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Toxoplasma gondii Encephalitis
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Toxoplasmic encephalitis (TE) is caused by the protozoan Toxoplasma gondii. Disease appears to occur almost exclusively because of reactivation of latent tissue cysts (184Luft BJ, Conley F, Remington JS, et al. Outbreak of central-nervous-system toxoplasmosis in Western Europe and North America. Lancet 1983;1:781-4., 185Luft BJ, Brooks RG, Conley FK. Toxoplasmic encephalitis in patients with acquired immune deficiency syndrome. JAMA 1984;252:913-7., 186Wong B, Gold JW, Brown AE, et al. Central-nervous-system toxoplasmosis in homosexual men and parenteral drug abusers. Ann Intern Med 1984;100:36-42., 187Israelski DM, Chmiel JS, Poggensee L, Phair JP, Remington JS. Prevalence of Toxoplasma infection in a cohort of homosexual men at risk of AIDS and toxoplasmic encephalitis. J Acquir Immune Defic Syndr 1993;6:414-8.). Primary infection occasionally is associated with acute cerebral or disseminated disease.

Epidemiology

Seroprevalence varies substantially among different communities (e.g., approximately 15% in the United States and 50%-75% in certain European countries) (187Israelski DM, Chmiel JS, Poggensee L, Phair JP, Remington JS. Prevalence of Toxoplasma infection in a cohort of homosexual men at risk of AIDS and toxoplasmic encephalitis. J Acquir Immune Defic Syndr 1993;6:414-8., 188Mathews WC, Fullerton SC. Use of a clinical laboratory database to estimate Toxoplasma seroprevalence among human immunodeficiency virus-infected patients. Overcoming bias in secondary analysis of clinical records. Arch Pathol Lab Med 1994;118:807-10.). In the pre-ART era, for patients with advanced immunosuppression who were seropositive for T. gondii and not receiving prophylaxis with drugs active against T. gondii, the 12-month incidence of TE was approximately 33%. The incidence of toxoplasmosis in patients who are seronegative for T. gondii is low. If well-documented cases did occur among seronegative patients, they would presumably represent either primary infection, reactivation of latent disease in patients unable to produce detectable antibody, or patients who were tested with insensitive assays. The incidence and associated mortality in Europe and the United States have decreased substantially with the initiation of ART and the broad use of prophylaxis regimens active against T. gondii (189Abgrall S, Rabaud C, Costagliola D. Incidence and risk factors for toxoplasmic encephalitis in human immunodeficiency virus-infected patients before and during the highly active antiretroviral therapy era. Clin Infect Dis 2001;33:1747-55., 190Leport C, Chene G, Morlat P, et al. Pyrimethamine for primary prophylaxis of toxoplasmic encephalitis in patients with human immunodeficiency virus infection: a double-blind, randomized trial. J Infect Dis 1996;173:91-7.).

Clinical disease is rare among patients with CD4+ counts >200 cells/µL. The greatest risk occurs among patients with a CD4+ count <50 cells/µL (184Luft BJ, Conley F, Remington JS, et al. Outbreak of central-nervous-system toxoplasmosis in Western Europe and North America. Lancet 1983;1:781-4., 185Luft BJ, Brooks RG, Conley FK. Toxoplasmic encephalitis in patients with acquired immune deficiency syndrome. JAMA 1984;252:913-7., 186Wong B, Gold JW, Brown AE, et al. Central-nervous-system toxoplasmosis in homosexual men and parenteral drug abusers. Ann Intern Med 1984;100:36-42., 190Leport C, Chene G, Morlat P, et al. Pyrimethamine for primary prophylaxis of toxoplasmic encephalitis in patients with human immunodeficiency virus infection: a double-blind, randomized trial. J Infect Dis 1996;173:91-7.). Primary infection occurs after eating undercooked meat containing tissue cysts or ingesting oocysts that have been shed in cat feces and have sporulated in the environment (sporulation requires at least 24 hours). No transmission of the organism occurs by person-to-person contact.

Clinical Manifestations

The most common clinical presentation of T. gondii infection among patients with AIDS is focal encephalitis with headache, confusion, or motor weakness and fever (184Luft BJ, Conley F, Remington JS, et al. Outbreak of central-nervous-system toxoplasmosis in Western Europe and North America. Lancet 1983;1:781-4., 185Luft BJ, Brooks RG, Conley FK. Toxoplasmic encephalitis in patients with acquired immune deficiency syndrome. JAMA 1984;252:913-7., 186Wong B, Gold JW, Brown AE, et al. Central-nervous-system toxoplasmosis in homosexual men and parenteral drug abusers. Ann Intern Med 1984;100:36-42.). Physical examination might demonstrate focal neurological abnormalities, and in the absence of treatment, disease progression results in seizures, stupor, and coma. Retinochoroiditis, pneumonia, and evidence of other multifocal organ system involvement can be observed after dissemination of infection but are rare manifestations in this patient population. CT scan or MRI of the brain will typically show multiple contrast-enhancing lesions, often with associated edema (184Luft BJ, Conley F, Remington JS, et al. Outbreak of central-nervous-system toxoplasmosis in Western Europe and North America. Lancet 1983;1:781-4., 185Luft BJ, Brooks RG, Conley FK. Toxoplasmic encephalitis in patients with acquired immune deficiency syndrome. JAMA 1984;252:913-7., 184Luft BJ, Conley F, Remington JS, et al. Outbreak of central-nervous-system toxoplasmosis in Western Europe and North America. Lancet 1983;1:781-4., 191Kupfer MC, Zee CS, Colletti PM, Boswell WD, Rhodes R. MRI evaluation of AIDS-related encephalopathy: toxoplasmosis vs. lymphoma. Magn Reson Imaging 1990;8:51-7., 182, 193Ruiz A, Ganz WI, Post MJ, et al. Use of thallium-201 brain SPECT to differentiate cerebral lymphoma from toxoplasma encephalitis in AIDS patients. Am J Neuroradiol 1994;15:1885-94.). However, toxoplasmosis also can manifest as single lesions in the brain.

Diagnosis

HIV-infected patients with TE are almost uniformly seropositive for anti-toxoplasma immunoglobulin G (IgG) antibodies (184Luft BJ, Conley F, Remington JS, et al. Outbreak of central-nervous-system toxoplasmosis in Western Europe and North America. Lancet 1983;1:781-4., 185Luft BJ, Brooks RG, Conley FK. Toxoplasmic encephalitis in patients with acquired immune deficiency syndrome. JAMA 1984;252:913-7., 186Wong B, Gold JW, Brown AE, et al. Central-nervous-system toxoplasmosis in homosexual men and parenteral drug abusers. Ann Intern Med 1984;100:36-42., 194Derouin F, Leport C, Pueyo S, et al. Predictive value of Toxoplasma gondii antibody titres on the occurrence of toxoplasmic encephalitis in HIV-infected patients. AIDS 1996;10:1521-7.). The absence of IgG antibody makes a diagnosis of toxoplasmosis unlikely but not impossible. Anti-toxoplasma immunoglobulin M (IgM) antibodies are usually absent. Quantitative antibody titers are not diagnostically useful.

Definitive diagnosis of TE requires a compatible clinical syndrome; identification of one or more mass lesions by CT, MRI, or other radiographic testing; and detection of the organism in a clinical sample. For TE, this requires a brain biopsy, which is most commonly performed by a stereotactic CT-guided needle biopsy. Organisms are demonstrable with hematoxylin and eosin stains, although immunoperoxidase staining by experienced laboratories might increase sensitivity (195Conley FK, Jenkins KA, Remington JS. Toxoplasma gondii infection of the central nervous system: use of the peroxidase-antiperoxidase method to demonstrate toxoplasma in formalin fixed, paraffin embedded tissue sections. Hum Pathol 1981;12:690-8.). Detection of T. gondii by polymerase chain reaction (PCR) in cerebrospinal fluid (CSF) has produced disappointing results; although specificity is high (96%-100%), sensitivity is low (50%) and the results usually are negative once specific anti-toxoplasma therapy has been started (196Novati R, Castagna A, Morsica G, et al. Polymerase chain reaction for Toxoplasma gondii DNA in the cerebrospinal fluid of AIDS patients with focal brain lesions. AIDS 1994;8:1691-4., 197Cinque P, Scarpellini P, Vago L, Linde A, Lazzarin A. Diagnosis of central nervous system complications in HIV-infected patients: cerebrospinal fluid analysis by the polymerase chain reaction. AIDS 1997;11:1-17.).

The differential diagnosis of focal neurological disease in patients with AIDS includes central nervous system (CNS) lymphoma; mycobacterial infection (especially TB); fungal infection (e.g., cryptococcosis); Chagas disease; bacterial abscess; and rarely PML, which can be distinguished on the basis of imaging studies (PML lesions typically involve white matter rather than gray matter, are noncontrast enhancing, and produce no mass effect).

The majority of clinicians rely initially on an empiric diagnosis, which can be established as an objective response, on the basis of 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. In patients with contrast-enhancing mass lesions, detection of Epstein-Barr virus (EBV) by PCR in CSF is highly suggestive of CNS lymphoma (198Antinori A, Ammassari A, De Luca A, et al. Diagnosis of AIDS-related focal brain lesions: a decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF. Neurology 1997;48:687-94., 199Antinori A, De Rossi G, Ammassari A. Value of combined approach with thallium-201 single-photon emission computed tomography and Epstein-Barr virus DNA polymerase chain reaction in CSF for the diagnosis of AIDS-related primary CNS lymphoma. J Clin Oncol 1999;17:554-60.). Positron emission tomography (PET) (192Pierce MA, Johnson MD, Maciunas RJ, et al. Evaluating contrast-enhancing brain lesions in patients with AIDS by using positron emission tomography. Ann Intern Med 1995;123:594-8.) or single-photon emission computed tomography (SPECT) scanning (193Ruiz A, Ganz WI, Post MJ, et al. Use of thallium-201 brain SPECT to differentiate cerebral lymphoma from toxoplasma encephalitis in AIDS patients. Am J Neuroradiol 1994;15:1885-94.) might be helpful for distinguishing between TE and primary CNS lymphoma, but no imaging technique is completely specific.

Preventing Exposure

HIV-infected persons should be tested for IgG antibody to Toxoplasma soon after the diagnosis of HIV infection to detect latent infection with T. gondii (BIII).

HIV-infected persons, including those who lack IgG antibody to Toxoplasma, should be counseled regarding sources of Toxoplasma infection. To minimize risk for acquiring toxoplasmosis, HIV-infected persons should be advised not to eat raw or undercooked meat, including undercooked lamb, beef, pork, or venison (BIII). Specifically, lamb, beef, venison, and pork should be cooked to an internal temperature of 165°F-170°F (200Department of Agriculture. FoodSafety.gov: gateway to government food safety information. www.foodsafety.gov. Last accessed December 22, 2008.); meat cooked until it is no longer pink inside usually has an internal temperature of 165°F-170°F and therefore, from a more practical perspective, satisfies this requirement. To minimize the risk for acquiring toxoplasmosis, HIV-infected persons should wash their hands after contact with raw meat and after gardening or other contact with soil; in addition, they should wash fruits and vegetables well before eating them raw (BIII). If the patient owns a cat, the litter box should be changed daily, preferably by an HIV-negative, nonpregnant person; alternatively, patients should wash their hands thoroughly after changing the litter box (BIII). Patients 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 need not be advised to part with their cats or to have their cats tested for toxoplasmosis (EII).

Preventing Disease
Initiating Primary Prophylaxis

Toxoplasma-seropositive patients who have a CD4+ count of <100 cells/µL should be administered prophylaxis against TE (AII) (113Carr A, Tindall B, Brew BJ, et al. Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS. Ann Intern Med 1992; 117:106-11.). The double-strength tablet daily dose of TMP-SMX recommended as the preferred regimen for PCP prophylaxis also is effective against TE and is therefore recommended (AII) (113Carr A, Tindall B, Brew BJ, et al. Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS. Ann Intern Med 1992; 117:106-11.). 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) (117Podzamczer D, Salazar A, Jimenez J, et al. Intermittent trimethoprim-sulfamethoxazole compared with dapsone-pyrimethamine for the simultaneous primary prophylaxis of Pneumocystis pneumonia and toxoplasmosis in patients infected with HIV. Ann Intern Med 1995;122:755-61., 118Opravil M, Hirschel B, Lazzarin A, et al. Once-weekly administration of dapsone/pyrimethamine vs. aerosolized pentamidine as combined prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus-infected patients. Clin Infect Dis 1995;20:531-41., 119Girard PM, Landman R, Gaudebout C, et al. Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. N Engl J Med 1993;328:1514-20.). Atovaquone with or without pyrimethamine/leucovorin also can be considered (CIII). Prophylactic monotherapy with dapsone, pyrimethamine, azithromycin, or clarithromycin cannot be recommended on the basis of available data (DII). Aerosolized pentamidine does not protect against TE and is not recommended (EI) (109Bozzette SA, Finkelstein DM, Spector SA, et al. A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. N Engl J Med 1995;332:693-9., 113Carr A, Tindall B, Brew BJ, et al. Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS. Ann Intern Med 1992; 117:106-11.).

Toxoplasma-seronegative persons who are not taking a PCP prophylactic regimen known to be active against TE (e.g., aerosolized pentamidine) should be retested for IgG antibody to Toxoplasma when their CD4+ counts decline to <100 cells/µL to determine whether they have seroconverted and are therefore at risk for TE (CIII). Patients who have seroconverted should be administered prophylaxis for TE as described previously (AII).

Discontinuing Primary Prophylaxis

Prophylaxis against TE should be discontinued among adult and adolescent patients who have responded to ART with an increase in CD4+ counts to >200 cells/µL for >3 months (AI). Multiple observational studies (126Dworkin MS, Hanson DL, Kaplan JE, Jones JL, Ward JW. Risk for preventable opportunistic infections in persons with AIDS after antiretroviral therapy increases CD4+ T lymphocyte counts above prophylaxis thresholds. J Infect Dis 2000;182:611-5., 132Kirk O, Lundgren JD, Pedersen C, Nielsen H, Gerstoft J. Can chemoprophylaxis against opportunistic infections be discontinued after an increase in CD4 cells induced by highly active antiretroviral therapy? AIDS 1999;13:1647-51., 201Furrer H, Opravil M, Bernasconi E, Telenti A, Egger M. Stopping primary prophylaxis in HIV-1-infected patients at high risk of toxoplasma encephalitis. Lancet 2000;355:2217-8.) and two randomized trials (127Mussini C, Pezzotti P, Govoni A, et al. Discontinuation of primary prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus type I-infected patients: the changes in opportunistic prophylaxis study. J Infect Dis 2000;181:1 635-42., 202Miro JM, Lopez JC, Podzamczer D, et al. Discontinuation of primary and secondary Toxoplasma gondii prophylaxis is safe in HIV-infected patients after immunological restoration with highly active antiretroviral therapy: results of an open, randomized, multicenter clinical trial. Clin Infect Dis 2006;43:79-89.) have reported that primary prophylaxis can be discontinued with minimal risk for developing TE among patients who have responded to ART with an increase in CD4+ count from <200 cells/µL to >200 cells/µL for >3 months. In these studies, the majority of patients were taking PI-containing regimens and the median CD4+ count at the time prophylaxis was discontinued was >300 cells/µL. At the time prophylaxis was discontinued, the majority of patients had sustained suppression of plasma HIV RNA levels below the detection limits of available assays; the median follow-up was 7-22 months. Although patients with CD4+ counts of <100 cells/µL are at greatest risk for having TE, the risk for TE occurring when the CD4+ count has increased to 100-200 cells/µL has not been studied as rigorously as an increase to >200 cells/µL. Thus, the recommendation specifies discontinuing prophylaxis after an increase to >200 cells/µL. Discontinuing primary TE prophylaxis is recommended because prophylaxis at CD4+ count >200 cells/ µL adds limited disease prevention for toxoplasmosis and because discontinuing drugs reduces pill burden, potential for drug toxicity, drug interaction, selection of drug-resistant pathogens, and cost. Prophylaxis for TE should be reintroduced if the CD4+ count decreases to <100-200 cells/µL (AIII).

Treatment of Disease

The initial therapy of choice for TE consists of the combination of pyrimethamine plus sulfadiazine plus leucovorin (AI) (203Katlama C, De Wit S, O'Doherty E, Van Glabeke M, Clumeck N. Pyrimethamine-clindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with AIDS. Clin Infect Dis 1996; 22:268-75., 204Dannemann B, McCutchan JA, Israelski D, et al. Treatment of toxoplasmic encephalitis in patients with AIDS. a randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. Ann Intern Med 1992;116:33-43., 206Luft BJ, Hafner R, Korzun AH, et al. Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome. N Engl J Med 1993;329:995-1000.). Pyrimethamine penetrates the brain parenchyma efficiently even in the absence of inflammation (207Leport C, Meulemans A, Robine D, Dameron G, Vilde JL. Levels of pyrimethamine in serum and penetration into brain tissue in humans. AIDS 1992;6:1040-1.). Use of leucovorin reduces the likelihood of the hematologic toxicities associated with pyrimethamine therapy (208Van Delden C, Hirschel B. Folinic acid supplements to pyrimethamine-sulfadiazine for Toxoplasma encephalitis are associated with better outcome. J Infect Dis 1996;173:1294-5., 209Frenkel JK, Hitchings GH. Relative reversal by vitamins (p-aminobenzoic, folic, and folinic acids) of the effects of sulfadiazine and pyrimethamine on Toxoplasma, mouse and man. Antibiotic Chemotherapy 1957:7:630-8.). 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) (203Katlama C, De Wit S, O'Doherty E, Van Glabeke M, Clumeck N. Pyrimethamine-clindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with AIDS. Clin Infect Dis 1996; 22:268-75., 204Dannemann B, McCutchan JA, Israelski D, et al. Treatment of toxoplasmic encephalitis in patients with AIDS. a randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. Ann Intern Med 1992;116:33-43.).

TMP-SMX was reported in a small (77 patients) randomized trial to be effective and better tolerated than pyrimethamine-sulfadiazine (210Torre D, Casari S, Speranza F, et al. Randomized trial of trimethoprim-sulfamethoxazole versus pyrimethamine-sulfadiazine for therapy of toxoplasmic encephalitis in patients with AIDS. Antimicrob Agents Chemother 1998;42:1346-9.). On the basis of less in vitro activity and less experience with TMP-SMX, treatment with this drug may be considered an option (BI). For patients who cannot take an oral regimen, no well-studied options exist. No parenteral formulation of pyrimethamine exists; the only widely available parenteral sulfonamide is the sulfamethoxazole component of TMP-SMX. Certain specialists will treat severely ill patients initially requiring parenteral therapy for TE with parenteral TMP-SMX or oral pyrimethamine plus parenteral clindamycin (CIII).

The following regimens have been show to be effective in the treatment of TE in at least two nonrandomized, uncontrolled trials, although their relative efficacy compared with the previous regimens is unknown: atovaquone (with meals or oral nutritional supplements) plus either pyrimethamine plus leucovorin or sulfadiazine or, for patients intolerant of both pyrimethamine and sulfadiazine, as a single agent (BII) (211Chirgwin K, Hafner R, Leport C, et al. Randomized phase II trial of atovaquone with pyrimethamine or sulfadiazine for treatment of toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome. Clin Infect Dis 2002;34:1243-50., 212Kovacs JA. Efficacy of atovaquone in treatment of toxoplasmosis in patients with AIDS. Lancet 1992;340:637-8., 213Torres RA, Weinberg W, Stansell J, et al. Atovaquone for salvage treatment and suppression of toxoplasmic encephalitis in patients with AIDS. Clin Infect Dis 1997;24:422-9., 214Katlama C, Mouthon B, Gourdon D, Lapierre D, Rousseau F. Atovaquone as long-term suppressive therapy for toxoplasmic encephalitis in patients with AIDS and multiple drug intolerance. AIDS 1996;10:1107-12.) (if atovaquone is used alone, clinicians should be aware that different patients experience a high variability of absorption of the drug; plasma levels of >18.5 µg/mL are associated with an improved response rate but measurements are not routinely available) (212-214); and azithromycin plus pyrimethamine plus leucovorin daily (BII) (215Saba J, Morlat P, Raffi F, et al. Pyrimethamine plus azithromycin for treatment of acute toxoplasmic encephalitis in patients with AIDS. Eur J Clin Microbiol Infect Dis 1993;12:853-6., 216Jacobsen J, Hafner R, Remington J, et al. Dose-escalation, phase I/II study of azithromycin and pyrimethamine for the treatment of toxoplasmic encephalitis in AIDS. AIDS 2001;15:583-9.).

The following regimens have been reported to have activity in the treatment of TE in small cohorts of patients or in case reports of one or several patients: clarithromycin plus pyrimethamine (CIII) (217Fernandez-Martin J, Leport C, Morlat P, Meyohas MC, Chauvin JP, Vilde JL. Pyrimethamine-clarithromycin combination for therapy of acute Toxoplasma encephalitis in patients with AIDS. Antimicrob Agents Chemother 1991;35:2049-52.); 5-fluorouracil plus clindamycin (CIII) (218Dhiver C, Milandre C, Poizot-Martin I, et al. 5-Fluoro-uracil-clindamycin for treatment of cerebral toxoplasmosis. AIDS 1993;7:143-4.), dapsone plus pyrimethamine plus leucovorin (CIII) (219Derouin F, Piketty C, Chastang C, Chau et al. Anti-Toxoplasma effects of dapsone alone and combined with pyrimethamine. Antimicrob Agents Chemother 1991;35:252-5.); and minocycline or doxycycline combined with either pyrimethamine plus leucovorin, sulfadiazine, or clarithromycin (CIII) (220Lacassin F, Schaffo D, Perronne C, et al. Clarithromycin-minocycline combination as salvage therapy for toxoplasmosis in patients infected with human immunodeficiency virus. Antimicrob Agents Chemother 1995;39:276-7., 221Hagberg L, Palmertz B, Lindberg J. Doxycycline and pyrimethamine for toxoplasmic encephalitis. Scand J Infect Dis 1993;25:157-60.). 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 MAC. Doses >500 mg twice a day should not be used (DIII).

Acute therapy for TE should be continued for at least 6 weeks, if there is clinical and radiologic improvement (BII) (184Luft BJ, Conley F, Remington JS, et al. Outbreak of central-nervous-system toxoplasmosis in Western Europe and North America. Lancet 1983;1:781-4., 185Luft BJ, Brooks RG, Conley FK. Toxoplasmic encephalitis in patients with acquired immune deficiency syndrome. JAMA 1984;252:913-7., 186Wong B, Gold JW, Brown AE, et al. Central-nervous-system toxoplasmosis in homosexual men and parenteral drug abusers. Ann Intern Med 1984;100:36-42., 187Israelski DM, Chmiel JS, Poggensee L, Phair JP, Remington JS. Prevalence of Toxoplasma infection in a cohort of homosexual men at risk of AIDS and toxoplasmic encephalitis. J Acquir Immune Defic Syndr 1993;6:414-8.). Longer courses might be appropriate if clinical or radiologic disease is extensive or response is incomplete at 6 weeks. CNS lesions must not have contrast enhancement on CT/MRI. Adjunctive corticosteroids (e.g., dexamethasone) should be administered to patients with TE when clinically indicated only for treatment of a mass effect associated with focal lesions or associated edema (BIII). Because of the potential immunosuppressive effects of corticosteroids, they should be discontinued as soon as clinically feasible. Patients receiving corticosteroids should be monitored closely for the development of other OIs, including cytomegalovirus (CMV) retinitis and TB disease.

Anticonvulsants should be administered to patients with TE who have a history of seizures (AIII), but should not be administered as prophylactics to all patients (DIII). Anticonvulsants, if administered, should be continued at least through the period of acute therapy.

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (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 include rash, nausea, and bone marrow suppression (neutropenia, anemia, and thrombocytopenia) that can often be reversed by increasing the dose of leucovorin to 50-100 mg/day administered in divided doses (CIII).

Common sulfadiazine toxicities include rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea, 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. Drug interactions between anticonvulsants and antiretroviral agents should be evaluated carefully and doses adjusted according to established guidelines.

Several cases of neurologic disease have been attributed to immune reconstitution and toxoplasmosis, but more data are needed to verify that such cases are IRIS related to T. gondii (222Lawn SD, Myer L, Bekker LG, Wood R. Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa. AIDS 2007;21:335-41.).

Management of Treatment Failure

A brain biopsy, if not previously performed, should be strongly considered for patients 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 lack of clinical improvement within 2 weeks. For those who undergo brain biopsy and have confirmed histopathologic evidence of TE, a switch to an alternative regimen as previously described should be considered (BIII). Recurrence of disease during secondary maintenance therapy following an initial clinical and radiographic response is unusual if patients adhere to their regimens.

Preventing Recurrence

Patients who have completed initial therapy for TE should be administered lifelong suppressive therapy (i.e., secondary prophylaxis or chronic maintenance therapy) (AI) (203Katlama C, De Wit S, O'Doherty E, Van Glabeke M, Clumeck N. Pyrimethamine-clindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with AIDS. Clin Infect Dis 1996; 22:268-75., 204Dannemann B, McCutchan JA, Israelski D, et al. Treatment of toxoplasmic encephalitis in patients with AIDS. a randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. Ann Intern Med 1992;116:33-43.) unless immune reconstitution occurs as a consequence of ART, in which case discontinuation of treatment 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 when using the same total daily dose in a twice a day or four times a day regimen (223Jordan MK, Burstein AH, Rock-Kress D, et al. Plasma pharmacokinetics of sulfadiazine administered twice daily versus four times daily are similar in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2004;48:635-7.), and limited clinical experience suggests that twice a day dosing is effective (224Podzamczer D, Miro JM, Ferrer E, et al. Thrice-weekly sulfadiazine-pyrimethamine for maintenance therapy of toxoplasmic encephalitis in HIV-infected patients. Eur J Clin Microbiol Infect Dis 2000;19:89-95.). A commonly used regimen as suppressive therapy for patients with TE who cannot tolerate sulfa drugs is pyrimethamine plus clindamycin (BI). Because of the high failure rate observed with lower doses (203Katlama C, De Wit S, O'Doherty E, Van Glabeke M, Clumeck N. Pyrimethamine-clindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with AIDS. Clin Infect Dis 1996; 22:268-75.), a dose of 600 mg clindamycin every 8 hours is recommended (CIII). However, this regimen does not provide protection against PCP (AII), and thus an additional agent (e.g., aerosol pentamidine) must be used. Atovaquone with or without pyrimethamine or sulfadiazine is also active against both TE and PCP (BII) but is substantially more expensive (121). 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 (225Duval X, Pajot O, Le Moing V, et al. Maintenance therapy with cotrimoxazole for toxoplasmic encephalitis in the era of highly active antiretroviral therapy. AIDS 2004; 18:1342-4.).

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

Adult and adolescent patients receiving secondary prophylaxis (i.e., chronic maintenance therapy) for TE are at low risk for recurrence of TE when they have successfully completed initial therapy for TE, remain asymptomatic with regard to signs and symptoms of TE, and have a sustained increase in their CD4+ counts of >200 cells/µL after ART (e.g., >6 months) (132Kirk O, Lundgren JD, Pedersen C, Nielsen H, Gerstoft J. Can chemoprophylaxis against opportunistic infections be discontinued after an increase in CD4 cells induced by highly active antiretroviral therapy? AIDS 1999;13:1647-51., 168Soriano V, Dona C, Rodriguez-Rosado R, Barreiro P, Gonzalez-Lahoz J. Discontinuation of secondary prophylaxis for opportunistic infections in HIV-infected patients receiving highly active antiretroviral therapy. AIDS 2000;14:383-6., 202Miro JM, Lopez JC, Podzamczer D, et al. Discontinuation of primary and secondary Toxoplasma gondii prophylaxis is safe in HIV-infected patients after immunological restoration with highly active antiretroviral therapy: results of an open, randomized, multicenter clinical trial. Clin Infect Dis 2006;43:79-89., 226Bertschy S, Opravil M, Cavassini M, et al. Discontinuation of maintenance therapy against Toxoplasma encephalitis in AIDS patients with sustained response to anti-retroviral therapy. Clin Microbiol Infect 2006;12:666-71.). Although the numbers of patients who have been evaluated in observational studies and in one randomized clinical trial remain limited, and occasional recurrences have been reported, on the basis of these observations and inference from more extensive cumulative data indicating the safety of discontinuing secondary prophylaxis for other OIs during advanced HIV disease, discontinuing chronic maintenance therapy among such patients is a reasonable consideration (BI). Certain specialists recommend obtaining an MRI of the brain as part of their evaluation to determine whether discontinuing therapy is appropriate by assessing whether the brain lesions had resolved.

Secondary prophylaxis (chronic maintenance therapy) for TE should be reintroduced if the CD4+ count decreases to <200 cells/µL (AIII).

Special Considerations During Pregnancy

Documentation of maternal T. gondii serologic status should be obtained during pregnancy. Indications for treatment of T. gondii during pregnancy should be based on confirmed or suspected symptomatic disease in the mother. Pediatric-care providers should be informed if the HIV-infected mother is seropositive for T. gondii infection to allow evaluation of the neonate for evidence of congenital infection. Pregnant HIV-infected women with suspected or confirmed primary T. gondii infection during pregnancy should be managed in consultation with a maternal-fetal medicine or other appropriate specialist (BIII) (227Mitchell CD, Erlich SS, Mastrucci MT, Hutto SC, Parks WP, Scott GB. Congenital toxoplasmosis occurring in infants perinatally infected with human immunodeficiency virus 1. Pediatr Infect Dis J 1990;9:512-8.).

Treatment should be the same as in nonpregnant adults (BIII). Although pyrimethamine has been associated with birth defects in animals, limited human data have not suggested an increased risk for defects and, therefore, it can be administered to pregnant women (228Deen JL, von Seidlein L, Pinder M, Walraven GE, Greenwood BM. The safety of the combination artesunate and pyrimethamine-sulfadoxine given during pregnancy. Trans R Soc Trop Med Hyg 2001;95:424-8., 229Dunn CS, Beyer C, Kieny MP, et al. High viral load and CD4 lymphopenia in rhesus and cynomolgus macaques infected by a chimeric primate lentivirus constructed using the env, rev, tat, and vpu genes from HIV-1 Lai. Virology 1996;223:351-61., 230Wong SY, Remington JS: Toxoplasmosis in pregnancy. Clin Infect Dis 1994;18:853-61.). Pediatric providers should be notified if sulfadiazine is continued until delivery because its use might increase the risk for neonatal hyperbilirubinemia and kernicterus (230Wong SY, Remington JS: Toxoplasmosis in pregnancy. Clin Infect Dis 1994;18:853-61.).

Although perinatal transmission of T. gondii normally occurs only with acute infection in the immunocompetent host, case reports have documented occurrences of transmission with reactivation of chronic infection in HIV-infected women with severe immunosuppression (229Dunn CS, Beyer C, Kieny MP, et al. High viral load and CD4 lymphopenia in rhesus and cynomolgus macaques infected by a chimeric primate lentivirus constructed using the env, rev, tat, and vpu genes from HIV-1 Lai. Virology 1996;223:351-61., 231Dunn DT, Newell ML, Gilbert R, et al. Low incidence of congenital toxoplasmosis in children born to women infected with human immunodeficiency virus. Eur J Obstet Gynecol Reprod Biol 1996;68:93-6.). Pregnant, HIV-infected women who have evidence of primary toxoplasmic infection or active toxoplasmosis, including TE, should be evaluated and managed during pregnancy in consultation with appropriate specialists (BIII). Because the risk for transmission with chronic infection appears low, routine evaluation of the fetus for infection with amniocentesis or cordocentesis is not indicated. 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.

TMP-SMX can be administered for primary prophylaxis against TE as described for PCP (AIII). Secondary prophylaxis should be provided using the same indications as for nonpregnant women. The risks of TMP-SMX in the first trimester, as discussed for PCP, must be balanced against the risk for recurrent TE.

Prophylaxis to prevent first episode of opportunistic disease: Toxoplasma gondii encephalitis
IndicationFirst choiceAlternative
Abbreviations: DS = double strength; SS = single strength
Toxoplasma IgG positive patients with CD4+ count <100 cells/µL (AII)

Seronegative patients receiving PCP prophylaxis not active against toxoplasmosis should have toxoplasma serology retested if CD4+ count decline to <100 cells/µL (CIII)

Prophylaxis should be initiated if seroconversion occurred (AII)

TMP-SMX, 1 DS PO daily (AII)
transparent gifgrey bulletTMP-SMX 1 DS PO tiw (BIII); or
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transparent gifgrey bulletTMP-SMX 1 SS PO daily (BIII);
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transparent gifgrey bulletDapsone 50 mg PO daily + pyrimethamine 50 mg PO weekly + leucovorin 25 mg PO weekly (BI); or
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transparent gifgrey bullet(Dapsone 200 mg + pyrimethamine 75 mg + leucovorin 25 mg) PO weekly (BI);
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transparent gifgrey bullet(Atovaquone 1,500 mg +/- pyrimethamine 25 mg + leucovorin 10 mg) PO daily (CIII)
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Drug therapy for treatment and chronic maintenance therapy of AIDS-associated opportunistic infections in adults and adolescents: Toxoplasma gondii encephalitis (TE)
Preferred therapy, duration of therapy, chronic maintenanceAlternative therapyOther options/issues
* Pyrimethamine and leucovorin doses as the same as in "Preferred therapy" for toxoplasmosis.
Preferred therapy
transparent gifgrey bulletPyrimethamine 200 mg PO x 1, then 50 mg (<60 kg) to 75 mg (≥60 kg) PO daily plus sulfadiazine 1,000 mg (<60 kg) to 1,500 mg (≥60 kg) PO q6h plus leucovorin 10-25 mg PO daily (can increase 50 mg) (AI)
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Duration for acute therapy
transparent gifgrey bulletAt least 6 weeks (BII); longer duration if clinical or radiologic disease is extensive or response is incomplete at 6 weeks
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Alternative therapy regimens
transparent gifgrey bulletPyrimethamine (leucovorin)* plus clindamycin 600 mg IV or PO q6h (AI); or
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transparent gifgrey bulletTMP-SMX (5 mg/kg TMP and 25 mg/kg SMX) IV or PO bid (BI); or
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transparent gifgrey bulletAtovaquone 1,500 mg PO bid with food (or nutritional supplement) plus pyrimethamine (leucovorin)* (BII); or
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transparent gifgrey bulletAtovaquone 1,500 mg PO bid with food - (or nutritional supplement) plus sulfadiazine 1,000-1,500 mg PO q6h (BII); or
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transparent gifgrey bulletAtovaquone 1,500 mg PO bid with food (BII); or
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transparent gifgrey bulletPyrimethamine (leucovorin)* plus azithromycin 900-1,200 mg PO daily (BII)
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Adjunctive corticosteroids (e.g., dexamethasone) should be administered when clinically indicated only for treatment of mass effect attributed to 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 the acute treatment; but should not be used prophylactically (DIII)
Preferred chronic maintenance therapy
transparent gifgrey bulletPyrimethamine 25-50 mg PO daily plus sulfadiazine 2,000-4,000 mg PO daily (in two to four divided doses) plus leucovorin 10-25 mg PO daily (AI)
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Alternative chronic maintenance therapy/secondary prophylaxis
transparent gifgrey bulletClindamycin 600 mg PO q8h plus pyrimethamine 25-50 mg PO daily plus leucovorin 10-25 PO daily (BI) [should add additional agent to prevent PCP (AII)]; or
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transparent gifgrey bulletAtovaquone 750 mg PO q6h-q12h +/- ([pyrimethamine 25 mg PO daily plus leucovorin 10 mg PO daily] or sulfadiazine 2,000-4,000 mg PO) daily (BII)
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