Abstract
<jats:p>Objective: To synthesize contemporary evidence on the pathogenesis, clinical spectrum, diagnostic challenges and therapeutic approaches in neuropsychiatric systemic lupus erythematosus (NPSLE), with particular emphasis on diffuse cognitive and psychiatric manifestations. Methods: A narrative review was conducted using PubMed and Scopus to identify peer-reviewed studies published between 2019 and 2025. Mechanistic, clinical, neuroimaging and biomarker-focused research was included, with selective incorporation of earlier foundational work relevant to core pathogenic concepts. Findings: Current evidence indicates that NPSLE arises from convergent mechanisms involving blood–brain barrier dysfunction, autoantibody-mediated neuronal injury, complement activation and microglial-driven synaptic loss. While focal presentations such as stroke or seizures typically reflect antiphospholipid-mediated vascular pathology, diffuse manifestations - including cognitive dysfunction, mood disorders and acute confusional states - primarily result from neuroinflammatory, excitotoxic and microglial-dependent processes. Despite progress in identifying candidate biomarkers such as anti-NR2, anti-ribosomal-P and CSF neopterin, no validated tool reliably differentiates inflammatory from non-inflammatory neuropsychiatric events. Advances in neuroimaging modalities (DTI, MRS, TSPO-PET) show promise but remain insufficiently standardized for routine clinical use. Acute inflammatory presentations may respond to high-dose glucocorticoids and immunosuppressants, however, chronic cognitive dysfunction remains largely refractory to current therapeutic strategies. Conclusions: Although significant progress has been made in defining the immunological and neurobiological underpinnings of NPSLE, translation into precise diagnostic tools and durable treatment remains limited. The development of integrated biomarker panels, harmonized neuroimaging protocols and mechanism-based therapeutic strategies is essential to improving attribution accuracy and long-term outcomes in patients with NPSLE.</jats:p>