In an adult HIV patient with a CD4+ T‑lymphocyte count of 15 cells/µL, brain CT findings suggestive of cerebral toxoplasmosis, cerebrospinal fluid showing mononuclear pleocytosis, markedly elevated protein, high lactate dehydrogenase, negative Toxoplasma gondii polymerase chain reaction, EBV DNA detected, and a low‑level CMV viral load, what is the recommended empiric treatment and overall management plan?

Management of Suspected CNS Toxoplasmosis with Concurrent EBV and Low-Level CMV in Severely Immunocompromised HIV Patient

Initiate empiric anti-toxoplasma therapy immediately with pyrimethamine plus sulfadiazine (or trimethoprim-sulfamethoxazole as an alternative) plus leucovorin, regardless of the negative Toxoplasma PCR, given the classic clinical presentation and severe immunosuppression. 1

Diagnostic Interpretation

Why Toxoplasmosis Remains the Primary Diagnosis

• Multiple bilateral ring-enhancing lesions on brain CT in an HIV patient with CD4+ count of 15 cells/µL is the classic presentation of CNS toxoplasmosis, making this the most likely diagnosis despite negative PCR 1
• The CSF findings (mononuclear pleocytosis of 16 cells/µL, elevated protein of 110 mg/dL, high LDH) are consistent with toxoplasmosis, though these findings are nonspecific 1
• CSF PCR for Toxoplasma has limited sensitivity (35.3% in one validation study) and is not standardized, meaning a negative result does not exclude the diagnosis 1, 2
• Greater numbers of brain lesions and higher CSF cellularity improve PCR sensitivity, but even with optimal conditions, sensitivity remains suboptimal 2

Significance of EBV Detection

• EBV DNA in CSF raises concern for primary CNS lymphoma (PCNSL), which is the main differential diagnosis for ring-enhancing lesions in AIDS patients 3
• However, toxoplasmosis lesions are typically located in basal ganglia and corticomedullary junction, while PCNSL more commonly involves periventricular regions 1
• The subacute presentation over several days favors toxoplasmosis over lymphoma 1
• EBV detection alone does not establish PCNSL diagnosis; tissue diagnosis would be required if empiric toxoplasmosis treatment fails 1

Significance of Low-Level CMV Viremia

• CMV end-organ disease in HIV occurs almost exclusively when CD4+ counts fall below 50 cells/µL, making this patient at risk 4
• However, a CMV viral load of 127 IU/mL is relatively low and CMV viremia can occur without end-organ involvement 4
• CMV encephalitis typically presents with more acute onset, focal neurologic signs, cranial nerve palsies, nystagmus, and rapid progression, which differs from this presentation 4
• The CSF profile (lymphocytic pleocytosis with normal glucose) is not typical for CMV neurologic disease, which usually shows mixed neutrophils and lymphocytes 4
• IgG CMV antibodies indicate prior exposure but do not confirm active CNS disease 4

Empiric Treatment Protocol

First-Line Anti-Toxoplasma Therapy

Initiate one of the following regimens immediately:

• Pyrimethamine 200 mg loading dose, then 50-75 mg daily (if <60 kg use 50 mg, if ≥60 kg use 75 mg) PLUS sulfadiazine 1000-1500 mg four times daily PLUS leucovorin (folinic acid) 10-25 mg daily 1, 5
• Alternative: Trimethoprim-sulfamethoxazole (TMP-SMX) 5 mg/kg (trimethoprim component) twice daily, which shows similar efficacy with practical advantages 1, 6

Critical Monitoring Requirements

• Perform semiweekly complete blood counts including platelet counts when using pyrimethamine-based regimens due to bone marrow suppression risk 5
• Leucovorin (folinic acid) administration is strongly recommended and mandatory to prevent hematologic toxicity 5
• If signs of folate deficiency develop (anorexia, vomiting, pallor, purpura, glossitis), pyrimethamine should be discontinued and leucovorin increased 5

Response Assessment Timeline

• Clinical and radiological response should be evident within 10-14 days of initiating therapy 1
• Lack of response at 14 days warrants brain biopsy for definitive diagnosis 1
• Repeat brain imaging (preferably MRI) at 2 weeks to assess treatment response 1

Antiretroviral Therapy Timing

Initiate or optimize combined antiretroviral therapy (cART) within 2 weeks after starting anti-toxoplasma therapy 6

• Immune reconstitution inflammatory syndrome (IRIS) is uncommon in cerebral toxoplasmosis, allowing earlier cART initiation 6
• Modern cART regimens are more effective and safer, supporting earlier initiation 6
• Do not delay cART beyond 2 weeks, as immune reconstitution is critical for long-term control 6

CMV Management Decision

Do not initiate empiric anti-CMV therapy at this time based on the following:

• The low CMV viral load (127 IU/mL) and clinical presentation are not consistent with CMV end-organ disease 4
• CMV neurologic disease requires compatible clinical syndrome AND presence of CMV in CSF or brain tissue, not just low-level viremia 4
• The CSF profile does not support CMV encephalitis (would expect mixed pleocytosis, possible low glucose) 4
• Monitor closely for development of CMV retinitis (floaters, visual field defects, decreased acuity), which is the most common CMV manifestation at this CD4+ count 4

However, if clinical deterioration occurs despite adequate toxoplasmosis treatment:

• Consider adding ganciclovir 5 mg/kg IV twice daily or foscarnet 90 mg/kg IV twice daily for possible CMV encephalitis 3, 4
• Repeat lumbar puncture with CMV PCR quantification in CSF 3

Additional Diagnostic Considerations

Rule Out Other Causes of Lymphocytic Pleocytosis

• The mildly elevated CSF protein (110 mg/dL) and normal glucose effectively exclude tuberculous meningitis, fungal infection, and untreated bacterial meningitis, which typically show CSF:plasma glucose ratio <0.5 and protein >200 mg/dL 7
• Cryptococcal antigen testing should be performed if not already done, as cryptococcal meningitis can present with lymphocytic pleocytosis 3, 7
• Listeria monocytogenes accounts for 20-40% of bacterial meningitis in immunocompromised patients and can show lymphocytic predominance, but the subacute presentation and imaging findings favor toxoplasmosis 7

Brain Biopsy Indications

Proceed to stereotactic brain biopsy if:

• No clinical improvement by day 10-14 of empiric therapy 1
• Radiological progression on repeat imaging at 2 weeks 1
• Development of new neurological deficits despite treatment 1

Biopsy findings that would confirm toxoplasmosis:

• Necrotizing inflammation with microglial nodules and gliosis 1
• Toxoplasma cysts or tachyzoites on histology 1

Prophylaxis After Acute Treatment

Once clinical and radiological improvement is documented:

• Continue acute-phase therapy for at least 6 weeks 3
• Transition to lifelong secondary prophylaxis (chronic maintenance therapy) with pyrimethamine plus sulfadiazine plus leucovorin to prevent relapse 3
• Alternative maintenance: pyrimethamine plus clindamycin for sulfa-intolerant patients 3
• Secondary prophylaxis can only be discontinued if CD4+ count increases to >200 cells/µL for at least 6 months on cART 3

Common Pitfalls to Avoid

• Do not wait for positive Toxoplasma PCR before initiating treatment—the test has poor sensitivity and negative results are common even in confirmed cases 2, 8
• Do not attribute all findings to CMV based solely on low-level viremia—CMV end-organ disease requires higher viral loads and specific clinical syndromes 4
• Do not delay cART initiation beyond 2 weeks—early immune reconstitution improves outcomes without significant IRIS risk 6
• Do not use pyrimethamine without leucovorin—this combination is mandatory to prevent life-threatening bone marrow suppression 5
• Do not assume treatment failure before 14 days—toxoplasmosis response takes time and premature biopsy may be unnecessary 1