In an AIDS patient with a CD4 count of 15 cells/µL and cerebrospinal fluid showing 16 mononuclear cells/µL, protein 110 mg/dL, and Epstein‑Barr virus, what is the most likely diagnosis and the appropriate next diagnostic and therapeutic steps?

Primary CNS Lymphoma (PCNSL) in AIDS

The most likely diagnosis is HIV-associated primary CNS lymphoma (HIV-PCNSL), and the next steps are brain MRI with contrast, consideration of empiric toxoplasmosis therapy with close monitoring, and brain biopsy if no response occurs within 10-14 days. 1, 2

Most Likely Diagnosis

EBV-positive CSF in an AIDS patient with CD4+ count of 15 cells/µL is highly specific for primary CNS lymphoma. The combination of:

• Severe immunosuppression (CD4+ 15 cells/µL)
• EBV DNA detected in CSF
• Mild mononuclear pleocytosis (16 cells/µL)
• Elevated CSF protein (110 mg/dL)

creates a clinical picture strongly suggestive of HIV-PCNSL. 1

EBV DNA in CSF has 100% sensitivity and 98.5% specificity for AIDS-related primary CNS lymphoma in retrospective autopsy studies. 3 However, EBV can be detected in CSF of 7-13% of HIV patients without lymphoma, making clinical correlation essential. 4, 5

Critical Differential Diagnosis

Toxoplasmosis Must Be Excluded First

Despite EBV positivity, CNS toxoplasmosis remains the primary differential and empiric therapy is often warranted before pursuing biopsy. 2 Key distinguishing features:

• Toxoplasmosis typically presents with multiple bilateral ring-enhancing lesions on MRI, most commonly in basal ganglia and corticomedullary junction 2
• PCNSL more commonly affects deep structures and white matter, can be solitary or multifocal 1
• EBV DNA may be present in CSF with toxoplasmosis (though less common), making it nonspecific 1

Neurosyphilis Should Be Considered

The CSF profile (16 mononuclear cells/µL, protein 110 mg/dL) could represent neurosyphilis, which requires CSF-VDRL testing. 1, 6, 7

• CSF-VDRL is highly specific; a reactive result establishes neurosyphilis diagnosis 6, 7
• CSF WBC >10 cells/µL plus reactive CSF-VDRL strongly supports neurosyphilis 6, 7
• In HIV patients with CD4+ <350 cells/µL, CSF examination for syphilis is indicated regardless of stage 6

Immediate Diagnostic Steps

Neuroimaging

Obtain contrast-enhanced brain MRI immediately—it is more sensitive than CT for detecting PCNSL and toxoplasmosis. 1, 2

• PCNSL shows T2-hyperintense, T1 ring-enhancing lesions, typically in deep structures 1
• Toxoplasmosis shows multiple T2-hyperintense, T1 ring-enhancing lesions, typically bilateral in basal ganglia 2

Additional CSF Testing

Send CSF for:

• CSF-VDRL to exclude neurosyphilis 6, 7
• Cryptococcal antigen to exclude cryptococcal meningitis 2
• Toxoplasma PCR (though sensitivity is limited and not standardized) 2
• CMV quantitative PCR if neurological deterioration occurs 2
• Cytology and flow cytometry if lumbar puncture can be safely repeated 1

Serum Testing

Obtain:

• Toxoplasma IgG serology (defines risk for reactivation; negative serology does not exclude diagnosis) 2
• Serum syphilis testing (RPR/VDRL confirmed by treponemal test) 6

Ophthalmology and Systemic Staging

Ophthalmology examination is essential as lymphomatous involvement occurs in 5-20% of PCNSL cases. 1

FDG-PET-CT and testicular ultrasound (in men) are recommended to exclude systemic lymphoma, which would change the diagnosis to secondary CNS lymphoma. 1

Therapeutic Approach

Empiric Toxoplasmosis Therapy

Initiate empiric anti-toxoplasma therapy with pyrimethamine plus sulfadiazine (or clindamycin if sulfa-allergic) plus leucovorin supplementation. 2

• Trimethoprim-sulfamethoxazole is an alternative with similar efficacy 2
• Clinical and radiological response should be evident within 10-14 days 2
• Lack of response after 10-14 days warrants brain biopsy to confirm PCNSL 1, 2

If PCNSL is Confirmed by Biopsy

The diagnosis of EBV-associated lymphoproliferative disease requires demonstration of EBV DNA, RNA, or protein in biopsy tissue. 1

First-line treatment for HIV-PCNSL is rituximab plus high-dose methotrexate (3 g/m²) combined with fully active antiretroviral therapy (ART). 1

• Rituximab is not FDA or EMA approved for PCNSL but is recommended by EHA-ESMO guidelines 1
• Concurrent ART is essential for immune reconstitution and contributes to long-term disease control 1
• A prospective trial of rituximab plus HD-MTX showed 5-year OS rate of 67% 1

Alternative Regimen for Patients on Established ART

For patients already established on effective ART where lymphoma resembles that of immunocompetent hosts, consider multi-agent induction (e.g., MATRix regimen) followed by consolidation ASCT. 1

If CMV Involvement is Suspected

If neurological deterioration occurs despite adequate anti-toxoplasma treatment, add intravenous ganciclovir (5 mg/kg twice daily) or foscarnet (90 mg/kg twice daily) to cover potential CMV encephalitis. 2

Repeat lumbar puncture with quantitative CMV PCR on CSF to assess for CMV CNS involvement. 2

Common Pitfalls to Avoid

Do not assume EBV-positive CSF automatically means PCNSL—up to 13% of HIV patients without lymphoma can have EBV in CSF. 5

Do not skip empiric toxoplasmosis therapy even with EBV-positive CSF—toxoplasmosis is more common and treatable, and EBV can be present in CSF with other CNS pathology including toxoplasmosis. 1, 2

Do not delay brain biopsy beyond 14 days if there is no clinical or radiological response to empiric toxoplasmosis therapy. 2

Do not forget to test for neurosyphilis—the CSF profile is compatible and HIV patients with CD4+ <350 cells/µL require CSF examination. 6, 7

Do not base neurosyphilis diagnosis solely on elevated CSF protein without reactive CSF-VDRL or elevated WBC >10 cells/µL. 7

HIV infection itself can cause mild mononuclear CSF pleocytosis (5-15 cells/µL), particularly in patients with CD4+ >500 cells/µL, but this patient's CD4+ is only 15 cells/µL, making HIV-related pleocytosis less likely to explain the findings. 1, 7