Neuropsychiatric Systemic Lupus Erythematosus (NPSLE) is a complex autoimmune condition affecting both the central and peripheral nervous systems, with symptoms including cognitive dysfunction, seizures, psychosis, and mood disorders. It occurs in 3–4 out of 10 SLE patients and can be the first sign of SLE. NPSLE is classified as primary (direct CNS autoimmune inflammation) or secondary (indirect complications of SLE). The pathogenesis involves immune dysregulation, autoantibodies, cytokines, and immune complexes, leading to tissue damage. Key factors include genetic predisposition (e.g., HLA alleles), environmental triggers (e.g., infections, stress), and immune system dysfunction. Autoantibodies such as anti-dsDNA, anti-SSA, and anti-SSB are characteristic of SLE, while anti-ribosomal P and anti-NMDA antibodies are associated with NPSLE. Cytokines like IFN-γ, IL-17F, and GM-CSF contribute to inflammation and neurological symptoms. The blood-brain barrier (BBB) can be compromised, allowing immune complexes and antibodies to enter the CNS, causing damage. NPSLE can also be triggered by treatments like corticosteroids, which have psychiatric side effects. Diagnosis is challenging due to overlapping symptoms with other conditions. Treatment is primarily symptomatic, involving antipsychotics, antidepressants, and immunosuppressants. Biomarkers like anti-UCH-L1 and anti-SS-A show promise for early diagnosis. Management aims to control symptoms and address underlying SLE, with challenges in accurate diagnosis and treatment. NPSLE complications include steroid-induced psychosis and PML, requiring careful monitoring and tailored treatment approaches.Neuropsychiatric Systemic Lupus Erythematosus (NPSLE) is a complex autoimmune condition affecting both the central and peripheral nervous systems, with symptoms including cognitive dysfunction, seizures, psychosis, and mood disorders. It occurs in 3–4 out of 10 SLE patients and can be the first sign of SLE. NPSLE is classified as primary (direct CNS autoimmune inflammation) or secondary (indirect complications of SLE). The pathogenesis involves immune dysregulation, autoantibodies, cytokines, and immune complexes, leading to tissue damage. Key factors include genetic predisposition (e.g., HLA alleles), environmental triggers (e.g., infections, stress), and immune system dysfunction. Autoantibodies such as anti-dsDNA, anti-SSA, and anti-SSB are characteristic of SLE, while anti-ribosomal P and anti-NMDA antibodies are associated with NPSLE. Cytokines like IFN-γ, IL-17F, and GM-CSF contribute to inflammation and neurological symptoms. The blood-brain barrier (BBB) can be compromised, allowing immune complexes and antibodies to enter the CNS, causing damage. NPSLE can also be triggered by treatments like corticosteroids, which have psychiatric side effects. Diagnosis is challenging due to overlapping symptoms with other conditions. Treatment is primarily symptomatic, involving antipsychotics, antidepressants, and immunosuppressants. Biomarkers like anti-UCH-L1 and anti-SS-A show promise for early diagnosis. Management aims to control symptoms and address underlying SLE, with challenges in accurate diagnosis and treatment. NPSLE complications include steroid-induced psychosis and PML, requiring careful monitoring and tailored treatment approaches.