What is the best course of action for a patient with Systemic Lupus Erythematosus (SLE) and normal Complement 3 (C3) levels, presenting with neurological symptoms, such as frequent headaches and vomiting, suggestive of increased intracranial pressure?

Management of SLE with Neurological Symptoms and Normal C3 Levels

Immediate Diagnostic Workup

In an SLE patient presenting with headaches, vomiting, and signs of increased intracranial pressure, you must urgently perform lumbar puncture with CSF analysis (primarily to exclude CNS infection), brain MRI with contrast (T1/T2, FLAIR, DWI, and gadolinium-enhanced sequences), and assess for non-SLE causes before attributing symptoms to lupus. 1

Critical First Steps

• Exclude CNS infection immediately through lumbar puncture with CSF analysis including PCR for HSV and other pathogens, as this is the primary reason for CSF analysis in suspected NPSLE 1
• Perform brain MRI with the complete protocol (T1/T2, FLAIR, diffusion-weighted imaging, and gadolinium-enhanced T1 sequences) to assess brain structure and exclude mass lesions, hemorrhage, or other structural causes 1
• Measure blood pressure and assess for hypertensive emergency, as hypertension is a common aggravating factor that must be treated 1
• Check for metabolic abnormalities (electrolytes, glucose, renal function) and exclude infection systemically 1

Understanding Normal C3 in This Context

Normal complement levels do NOT exclude active neuropsychiatric lupus. 1 While low C3 is associated with renal involvement and can indicate generalized SLE activity, neuropsychiatric manifestations can occur independently of complement consumption. The absence of low C3 should not delay appropriate workup and treatment if clinical suspicion for NPSLE is high based on symptoms. 1

Attribution to SLE vs. Non-SLE Causes

The diagnostic approach for SLE patients with neuropsychiatric symptoms should initially be identical to non-SLE patients presenting with the same manifestations 1. This is a critical principle that prevents premature attribution to lupus and inappropriate immunosuppression.

Key Risk Factors Supporting NPSLE Attribution

• Generalized SLE disease activity (present in 40-50% of NPSLE cases) 1
• Previous severe NPSLE manifestations (fivefold increased risk) 1
• Antiphospholipid antibodies (fivefold increased risk, especially for cerebrovascular disease and seizures) 1
• Timing: 50-60% of NPSLE events occur within the first year after SLE diagnosis 1

Differential Diagnosis Requiring Exclusion

• Infection (bacterial, viral, fungal meningitis/encephalitis) - most critical to exclude 1, 2
• Metabolic encephalopathy (uremia, electrolyte disturbances, hypoglycemia) 1
• Hypertensive emergency with posterior reversible encephalopathy syndrome (PRES) 1
• Medication effects (corticosteroid-induced psychosis, drug toxicity) 1
• Thrombotic events (stroke, venous sinus thrombosis, especially if antiphospholipid antibodies present) 1, 2

Treatment Algorithm Based on Mechanism

If Inflammatory/Immune-Mediated NPSLE is Confirmed

After excluding infection and other non-SLE causes, initiate high-dose glucocorticoids combined with immunosuppressive therapy for severe inflammatory NPSLE manifestations. 1, 2

Specific Regimen (Category 1A Evidence)

• Methylprednisolone IV 0.25-0.50 g/day (or up to 1 g/day for severe cases) for 1-3 days 2, 3
• Followed by oral prednisone approximately 0.35-1.0 mg/kg/day, tapered gradually over months 2, 3
• Plus cyclophosphamide IV 500 mg every 2 weeks for 6 doses (or monthly dosing per institutional protocol) 2, 3
• Maintenance therapy with azathioprine or mycophenolate after induction to prevent relapses (which occur in 50-60% during steroid taper) 1, 4

This combination achieves 60-80% response rates in severe inflammatory NPSLE, though relapses may occur in up to 50% of cases. 1, 4

If Thrombotic/Antiphospholipid-Mediated

If antiphospholipid antibodies are present with thrombotic features (stroke, venous sinus thrombosis), antiplatelet and/or anticoagulation therapy is indicated rather than immunosuppression. 1, 2

• Anticoagulation is the primary therapy for thrombotic cerebrovascular disease in antiphospholipid syndrome 1
• Immunosuppression is rarely indicated for atherosclerotic/thrombotic/embolic cerebrovascular disease, as vasculitis is very rare in SLE 1
• Long-term anticoagulation should be considered for secondary stroke prevention in patients fulfilling antiphospholipid syndrome criteria 1

Symptomatic Management

Regardless of underlying mechanism, symptomatic therapies must be initiated concurrently: 1

• Anticonvulsants if seizures occur 1
• Antihypertensives for blood pressure control 1
• Osmotic agents (mannitol) or acetazolamide if increased intracranial pressure confirmed 1
• Antiemetics for nausea/vomiting 1

Special Considerations for Aseptic Meningitis

If CSF shows inflammatory changes (elevated WBC, protein) but cultures are negative, consider aseptic meningitis as a rare (<1% incidence) but recognized NPSLE manifestation. 1

• This requires glucocorticoids and immunosuppressive therapy after infection exclusion 1
• High-dose glucocorticoids may be given early while awaiting MRI confirmation if CSF resembles bacterial/HSV meningitis, and continued if infection ruled out 1

Refractory Cases

For patients not responding to standard therapy (glucocorticoids plus cyclophosphamide), rituximab has demonstrated rapid significant improvement in refractory NPSLE cases. 1, 4

• Rituximab is increasingly used as second-line therapy when first-line treatment fails 1, 4
• Plasma exchange therapy has been used in severe refractory cases with variable success 1, 4
• Intravenous immunoglobulins (IVIG) may be considered in refractory cases 4

Critical Pitfalls to Avoid

Do Not Assume NPSLE Without Exclusion

The most dangerous error is attributing neurological symptoms to lupus without excluding infection, metabolic causes, and other treatable conditions. 1, 2 This can lead to inappropriate immunosuppression in a patient with CNS infection, resulting in catastrophic outcomes.

Do Not Delay Treatment Once Infection Excluded

Conversely, once infection and other causes are reasonably excluded, delay in initiating immunosuppressive therapy (>2 weeks) is associated with worse neurological outcomes and severe deficits. 1 Prompt treatment within the first few hours to days is critical for optimal response.

Do Not Ignore Antiphospholipid Antibodies

Check antiphospholipid antibodies (anticardiolipin, anti-β2-glycoprotein I, lupus anticoagulant) in all NPSLE cases, as their presence fundamentally changes management from immunosuppression to anticoagulation. 1, 2

Do Not Forget Maintenance Therapy

Relapses occur in 50-60% of NPSLE cases during corticosteroid dose reduction, underscoring the absolute need for maintenance immunosuppressive therapy (azathioprine or mycophenolate) after induction. 1

Expected Timeline and Monitoring

• Neurological response to methylprednisolone plus cyclophosphamide typically occurs within a few days to 3 weeks 1
• MRI improvement should parallel clinical improvement 1
• Most psychiatric/neurological episodes resolve within 2-4 weeks with appropriate therapy 1
• Follow-up MRI should be performed to document response 1
• Reassess immediately if new or worsening neurological findings develop, no improvement within 2-3 weeks, or incomplete recovery at 3 months 2