Toxoplasmosis can affect various organ systems, but in HIV-infected patients it most commonly manifests itself as CNS toxoplasmosis, a leading cause of focal central nervous system (CNS) disease in AIDS.[1] CNS toxoplasmosis in HIV-infected patients usually is a complication of the advanced phase of the disease.
Primary infection with Toxoplasma gondii can occur in up to 50% of individuals even without conventional risk factors. Additionally, the infection can be transmitted congenitally, or less commonly, through organ transplants or blood transfusions. It is important to note that the organism does not spread through direct person-to-person contact.[1]
Typically, lesions are found in the brain, and their effects dominate the clinical presentation. Rarely, intraspinal lesions need to be considered in the differential diagnosis of myelopathy.
The decision to treat a patient for CNS toxoplasmosis usually is empiric. Primary therapy is followed by long-term suppressive therapy, which is continued until antiretroviral therapy can raise CD4+ counts above 200 cells/µL.[1]
Prognosis is guarded. Patients may relapse because of noncompliance or increasing dose requirements.
Toxoplasma gondii, a protozoan parasite, is transmitted to humans primarily through the ingestion of contaminated food and water. The most common sources of infection include undercooked meats, unwashed fruits or vegetables, and unpasteurized milk. Additionally, humans can become infected by ingesting oocysts from cat feces that have undergone sporulation in the environment, a process that takes a minimum of 24 hours to complete.[1, 2] T gondii usually causes asymptomatic or mild acute disease, and remains dormant in latent phase in healthy immunocompetent hosts. CNS toxoplasmosis almost always is due to reactivation of a latent infection in an immunocompromised host. CNS disease occurs during advanced HIV infection when CD4+ counts are less than 200 cells/µL. The greatest risk is in patients with CD4+ counts less than 50 cells/µL.[1] CNS toxoplasmosis rarely results from primary infection.[3]
The seroprevalence of anti-Toxoplasma antibodies, indicating prior infection, varies significantly based on geography and demographics.[4] In the United States, the overall prevalence is approximately 11%, compared to 40-80% in certain regions of Europe, Latin America, Asia, and Africa.[1] The incidence and prevalence of CNS toxoplasmosis, a condition associated with HIV, also vary by geographic area and demographics, with an increased risk observed with age due to higher exposure over time.
Before the widespread use of antiretroviral therapy (ART), the 12-month incidence of toxoplasmic encephalitis (TE) was about 33% among patients with advanced immunodeficiency who were seropositive for T gondii and did not receive prophylaxis.[5] In contrast, a very low incidence of toxoplasmosis was noted in HIV-positive individuals who were seronegative for T gondii, suggesting primary infection, reactivation of latent disease in those unable to produce detectable antibodies, or the use of insensitive assays.
In the United States, clinical CNS toxoplasmosis occurs in 3-15% of individuals with AIDS, with 789 deaths recorded over an 11-year period from 2000 to 2010.[6] However, in some European countries and Africa, clinical CNS toxoplasmosis occurs in as many as 50–75% of patients. The probability of developing reactivated toxoplasmosis is as high as 30% among AIDS patients with a CD4 count below 100 cells/microL who are toxoplasma seropositive and not receiving effective prophylaxis or ART.[6] The central nervous system is the most common site of reactivation.
An epidemiologic study in Mexico City involving 320 AIDS patients highlighted brain toxoplasmosis as the main condition related to HIV/AIDS, affecting 42% of the cohort. Other conditions included cerebral cryptococcosis (28%), tuberculous meningitis (8.7%), non-Hodgkin lymphoma (3.75%), acute HIV infection (3.4%), and AIDS dementia complex (3%).[7]
The introduction and widespread use of ART have significantly decreased the incidence of toxoplasmic encephalitis. For instance, in the United States, annual toxoplasmosis-related hospitalizations peaked at over 10,000 in 1995 but dropped sharply to 3643 in 2001 and further decreased to 2985 by 2008.[5]
In individuals with HIV, clinical disease related to Toxoplasma gondii infection primarily manifests as focal encephalitis, characterized by a subacute onset of headache, focal neurologic deficits such as hemiparesis, and sometimes fever.[1] Non-focal encephalitis also may occur, presenting with isolated headache and generalized seizures. Physical examination can reveal focal neurologic abnormalities, and without treatment, the disease may progress to seizures, stupor, coma, and death.
Computed tomography (CT) scans or magnetic resonance imaging (MRI) of the brain, following intravenous contrast administration, typically reveal multiple contrast-enhancing lesions, often located in the basal ganglia, accompanied by edema and associated mass effect.[1] In rarer cases, toxoplasmosis can manifest as a single brain lesion or as diffuse encephalitis without focal brain lesions on imaging, which tends to be rapidly progressive and fatal.[1]
The risk for clinical disease increases significantly with immunodeficiency, particularly in people with HIV who have CD4 T lymphocyte (CD4) cell counts below 50 cells/mm3, whereas it is rare in those with CD4 counts above 200 cells/mm3.[1] CNS toxoplasmosis typically begins with encephalitis, constitutional symptoms, and headache. Fever is common but not universal. As the condition progresses, patients may experience confusion, drowsiness, seizures, focal weakness, and language disturbances, eventually progressing to coma within days to weeks if untreated.
Extracerebral manifestations of toxoplasmosis, such as pneumonitis and chorioretinitis, also can occur, though they are less common in people with HIV. On physical examination, changes in personality and mental status, as well as seizures, hemiparesis, hemianopia, aphasia, ataxia, and cranial nerve palsies may be observed. Occasionally, symptoms and signs of radiculomyelopathy may predominate.
In patients with AIDS, the differential diagnosis for CNS lesions exhibiting mass effect predominantly encompasses primary CNS lymphoma, tuberculosis, and endemic fungal infections, such as cryptococcosis.[1] Radiologically, lymphoma may resemble toxoplasmic encephalitis (TE), as both pathologies often present with ring-enhancing lesions; however, lymphoma more typically is associated with solitary lesions. Excluding cases involving immune reconstitution inflammatory syndrome (IRIS), progressive multifocal leukoencephalopathy (PML) can be distinguished by its imaging features. PML predominantly involves the white matter, typically does not enhance with contrast, and lacks associated mass effect. Other less frequent causes of focal neurologic disorders in individuals with AIDS include Chagas disease, metastatic tumors, and pyogenic brain abscesses, especially prevalent among intravenous drug users.
The differential diagnosis of CNS toxoplasmosis includes the following:
Serologic studies in patients with CNS toxoplasmosis may demonstrate rising titers of anti-toxoplasma immunoglobulin G (IgG) antibodies. An immunoglobulin M (IgM) antibody response is seen in cases of newly acquired toxoplasmosis or Toxoplasma encephalitis for up to a year.[8, 1]
However, anti-Toxoplasmagondii IgG detection may be unreliable in immunodeficient individuals who fail to produce significant titers of specific antibodies. In one study, 16% of patients with a clinical diagnosis and 22% of patients with a histologic diagnosis of toxoplasmosis had undetectable anti-T gondii IgG levels. Causes of false-negative results also include recent infection and insensitive assays.
Definitive diagnosis of CNS toxoplasmosis requires the following[1] :
Compatible clinical findings
Identification of one or more mass lesions by CT, MRI, or other radiographic testing
Detection of T gondii in a clinical sample
Detection of T gondii DNA on polymerase chain reaction (PCR) testing of cerebrospinal fluid (CSF) samples may facilitate the diagnosis and follow-up of toxoplasmosis in patients with AIDS.[9] In a study using the B1 gene, rapid PCR showed a sensitivity of 83.3% and specificity of 95.7%.[10]
CSF findings also may include elevated protein and variable glucose and WBC counts. The presence of Epstein-Barr virus DNA in the CSF favors the diagnosis of lymphoma.
Lumbar puncture
If clinically appropriate and safe, lumbar puncture is recommended for the detection of T gondii via PCR, along with cytology, culture, and PCR testing for Mycobacterium tuberculosis, Epstein-Barr virus (EBV), JC virus (JCV), cytomegalovirus, and varicella-zoster virus. Additional assays for cryptococcal antigen and syphilis should be considered based on radiological findings. The PCR assay for T gondii in cerebrospinal fluid (CSF) demonstrates high specificity (96% to 100%) but exhibits limited sensitivity (50%), particularly after the commencement of targeted anti-Toxoplasma therapy.[1]
However, lumbar puncture may be contraindicated in cases of elevated intracranial pressure. Therefore, CNS toxoplasmosis often necessitates an empiric diagnosis, reliant on clinical and radiographic response to specific anti-T gondii treatment. In instances where therapeutic response is inadequate, a brain biopsy may be necessary to obtain a definitive clinical sample for diagnostic testing.[1]
In imaging studies, toxoplasmosis typically appears as contrast-enhancing lesions, often ring-enhancing, with a preference for the basal ganglia.[1] MRI is more sensitive than CT and is recommended for patients with inconclusive or negative CT results. Positron emission tomography and single-photon emission CT scanning can aid in differentiating toxoplasmic encephalitis (TE) from primary CNS lymphoma; however, no imaging modality is entirely specific. Diagnosis of TE requires detection of the organism, either through a stereotactic brain biopsy or a positive CSF PCR test. Although hematoxylin and eosin stains are used for identifying T gondii in biopsy samples, immunoperoxidase staining significantly enhances sensitivity, particularly when processed in experienced laboratories.
A brain CT scan or MRI with and without contrast is indicated for all patients presenting with altered mental status, headaches, seizures, or focal neurologic signs. MRI clearly is the superior technique but is not available universally.
Single or multiple hypodense or hypointense lesions in white matter and basal ganglia with mass effects may be observed on CT or MRI scans. Lesions may enhance in a homogeneous or ring pattern with contrast (see the images below). Imaging studies may be normal in diffuse toxoplasmosis.
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T1-weighted MRI after gadolinium contrast shows a hyperintense lesion in the left cerebellar hemisphere.
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T2-weighted MRI demonstrates intense edema surrounding the lesion.
Single lesions favor the diagnosis of lymphoma over that of toxoplasmosis. However, while multiple lesions are more common than single lesions in toxoplasmosis, in one study 27% of patients had a single lesion on CT scan. In the same study, 14% had a single lesion on MRI. MRI is more sensitive than CT scan in detecting multiple lesions.
Several MRI patterns have been described in cerebral toxoplasmosis. A concentric target sign is a recently described MRI sign on T2-weighted imaging of cerebral toxoplasmosis; it has concentric alternating zones of hypointensity and hyperintensity.[11]
If the initial imaging study is normal or shows atrophy or focal signal abnormalities (but no mass lesion), diagnostic consideration should be given to meningitides, AIDS dementia complex, or progressive multifocal leukoencephalopathy.
If imaging shows one or more focal mass lesions with impending herniation, an open biopsy with decompression is indicated. Treatment for lymphoma, toxoplasmosis, or other opportunistic infections and neoplasms is initiated, depending on biopsy results.
If imaging shows one or more focal mass lesions without impending herniation, additional studies are warranted.
Scintigraphy
Magnetic resonance spectroscopy (MRS) was not found helpful in differentiating CNS lymphoma from nonmalignant CNS lesions in HIV-infected patients, particularly CNS toxoplasmosis.[12]
Given the inherent risks and the difficulty in performing brain biopsies at many medical facilities, a presumptive diagnosis of toxoplasmic encephalitis (TE) typically is based on the patient's response to empiric therapy.[1] A brain biopsy generally is reserved for cases where patients do not show improvement with specific anti-Toxoplasma treatment. However, consideration for an earlier biopsy is advised if diagnostic tests such as imaging, serology, or CSF PCR fail to confirm toxoplasmosis or suggest an alternative diagnosis.
In scenarios where patients exhibit contrast-enhancing lesions and Epstein-Barr virus (EBV) is detected in the CSF by PCR—especially when the EBV load exceeds 10,000 copies/mL—clinicians should consider CNS lymphoma as a potential diagnosis, although this alone does not confirm the disease. For individuals with HIV on antiretroviral therapy (ART) who present with contrast-enhancing lesions, the detection of JC virus (JCV) by PCR in the CSF is highly indicative of progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome (PML-IRIS).
Indications for brain biopsy include either of the following:
Single mass lesion and negative serologic results
No response to 14 days of empiric therapy
Diagnostic yield of stereotactic biopsies increases with the number of specimens obtained.
Histologic findings include the following (also see the images below):
Toxoplasma gondii abscesses are seen on this brain slice. Contributed by Dr Beth Levy, Saint Louis University School of Medicine, St Louis, Missouri.
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High-magnification photomicrograph shows a tissue cyst and tachyzoites in the brain parenchyma. Contributed by Dr Beth Levy, Saint Louis University Sc....
Due to the cystic latent stage of toxoplasmosis and its resistance to medications, eradication of the disease is difficult[13] ; however, effective treatments for reactivation exist.
In patients in whom brain imaging shows multiple lesions, whether serologic results are negative or positive, antitoxoplasmosis therapy should be initiated. In cases of impending herniation, an open biopsy with decompression is indicated. Corticosteroid treatment may be warranted in cases of impending brain herniation. However, their use may complicate the interpretation of a response to antitoxoplasmosis therapy.
In a study of 100 patients treated with pyrimethamine-sulfadiazine, the use of adjunctive steroids to treat cerebral edema associated with focal lesions appeared safe but was not associated with better neurologic outcomes.[14]
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Antibiotic combinations usually are recommended to circumvent resistance from bacterial subpopulations (which may be resistant to one of the antibiotic components) and to provide additive or synergistic effect.
In 1989, the US government published its first HIV-related treatment guideline on the prevention of Pneumocystis carinii pneumonia, marking the beginning of a series of guidelines that expanded over the years to include various HIV-related opportunistic infections (OIs). These guidelines, co-sponsored by the NIH, HIVMA, and IDSA, have been updated regularly and maintained as a living document online since 2009. They are a crucial resource, with significant online engagement in 2023, demonstrating their continued relevance to clinicians, healthcare providers, and policymakers, primarily in the United States. The guidelines are rigorously rated based on evidence quality, ensuring that users can assess the importance of each recommendation. Separate pediatric guidelines also are available, addressing the prevention and treatment of HIV-related OIs.[1]
Preferred regimens for acute infection
Standard therapy consists of pyrimethamine or TMP-SMX.[1]
Suggested dosing
Pyrimethamine 200 mg PO once, followed by weight-based dosing
Body weight ≤60 kg: pyrimethamine 50 mg PO daily + sulfadiazine 1,000 mg PO every 6 hours + leucovorin 10–25 mg PO daily (can increase to 50 mg daily or twice daily)
Body weight >60 kg: pyrimethamine 75 mg PO daily + sulfadiazine 1,500 mg PO every 6 hours + leucovorin 10–25 mg PO daily (can increase to 50 mg daily or twice daily)
or
TMP-SMX (TMP 5 mg/kg and SMX 25 mg/kg) (IV or PO) twice daily
Note: If pyrimethamine is unavailable or cannot be obtained without delay due to costs or other factors, TMP-SMX should be used in place of pyrimethamine-sulfadiazine.
Alternative regimens for acute infection
(Pyrimethamine + leucovorin)c plus clindamycin 600 mg IV or PO every 6 hours; preferred alternative for patients intolerant of sulfadiazine or who do not respond to pyrimethamineb-sulfadiazine; must add additional agent for PCP prophylaxis,or
Atovaquoneb 1,500 mg PO twice daily + (pyrimethamine +leucovorin)c,or
Atovaquoneb 1,500 mg PO twice daily + sulfadiazined,or
Atovaquoneb 1,500 mg PO twice daily
For patients with a history of sulfa allergy, rapid sulfa desensitization may be attempted using one of several published strategies.
During the desensitization phase, atovaquone 1,500 mg PO should be administered twice daily until therapeutic doses of TMP-SMX (TMP 5 mg/kg and SMX 25 mg/kg) twice daily are achieved.
Total duration for treating acute infection
At least 6 weeks; 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.
Please see these guidelines for information regarding chronic maintenace therapy.[1]
Pregnancy
In the clinical management of suspected or confirmed acute toxoplasmosis during pregnancy, therapeutic strategies are tailored based on the gestational age at diagnosis.[1] For initial therapy prior to 14 weeks of gestation, spiramycin is administered orally at a dosage of 1.0 g (or 3 million U) every 8 hours, achieving a total daily dosage of 3 g (or 9 million U). This regimen is aimed at reducing vertical transmission of T gondii. For infections identified from 14 weeks of gestation onwards, the recommended treatment involves a combination of pyrimethamine, initiated with a double dose on the first 2 days followed by a daily dose, along with sulfadiazine and leucovorin. This combination therapy is critical for effectively managing the infection and mitigating potential adverse outcomes.
Fetal assessment protocols are integral to the management strategy. Amniocentesis is advised at 18 weeks of gestation or later to conduct a PCR test for toxoplasmosis, which ascertains fetal involvement. Furthermore, serial fetal ultrasonography is recommended every 4 weeks until delivery to monitor for developmental abnormalities. Continuation of the initial therapeutic regimen is contingent upon negative results from both amniotic fluid PCR and ultrasonographic evaluations, indicating no fetal infection.
In instances where fetal infection is established—evidenced by a positive amniotic fluid PCR or ultrasonographic signs suggestive of congenital toxoplasmosis—the treatment regimen includes pyrimethamine, sulfadiazine, and leucovorin continued until delivery. This treatment is essential for managing the infection in the fetus. Should pyrimethamine be unavailable or not promptly accessible, an alternative regimen of TMP-SMX DS, spiramycin, and leucovorin is recommended to ensure timely initiation of therapy, which is crucial for optimal clinical outcomes for both the birthing parent and the fetus.
To reduce the risk for toxoplasmosis, individuals with HIV, particularly those with CD4 counts below 200 cells/mm3, should receive counseling on potential sources of Toxoplasma infection.[1] It is recommended that these individuals be tested for IgG antibodies to Toxoplasma soon after their HIV diagnosis to identify any latent infections with T gondii.
Dietary precautions are crucial for minimizing the risk of acquiring toxoplasmosis. People with HIV, especially those with lower CD4 counts, should avoid consuming raw or undercooked meats such as lamb, beef, pork, venison, and raw shellfish like oysters, clams, and mussels. Meats should be cooked to an internal temperature of 165 °F to 170 °F, which typically corresponds to the meat no longer being pink inside. Additionally, individuals should practice good hygiene by washing hands after handling raw meat, after gardening, or any contact with soil, and by thoroughly washing fruits and vegetables before consuming them raw.
For cat owners with HIV who have CD4 counts under 200 cells/mm3 and are seronegative, it is advisable to have someone else who is not pregnant and does not have HIV change the cat litter daily. If they must change the litter themselves, they should wear gloves and wash their hands thoroughly afterwards. Keeping cats indoors, avoiding the adoption or handling of stray cats, and feeding cats only canned or dried commercial food or well-cooked table food are additional preventive measures. There is no need for individuals with HIV to part with their cats or to have their cats tested for toxoplasmosis.
Preventing 1st episode of Toxoplasma gondii encephalitis (primary prophylaxis)
Indications for initiating primary prophylaxis
Toxoplasma IgG positive patients with CD4 count < 100 cells/mm3
Note: Listed regimens also are effective against PCP.
Preferred regimen
TMP-SMX one DS PO daily
Alternative regimens
TMP-SMX one DS PO three times weekly,or
TMP-SMX one SS PO daily,or
Dapsonea 50 mg PO daily + (pyrimethamine 50 mg + leucovorin 25 mg) PO weekly,or
CD4 count >200 cells/mm3 for >3 months and sustained HIV RNA below limits of detection in response to ARV therapy; or
Can consider if CD4 count is 100–200 cells/mm3 and HIV RNA remains below limits of detection for at least 3–6 months
Indication for restarting primary prophylaxis
CD4 count < 100 cells/mm3
CD4 count 100–200 cells/mm3 and HIV RNA above detection limits
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.
Pregnancy considerations
Indication, drugs, and doses are the same as for nonpregnant individuals.
What is CNS toxoplasmosis in HIV infection?What is the pathophysiology of CNS toxoplasmosis in HIV infection?What is the prevalence of CNS toxoplasmosis in HIV infection?Which clinical history findings are characteristic of CNS toxoplasmosis in HIV-infected patients?Which physical findings are characteristic of CNS toxoplasmosis in HIV-infected patients?Which conditions are included in the differential diagnoses of CNS toxoplasmosis in HIV infection?What is the role of serologic studies in the workup of CNS toxoplasmosis in HIV infection?How is CNS toxoplasmosis in HIV infection diagnosed?What is the role of imaging studies in the workup of CNS toxoplasmosis in HIV infection?What is the role of MRS in the workup of CNS toxoplasmosis in HIV infection?What is the role of brain biopsy in the workup of CNS toxoplasmosis in HIV infection?Which histologic findings are characteristic of CNS toxoplasmosis in HIV infection?How is CNS toxoplasmosis prevented in patients with HIV infection?How is CNS toxoplasmosis treated in patients with HIV infection?
Hao Huang, MD, Neurologist, Hackensack University Medical Group
Disclosure: Nothing to disclose.
Coauthor(s)
Florian P Thomas, MD, PhD, MA, MS, Chair, Neuroscience Institute and Department of Neurology, Director, Hereditary Neuropathy Center, Co-Director, Center for Memory Loss and Brain Health, Co-Director, ALS Center, Hackensack University Medical Center; Associate Dean of Faculty, Founding Chair and Professor, Department of Neurology, Hackensack Meridian School of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM, Adjunct Associate Professor of Neurology, University of Missouri-Columbia School of Medicine; Medical Director of St Mary's Stroke Program, SSM Neurosciences Institute, SSM Health
Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Abbie and Pfizer.
Additional Contributors
Gulshan Uppal, MD, Private Practice at Freeman Hospital
Disclosure: Nothing to disclose.
References
[Guideline] HIV.gov. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Clinical Info HIV.gov. Available at https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections. Sept 26, 2024; Accessed: February 25, 2025.
T1-weighted MRI after gadolinium contrast shows a hyperintense lesion in the left cerebellar hemisphere.
T2-weighted MRI demonstrates intense edema surrounding the lesion.
Toxoplasma gondii abscesses are seen on this brain slice. Contributed by Dr Beth Levy, Saint Louis University School of Medicine, St Louis, Missouri.
High-magnification photomicrograph shows a tissue cyst and tachyzoites in the brain parenchyma. Contributed by Dr Beth Levy, Saint Louis University School of Medicine, St Louis, Missouri.
T1-weighted MRI after gadolinium contrast shows a hyperintense lesion in the left cerebellar hemisphere.
T2-weighted MRI demonstrates intense edema surrounding the lesion.
Toxoplasma gondii abscesses are seen on this brain slice. Contributed by Dr Beth Levy, Saint Louis University School of Medicine, St Louis, Missouri.
High-magnification photomicrograph shows a tissue cyst and tachyzoites in the brain parenchyma. Contributed by Dr Beth Levy, Saint Louis University School of Medicine, St Louis, Missouri.
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