In an HIV‑positive patient with a CD4 count of 15 cells/µL, EBV DNA positive cerebrospinal fluid, negative Toxoplasma IgG, and a rapid rise in serum lactate dehydrogenase from 70 to 120 U/L (now 90 U/L), what is the most appropriate next diagnostic step?

Primary CNS Lymphoma is the Most Likely Diagnosis—Proceed Directly to Stereotactic Brain Biopsy

In an HIV-positive patient with CD4 count of 15 cells/µL, EBV DNA-positive CSF, negative Toxoplasma IgG, and fluctuating serum LDH, stereotactic brain biopsy is the definitive next diagnostic step to confirm primary CNS lymphoma. 1

Why Biopsy is Indicated Now

Toxoplasmosis is Effectively Ruled Out

• Negative Toxoplasma IgG serology makes cerebral toxoplasmosis extremely unlikely, as toxoplasmic encephalitis in AIDS almost always represents reactivation of latent infection in seropositive patients 2, 3
• The absence of anti-Toxoplasma antibodies eliminates the need for empiric anti-toxoplasma therapy, which would otherwise be the standard first-line approach for ring-enhancing lesions in HIV patients 1, 4
• While Toxoplasma seropositivity ranges from 40-73% in HIV populations, seronegative patients have negligible risk of developing toxoplasmic encephalitis 2, 5

EBV DNA in CSF Points Toward CNS Lymphoma

• EBV DNA detection in CSF is highly suggestive of primary CNS lymphoma in the appropriate clinical context, though it is not entirely specific 1, 6
• In HIV-infected patients without lymphoma, EBV DNA is found in only 7-13% of CSF samples, making its presence clinically significant 1
• However, EBV can also be detected in other CNS infections (toxoplasmosis, pyogenic abscesses), which is why tissue diagnosis remains essential 1
• CSF cytology alone has a false-negative rate of 20-60%, making stereotactic biopsy the gold standard when non-invasive tests are inconclusive 1

Serum LDH Elevation Supports Lymphoma

• The rapid rise in serum LDH from 70 to 120 U/L, even with subsequent decline to 90 U/L, reflects high tumor proliferation typical of AIDS-related primary CNS lymphoma 1
• Primary CNS lymphoma in this population often exhibits rapid proliferation with Ki-67 >90%, explaining the dynamic LDH changes 1

Optimal Biopsy Strategy

Target Selection

• Prioritize periventricular or corpus callosum lesions for stereotactic biopsy, as these locations yield the highest diagnostic accuracy for primary CNS lymphoma 1
• Select lesions demonstrating homogeneous or thick irregular ring enhancement rather than thin ring enhancement, as these patterns are more predictive of lymphoma 1
• Avoid deep brain-stem or basal-ganglia lesions unless they are the sole viable target 1

Critical Pre-Biopsy Considerations

• If any corticosteroids have been administered, they must be stopped immediately and repeat MRI obtained before biopsy, as steroids cause false-negative cytology in 20-60% of cases and obscure characteristic imaging features 1
• Contrast-enhanced MRI must be obtained immediately before biopsy planning to verify target lesion visibility 1
• Biopsy should be performed within 14 days of the latest imaging due to rapid tumor proliferation 1

Alternative Diagnoses to Consider (But Less Likely)

Other Opportunistic Infections at CD4 <50 cells/µL

While less probable given the negative Toxoplasma serology, the differential diagnosis at this CD4 count includes:

• Cytomegalovirus (CMV) encephalitis: occurs in approximately 13% of patients with CD4 <50 cells/µL; CSF PCR for CMV should be sent if not already done 7, 1
• Progressive multifocal leukoencephalopathy (PML): JC virus PCR of CSF should be considered 7
• Cryptococcal meningoencephalitis with parenchymal lesions: CSF cryptococcal antigen and India ink staining are essential 7, 1
• Tuberculous meningitis with tuberculomas: CSF PCR and culture for Mycobacterium tuberculosis 7

However, EBV DNA positivity in CSF makes primary CNS lymphoma the leading diagnosis 1, 6

Concurrent Management

Immediate ART Initiation

• Antiretroviral therapy (ART) should be initiated immediately and continued during diagnostic workup to improve immune recovery and overall outcomes 4
• Sustained viral suppression is critical, though immune reconstitution inflammatory syndrome (IRIS) may cause temporary worsening of lesions 1, 4

Avoid Empiric Anti-Toxoplasma Therapy

• The standard approach of empiric pyrimethamine plus sulfadiazine or clindamycin for 10-14 days is not indicated in Toxoplasma-seronegative patients 1, 4
• Proceeding directly to biopsy avoids unnecessary treatment delay in this seronegative patient 1

Common Pitfalls to Avoid

• Do not delay biopsy waiting for clinical response to empiric therapy when Toxoplasma serology is negative 1
• Do not administer corticosteroids before obtaining tissue diagnosis, as this dramatically reduces diagnostic yield 1
• Do not rely solely on imaging characteristics or CSF EBV PCR to make a definitive diagnosis, as specificity is insufficient 1
• Do not assume EBV DNA in CSF is always lymphoma—it can occur in other infections, though the clinical context here strongly favors lymphoma 1, 6