In an AIDS patient with CD4 count 15 cells/µL, EBV DNA detected in CSF and MR spectroscopy showing a necrotic core with high choline, could the brain lesions represent something other than primary CNS lymphoma?

Can Brain Lesions in AIDS Patients with Low CD4 and EBV-Positive CSF Represent Something Other Than Primary CNS Lymphoma?

Yes, despite the highly suggestive clinical picture of primary CNS lymphoma (PCNSL), these lesions can represent other pathologies—most importantly cerebral toxoplasmosis, which remains the most common cause of ring-enhancing brain lesions in AIDS patients and must be empirically treated first. 1, 2

Critical Diagnostic Context

Why EBV-Positive CSF Is Not Definitively Diagnostic

• EBV DNA is detected in the CSF of 7-13% of HIV-infected patients without lymphoma, making it a nonspecific finding that must be interpreted within the full clinical context 3, 2
• EBV DNA can be present in CSF with other CNS abnormalities including toxoplasmosis and pyogenic brain abscesses, not just lymphoma 3
• While EBV-positive CSF has high sensitivity (>96%) for HIV-associated PCNSL, the positive predictive value remains too low (approximately 50% even at high viral loads >10,000 copies/mL) to use as an isolated diagnostic marker 4
• A cut-off of 200 copies/mL provides 70% sensitivity and 85% specificity, while 2,000 copies/mL provides 100% specificity but only 50% sensitivity for CNS lymphoma 5

Primary Differential Diagnoses to Consider

Cerebral toxoplasmosis is the most critical alternative diagnosis:

• Remains the most common cause of ring-enhancing lesions in AIDS patients with CD4 counts <100 cells/µL 1, 2
• Typically presents with multiple lesions (though can be solitary), preferentially at the basal ganglia and corticomedullary junction 1
• Shows surrounding edema with mass effect on imaging 1
• Empiric anti-toxoplasma therapy must not be omitted even when EBV-positive CSF is present because toxoplasmosis is more common and treatable 2

Other important differential diagnoses in this immunocompromised population include 3:

• CMV encephalitis (CMV is the most frequently identified herpesvirus in HIV-positive patients with CD4 <50, occurring in 13% of cases) 3
• Progressive multifocal leukoencephalopathy (PML) due to JC virus 3
• Cryptococcal meningoencephalitis with parenchymal involvement 3
• Tuberculous meningitis with tuberculomas 3
• Pyogenic brain abscesses (bacterial, fungal including Aspergillus, Nocardia) 3
• HIV encephalitis itself can cause brain lesions and may coexist with lymphoma 6

Algorithmic Diagnostic Approach

Step 1: Imaging Characteristics Analysis

Features favoring PCNSL over toxoplasmosis 1, 7:

• Solitary or few lesions (50% are periventricular) 7
• Periventricular location with subependymal spread or ventricular encasement (38% of cases) 7
• Homogeneous or thick irregular ring enhancement rather than thin ring enhancement 1
• Less surrounding edema compared to toxoplasmosis 1
• Hyperattenuation on nonenhanced CT (one-third of lesions) 7
• Hypointensity on T2-weighted MRI in some cases 7
• Restricted diffusion on DWI may be present 1

Features favoring toxoplasmosis 1, 7:

• Multiple lesions (only 3% are periventricular) 7
• Basal ganglia or corticomedullary junction location 1
• Prominent surrounding edema 1
• No subependymal spread or ventricular encasement 7

Step 2: MR Spectroscopy Interpretation

Your patient's finding of "necrotic core with high choline" requires careful interpretation:

• Lymphoma typically shows elevated choline and lipid peaks with reduced N-acetylaspartate 1
• Toxoplasmosis shows elevated lactate and lipid peaks 1
• High choline supports but does not confirm lymphoma, as it reflects increased cell membrane turnover present in both neoplastic and some inflammatory processes 1

Step 3: Mandatory Empiric Treatment Trial

Regardless of EBV-positive CSF, initiate empiric anti-toxoplasma therapy immediately 1, 2:

• Start pyrimethamine plus sulfadiazine or clindamycin 1
• Alternative: trimethoprim-sulfamethoxazole 1
• Reassess clinically and radiologically after 10-14 days 2
• Lack of clinical or radiologic improvement mandates stereotactic brain biopsy to confirm PCNSL 2

Step 4: When to Proceed Directly to Biopsy

Stereotactic biopsy remains the gold standard and should be performed when 3, 1:

• No response to empiric toxoplasmosis therapy after 10-14 days 2
• Radiological findings are inconclusive despite advanced imaging 1
• Definitive diagnosis of CNSL requires positive CSF cytology or histopathologic confirmation 3
• The patient's clinical condition deteriorates rapidly

Critical Pitfalls to Avoid

1. Never rely solely on EBV-positive CSF to diagnose PCNSL without tissue confirmation or therapeutic trial 3, 2, 4

2. Do not skip empiric toxoplasmosis treatment even with highly suggestive imaging and EBV-positive CSF, as toxoplasmosis remains more common and is readily treatable 1, 2

3. Avoid corticosteroids before definitive diagnosis as they can cause false-negative results on CSF cytology (20-60% false-negative rate) and obscure imaging findings 3, 8

4. CSF cytology has limited sensitivity (20-60% false-negative rate), particularly with small volumes, delayed processing, or after corticosteroid use 3

5. Imaging patterns have relatively low specificity and cannot be considered truly diagnostic even in previously diagnosed cases, particularly after corticosteroid therapy 3

6. FDG-PET/CT should be interpreted with caution in HIV patients due to higher false-positive rates from immune deficiency-related lymphoid hyperplasia 1

Additional Diagnostic Considerations

• Check Toxoplasma serology (IgG) to assess risk for reactivation disease 1
• Serum LDH serves as an additional tumor marker supporting lymphoma 8
• Ophthalmologic examination is recommended as intraocular lymphoma occurs in 5-20% of PCNSL cases 2, 8
• Whole-body FDG-PET/CT and testicular ultrasound (in men) should be performed to exclude systemic lymphoma, which would reclassify the disease as secondary CNS lymphoma 2, 8