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 1Infectious 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?
AImmune complex deposition in cerebral vessels triggering a focal necrotizing vasculitis
BNewly acquired primary infection seeding the brain hematogenously after gut invasion
CDirect viral cytopathic injury to oligodendrocytes causing white-matter demyelination
DReactivation of latent tissue cysts as bradyzoites convert to dividing tachyzoites
Reveal answer & full explanation
Correct answer: D — Reactivation of latent tissue cysts as bradyzoites convert to dividing tachyzoites
AImmune complex deposition in cerebral vessels triggering a focal necrotizing vasculitis
BNewly acquired primary infection seeding the brain hematogenously after gut invasion
CDirect viral cytopathic injury to oligodendrocytes causing white-matter demyelination
DReactivation of latent tissue cysts as bradyzoites convert to dividing tachyzoites✓
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
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.
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.
Direct viral cytopathic injury to oligodendrocytes causing white-matter demyelination is the mechanism of PML (JC virus), which causes non-enhancing white-matter lesions without mass effect; Toxoplasma is a protozoan and these lesions enhance with edema and mass effect.
Question 2Infectious DiseaseMedium
A 38-year-old man with untreated HIV (CD4 count 42 cells/µL) presents with a 10-day history of worsening headache, low-grade fever, and new right-arm weakness. On exam he is afebrile, somnolent but arousable, with right-sided hemiparesis. MRI of the brain with contrast shows multiple ring-enhancing lesions with surrounding edema in the basal ganglia and at the gray-white junction. Serum Toxoplasma IgG is positive. Which of the following is the most appropriate initial management?
AVancomycin, ceftriaxone, and IV ampicillin
BLiposomal amphotericin B and oral flucytosine
CPyrimethamine, sulfadiazine, and leucovorin
DIsoniazid, rifampin, pyrazinamide, ethambutol
Reveal answer & full explanation
Correct answer: C — Pyrimethamine, sulfadiazine, and leucovorin
AVancomycin, ceftriaxone, and IV ampicillin
BLiposomal amphotericin B and oral flucytosine
CPyrimethamine, sulfadiazine, and leucovorin✓
DIsoniazid, rifampin, pyrazinamide, ethambutol
Why Pyrimethamine, sulfadiazine, and leucovorin is correct
The clinical picture — advanced HIV with CD4 below 100, subacute focal neurologic deficits, multiple ring-enhancing lesions favoring the basal ganglia/gray-white junction, and positive Toxoplasma IgG — is CNS toxoplasmosis until proven otherwise.
IDSA/NIH OI guidelines name pyrimethamine + sulfadiazine + leucovorin as preferred first-line induction therapy (6 weeks), with leucovorin to prevent pyrimethamine-induced myelosuppression; clinical and radiographic improvement within ~2 weeks supports the empiric diagnosis. TMP-SMX is an accepted alternative.
Why the others are wrong
Liposomal amphotericin B and oral flucytosine treat cryptococcal CNS disease; cryptococcomas are typically smaller and accompanied by a positive cryptococcal antigen, not the multifocal basal-ganglia ring lesions seen here.
Isoniazid, rifampin, pyrazinamide, ethambutol treat CNS tuberculosis/tuberculoma, which classically shows an indolent course with basal meningeal enhancement, not multiple gray-white-junction ring lesions in this CD4 range.
Vancomycin, ceftriaxone, and IV ampicillin provide empiric coverage for acute bacterial meningitis (including Listeria in an immunocompromised host), which presents more acutely with meningismus and does not match this subacute, multifocal, IgG-positive presentation.
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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 to prevent fetal transmission; if fetal infection confirmed (amniotic fluid PCR), switch to pyrimethamine + sulfadiazine + leucovorin after 14 weeks gestation (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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