Central nervous system (CNS) involvement is a significant complication in systemic lupus erythematosus (SLE), affecting approximately 40% of patients. Increasingly, subtle psychiatric symptoms and abnormalities detected through neuropsychological testing are being recognized as part of the spectrum of CNS lupus. This article aims to provide a comprehensive overview of the current understanding surrounding the diagnosis of CNS lupus and its underlying mechanisms.
The clinical manifestations of CNS lupus are diverse, ranging from diffuse symptoms like generalized seizures and psychosis to focal neurological deficits such as stroke and peripheral neuropathies. While neuropsychiatric symptoms frequently emerge within the first year of SLE diagnosis, they uncommonly serve as the initial presenting features of the disease.
Pathological examinations of CNS lupus patients often reveal vasculopathy, infarcts, and hemorrhages. Interestingly, overt vasculitis is rarely observed. Endocardial lesions and mural thrombi, potential sources of emboli, have been reported in a substantial proportion, between 33% and 50%, of individuals with CNS lupus.
Diagnostic imaging plays a crucial role in evaluating CNS lupus. Magnetic resonance imaging (MRI) is particularly sensitive, often demonstrating evidence of edema or small infarcts in both diffuse and focal presentations of CNS lupus. In contrast, computerized tomography (CT) scans are generally less sensitive and may only detect more pronounced abnormalities. Early studies utilizing position emission tomography (PET) scans in CNS lupus patients have indicated reduced glucose metabolism within the brain. Furthermore, cerebral blood flow is observed to decrease during active phases of both diffuse and focal CNS lupus. The blood-brain barrier, which protects the brain from harmful substances in the bloodstream, shows impairment somewhat more frequently in diffuse CNS lupus. Intrathecal production of IgG and IgM, antibodies within the cerebrospinal fluid, is found in a considerable proportion, 25% to 66%, of all CNS lupus patients, suggesting immune activity within the CNS.
Various autoantibodies have been implicated in CNS lupus. Among these, anticardiolipin antibodies (ACA) exhibit a well-established association with focal CNS involvement in SLE. These antibodies are thought to contribute to thrombosis by interfering with the protein C pathway, a critical regulator of coagulation. Furthermore, ACA are linked to endocardial and valvular heart disease, common in SLE, which can also lead to embolic events affecting the brain. The relationship between ACA and diffuse CNS lupus remains less clear and is an area of ongoing research.
Low-avidity anti-DNA antibodies have also been detected in CNS lupus, potentially due to cross-reactivity with cardiolipin. Antineuronal antibodies and lymphocytotoxic antibodies have been associated with diffuse CNS lupus and neuropsychological abnormalities. However, these antibody populations are heterogeneous, and a consistent common target antigen has not been identified. Consequently, the precise mechanisms underlying the diffuse form of CNS lupus and the potential role of distinct immune-mediated processes are still under investigation. Further research is needed to fully elucidate the complex pathogenesis of cerebral lupus and refine diagnostic strategies.
