What is the most likely diagnosis and immediate management for a patient presenting with leukopenia, a malar rash, fever, and a new‑onset seizure?

Systemic Lupus Erythematosus (SLE) with Neuropsychiatric Manifestations

This patient most likely has systemic lupus erythematosus (SLE) with neuropsychiatric involvement, and immediate management requires high-dose corticosteroids (intravenous methylprednisolone 1000 mg daily for 3–5 days) plus urgent rheumatology consultation, with seizure control using standard anticonvulsants while simultaneously excluding infectious encephalitis.

Diagnostic Rationale

The constellation of leukopenia, malar rash, fever, and new-onset seizure strongly suggests SLE with central nervous system involvement. This clinical presentation meets multiple diagnostic criteria:

• Leukopenia is present in this patient and occurs in approximately 50% of SLE patients, representing one of the hematologic criteria for SLE diagnosis 1
• Malar rash is a pathognomonic cutaneous manifestation of SLE, appearing as erythema over the cheeks and nasal bridge 1
• Seizures occur in 9–58% of SLE patients in reported series and often appear early in the disease course, with approximately 75% being generalized tonic-clonic type 2
• Fever is a common presenting feature in active SLE, particularly when associated with neuropsychiatric manifestations 1, 3

Critical Immediate Actions

Rule Out Infectious Encephalitis First (Life-Threatening Priority)

Before attributing symptoms solely to SLE, infectious encephalitis must be excluded because it requires different urgent treatment:

• Obtain lumbar puncture immediately (after neuroimaging if focal deficits present) to evaluate for viral encephalitis, particularly HSV, which requires acyclovir within hours to prevent mortality 4
• The International Encephalitis Consortium requires altered mental status lasting ≥24 hours plus at least 2 of the following minor criteria: documented fever ≥38°C within 72 hours, generalized or partial seizures not fully attributable to preexisting disorder, new focal neurologic findings, CSF WBC ≥5/mm³, abnormal neuroimaging, or abnormal EEG 4
• Start empiric acyclovir 10 mg/kg IV every 8 hours immediately if encephalitis cannot be excluded, as 85–91% of HSV encephalitis patients present with fever, and delays in treatment significantly worsen outcomes 4

Obtain Essential Diagnostic Studies

• Draw blood for complete blood count with differential, comprehensive metabolic panel, ESR, CRP, ANA, anti-dsDNA antibodies, complement levels (C3, C4), anti-Smith antibodies, and anti-ribosomal P antibodies before initiating immunosuppression 1, 3
• High titers of anti-ribosomal P antibodies in CSF are associated with neuropsychiatric lupus and can help confirm the diagnosis 3
• Obtain brain MRI with and without contrast to evaluate for brainstem encephalitis, which can present with fever, seizures, and altered mental status in SLE patients 1
• Two sets of blood cultures must be obtained before any antibiotics, as approximately 50% of seizures in SLE patients are associated with infection, metabolic derangements, or iatrogenic complications 2

Definitive Management Once Infection Excluded

Immunosuppressive Therapy

• Initiate intravenous methylprednisolone pulse therapy (1000 mg daily for 3–5 days) for severe neuropsychiatric SLE manifestations, as this has been shown effective in patients with brainstem encephalitis and other CNS complications 1
• Consider adding cyclophosphamide or plasma exchange for refractory cases or when rapid deterioration occurs despite corticosteroids alone 1
• Intermediate-dose oral prednisolone (40–60 mg daily) may be insufficient for acute neuropsychiatric manifestations and should be escalated to pulse-dose IV therapy 1

Seizure Management

• Start standard anticonvulsant therapy (levetiracetam 500–1000 mg twice daily or phenytoin loading dose 15–20 mg/kg) for acute seizure control 2
• Generalized tonic-clonic seizures in SLE often begin during and recur only with disease flares, suggesting that aggressive immunosuppression may reduce seizure recurrence 2
• In contrast, focal-onset seizures in SLE patients often recur irrespective of disease activity and typically require long-term anticonvulsant therapy 2
• Avoid hydantoin (phenytoin) for long-term management if possible, as anticonvulsants are associated with drug-induced lupus, though this patient's presentation with high anti-dsDNA titers, hypocomplementemia, and renal involvement strongly favors true SLE over drug-induced lupus 5

Critical Pitfalls to Avoid

• Never delay lumbar puncture and empiric acyclovir when encephalitis cannot be excluded—HSV encephalitis has high mortality without early treatment, and subtle presentations with low-grade fever and behavioral changes can be mistaken for psychiatric illness or SLE alone 4
• Do not assume all neurologic symptoms are due to SLE activity—approximately 50% of seizures in SLE patients result from infection, metabolic abnormalities, or medication effects, requiring thorough evaluation 2
• Avoid attributing fever solely to lupus without excluding infection—patients with SLE on immunosuppression are at high risk for opportunistic infections including CNS infections 4, 1
• Do not use intermediate-dose corticosteroids for severe neuropsychiatric manifestations—pulse-dose IV methylprednisolone is required for life-threatening CNS involvement 1

Monitoring and Follow-Up

• Clinical improvement should be evident within 48–72 hours of initiating appropriate immunosuppression, with resolution of fever and stabilization of neurologic status 1
• Persistent or worsening symptoms despite aggressive immunotherapy should trigger consideration of alternative diagnoses including hemophagocytic lymphohistiocytic syndrome (HLH), which can complicate SLE and presents with prolonged fever, cytopenias, and requires evaluation for hypertriglyceridemia, hypofibrinogenemia, and elevated ferritin 6
• Long-term neurologic sequelae may persist even after successful treatment—in one case report, dysphagia and hoarseness persisted as Wallenberg's syndrome despite improvement in systemic disease 1