How do you tell toxoplasmosis from CNS lymphoma in HIV?

Both cause ring-enhancing brain lesions in advanced HIV. Toxoplasmosis usually produces multiple lesions with a basal ganglia predilection in a patient who is Toxoplasma IgG positive, and it improves within about 2 weeks of anti-Toxoplasma therapy. Lymphoma is more often a single, larger lesion next to the ventricles, is EBV-associated (EBV DNA may be found in the CSF), shows increased uptake on PET, and needs a biopsy if the patient does not respond to toxoplasmosis treatment.

What CD4 count is associated with cerebral toxoplasmosis?

Toxoplasma encephalitis is rare when the CD4 count is above 200 cells/mm3; the classic board cutoff is below 100, and the risk is greatest below 50. It results from reactivation of tissue cysts, so it affects people who are Toxoplasma IgG positive. The same CD4 threshold of 100 is used to start primary prophylaxis with TMP-SMX in IgG-positive patients.

What is the treatment for toxoplasmosis in HIV?

The NIH/CDC/IDSA adult opportunistic infection guidelines list two preferred regimens, pyrimethamine plus sulfadiazine plus leucovorin or TMP-SMX, given for at least 6 weeks; TMP-SMX is the choice when pyrimethamine is unavailable or delayed. Pyrimethamine and leucovorin with clindamycin is used for sulfa allergy. Lower-dose maintenance therapy then continues until the CD4 count has stayed above 200 for more than 6 months on ART.

Why is leucovorin given with pyrimethamine?

Pyrimethamine is a folic acid antagonist that can cause megaloblastic anemia, leukopenia and thrombocytopenia at the doses used for toxoplasmosis. Leucovorin (folinic acid) protects the patient's bone marrow from this toxicity, and the blood count is still checked weekly. Plain folic acid should not be substituted because it can block the drug's therapeutic effect.

When should TMP-SMX prophylaxis for toxoplasmosis be started and stopped?

One double-strength TMP-SMX tablet daily is recommended for people with HIV who are Toxoplasma IgG positive and have a CD4 count below 100 cells/mm3. It can be stopped when the CD4 count has been above 200 for more than 3 months with suppressed HIV RNA on ART, and stopping can be considered when the CD4 count is 100 to 200 with HIV RNA undetectable for at least 3 to 6 months. Aerosolized pentamidine does not protect against toxoplasmosis.

How do you distinguish PML from toxoplasmosis on MRI?

Toxoplasmosis lesions are ring-enhancing, usually multiple, often in the basal ganglia and surrounded by edema with mass effect. PML lesions sit in the white matter, are bright on T2 and FLAIR, are usually non-enhancing and produce no mass effect. Clinically, PML progresses insidiously without headache or fever, and it is treated with ART because there is no specific antiviral.

Toxoplasmosis in HIV: Ring Lesions vs Lymphoma & Treatment

Cerebral toxoplasmosis (Toxoplasma encephalitis) is reactivation of latent Toxoplasma gondii tissue cysts in advanced HIV. It is rare when the CD4 count is above 200 cells/mm³; the classic board cutoff, which is also the threshold for primary prophylaxis, is CD4 below 100 cells/mm³, and risk is greatest below 50. The classic stem is subacute headache, focal deficits and sometimes fever, with contrast MRI showing multiple ring-enhancing lesions with edema and a predilection for the basal ganglia, in a patient who is Toxoplasma IgG positive and not taking TMP-SMX. Treatment is empiric pyrimethamine + sulfadiazine + leucovorin, the classic board answer (current NIH/CDC/IDSA guidelines list TMP-SMX as an equally preferred option); about 90% of patients improve within 14 days, and worsening or no improvement sends you to brain biopsy to look for primary CNS lymphoma.

The Q-bank vignette

A 38-year-old man with HIV who stopped antiretroviral therapy 2 years ago has had 10 days of worsening headache, confusion and weakness of the right arm. Temperature is 38.1°C (100.6°F). He has a right pronator drift and right-sided hyperreflexia, with no neck stiffness. His CD4 count is 38 cells/mm³, serum anti-Toxoplasma IgG is positive, and he takes no prophylaxis. Contrast-enhanced MRI shows three ring-enhancing lesions with surrounding edema, the largest in the left basal ganglia, with mild mass effect.

Question 1. What is the most likely diagnosis?

A. Cerebral toxoplasmosis
B. Primary CNS lymphoma
C. Progressive multifocal leukoencephalopathy (PML)
D. Cryptococcal meningoencephalitis
E. Tuberculoma
F. Pyogenic brain abscess

Answer: A, cerebral toxoplasmosis. CD4 below 100, a positive IgG, no TMP-SMX and several ring-enhancing basal ganglia lesions with edema are the textbook pattern. The disease is reactivation of cysts from an earlier infection (acquired from undercooked meat, unwashed produce or oocysts in cat feces), which is why patients are usually IgG positive.

Why every other answer is wrong

B. Primary CNS lymphoma. Tempting because it strikes the same host and can look identical, since both often produce ring-enhancing lesions. Wrong here because lymphoma more often presents as a single, larger lesion, often next to the ventricles, while three lesions in an IgG-positive patient favor toxoplasmosis. Pick it when the stem gives a solitary periventricular mass, EBV DNA in the CSF (concerning above 10,000 copies/mL, though not diagnostic alone), increased uptake on PET or SPECT, or no response to anti-Toxoplasma therapy. AIDS-related CNS lymphoma is an aggressive EBV-associated B-cell lymphoma; it usually needs a tissue diagnosis, and steroids should be avoided before biopsy because they can shrink it and cause a false-negative result.

C. PML. Tempting because it is another opportunistic brain disease with focal deficits. Wrong here because PML is JC virus demyelination of white matter: lesions are bright on T2 and FLAIR, usually non-enhancing, with no mass effect, and headache and fever are not characteristic. Pick it when a patient has insidious, steadily progressive deficits (hemiparesis, aphasia, hemianopia, ataxia) and non-enhancing white matter lesions. CSF JC virus PCR is positive in about 70% to 90% of patients not taking ART, and treatment is ART, because no specific antiviral works.

D. Cryptococcal meningoencephalitis. Tempting because it also occurs at CD4 below 100 and causes headache, fever and confusion. Wrong here because it is a subacute meningitis or meningoencephalitis, not a cluster of ring-enhancing masses. Pick it when the stem gives weeks of headache and malaise, a high CSF opening pressure and a positive cryptococcal antigen or India ink stain. Induction is liposomal amphotericin B plus flucytosine, and ART is deferred 4 to 6 weeks (see the Cryptococcus neoformans mnemonic).

E. Tuberculoma. Tempting because tuberculosis is on the short list of mass lesions in advanced HIV. Wrong here because nothing points to TB: no exposure, no lung disease and no meningitis. Pick it when focal signs come with tuberculous meningitis: low-grade fever, unremitting headache, drowsiness and CSF with elevated protein and glucose below 50% of the serum level.

F. Pyogenic brain abscess. Tempting because an abscess is also an edematous, ring-enhancing mass. Wrong here because there is no bacterial source. Pick it when the patient has sinusitis, mastoiditis, endocarditis, injection drug use or recent neurosurgery; treat with ceftriaxone or cefotaxime plus metronidazole (add vancomycin if Staphylococcus aureus is suspected) and aspiration or drainage. Fever and leukocytosis can be absent.

Toxoplasmosis vs lymphoma vs PML

Feature	Cerebral toxoplasmosis	Primary CNS lymphoma	PML
Cause	Reactivated T. gondii tissue cysts	EBV-associated aggressive B-cell lymphoma	JC virus infection of oligodendrocytes (demyelination)
Host	CD4 <100, greatest risk <50; IgG positive	Low CD4, high viral load, debilitated	Advanced HIV, but still occurs occasionally at higher CD4 counts
Course	Subacute headache, focal deficits, ± fever, confusion, seizures	Focal deficits, seizures, mental status change	Insidious, steady focal deficits; headache and fever not typical
Lesions	Usually multiple, ring-enhancing, basal ganglia predilection, edema, mass effect	Often single and larger, enhancing, next to the ventricles; can be multiple	White matter, T2/FLAIR bright, usually non-enhancing, no mass effect
Best clue	Positive IgG; improvement on therapy within about 2 weeks	CSF EBV DNA; increased PET or SPECT uptake; biopsy	CSF JC virus PCR; biopsy
Treatment	Pyrimethamine + sulfadiazine + leucovorin	Biopsy first; ART plus high-dose methotrexate-based chemotherapy	ART; no specific antiviral

Question 2: the next step

Same patient. What is the most appropriate next step in management?

A. Pyrimethamine, sulfadiazine and leucovorin
B. Stereotactic brain biopsy before any treatment
C. High-dose methotrexate
D. Dexamethasone alone
E. Antiretroviral therapy alone
F. Liposomal amphotericin B plus flucytosine

Answer: A. Most diagnoses are presumptive: treat, then watch for response. (Current guidelines rate TMP-SMX as an equally preferred regimen, but it is not among the choices.) Clinical response occurs in about 90% of patients within 14 days; a lumbar puncture for T. gondii PCR (specificity 96% to 100%, sensitivity about 50%) plus EBV, JC virus, cryptococcal antigen and TB testing is done only if it is safe with the mass effect.

B, biopsy now: a typical picture like this one is treated first. Brain biopsy is strongly considered when a patient deteriorates during the first week or has not improved clinically by 10 to 14 days of adequate therapy.
C, methotrexate: treats biopsy-proven lymphoma, not a presumptive diagnosis.
D, dexamethasone alone: steroids are for significant mass effect or IRIS only. They do not treat the parasite, and lymphoma can also shrink on steroids, clouding the diagnosis.
E, ART alone: ART is essential but is usually started within 2 to 3 weeks of diagnosis, alongside anti-Toxoplasma therapy, not instead of it.
F, amphotericin plus flucytosine: induction for cryptococcal meningitis.

Treatment and prophylaxis (NIH/CDC/IDSA adult OI guidelines)

Situation	What to give
Preferred acute therapy	Pyrimethamine 200 mg once, then 50 mg daily (≤60 kg) or 75 mg daily (>60 kg), plus sulfadiazine 1,000 mg or 1,500 mg every 6 hours (by the same weight cutoff), plus leucovorin 10–25 mg daily
Also preferred; the choice if pyrimethamine is unavailable or delayed	TMP-SMX (TMP 5 mg/kg, SMX 25 mg/kg) IV or PO twice daily; a meta-analysis cited by the guideline found it as effective as pyrimethamine-sulfadiazine, with less toxicity
Sulfa allergy	Pyrimethamine + leucovorin + clindamycin 600 mg IV or PO every 6 hours
Duration	At least 6 weeks, longer if disease is extensive or the response incomplete
Adjuncts	Dexamethasone only for mass effect or IRIS; anticonvulsants only if seizures occur, never as prophylaxis
ART	Usually started within 2 to 3 weeks of diagnosis
Chronic maintenance (secondary prophylaxis)	Lower-dose pyrimethamine + sulfadiazine + leucovorin, or TMP-SMX DS twice daily; stop after initial therapy is complete, symptoms have resolved and CD4 has been >200 for >6 months on ART
Primary prophylaxis	Toxoplasma IgG positive with CD4 <100: TMP-SMX 1 DS tablet daily; alternatives include dapsone + pyrimethamine + leucovorin or atovaquone-based regimens. Aerosolized pentamidine does not protect
Stopping primary prophylaxis	CD4 >200 for >3 months with HIV RNA suppressed on ART; can be considered at CD4 100–200 if HIV RNA has stayed undetectable for at least 3 to 6 months. Restart if CD4 falls below 100, or to 100–200 with detectable HIV RNA

Pharmacology the exam loves:

Pyrimethamine is a folic acid antagonist (a dihydrofolate reductase inhibitor), and the sulfonamide greatly enhances its effect. At toxoplasmosis doses it can cause megaloblastic anemia, leukopenia, thrombocytopenia and pancytopenia.
Leucovorin (folinic acid) protects the marrow; plain folic acid does not and can block the therapeutic effect. Check a CBC weekly anyway.
One drug, two infections: PCP prophylaxis starts at CD4 <200, and TMP-SMX also protects against toxoplasmosis. The CD4 cutoffs for every opportunistic infection are in the CD4 count and opportunistic infections table.
Prevention in seronegative patients: people with CD4 <200 should be tested for Toxoplasma IgG soon after HIV diagnosis. Those who are negative should avoid raw or undercooked meat, wash their hands after handling raw meat and after gardening and, if they own a cat, have a nonpregnant person without HIV change the litter box daily.

Exam traps

Negative IgG makes toxoplasmosis unlikely but not impossible.
Lesion count is a clue, not a rule. Toxoplasmosis can rarely present as a single lesion, and lymphoma can be multiple.
Steroids before biopsy can make lymphoma melt away and produce a false-negative biopsy.
EBV is the lymphoma clue. AIDS-related CNS lymphoma is EBV-associated, and PET shows increased uptake in lymphoma but not in toxoplasmosis lesions. The virus itself is covered in the herpesviruses guide.
No enhancement and no mass effect means PML, not toxoplasmosis or lymphoma.

Key takeaways

Cerebral toxoplasmosis = reactivation at CD4 <100 (highest risk <50) in an IgG-positive patient not on TMP-SMX.
Multiple ring-enhancing lesions with edema and a basal ganglia predilection; lymphoma is more often single and periventricular; PML is non-enhancing white matter disease without mass effect.
Treat empirically with pyrimethamine + sulfadiazine + leucovorin or, equally preferred in current guidelines, TMP-SMX (clindamycin replaces sulfadiazine in sulfa allergy) for at least 6 weeks.
Biopsy if the patient worsens in week 1 or has not improved by 10 to 14 days.
Primary prophylaxis: TMP-SMX 1 DS daily when IgG positive and CD4 <100; aerosolized pentamidine does not cover it.
Leucovorin, not folic acid, prevents pyrimethamine marrow toxicity.