Toxoplasma gondii Encephalitis

Updated Reviewed

Toxoplasmic encephalitis (TE) is caused by the protozoan Toxoplasma gondii. Disease appears to occur almost exclusively because of reactivation of latent tissue cysts.1-4 Primary infection occasionally is associated with acute cerebral or disseminated disease.

Epidemiology

Seroprevalence of anti-Toxoplasma antibody varies substantially among different geographic locales, with a prevalence of approximately 11% in the United States, versus 50% to 80% in certain European, Latin American, and African countries.4-6 In the era before antiretroviral therapy (ART), the 12-month incidence of TE was approximately 33% in patients with advanced immunosuppression who were seropositive for T. gondii and not receiving prophylaxis with drugs against the disease. A low incidence of toxoplasmosis is seen in patients who are seronegative for T. gondii. If patients are truly seronegative, their toxoplasmosis presumably represents one of three possible scenarios:

  1. Primary infection,
  2. Re-activation of latent disease in individuals who cannot produce detectable antibodies, or
  3. Testing with insensitive assays.7,8

Clinical disease is rare among patients with CD4 T lymphocyte (CD4) cell counts >200 cells/µL. Patients with CD4 counts <50 cells/µL are at greatest risk.1,3,8,9 Primary infection occurs after eating undercooked meat containing tissue cysts or ingesting oocysts that have been shed in cat feces and sporulated in the environment, a process that takes at least 24 hours. In the United States, eating raw shellfish including oysters, clams, and mussels recently was identified as a novel risk factor for acute infection.10 Up to 50% of individuals with documented primary infection do not have an identifiable risk factor.11 Patients may be infected with the parasite even in the absence of conventional risk factors for infection in their epidemiological history. The organism is not transmitted through person-to-person contact.

Clinical Manifestations

Among patients with AIDS, the most common clinical presentation of T. gondii infection is focal encephalitis with headache, confusion, or motor weakness and fever.1,3,9 Patients may also present with non-focal manifestations, including only non-specific headache and psychiatric symptoms. Focal neurological abnormalities may be present on physical examination, and in the absence of treatment, disease progression results in seizures, stupor, coma, and death. Retinochoroiditis, pneumonia, and evidence of other multifocal organ system involvement can occur but are rare in patients with AIDS. Computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain will typically show multiple contrast-enhancing lesions in the grey matter of the cortex or basal ganglia, often with associated edema.1,9,12-14 Toxoplasmosis also can manifest as a single brain lesion or diffuse encephalitis without evidence of focal brain lesions on imaging studies.15 This latter presentation tends to be rapidly progressive and fatal.

Diagnosis

HIV-infected patients with TE are almost uniformly seropositive for anti-toxoplasma immunoglobulin G (IgG) antibodies.1,3,9,16 The absence of IgG antibody makes a diagnosis of toxoplasmosis unlikely but not impossible. Anti-toxoplasma immunoglobulin M (IgM) antibodies usually are absent. Quantitative antibody titers are not useful for diagnosis.

Definitive diagnosis of TE requires a compatible clinical syndrome; identification of one or more mass lesions by CT or MRI, and detection of the organism in a clinical sample. On imaging studies, lesions are usually ring-enhancing and have a predilection for the basal ganglia. MRI has sensitivity superior to that of CT studies for radiological diagnosis of TE. MRI should be obtained in patients with equivocal or negative CT studies. Positron emission tomography13 or single-photon emission computed tomography scanning14 may be helpful in distinguishing between TE and primary central nervous system (CNS) lymphoma, but no imaging technique is completely specific. For TE, detection of the organism requires a brain biopsy, which is most commonly performed by a stereotactic CT-guided needle biopsy. Hematoxylin and eosin stains can be used for detection of T. gondii, but sensitivity is significantly increased if immunoperoxidase staining is used and if experienced laboratories process the specimens.17 If safe and feasible, a lumbar puncture should be performed for T. gondii polymerase chain reaction (PCR), as well as for cytology, culture, cryptococcal antigen and PCR for Mycobacterium tuberculosis, Epstein-Barr Virus (EBV) and JC Virus (JCV), either at initial presentation or subsequently, especially in patients in whom empiric therapy fails. Detection of T. gondii by PCR in CSF has high specificity (96%–100%), but low sensitivity (50%), especially once specific anti-toxoplasma therapy has been started.18-20

The differential diagnosis of focal neurological disease in patients with AIDS most often includes primary CNS lymphoma and progressive multifocal leucoencephalopathy (PML). In the absence of immune reconstitution inflammatory syndrome (IRIS), PML (but not lymphoma) can be distinguished on the basis of imaging studies. PML lesions typically involve white matter rather than gray matter, are non-contrast enhancing, and produce no mass effect. Less common causes of focal neurologic disease in patients with AIDS include mycobacterial infection (especially tuberculosis [TB]); fungal infection, such as cryptococcosis; Chagas disease; and pyogenic brain abscess, particularly in IV drug abusers.

Most clinicians initially rely on an empiric diagnosis, which can be established as an objective response, documented by clinical and radiographic improvement, to specific anti-T. gondii therapy in the absence of a likely alternative diagnosis. Brain biopsy is reserved for patients who fail to respond to specific therapy, although earlier biopsy should be strongly considered if results from imaging, serology, or CSF PCR studies are negative and/or suggest an etiology other than toxoplasmosis. In patients with contrast-enhancing mass lesions, detection of EBV and JCV by PCR in CSF is highly suggestive of CNS lymphoma21,22 or PML,23 respectively.

Preventing Exposure

HIV-infected individuals should be tested for IgG antibody to Toxoplasma soon after they are diagnosed with HIV to detect latent infection with T. gondii (BIII). They also should be counseled regarding sources of Toxoplasma infection, especially if they lack IgG antibody to Toxoplasma.

To minimize risk of acquiring toxoplasmosis, HIV-infected individuals should be advised not to eat raw or undercooked meat, including undercooked lamb, beef, pork, or venison, and not to eat raw shellfish including oysters, clams, and mussels (BIII). Lamb, beef, venison, and pork should be cooked to an internal temperature of 165°F to 170°F;24 meat cooked until it is no longer pink inside usually has an internal temperature of 165°F to 170°F, and therefore, from a more practical perspective, satisfies this requirement. To minimize the risk for acquiring toxoplasmosis, HIV-infected individuals should wash their hands after contact with raw meat and after gardening or other contact with soil; they should also wash fruits and vegetables well before eating them raw (BIII). Patients who are seronegative and who own cats should be advised to have someone who is HIV-negative and not pregnant change the litter box daily. If they must change the litter box themselves, they should wear gloves and wash their hands thoroughly afterwards (BIII). HIV-infected patients also should be encouraged to keep their cats inside and not to adopt or handle stray cats (BIII). Cats should be fed only canned or dried commercial food or well-cooked table food, not raw or undercooked meats (BIII). Patients do not need to be advised to part with their cats or to have their cats tested for toxoplasmosis (AII).

Preventing Disease

Indication for Primary Prophylaxis

Toxoplasma-seropositive patients who have CD4 counts <100 cells/µL should receive prophylaxis against TE (AII).25,26 All patients at risk for toxoplasmosis are also at risk for developing Pneumocystis jirovecii pneumonia (PCP), and should be receiving PCP prophylaxis. They should be managed as follows: patients receiving trimethoprim-sulfamethoxazole (TMP-SMX) or atovaquone for PCP prophylaxis require no additional medications; patients receiving dapsone should have pyrimethamine plus leucovorin added to the regimen or be switched to TMP-SMX or atovaquone; patients receiving aerosol pentamidine should be switched if possible to a regimen which also has anti-toxoplasma activity, i.e. switching to either trimethoprim-sulfamethoxazole or atovaquone if that is feasible. For patients in whom other alternatives are not possible, pyrimethamine alone (plus leucovorin) may have some efficacy as primary prophylaxis (CIII).8

The double-strength-tablet daily dose of TMP-SMX, which is the preferred regimen for PCP prophylaxis, is also effective against TE and is recommended (AII). TMP-SMX, one double-strength tablet three times weekly, is an alternative (BIII). If patients cannot tolerate TMP-SMX, the recommended alternative is dapsone-pyrimethamine plus leucovorin, which is also effective against PCP (BI).27-29 Atovaquone with or without pyrimethamine/leucovorin is active against PCP and also can be considered for toxoplasmosis as well as PCP, (CIII). Aerosolized pentamidine does not protect against TE and is not recommended for antitoxoplasma prophylaxis (AI).25,30

Discontinuing Primary Prophylaxis

Prophylaxis against TE should be discontinued in adult and adolescent patients receiving ART whose CD4 counts increase to >200 cells/µL for more than 3 months (AI). Multiple observational studies31-33 and two randomized trials34,35 have reported that primary prophylaxis can be discontinued, with minimal risk for development of TE, in patients receiving ART whose CD4 counts increase from <200 cells/µL to >200 cells/µL for more than 3 months. In these studies, most patients were taking HIV protease inhibitor-containing regimens and the median CD4 count at the time prophylaxis was discontinued was >300 cells/µL. At the time prophylaxis was discontinued, most patients had sustained suppression of plasma HIV RNA levels below the detection limits of available assays; the median follow-up was 7 to 22 months. CD4 count increases to >200 cells/µL were studied because regimens used for prophylaxis of TE also provide PCP prophylaxis, and the risk of PCP in untreated patients increases once the CD4 count is <200 cells/µL. Thus, the recommendation specifies discontinuing prophylaxis after an increase to >200 cells/µL. When CD4 counts are >200 cells/μL for at least 3 months, primary TE prophylaxis should be discontinued because it adds little value in preventing toxoplasmosis and increases pill burden, potential for drug toxicity and interaction, likelihood of development of drug-resistant pathogens, and cost.

A combined analysis of 10 European cohorts found a low incidence of TE in patients with CD4 counts between 100 and 200 cells/mm3, who were receiving ART and had HIV RNA plasma viral loads <400 copies/mL, and who had stopped or never received TE prophylaxis, suggesting that primary TE prophylaxis can be safely discontinued in patients with CD4 counts 100 to 200 cells/mm3 and HIV plasma RNA levels below limits of detection with commercial assays.36 Similar observations have been made with regard to stopping primary or secondary prophylaxis for PCP.36-38 Data on which to base specific recommendations are inadequate, but one approach would be to stop primary prophylaxis in patients with CD4 counts of 100 to 200 cells/mm3 if HIV plasma RNA levels remain below limits of detection for at least 3 to 6 months (BII).36

Treating Disease

The initial therapy of choice for TE consists of the combination of pyrimethamine plus sulfadiazine plus leucovorin (AI).2,39-41 Pyrimethamine penetrates the brain parenchyma efficiently even in the absence of inflammation.42 Leucovorin reduces the likelihood of development of hematologic toxicities associated with pyrimethamine therapy.43 Pyrimethamine plus clindamycin plus leucovorin (AI)39,40 is the preferred alternative regimen for patients with TE who cannot tolerate sulfadiazine or do not respond to first-line therapy. This combination, however, does not prevent PCP, therefore additional PCP prophylaxis must be administered when it is used (AII) (see discussion under Preventing Recurrence).

In a small (77 patients) randomized trial, TMP-SMX was reported to be effective and better tolerated than pyrimethamine-sulfadiazine.44 Others have reported similar efficacy in open-label observational studies.45 TMP-SMX has less in vitro activity and experience using this drug to treat toxoplasmosis in developed countries is limited. However, if pyrimethamine is unavailable or there is a delay in obtaining it, TMP-SMX should be utilized in place of pyrimethamine-sulfadiazine or pyrimethamine-clindamycin (BI). For patients with a history of sulfa allergy, sulfa desensitization should be attempted using one of several published strategies (BI).46-51 During the desensitization period, atovaquone with or without pyrimethamine should be administered until therapeutic doses of TMP-SMX are achieved (CIII).

No well-studied options exist for patients who cannot take an oral regimen. No parenteral formulation of pyrimethamine exists and the only widely available parenteral sulfonamide is the sulfamethoxazole component of TMP-SMX. Some specialists will use parenteral TMP-SMX (BI) or oral pyrimethamine plus parenteral clindamycin (CIII) as initial treatment in severely ill patients who require parenteral therapy.

Atovaquone (with meals or oral nutritional supplements) plus pyrimethamine plus leucovorin, or atovaquone plus sulfadiazine, or, for patients intolerant of both pyrimethamine and sulfadiazine, atovaquone as a single agent, have also been shown to be effective in treating TE, although the relative efficacy compared with the previous regimens is unknown (BII).52,53,54 If atovaquone is used alone, clinicians should be aware that the absorption of the drug from patient to patient is highly variable; plasma levels >18.5 µg/mL are associated with an improved response rate but atovaquone therapeutic drug monitoring is not routinely available.53-55

The following regimens have been reported to have activity in treatment of TE in small cohorts of patients or in case reports of one or several patients: azithromycin plus pyrimethamine plus leucovorin (CII);56,57 clarithromycin plus pyrimethamine plus leucovorin (CIII);58 5-fluorouracil plus clindamycin (CIII),59 dapsone plus pyrimethamine plus leucovorin;60 and minocycline or doxycycline combined with either pyrimethamine plus leucovorin, sulfadiazine, or clarithromycin (CIII).61,62 Although the clarithromycin dose used in the only published study was 1g twice a day, doses >500 mg have been associated with increased mortality in HIV-infected patients treated for disseminated Mycobacterium avium Complex. Doses >500 mg twice a day should not be used (BIII).

Clinical response to acute therapy occurs in 90% of patients with TE within 14 days of initiation of appropriate anti-toxoplasma treatment.2 The reasons why some patients fail therapy are not clearly proven; whether such failures are due to poor adherence or to other host factors or antimicrobial resistance has not been well delineated. Acute therapy for TE should be continued for at least 6 weeks, if there is clinical and radiologic improvement (BII).1-4 Longer courses may be necessary if clinical or radiologic disease is extensive or response is incomplete at 6 weeks. After completion of the acute therapy, all patients should be continued on chronic maintenance therapy as outlined below (see Preventing Recurrence section below). The radiologic goals for treatment include resolution of the lesion(s) in terms of size, contrast enhancement, and associated edema, although residual contrast-enhancing lesions may persist for prolonged periods. Adjunctive corticosteroids such as dexamethasone should only be administered to patients with TE when they are clinically indicated to treat a mass effect associated with focal lesions or associated edema (BIII). In those treated with corticosteroids, caution may be needed in diagnosing CNS toxoplasmosis on the basis of treatment response, since primary CNS lymphoma may respond clinically and radiographically to corticosteroids alone; these patients should be monitored carefully as corticosteroids are tapered. In addition, corticosteroids should be discontinued as soon as clinically feasible because of their potential to cause immunosuppression. Patients receiving corticosteroids should be monitored closely for development of other opportunistic infections (OIs), including cytomegalovirus retinitis and TB.

Anticonvulsants should be administered to patients with TE who have a history of seizures (AII), but should not be administered prophylactically to all patients (BII). Anticonvulsants, if indicated, should be continued at least through the period of acute therapy.

Special Considerations with Regard to Starting Antiretroviral Therapy

There are no data on which to base a recommendation regarding when to start ART in a patient with TE. However, many physicians would initiate ART within 2 to 3 weeks after the diagnosis of toxoplasmosis (CIII), based on the significantly lower incidence of AIDS progression or death (a secondary study endpoint) seen in the ART arm of a controlled trial of 282 patients with OIs other than TB (only 5% of whom had toxoplasmosis) who were randomized to early (median 12 days after initiation of OI therapy) versus deferred (median 45 days) initiation of ART.63

Monitoring of Response to Therapy and Adverse Events (including IRIS)

Changes in antibody titers are not useful for monitoring responses to therapy. Patients with TE should be monitored routinely for adverse events and clinical and radiologic improvement (AIII). Common pyrimethamine toxicities such as rash, nausea, and bone marrow suppression (neutropenia, anemia, and thrombocytopenia) often can be reversed by increasing the leucovorin dose to 10, 25, or 50 mg 4 times daily (CIII).

Common sulfadiazine toxicities include rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea, renal insufficiency, and crystalluria. Common clindamycin toxicities include fever, rash, nausea, diarrhea (including pseudomembranous colitis or diarrhea related to Clostridium difficile toxin), and hepatotoxicity. Common TMP-SMX toxicities include rash, fever, leukopenia, thrombocytopenia, and hepatotoxicity. Common atovaquone toxicities include nausea, vomiting, diarrhea, rash, headache, hepatotoxicity, and fever. Drug interactions between anticonvulsants and antiretroviral agents should be evaluated carefully; if necessary, doses should be adjusted or alternative anticonvulsants should be used.

IRIS associated with TE has been reported but appears to be rare (~5% in one report).64-66 Most cases develop as paradoxical worsening with increase in the size and number of lesions, peri-lesional edema, and greater enhancement in T1.65,67,68 Given the rarity of TE-associated IRIS, recommendations for management of such events are difficult to develop.

Managing Treatment Failure

A brain biopsy should be strongly considered in patients who did not have an initial biopsy prior to therapy and who fail to respond to initial therapy for TE (BII) as defined by clinical or radiologic deterioration during the first week despite adequate therapy, or who do not show clinical improvement within 10 to 14 days. A switch to an alternative regimen, as previously described, should be considered for those who undergo brain biopsy and have confirmed histopathologic evidence of TE, or who have a CSF PCR positive for T. gondii (BIII). In patients who adhere to their regimens, disease recurrence is unusual in the setting of chronic maintenance therapy after an initial clinical and radiographic response.

Preventing Recurrence

When to Start Chronic Maintenance Therapy

Patients who have completed initial therapy for TE should be given chronic maintenance therapy to suppress infection (AI)39,40 until immune reconstitution occurs as a consequence of ART, in which case treatment discontinuation is indicated. The combination of pyrimethamine plus sulfadiazine plus leucovorin is highly effective as suppressive therapy for patients with TE (AI) and provides protection against PCP (AII). Although sulfadiazine is routinely dosed as a four-times-a-day regimen, a pharmacokinetic study suggests bioequivalence for the same total daily dose when given either twice or four times a day,69 and limited clinical experience suggests that twice-daily dosing is effective.70 Pyrimethamine plus clindamycin is commonly used as suppressive therapy for patients with TE who cannot tolerate sulfa drugs (BI). Because of the high failure rate observed with lower doses,39 a dose of 600 mg clindamycin every 8 hours is recommended (CIII). Because this regimen does not provide protection against PCP (AII), an additional agent, such as aerosol pentamidine, must be used. Atovaquone with or without pyrimethamine or sulfadiazine is also active against both TE54,55 and PCP71 (BII). A small, uncontrolled study in patients who had been receiving ART for a median of 13 months suggested that TMP-SMX could be used as a suppressive regimen to reduce pill burden.72 For patients being treated with TMP-SMX, this drug should be continued as chronic maintenance, at a reduced dose of 1 double-strength tablet twice daily (BII) or once daily (BII). The lower dose may be associated with an increased risk of relapse, and if the once daily dosing is used, a gradual transition may be beneficial (e.g. follow acute therapy with 4-6 weeks of 1 double-strength tablet twice daily before lowering to 1 double-strength tablet once daily (CIII).44,45,72

Although there are no data on the long-term suppressive efficacy of the other alternative regimens noted above, clinicians might consider using these agents in unusual situations in which the recommended agents cannot be administered (CIII).

When to Stop Chronic Maintenance Therapy

Adult and adolescent patients receiving chronic maintenance therapy for TE are at low risk for recurrence of TE if they have successfully completed initial therapy for TE, remain asymptomatic with regard to signs and symptoms of TE, and have an increase in their CD4 counts to >200 cells/µL after ART that is sustained for more than 6 months.32,35,73,74 Discontinuing chronic maintenance therapy in such patients is a reasonable consideration, although occasional recurrences have been reported. The recommendation is based on results in a limited number of patients from observational studies and one randomized clinical trial and inference from more extensive cumulative data indicating the safety of discontinuing secondary prophylaxis for other OIs during advanced disease (BI). As part of the evaluation to determine whether discontinuation of therapy is appropriate, some specialists recommend obtaining an MRI of the brain to assess for resolution of brain lesions.

When to Restart Primary Prophylaxis or Maintenance Therapy

Primary prophylaxis should be reintroduced if the CD4 count decreases to <100 cells/mm3 (AIII) regardless of the HIV plasma viral load. Based on results from the COHERE study, primary prophylaxis may not need to be restarted in patients with CD4 counts of 100 to 200 cells/mm3 who have had HIV plasma RNA levels below limits of detection for at least 3 to 6 months (BII).36,37 For patients with CD4 counts of 100-200 cells/µL with HIV plasma viral load above detection limits of the utilized assay, PCP prophylaxis should be reintroduced, and this will provide prophylaxis for toxoplasmosis as well.

Because there are no published data examining the risk of recurrence in patients stopping chronic maintenance therapy for TE when the CD4 count is between 100 and 200 cells/µL, and recurrent TE can be debilitating and potentially life-threatening, maintenance therapy should be reintroduced if the CD4 count decreases to <200 cells/µL (AIII) regardless of the HIV plasma viral load.75

Special Considerations During Pregnancy

Documentation of baseline maternal T. gondii serologic status (IgG) should be obtained in HIV-infected women who become pregnant because of concerns regarding congenital toxoplasmosis. Although perinatal transmission of T. gondii normally occurs only with acute infection in the immunocompetent host, case reports have documented transmission with reactivation of chronic infection in HIV-infected women with severe immunosuppression.76,77 Knowing maternal toxoplasmosis sero-status at the beginning of pregnancy may be helpful in delineating future risks and interpreting serologic testing performed later in pregnancy should there be heightened concerns for maternal infection and/or fetal transmission.

Primary T. gondii infection can typically be distinguished from chronic infection with the use of multiple serologic assays, including IgG, IgM, IgA, and IgE antibodies; IgG avidity; and the differential agglutination tests.78,79 Because serologic testing is often difficult to interpret, pregnant HIV-infected women with suspected primary T. gondii infection during pregnancy should be managed in consultation with a maternal-fetal medicine specialist who can access specialized laboratory testing (BIII)79,80 (e.g., the Palo Alto Medical Foundation Toxoplasmosis Serology Laboratory; Palo Alto, CA; http://www.pamf.org/serology/ at 650-853-4828 and toxolab@pamf.org; and the National Collaborative Chicago-based Congenital Toxoplasmosis Study; Chicago, IL; http://www.uchospitals.edu/specialties/infectious-diseases/toxoplasmosis/ at 773-834-4131 and rmcleod@midway.uchicago.edu).

Toxoplasmosis diagnostic considerations are the same in pregnant women as in non-pregnant women.

While maternal infection is usually asymptomatic, after a 5-23 day incubation period, non-specific symptoms may develop including fever, fatigue, headache, and myalgia. Parasitemia can seed the placenta and lead to fetal infection. With respect to congential toxoplasmosis, the risk of transmission is highest in the setting of an acute maternal infection as compared to reactivation. While the risk of transmission increases with advancing gestational age, the severity of fetal sequelae is more pronounced the earlier in gestation the fetus is affected.81 Detailed ultrasound examination of the fetus specifically evaluating for hydrocephalus, cerebral calcifications, and growth restriction should be done for HIV-infected women with suspected primary or symptomatic reactivation of T. gondii during pregnancy (AIII).79 Prenatal diagnosis requires an amniocentesis with PCR testing for T. gondii DNA in the amniotic fluid.82 Amniocentesis does not appear to increase the risk of perinatal HIV transmission, particularly in women receiving HAART.83 Therefore, PCR of amniotic fluid can be considered during gestation in pregnant women on ART with serologic evidence of recently acquired infection, women suspected to have reactivated their toxoplasma latent infection during pregnancy, and those with ultrasound findings suggestive of fetal T. gondii infection (BIII).79 Amniotic fluid testing for T. gondii PCR should be avoided at less than 18-week gestation. in an effort to minimize false-negative results.84 Because the risk for transmission with chronic infection that does not reactivate during gestation appears to be low, routine fetal evaluation for infection with amniocentesis is not indicated.

Pediatric-care providers should be informed about HIV-infected mothers who have suspected or confirmed T. gondii infection to allow evaluation of their neonates for evidence of congenital infection (AIII).

Indications for treatment of T. gondii during pregnancy should be based on confirmed or suspected infection in the mother and the risk of transmission of the parasite from mother to fetus. The value of routine toxoplasmosis screening programs is debated in the United States but generally accepted in other countries. In countries such as France where pregnant women are universally screened and treated, infected offspring are reported to have primarily mild disease and rarely severe disease. In contrast, in countries without a universal screening program (e.g. United States), infected offspring mostly present with severe disease.85

Pregnant HIV-infected women who have evidence of primary toxoplasmic infection, without TE, should be evaluated and managed during pregnancy in consultation with appropriate specialists (BIII). Studies published since 2007 support treatment of toxoplasmosis during pregnancy in an effort to decrease vertical transmission and reduce the severity of clinical signs in the offspring.86-89 In the setting of primary infection during pregnancy, spiramcyin is recommended to prevent congenital transmission. Spiramycin is not commercially available in the United States but can be obtained at no cost after consultation with PAMF-TSL, telephone number (650) 853-4828, or the US [Chicago, IL] National Collaborative Treatment Trial Study [NCCTS], telephone number (773) 834-4152) through the US Food and Drug Administration, telephone number (301) 796-1400. It is administered orally at a dosage of 1.0 g (or 3 million U) every 8 h (total dosage of 3 g or 9 million U per day). Spiramcyn is not teratogenic, does not treat infection in the fetus and is primarily indicated for fetal prophylaxis. Spiramycin should be continued until delivery in women with low suspicion of fetal infection or those with documented negative results of amniotic fluid PCR and negative findings on ultrasounds at follow-up.

Pyrimethamine/sulfadiazine/leucovorin is recommended for pregnant women with a strong suspicion of fetal infection: those suspected of having acquired the infection at ≥18 weeks of gestation,90 those with positive AF PCR, or those with ultrasounds suggestive of congenital toxoplasmosis. Pyrimethamine should not be used in the first trimester because of teratogenicity concerns. The combination of pyrimethamine and sulfadiazine can decrease disease severity.

Treatment of pregnant women with TE should be the same as in non-pregnant adults (BIII), including pyrimethamine plus sulfadiazine plus leucovorin (AI), and in consultation with appropriate specialists (BIII).2,39-41 Of note, this regimen is often used to treat the infected fetus.79

Although pyrimethamine has been associated with birth defects in animals, human data have not suggested an increased risk for defects, therefore, it can be administered to pregnant women after the first trimester.77,91-94 Similarly, sulfadiazine appears safe in pregnancy.95 A randomized, controlled trial published in 1956 found that premature infants receiving prophylactic penicillin/sulfisoxazole were at significantly higher risk of mortality (specifically kernicterus), compared with infants who received oxytetracycline.96 Because of these findings, some clinicians are concerned about the risk of neonatal kernicterus in the setting of maternal use of sulfa (including sulfadiazine) near delivery, although are no studies published to date link late third-trimester maternal sulfa use and neonatal death or kernicterus. The infant’s care provider should be notified of maternal sulfa use in late pregnancy.

The preferred alternative regimen for patients with TE who are unable to tolerate or who fail to respond to first-line therapy is pyrimethamine plus clindamycin plus leucovorin (AI).39,40 Clindamycin is considered safe throughout pregnancy. Atovaquone may be used if indicated. While there are limited data on atovaquone safety in humans, preclinical studies have not demonstrated toxicity.92

TMP-SMX can be administered for primary prophylaxis against TE as described for PCP (AIII). The risks of TMP-SMX in the first trimester, as discussed for PCP, must be balanced against the risk of TE. Maintenance therapy should be provided, using the same indications as for non-pregnant women. As noted above, pyrimethamine and sulfadiazine are considered safe in pregnancy. Clindamycin may be substituted for sulfadiazine for sulfa-intolerant patients. Dapsone appears to cross the placenta.97,98 Over the past several decades, dapsone (used for primary prophylaxis) has been used safely in pregnancy to treat leprosy, malaria, and various dermatologic conditions.98,99 With long-term therapy, there is a risk of mild maternal hemolysis and a potential—although extremely low— risk of hemolytic anemia in exposed fetuses with G6PD deficiency.100

When providing preconception care for HIV-infected women receiving TE prophylaxis, providers should discuss the option of deferring pregnancy until TE prophylaxis can be safely discontinued (BIII).

Recommendations for Preventing and Treating Toxoplasma gondii Encephalitis
Preventing 1st Episode of Toxoplasma gondii Encephalitis (Primary Prophylaxis)

Indications for Initiating Primary Prophylaxis:
  • Toxoplasma IgG positive patients with CD4 count <100 cells/mm3 (AII)
Note: All the recommended regimens for preventing 1st episode of toxoplasmosis are also effective in preventing PCP.

Preferred Regimen:
  • TMP-SMX 1 DS PO daily (AII)
Alternative Regimens:
  • TMP-SMX 1 DS PO three times weekly (BIII), or
  • TMP-SMX SS PO daily (BIII), or
  • Dapsonea 50 mg PO daily + (pyrimethamine 50 mg + leucovorin 25 mg) PO weekly (BI), or
  • (Dapsonea 200 mg + pyrimethamine 75 mg + leucovorin 25 mg) PO weekly (BI), or
  • Atovaquoneb 1500 mg PO daily (CIII), or
  • (Atovaquoneb 1500 mg + pyrimethamine 25 mg + leucovorin 10 mg) PO daily (CIII)
Indication for Discontinuing Primary Prophylaxis:
  • CD4 count >200 cells/mm3 for >3 months in response to ART (AI); or
  • Can consider if CD4 count is 100-200 cells/mm3 and HIV RNA levels remain below limits of detection for at least 3-6 months (BII).
Indication for Restarting Primary Prophylaxis:
  • CD4 count <100 to 200 cells/mm3 (AIII)
Treating Toxoplasma gondii Encephalitis

Preferred Regimen (AI):
  • Pyrimethamine 200 mg PO once, followed by dose based on body weight:
    • Body weight ≤60 kg: pyrimethamine 50 mg PO daily + sulfadiazine 1000 mg PO q6h + leucovorin 10–25 mg PO daily (can increase to 50 mg daily or BID)
    • Body weight >60 kg: pyrimethamine 75 mg PO daily + sulfadiazine 1500 mg PO q6h + leucovorin 10–25 mg PO daily (can increase to 50 mg daily or BID)
Note: if pyrimethamine is unavailable or there is a delay in obtaining it, TMP-SMX should be used in place of pyrimethamine-sulfadiazine (BI). For patients with a history of sulfa allergy, sulfa desensitization should be attempted using one of several published strategies (BI). Atovaquone should be administered until therapeutic doses of TMP-SMX are achieved (CIII).

Alternative Regimens:
  • Pyrimethamine (leucovorin)c plus clindamycin 600 mg IV or PO q6h (AI); preferred alternative for patients intolerant of sulfadiazine or who do not respond to pyrimethamineb-sulfadiazine; must add additional agent for PCP prophylaxis, or
  • TMP-SMX (TMP 5 mg/kg and SMX 25 mg/kg) (IV or PO) BID (BI), or
  • Atovaquoneb 1500 mg PO BID + pyrimethamine (leucovorin)c (BII), or
  • Atovaquoneb 1500 mg PO BID + sulfadiazined (BII), or
  • Atovaquoneb 1500 mg PO BID (BII)
Total Duration for Treating Acute Infection:
  • At least 6 weeks (BII); longer duration if clinical or radiologic disease is extensive or response is incomplete at 6 weeks
  • After completion of the acute therapy, all patients should be continued on chronic maintenance therapy as outlined below
Chronic Maintenance Therapy for Toxoplasma gondii Encephalitis

Preferred Regimen:
  • Pyrimethamine 25–50 mg PO daily + sulfadiazine 2000–4000 mg PO daily (in 2 to 4 divided doses) + leucovorin 10–25 mg PO daily (AI)
Alternative Regimen:
  • Clindamycin 600 mg PO q8h + (pyrimethamine 25–50 mg + leucovorin 10–25 mg) PO daily (BI); must add additional agent to prevent PCP (AII), or
  • TMP-SMX DS 1 tablet BID (BII), or
  • TMP-SMX DS 1 tablet daily (BII), or
  • Atovaquoneb 750–1500 mg PO BID + (pyrimethamine 25 mg + leucovorin 10 mg) PO daily, or
  • Atovaquoneb 750–1500 mg PO BID + sulfadiazine 2000–4000 mg PO daily (in 2 to 4 divided doses) (BII), or
  • Atovaquoneb 750–1500 mg PO BID (BII)
Discontinuing Chronic Maintenance Therapy:
  • Successfully completed initial therapy, remain asymptomatic of signs and symptoms of TE, and CD4 count >200 cells/mm3 for >6 months in response to ART (BI)
Criteria for Restarting Secondary Prophylaxis/Chronic Maintenance
  • CD4 count <200 cells/mm3 (AIII)
Other Considerations:
  • Adjunctive corticosteroids (e.g., dexamethasone) should only be administered when clinically indicated to treat a mass effect associated with focal lesions or associated edema (BIII); discontinue as soon as clinically feasible.
  • Anticonvulsants should be administered to patients with a history of seizures (AIII) and continued through at least through the period of acute treatment; anticonvulsants should not be used as seizure prophylaxis (BIII).
a Whenever possible, patients should be tested for G6PD deficiency before administrating dapsone. Alternative agent should be used if the patient is found to have G6PD deficiency.
b Atovaquone should be taken with meals or nutritional supplement to ensure adequate oral absorption.
c Pyrimethamine and leucovorin doses: Same as doses listed in Preferred Regimen for Acute Infection
d Sulfadiazine dose: Same as weight-based dose listed in Preferred Regimen for Acute Infection


Key to Acronyms: ART = antiretroviral therapy; BID = twice daily; CD4 = CD4 T lymphocyte cell; DS = double strength; G6PD = glucose-6-phosphate dehydrogenase; IgG = immunoglobulin G; IV = intravenous; PCP = Pneumocystis Pneumonia; PO = orally; q(n)h = every “n” hours; SS = single strength; TE = toxoplasmic encephalitis; TMP-SMX = trimethoprim-sulfamethoxazole

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Recommendations for Preventing and Treating Toxoplasma gondii Encephalitis

Preventing 1st Episode of Toxoplasma gondii Encephalitis (Primary Prophylaxis)

Indications for Initiating Primary Prophylaxis:

  • Toxoplasma IgG positive patients with CD4 count <100 cells/mm3 (AII)

Note: All the recommended regimens for preventing 1st episode of toxoplasmosis are also effective in preventing PCP.

Preferred Regimen:

  • TMP-SMX 1 DS PO daily (AII)

Alternative Regimens:

  • TMP-SMX 1 DS PO three times weekly (BIII), or
  • TMP-SMX SS PO daily (BIII), or
  • Dapsonea 50 mg PO daily + (pyrimethamine 50 mg + leucovorin 25 mg) PO weekly (BI), or
  • (Dapsonea 200 mg + pyrimethamine 75 mg + leucovorin 25 mg) PO weekly (BI), or
  • Atovaquoneb 1500 mg PO daily (CIII), or
  • (Atovaquoneb 1500 mg + pyrimethamine 25 mg + leucovorin 10 mg) PO daily (CIII)

Indication for Discontinuing Primary Prophylaxis:

  • CD4 count >200 cells/mm3 for >3 months in response to ART (AI); or
  • Can consider if CD4 count is 100-200 cells/mm3 and HIV RNA levels remain below limits of detection for at least 3-6 months (BII).

Indication for Restarting Primary Prophylaxis:

  • CD4 count <100 to 200 cells/mm3 (AIII)

Treating Toxoplasma gondii Encephalitis 

Preferred Regimen (AI):

  • Pyrimethamine 200 mg PO once, followed by dose based on body weight:
    • Body weight ≤60 kg: pyrimethamine 50 mg PO daily + sulfadiazine 1000 mg PO q6h + leucovorin 10–25 mg PO daily (can increase to 50 mg daily or BID)
    • Body weight >60 kg: pyrimethamine 75 mg PO daily + sulfadiazine 1500 mg PO q6h + leucovorin 10–25 mg PO daily (can increase to 50 mg daily or BID)

Note: if pyrimethamine is unavailable or there is a delay in obtaining it, TMP-SMX should be used in place of pyrimethamine-sulfadiazine (BI). For patients with a history of sulfa allergy, sulfa desensitization should be attempted using one of several published strategies (BI). Atovaquone should be administered until therapeutic doses of TMP-SMX are achieved (CIII).

Alternative Regimens:

  • Pyrimethamine (leucovorin)c plus clindamycin 600 mg IV or PO q6h (AI); preferred alternative for patients intolerant of sulfadiazine or who do not respond to pyrimethamineb-sulfadiazine; must add additional agent for PCP prophylaxis, or
  • TMP-SMX (TMP 5 mg/kg and SMX 25 mg/kg) (IV or PO) BID (BI), or
  • Atovaquoneb 1500 mg PO BID + pyrimethamine (leucovorin)c (BII), or
  • Atovaquoneb 1500 mg PO BID + sulfadiazined (BII), or
  • Atovaquoneb 1500 mg PO BID (BII)

Total Duration for Treating Acute Infection:

  • At least 6 weeks (BII); longer duration if clinical or radiologic disease is extensive or response is incomplete at 6 weeks
  • After completion of the acute therapy, all patients should be continued on chronic maintenance therapy as outlined below

Chronic Maintenance Therapy for Toxoplasma gondii Encephalitis 

Preferred Regimen:

  • Pyrimethamine 25–50 mg PO daily + sulfadiazine 2000–4000 mg PO daily (in 2 to 4 divided doses) + leucovorin 10–25 mg PO daily (AI)

Alternative Regimen:

  • Clindamycin 600 mg PO q8h + (pyrimethamine 25–50 mg + leucovorin 10–25 mg) PO daily (BI); must add additional agent to prevent PCP (AII), or
  • TMP-SMX DS 1 tablet BID (BII), or
  • TMP-SMX DS 1 tablet daily (BII), or
  • Atovaquoneb 750–1500 mg PO BID + (pyrimethamine 25 mg + leucovorin 10 mg) PO daily, or
  • Atovaquoneb 750–1500 mg PO BID + sulfadiazine 2000–4000 mg PO daily (in 2 to 4 divided doses) (BII), or
  • Atovaquoneb 750–1500 mg PO BID (BII)

Discontinuing Chronic Maintenance Therapy:

  • Successfully completed initial therapy, remain asymptomatic of signs and symptoms of TE, and CD4 count >200 cells/mm3 for >6 months in response to ART (BI)

Criteria for Restarting Secondary Prophylaxis/Chronic Maintenance

  • CD4 count <200 cells/mm3 (AIII)

Other Considerations:

  • Adjunctive corticosteroids (e.g., dexamethasone) should only be administered when clinically indicated to treat a mass effect associated with focal lesions or associated edema (BIII); discontinue as soon as clinically feasible.
  • Anticonvulsants should be administered to patients with a history of seizures (AIII) and continued through at least through the period of acute treatment; anticonvulsants should not be used as seizure prophylaxis (BIII).
a Whenever possible, patients should be tested for G6PD deficiency before administrating dapsone. Alternative agent should be used if the patient is found to have G6PD deficiency.
b Atovaquone should be taken with meals or nutritional supplement to ensure adequate oral absorption.
c Pyrimethamine and leucovorin doses: Same as doses listed in Preferred Regimen for Acute Infection
d Sulfadiazine dose: Same as weight-based dose listed in Preferred Regimen for Acute Infection


Key to Acronyms: ART = antiretroviral therapy; BID = twice daily; CD4 = CD4 T lymphocyte cell; DS = double strength; G6PD = glucose-6-phosphate dehydrogenase; IgG = immunoglobulin G; IV = intravenous; PCP = Pneumocystis Pneumonia; PO = orally; q(n)h = every “n” hours; SS = single strength; TE = toxoplasmic encephalitis; TMP-SMX = trimethoprim-sulfamethoxazole

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