In an adult HIV patient with CD4 count 15 cells/µL presenting with fever, headache, vomiting, altered mental status, rapid weight loss and MRI showing three large ring‑enhancing necrotic brain lesions, CSF with mononuclear pleocytosis, elevated protein, high LDH and EBV DNA but negative Toxoplasma PCR, what is the recommended empiric first‑line treatment?

Primary CNS Lymphoma (PCNSL), Not Toxoplasmosis: Treat with High-Dose Methotrexate-Based Chemotherapy After Biopsy Confirmation

Given the CSF findings of EBV DNA, negative Toxoplasma PCR, mononuclear pleocytosis with elevated protein and LDH, combined with large necrotic ring-enhancing lesions in a patient with CD4 count of 15, this presentation is most consistent with EBV-associated primary CNS lymphoma (PCNSL) rather than toxoplasmosis, and empiric anti-toxoplasma therapy should be discontinued in favor of brain biopsy followed by appropriate lymphoma-directed therapy.

Critical Diagnostic Reasoning

Why This Is Likely PCNSL, Not Toxoplasmosis

• EBV DNA detection in CSF is highly specific for PCNSL in AIDS patients and is rarely present in toxoplasmosis 1
• Negative Toxoplasma gondii PCR in CSF argues strongly against cerebral toxoplasmosis, especially when combined with positive EBV findings 1
• The CSF profile (mononuclear pleocytosis, elevated protein >100 mg/dL, high LDH) is more consistent with lymphoma than toxoplasmosis 1
• Large lesion size (32mm, 23mm, 21mm) with thick irregular enhancement and heterogeneous necrotic cores favors lymphoma over toxoplasmosis 2

Toxoplasmosis Would Be Expected To Show:

• Positive Toxoplasma serology (IgG) in 97% of cases - your case shows negative PCR 1, 3
• Clinical response to empiric anti-toxoplasma therapy within 7-14 days - while PCR decreased, this may reflect bacterial/inflammatory response rather than toxoplasma-specific improvement 1
• Toxoplasma PCR in CSF, while having limited sensitivity, when negative in the context of positive EBV DNA strongly suggests alternative diagnosis 1

Recommended Management Algorithm

Immediate Actions

1. Discontinue empiric anti-toxoplasma therapy (pyrimethamine/sulfadiazine or trimethoprim-sulfamethoxazole) given the strong evidence against toxoplasmosis 1

2. Pursue stereotactic brain biopsy of the largest accessible lesion to confirm PCNSL histologically, as this will definitively distinguish between toxoplasmosis, lymphoma, and other opportunistic infections 1

3. Initiate antiretroviral therapy (ART) immediately if not already started, as immune reconstitution is critical for any CNS opportunistic process in AIDS 1

If PCNSL Is Confirmed on Biopsy

• High-dose methotrexate-based chemotherapy (3-8 g/m² every 2 weeks) is the standard of care for AIDS-related PCNSL, though guidelines for this specific scenario are extrapolated from general PCNSL management 1
• Whole-brain radiotherapy may be considered as consolidation or salvage therapy 1
• Corticosteroids should be avoided before biopsy as they can cause lymphoma regression and false-negative pathology 1

If Biopsy Shows Toxoplasmosis Despite Negative PCR

• Resume pyrimethamine (200 mg loading dose, then 50-75 mg daily) plus sulfadiazine (1-1.5 g four times daily) plus leucovorin (10-25 mg daily) for at least 6 weeks 1
• Alternative: Trimethoprim-sulfamethoxazole (5 mg/kg TMP component twice daily) 1
• For patients intolerant to sulfa drugs: pyrimethamine plus clindamycin (600 mg IV/PO four times daily) plus leucovorin 1

Critical Pitfalls to Avoid

• Do not continue empiric anti-toxoplasma therapy indefinitely without tissue diagnosis when the clinical picture strongly suggests lymphoma - this delays appropriate cancer treatment and worsens outcomes 1

• Do not rely solely on radiographic response to empiric therapy - PCNSL can occasionally show initial improvement with anti-toxoplasma drugs due to corticosteroid effects or natural fluctuation 1

• Do not assume all ring-enhancing lesions in AIDS patients are toxoplasmosis - at CD4 counts <50, PCNSL becomes increasingly common and must be excluded 1, 4

• The presence of EBV DNA in CSF is a game-changer - this finding has high specificity for PCNSL and should prompt immediate reconsideration of the diagnosis 1

Monitoring Elevated Intracranial Pressure

• Serial neurological examinations and consideration of repeat imaging to assess for herniation risk given the large lesion sizes and edema 1
• Mannitol or hypertonic saline may be needed for acute ICP management 1
• Surgical decompression should be considered if mass effect worsens despite medical management 2

Long-Term Considerations

• Lifelong ART is essential regardless of final diagnosis 1
• If PCNSL: Secondary CNS lymphoma prophylaxis is not standard, but close monitoring with serial MRI every 2-3 months is recommended 1
• If toxoplasmosis (unlikely): Chronic suppressive therapy with trimethoprim-sulfamethoxazole or pyrimethamine/sulfadiazine/leucovorin indefinitely until CD4 >200 for >6 months on ART 1