What is the diagnosis for an immunocompromised adult patient with a history of Human Immunodeficiency Virus (HIV) infection, a low Cluster of Differentiation 4 (CD4) count, multiple ring-enhancing lesions on Magnetic Resonance Imaging (MRI), a negative Cerebrospinal Fluid (CSF) toxoplasmosis test, but positive Immunoglobulin G (IgG) serum toxoplasmosis?

Diagnosis: Presumptive CNS Toxoplasmosis

This patient has presumptive CNS toxoplasmosis based on the classic triad: multiple bilateral ring-enhancing lesions on MRI, positive serum IgG for Toxoplasma (indicating prior exposure and risk for reactivation), and severe immunosuppression (CD4 count 94 cells/mm³) in an HIV-infected patient. 1

Diagnostic Reasoning

Why Toxoplasmosis is the Most Likely Diagnosis

• The CDC states that multiple bilateral ring-enhancing lesions in an HIV-positive patient with low CD4 count is the classic presentation of CNS toxoplasmosis 1

• The lesions are characteristically located in the basal ganglia and cerebral corticomedullary junction, which matches this presentation 2, 1

• Positive serum IgG defines patients at risk for reactivation disease in the setting of severe immunosuppression (CD4 <100 cells/mm³) 2, 3

• Negative CSF toxoplasmosis testing does NOT exclude the diagnosis, as CSF PCR has limited sensitivity and is not standardized 2, 1—cases of toxoplasma encephalitis have been documented even without detectable Toxoplasma-specific IgG antibodies 2

Alternative Diagnoses to Consider (But Less Likely)

• Primary CNS lymphoma: Can present similarly with ring-enhancing lesions in HIV patients 4, but typically shows single or fewer lesions, and FDG-PET can help differentiate (lymphoma shows higher metabolic activity than toxoplasmosis) 2

• Tuberculomas: Less likely because they tend to be more numerous and smaller, often associated with basilar meningitis, and present more indolently 1

• Bacterial brain abscess: Unlikely because staphylococcal abscesses present more acutely with fever and systemic signs, usually as complications of endocarditis or trauma 1

• Neurocysticercosis: Unlikely due to typically more numerous and smaller lesions with calcifications, and lack of epidemiological risk factors 1

Diagnostic Confirmation Strategy

Empiric Treatment Trial (Standard Approach)

• Begin empiric anti-toxoplasma therapy immediately without waiting for definitive diagnosis 2, 1

• Clinical and radiological response should be evident within 10-14 days; this therapeutic response serves as diagnostic confirmation 2, 1, 5

• If no improvement after 10-14 days of appropriate therapy, proceed to brain biopsy 2, 1

Definitive Diagnosis (If Needed)

• Brain biopsy (preferably stereotactic) remains the gold standard, showing necrotizing inflammation with microglial nodules, gliosis, and Toxoplasma cysts or tachyzoites 2, 1

• Biopsy is indicated when: early neurologic deterioration occurs despite empiric treatment, or failure to respond after 10-14 days 2, 1

Recommended Treatment Regimen

First-Line Therapy

Pyrimethamine plus sulfadiazine (or clindamycin if sulfa-allergic) with leucovorin supplementation is the treatment of choice 2, 1, 3

• Pyrimethamine: Loading dose 2 mg/kg/day for 2 days, then 1 mg/kg/day 3, 6
• Sulfadiazine: 50 mg/kg/dose twice daily 3, 6
• Leucovorin (folinic acid): 10-25 mg/day to prevent bone marrow suppression 6

Alternative Regimen

• Trimethoprim-sulfamethoxazole (TMP-SMX) is an alternative with similar efficacy and practical advantages 2, 1

Critical Monitoring

• Complete blood count must be performed at least weekly during daily pyrimethamine dosing and at least monthly during less frequent dosing to monitor for bone marrow suppression 3, 6

Important Clinical Pitfalls

Common Diagnostic Errors to Avoid

• Do not exclude toxoplasmosis based on negative CSF studies alone—CSF PCR lacks sensitivity 2, 1

• Do not wait for biopsy results before starting empiric therapy in a patient with this classic presentation 1

• Be cautious interpreting FDG-PET results in HIV patients, as immune deficiency-related lymphoid hyperplasia can cause false-positives 2

Management Considerations

• Initiate or continue antiretroviral therapy (ART) during treatment—ART improves chemotherapy tolerability, immune recovery, and patient outcomes 2

• Check for drug-drug interactions between anti-toxoplasma medications and ART using resources like hiv-druginteractions.org 2

• Consider prophylaxis against Pneumocystis jirovecii pneumonia (PCP) with TMP-SMX, which also provides toxoplasmosis prophylaxis 3