Obligate intracellular protozoan infection (Toxoplasma gondii) — usually asymptomatic, but causes severe congenital disease and CNS lesions in immunocompromised hosts.
Also known as: toxoplasmosis, Toxoplasma gondii, congenital toxoplasmosis, CNS toxoplasmosis
Overview
Infection by Toxoplasma gondii, an obligate intracellular protozoan with cats as the definitive host. Humans are intermediate hosts, acquiring infection via ingestion of oocysts (cat feces, contaminated water/soil) or tissue cysts (undercooked meat). Lifelong latent infection persists in tissue cysts.
Epidemiology
Seroprevalence ~10-20% in US adults, higher in older adults and immigrants; up to 60-80% in parts of Europe and South America. Estimated 750,000-1.1 million new US infections yearly. Second leading cause of foodborne deaths in the US.
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Question 1NeurologyMedium
A 48-year-old man with HIV and a CD4 count of 55 cells/microliter presents with focal seizures. MRI of the brain shows multiple ring-enhancing lesions involving the basal ganglia and right frontal lobe. Toxoplasma IgG is positive and the CSF white blood cell count is normal. Which of the following is the most likely diagnosis?
ABacterial brain abscess
BPrimary CNS lymphoma
CNeurocysticercosis
DCNS toxoplasmosis
EGlioblastoma multiforme
Reveal answer & full explanation
Correct answer: D — CNS toxoplasmosis
ABacterial brain abscess
BPrimary CNS lymphoma
CNeurocysticercosis
DCNS toxoplasmosis✓
EGlioblastoma multiforme
Why CNS toxoplasmosis is correct
Advanced HIV (CD4 below 100), multiple ring-enhancing lesions with a basal ganglia predilection, and positive Toxoplasma IgG make reactivation cerebral toxoplasmosis the most likely diagnosis
Toxoplasma IgG is positive in roughly 95% of cases, reflecting prior exposure and latent infection that reactivates with profound immunosuppression
Per IDSA/NIH-CDC opportunistic-infection guidance, empiric pyrimethamine plus sulfadiazine plus leucovorin is started, with clinical and radiographic improvement by day 14 confirming the diagnosis
Multiplicity and basal ganglia location favor toxoplasmosis over a solitary periventricular lymphomatous lesion
Why the others are wrong
Bacterial brain abscess — produces ring enhancement but typically follows bacteremia, sinusitis, or otitis with systemic signs, and is not linked to Toxoplasma IgG positivity at CD4 below 100 (anchoring on ring enhancement)
Glioblastoma multiforme — occurs in immunocompetent older adults as a solitary infiltrative lesion and is not an AIDS-defining process driven by advanced HIV (confused-with primary brain tumor)
Primary CNS lymphoma — in HIV is EBV-driven and classically a solitary periventricular lesion with positive CSF EBV DNA, making it less likely with multiple basal ganglia lesions and positive Toxoplasma IgG (right-concept-wrong-diagnosis)
Neurocysticercosis — seizures with ring-enhancing lesions are its classic presentation, but neurocysticercosis depends on Taenia solium exposure, typically shows cysts with a scolex at the gray-white junction, and is not an opportunistic infection driven by a CD4 count below 100 (confused-with the classic seizure-plus-cyst picture)
Additional high-yield points
Failure to improve by day 14 prompts stereotactic brain biopsy to evaluate for primary CNS lymphoma
TMP-SMX double-strength daily provides primary prophylaxis against toxoplasmosis once CD4 falls below 100
Question 2Infectious DiseaseMedium
A 41-year-old man with untreated HIV infection (CD4 count 42 cells/µL) presents with 10 days of worsening headache, low-grade fever, and new right-arm weakness. Toxoplasma IgG is positive and IgM is negative. MRI of the brain shows multiple ring-enhancing lesions with surrounding edema in the basal ganglia and at the gray-white junction. He is diagnosed with CNS toxoplasmosis. Which of the following best explains the findings?
AReactivation of latent tissue cysts as bradyzoites convert to dividing tachyzoites
BLoss of humoral antibody control over tachyzoites circulating in the bloodstream
CInflammatory host reaction to degenerating tissue cysts as the encysted parasites die
DImmune complex deposition in cerebral vessels triggering a focal necrotizing vasculitis
ENewly acquired primary infection seeding the brain hematogenously after gut invasion
Reveal answer & full explanation
Correct answer: A — Reactivation of latent tissue cysts as bradyzoites convert to dividing tachyzoites
AReactivation of latent tissue cysts as bradyzoites convert to dividing tachyzoites✓
BLoss of humoral antibody control over tachyzoites circulating in the bloodstream
CInflammatory host reaction to degenerating tissue cysts as the encysted parasites die
DImmune complex deposition in cerebral vessels triggering a focal necrotizing vasculitis
ENewly acquired primary infection seeding the brain hematogenously after gut invasion
Why Reactivation of latent tissue cysts as bradyzoites convert to dividing tachyzoites is correct
After primary Toxoplasma infection, cell-mediated immunity (CD4 T cells, IFN-gamma) contains the organism but never eliminates it; latent tissue cysts containing bradyzoites persist for life in brain, muscle, eye, and heart.
When CD4 counts fall below 100 cells/µL in HIV (here 42), this surveillance fails and bradyzoites reactivate into rapidly dividing tachyzoites, producing necrotizing encephalitis seen as multiple ring-enhancing lesions in the basal ganglia and gray-white junction.
A positive IgG with negative IgM reflects remote, latent infection that has reactivated, the expected serologic pattern; a negative IgG essentially excludes CNS toxoplasmosis in HIV.
Why the others are wrong
Immune complex deposition in cerebral vessels triggering a focal necrotizing vasculitis is a humoral, type III mechanism; toxoplasmosis is a cell-mediated, intracellular process and the lesions are abscess-like necrosis, not vasculitic infarcts.
Newly acquired primary infection seeding the brain hematogenously after gut invasion describes the initial-infection cascade; CNS disease in AIDS is reactivation of old cysts, not fresh ingestion, and the negative IgM argues against acute primary infection.
Loss of humoral antibody control over tachyzoites circulating in the bloodstream misplaces both the defect and the site: control of this obligate intracellular parasite depends chiefly on CD4 T cells and IFN-gamma, the arm AIDS destroys, while antibody plays only a secondary role (this patient still has Toxoplasma IgG); his lesions arise from cysts reactivating within brain tissue, not from bloodstream tachyzoites escaping antibody control.
Inflammatory host reaction to degenerating tissue cysts as the encysted parasites die — this is the mechanism of neurocysticercosis, where ring-enhancing lesions and seizures arise from the host inflammatory response to dying Taenia solium cysticerci; in AIDS the problem is the opposite, as failed cell-mediated immunity lets released bradyzoites convert to proliferating tachyzoites that cause necrotizing encephalitis, not an inflammatory reaction to dead parasites.
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Ingestion of undercooked or raw meat (especially pork, lamb, venison)
Cat litter exposure (especially outdoor cats); soil/garden contact without gloves
Unfiltered/untreated water in endemic areas
Pregnancy (highest risk if primary infection in second/third trimester)
Immunocompromise: HIV with CD4 <100, hematopoietic transplant, lymphoma
Pathophysiology
Ingested oocysts/cysts release sporozoites/bradyzoites that invade gut epithelium, transform into tachyzoites, and disseminate hematogenously. Cell-mediated immunity controls infection but does not eliminate tissue cysts (containing bradyzoites) in brain, muscle, eye, and heart. Reactivation occurs when CD4 cells decline (HIV) or with immunosuppression. Congenital transmission risk rises from ~10% in first trimester to ~80% in third trimester, but severity is inverse (severe disease more common with early transmission).
Congenital toxoplasmosis: classic triad of chorioretinitis, hydrocephalus, and diffuse intracranial calcifications; may also have seizures, hepatosplenomegaly, jaundice, microcephaly, IUGR; many asymptomatic at birth but develop chorioretinitis or learning disabilities later
Chorioretinitis on funduscopy: yellow-white focal retinal lesion with overlying vitreous inflammation
Focal CNS deficits, hemiparesis, papilledema
Congenital: hepatosplenomegaly, jaundice, blueberry-muffin rash, microcephaly or macrocephaly
Classic findings
AIDS patient with CD4 <100, headache, focal neuro deficit, and multiple ring-enhancing brain lesions on MRI in the basal ganglia or gray-white junction — toxoplasmosis until proven otherwise. Congenital infection: diffuse intracranial calcifications (vs. periventricular in CMV).
Differential diagnosis
CNS lymphoma (HIV) — Single lesion (toxoplasmosis usually multiple), no response to empiric anti-toxo therapy, positive EBV PCR in CSF; thallium SPECT positive (negative in toxo)
CMV/other TORCH (congenital) — Overlapping features; targeted serology and PCR
Glioma or metastasis — Less typical for HIV-stage 3; biopsy if no response to empiric therapy
Diagnostic workup
Diagnostic criteria
Clinical syndrome + serology/PCR + imaging. CNS toxoplasmosis in HIV often diagnosed empirically with response to therapy (2-week trial); biopsy if no improvement.
Labs
Toxoplasma IgG (lifelong) and IgM (acute; IgM can persist >1 year)
• Pyrimethamine 200 mg load then 50-75 mg PO daily + sulfadiazine 1-1.5 g PO QID + leucovorin 10-25 mg daily × 6 weeks induction
• Then chronic suppression at half doses until CD4 >200 × ≥6 months on ART
Alternative: TMP-SMX (effective and more accessible)
Pregnancy with primary infection: spiramycin if infection acquired before 18 weeks gestation (to prevent fetal transmission); pyrimethamine + sulfadiazine + leucovorin if acquired at or after 18 weeks or if fetal infection is confirmed or suspected by positive amniotic fluid PCR or abnormal ultrasound (avoid pyrimethamine in first trimester due to teratogenicity)
Congenital toxoplasmosis: pyrimethamine + sulfadiazine + leucovorin × 1 year
Toxoplasma IgM can persist >1 year — do not interpret a positive IgM as recent infection without IgG avidity testing.
In HIV with CD4 <100 + positive toxoplasma IgG, TMP-SMX prophylaxis prevents both PCP and toxoplasmosis.
Empiric anti-toxo therapy in HIV with ring-enhancing lesions — clinical/radiographic response within 2 weeks supports the diagnosis; failure → biopsy to evaluate for lymphoma.
Congenital intracranial calcifications: toxoplasmosis is diffuse; CMV is periventricular.
References
DHHS OI — Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV — Toxoplasmosis section
CDC — Toxoplasmosis: Information for Healthcare Providers
Maldonado 2017 — AAP Diagnosis, Treatment, and Prevention of Congenital Toxoplasmosis in the United States (Pediatrics)
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