How should I diagnose central nervous system lupus in a patient with known systemic lupus erythematosus who develops new neuro‑psychiatric symptoms such as seizures, headache, psychosis, or cognitive decline?

Diagnosing CNS Lupus

Diagnose CNS lupus clinically after systematically excluding alternative causes—infection, metabolic disturbances, medication effects, and thrombotic events—in a patient with known SLE who develops specific neuropsychiatric manifestations such as seizures, psychosis, acute confusional state, or focal neurological deficits, particularly when accompanied by systemic lupus activity. 1

Prioritize Specific Over Non-Specific Manifestations

• Focus your diagnostic evaluation on specific NPSLE manifestations: aseptic meningitis, optic neuritis, transverse myelitis, peripheral/cranial neuropathy, refractory seizures, psychosis, acute confusional state, cerebrovascular disease, and movement disorders 1
• Common non-specific symptoms (headache, mood disorder, anxiety, mild cognitive dysfunction) rarely reflect overt CNS lupus activity and should be interpreted cautiously, as excluding these raises diagnostic specificity from 46% to 93% 1
• Neuropsychiatric manifestations occur within the first year of SLE diagnosis in 50-60% of cases, commonly coinciding with generalized disease activity 1

Systematic Diagnostic Algorithm

Step 1: Exclude Alternative Etiologies First

• Always exclude CNS infections, metabolic disturbances, steroid-induced psychosis, and thrombotic/embolic events before attributing symptoms to lupus cerebritis 1
• The diagnostic workup should mirror the evaluation of any non-SLE patient presenting with the same neuropsychiatric symptoms 1
• Steroid-induced psychosis occurs in 10% of patients on prednisone ≥1 mg/kg, manifests primarily as mood disorder, and can be distinguished from lupus cerebritis by clinical context and MRI findings 1

Step 2: Perform Lumbar Puncture

• Perform lumbar puncture primarily to exclude CNS infection, not to confirm NPSLE 1, 2
• Include PCR for herpes simplex virus (HSV) and JC virus when clinically indicated 1, 2
• Mild CSF abnormalities (elevated protein, pleocytosis) occur in 40-50% of NPSLE cases but are non-specific and do not confirm the diagnosis 1, 2
• Intrathecal IgG production is observed in 25-66% of CNS lupus patients but lacks specificity 3

Step 3: Obtain Brain MRI with Specific Protocol

• Order MRI with T1/T2, FLAIR, diffusion-weighted imaging (DWI), and gadolinium-enhanced T1 sequences 1
• MRI sensitivity for active NPSLE is only 57%, with specificity of 60-82%, meaning a normal scan does not exclude NPSLE and an abnormal scan does not confirm it 1
• The most frequent MRI pattern is small punctate T2-hyperintense focal lesions in subcortical and periventricular white matter, typically in frontal-parietal regions 1
• These lesions are also seen in many SLE patients without neuropsychiatric symptoms, limiting diagnostic utility 1
• Cortical atrophy is commonly detected and correlates with cognitive dysfunction 4

Step 4: Order EEG When Indicated

• Order EEG to diagnose underlying seizure disorder or when acute confusional state is present 1
• EEG abnormalities are common (60-70%) in SLE patients with seizure disorder and have predictive value for seizure recurrence 1
• The EEG is the most frequently abnormal study (71% sensitivity) but does not correlate with specific clinical patterns 5

Step 5: Test for Antiphospholipid Antibodies

• Test for antiphospholipid antibodies (anticardiolipin, anti-β₂-glycoprotein I IgG/IgM, lupus anticoagulant) in all suspected NPSLE cases to guide the choice between anticoagulation and immunosuppression 1
• Persistent moderate-to-high antiphospholipid antibodies are strongly associated with cerebrovascular disease, seizures, cognitive dysfunction, myelopathy, and movement disorders 1
• These antibodies may cause thrombosis by interfering with the protein C pathway of fibrinolysis 3

Key Clinical Correlations

• High overall SLE disease activity or accumulated organ damage is a strong predictor of NPSLE, especially for seizures and severe cognitive dysfunction 1
• Vasculitis and thrombocytopenia show significant correlations with neuropsychiatric involvement 5
• In 63% of patients, neuropsychiatric manifestations precede the diagnosis of SLE or occur within the first year of diagnosed disease 5

Critical Diagnostic Pitfalls

• No single test definitively confirms NPSLE; diagnosis remains clinical after thorough exclusion of alternative causes 1, 6
• Do not rely on MRI alone: its limited sensitivity (57%) means normal imaging does not exclude disease, and abnormal findings are often present in asymptomatic SLE patients 1
• CSF abnormalities are supportive but not diagnostic—their primary value is ruling out infection 1, 2
• Only 2 of 140 patients in one series were felt to have steroid-induced psychoses, and in approximately one-half of neuropsychiatric episodes, patients were receiving no corticosteroids on presentation 5

Determining Inflammatory vs. Thrombotic Mechanism

• Manifestations such as aseptic meningitis, optic neuritis, transverse myelitis, refractory seizures, psychosis, or acute confusional state—especially when accompanied by systemic SLE activity—suggest an inflammatory mechanism requiring immunosuppression 1
• Cerebrovascular events in the presence of positive antiphospholipid antibodies point toward a thrombotic mechanism requiring anticoagulation 1
• In patients exhibiting both inflammatory and thrombotic features, combined immunosuppression and anticoagulation may be required 1