cause neuronal death by excito-toxicity and apoptosis. 5 Under normal circumstances, the BBB prevents these antibodies from penetrating tissue and causing neuronal damage. Using an animal model, they showed that antiNMDAR antibodies cause hippocampal damage and cognitive dysfunction only when a breach of the BBB was induced by bacterial lipopolysaccharide. The same mouse model was used to demonstrate that antiNMDAR antibodies in the presence of epinephrine, a stress hormone also known to disrupt the BBB, induce brain damage in the amygdala, the part of the brain that regulates emotions and triggers responses. These animals then developed a behavioral disorder. 6,7 . Recently, data from two small studies have suggested that this model might indeed be operative in patients with SLE as well. 8 In one study, an MRI technique was used which is called diffusion weighted imaging to examine the brain of several patients with NPSLE or SLE and the brain of several healthy individuals. Using this technique, it is possible to quantify