Cerebral toxoplasmosis

I. What every physician needs to know.

Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii. Despite infecting a large proportion of the world’s human populations, it is an uncommon cause of disease.

In the majority of immunocompetent individuals, primary or chronic (latent) infections are asymptomatic, however certain populations are at higher risk for severe disease, including congenitally infected fetuses, newborns and immunodeficient patients, particularly those with T-cell immunity deficiency, such as hematologic malignancies, bone marrow and solid organ transplant and acquired immune deficiency syndrome (AIDS).

Cerebral toxoplasmosis is usually caused by reactivation of the latent cystic form of T. gondii in the central nervous system (CNS) and it as a major cause of morbidity and mortality among human immunodeficiency virus (HIV) infected patients, particularly in developing countries.

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The incidence of toxoplasmic encephalitis (TE) has decreased since the availability of highly active anti-retroviral therapy (HAART), however it remains the most important opportunistic disease of the CNS in HIV infected patients, affecting usually those with cluster of differentiation 4 (CD4) counts of less than 100/mcL.

T. gondii is considered a worldwide zoonosis. Infection in humans occurs through the ingestion of cysts often found in raw or undercooked meat, oocysts present in contaminated water or other food (vegetables) or congenitally through transplacental transmission of tachyzoites if the mother suffered acute infection during pregnancy. Other forms of transmission have been described including transplantation of an infected organ or transfusion of contaminated blood cells.

T. gondii life cycle is complex and may involve multiple hosts. Felines (domestic cats) are considered definitive hosts and humans as well as other various warm-blooded animals serve as intermediate hosts. Infection of both kinds of hosts occurs through ingestion of tissue cysts. Intermediate hosts can also be infected through ingestion of oocysts and tachyzoites.

After ingestion, cysts will release slow-multiplying bradyzoites in the intestinal tract, which will invade epithelial cells and become rapidly-multiplying and highly-infective tachyzoites, which will continue to replicate and infect any nucleated cell until T-cell mediated immune response suppresses this replication resulting in chronic infection with tissue cyst formation.

Sexual stages of parasite will only occur in intestinal epithelial cells of definitive hosts. This will lead to the shedding of oocysts in feces, which will then sporulate and become infective once in contact with atmosphere.

In the intermediate hosts, tissue cysts can persist indefinitely in the brain or muscles. However, when asymptomatic individuals present some immunodeficiency, re-activation of a latent form can occur, resulting in severe tissue damage. As cysts (filled with bradyzoites) have predilection for neural, ocular and muscle cells, reactivation (tachyzoites) will often present as chorioretinitis, myalgias and cerebral toxoplasmosis , which is usually fatal if left untreated.

II. Diagnostic Confirmation: Are you sure your patient has cerebral toxoplasmosis?

Typical presentation is that of a patient suffering from HIV/AIDS with a low CD4 count presenting with seizures and headache to the emergency department (ED), where he/she had a computed tomography (CT) scan of the head showing characteristic ring enhancing lesions.

A. History Part I: Pattern Recognition:

Globally, T. gondii is the most common causative agent of focal brain lesions in HIV-infected patients. Typically, a patient with cerebral toxoplasmosis will present to an ED or outpatient clinic complaining of worsening headaches, with or without focal deficits or recent seizures.

Example: The patient is originally from Brazil, has history of HIV infection, but has never been on HAART. Last CD4 count is 88 cells/µL. You suspect cerebral toxoplasmosis versus other intracranial lesions in a HIV/AIDS patient and order toxoplasmosis serology, which is positive and a CT scan of the head that shows multiple sub-centimeter hypodense lesions with ring-enhancing and perilesional edema.

Clinically you are able to make a presumptive diagnosis of cerebral toxoplasmosis, based on serological, clinical and radiologic information. Diagnosis is confirmed with a response to empiric anti-toxoplasma therapy after 10-14 days.

B. History Part 2: Prevalence:

T.gondii infects up to 80% of some European populations, up to 90% of some Latin-American populations and 20% of people in the United States (US).

The overall age-adjusted seroprevalence of T. gondii infection in the US, in persons aged 6 to 49 years, was reported to be 10.8%, with a seroprevalence among women aged 15 to 44 years of 11%.

It has been estimated that 20% to 47% of AIDS patients who are infected with T. gondii but are not taking anti-toxoplasma prophylaxis or antiretroviral drugs will ultimately develop TE.

Data available regarding prevalence of cerebral toxoplasmosis in AIDS patients indicate that around 25% of those patients in Paris had TE prior to HAART era, compared to 10% in some cities from the US.

C. History Part 3: Competing diagnoses that can mimic cerebral toxoplasmosis

While considering differential diagnosis of expansive brain lesions in HIV-infected patients, certain geographical particularities (local neuroepidemiology) as well as degree of host immunosuppression need to be accounted for.

In developed countries, primary CNS lymphoma constitutes the main differential diagnosis of TE.

In developing countries, however, a focal form of cerebral tuberculosis (tuberculoma) is the main alternative diagnosis. CNS lymphoma usually presents inpatient with CD4 count below 50/µL, TE frequently below 100/µL and tuberculoma often inpatient with CD4 200/µL or less, however the latter may also present if the patient has higher CD4 counts.

Other causes of focal brain lesions in both AIDS and non-AIDS patients include cryptococcosis (AIDS), aspergillosis and Chagas disease (neuro-chagas or chagoma), metastases of disseminated lymphomas, glioblastoma multiform (GBM), and vascular pathologies, as well as cerebral abscesses.

D. Physical Examination Findings.

Cerebral toxoplasmosis causes unifocal or more often multifocal lesions and less frequently diffuse encephalitis. Patients usually present with subacute manifestations, but they can be acute in up to 10% of cases.

Clinical findings and manifestations depend on location and number of lesions. Most frequent complaints from different published series include: headache (49-63%), fever (41-68%), focal deficits (22-80%), seizures (19-29%), confusion (15-52%), ataxia (15-25%), lethargy (12-44%), cranial nerve alterations (12-19%), visual deficits (8-15%), among many other possible findings.

E. What diagnostic tests should be performed?

CT scan or magnetic resonance imaging (MRI) of the head and immunoglobulin (Ig) G antibody detection.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Most patients will show serological evidence of infection, with high titers of IgG, however, antibodies may not be detected in up to 5% of patients with AIDS and cerebral TE owing to immune suppression. The presence of positive antibody titers does not distinguish between patients with TE and asymptomatic, chronically infected individuals.

IgG antibody detection: different tests are used for detection of anti-T.gondii IgG including Sabin-Feldman dye test, enzyme-linked immunosorbent assay (ELISA), indirect fluorescent antibody test (IFA) and the modified direct agglutination test. IgG antibodies usually appear 1-2 weeks after infection, peaking at 1-2 months, fall at variable rates and persist for life. TE is usually reactivation of latent disease so antibodies should be detectable in most cases (>95%).

No need to check for IgM, IgA or IgE: useful either in acute infections or in congenital toxoplasmosis.

Polymerase chain reaction (PCR): is available and detects T.gondiideoxyribonucleic acid (DNA) in body fluids and tissue. Several studies show its utility in the diagnosis of TE however it is not widely used.

Histologic diagnosis: detects tachyzoites in tissue sections of smears of body fluid and establishes the diagnosis of acute infection. Brain biopsy needs to be considered in immunodeficient patients with presumptive TE if there is failure to respond to empirical treatment or atypical presentation (negative serology, atypical images, etc.).

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

CT scan and MRI with intravenous (IV) contrast are the preferred imaging modalities. MRI is more sensitive, often finding multiple lesions when a single lesion was found by CT.

Radiologic pattern could be typical or atypical. Typical findings are present in 80% of cases and include hypodense lesions with ring-enhancing and perilesional edema and hypodense lesions with nodular enhancing and perilesional edema.

The eccentric target sign, which is a small nodule along the wall of the enhancing ring, is highly suggestive of cerebral toxoplasmosis, although uncommonly seen.

Atypical patterns are seen in 20% of cases and include hypodense lesions without contrast enhancing and with expansive effect, CT without focal lesions but MRI showing focal lesions and diffuse cerebral encephalitis.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Even though CT brain scan is often obtained as the first imaging diagnostic approach, MRI is preferred in most cases unless the patient is unstable or has contraindications for undergoing MRI.

  • Cerebrospinal fluid (CSF) PCR tests are available, however their use is limited to atypical presentation.

  • A brain biopsy is not needed before initiation of treatment if presumptive diagnosis of TE was made in the right clinical settings.

III. Default Management.

A. Immediate management.

  • Supportive management will vary among individuals and form of presentation. Make sure the airway is protected, especially in confused or obtunded patients. Make sure breathing and ventilation are appropriate and carry out evaluation and monitoring of circulation with a focus on those patients with intracranial hypertension syndrome.

  • Anti-toxoplasma specific treatment: Treatment is to be initiated as soon as possible after presumptive diagnosis is made. Duration of acute treatment is 6 weeks (at least 3), followed by secondary prophylaxis, which may be life-long.

    Standard regimen: pyrimethamine 200mg per os (PO) loading dose followed by 50-75mg PO daily, plus folinic acid (leucovorin) 10-20mg daily (up to 50mg daily) PO, IV or intramuscular (IM), plus one of the following: sulfadiazine 1-1.5 g every 6 hours PO versus clindamycin 600mg every 6 hours (up to IV 1200 every 6 hours) PO or IV.

    Alternative regimens: Trimethoprim-sulfamethoxazole 3-5 mg/kg every 6 hours (trimethoprim component) PO or IV versus: pyrimethamine 200mg PO loading dose followed by 50-75mg PO daily, plus folinic acid (leucovorin) 10-20mg daily (up to 50mg daily) PO, IV or IM, plus one of the following: clarithromycin 1g every 12 hours PO versus atovaquone 750mg every 6 hours PO versus azithromycin 1200-1500mg every day PO versus dapsone 100mg daily PO.

  • Corticosteroids: often used in patients with intracranial hypertension.

  • Anti-seizure medications: used if form of presentation was seizures or status epilepticus.

  • HAART: there is no consensus on timing to initiation of HAART.

See Table I for Anti-toxoplasma specific treatment.

Table I.
Drug Dosage schedule
Standard regimens
Pyrimethamine PO 200mg loading dose and then 50-75mg daily
Folinic acid (leucovorin) PO, IV or IM 10-20mg daily (up to 50mg daily)
Plus one of the following:
Sulfadiazine PO 1-1.5 g every 6 hrs
Clindamycin PO or IV 600mg every 6 hrs (up to IV 1200 every 6h)
Possible alternative regimens
Trimethoprim-sulfamethoxazole PO or IV 3-5 mg/kg every 6h(trimethoprim component)
Pyrimethamine plus folinic acid (as in standard regime)
Plus one of the following:
Clarithromycin PO 1g every 12h
Atovaquone PO 750mg every 6h
Azithromycin PO 1200-1500mg every day
Dapsone PO 100mg every day

PO: per os

IV: intravenous

IM: intramuscular

B. Physical Examination Tips to Guide Management.

If there is no clinical improvement by day 10-14, or clinical deterioration by day 3, then further work-up is needed including new imaging, lumbar puncture with CSF analysis and consideration of cerebral biopsy. Clinical findings will depend on the location of lesions and the individual’s initial presentation

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

No imaging or specific laboratory test follow-up is needed if there is clinical improvement.

D. Long-term management.

Secondary prophylaxis

This is to be initiated after completion of initial regimen and can be safely discontinued when HIV-infected patients receiving HAART have a sustained (i.e. for 6 months) increase of CD4 count (>200 cells/µL). It should be re-started if CD4 count drops below 200 cells/µL.

Regimens include the combination of pyrimethamine 25-50 mg/day plus sulfadiazine 500mg every 6 hours plus leucovorin 10-20 mg/day versus trimethoprim/sulfamethoxazole (TMP/SMX) 2.5/12.5 mg/k twice daily. In patients with sulfa allergy, clindamycin 600mg every 8 hours is recommended.

Primary prophylaxis

This is recommended in patients with detectable T.gondii serology and CD4 count below 200cells/µL. Proven effective regimens include TMP-SMX 1 Double Strength or Single Strength tablet per day versus dapsone plus pyrimethamine versus Fansidar (sulfadoxine/pyrimethamine).

E. Common Pitfalls and Side-Effects of Management

Up to 40% of patients will develop side effects from one or more of the drugs requiring switching of medication regimen or even discontinuation of treatment. Toxoplasmosis in immunodeficient patients is often lethal if left untreated, which is why it is extremely important to discuss treatment compliance with patients and make them aware of possible alternative treatments available.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

Dose adjustments needed for renal patients when using TMP-SMX.

B. Liver Insufficiency.

Adjust dose of clindamycin (if used) in severe liver disease patients.

C. Systolic and Diastolic Heart Failure

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

No change in standard management. Glycemic control in patients on steroids.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No consensus reached on timing for initiation of HAART.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

No change in standard management.

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management. However be aware of a patient’s pre-existing psychiatric illness as this will affect assessment of clinical improvement if presentation of TE was confusion.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Neurologic status/neuro check: consider re-imaging patient if there is neurologic deterioration or acute systemic hypertension as the patient may be developing cerebral herniation syndrome and Cushing’s response secondary to intracranial hypertension.

B. Anticipated Length of Stay.

Length of stay will vary upon clinical initial presentation and clinical response to treatment.

C. When is the Patient Ready for Discharge.

Resolution of symptoms is usually obvious by 1 week, at which point the patient can be discharged and continued on oral treatment. However if there is no improvement in clinical status, the patient may need further work-up

D. Arranging for Clinic Follow-up

1. When should clinic follow up be arranged and with whom.

Follow up in infectious disease (ID) of HIV clinic within 1 week of discharge. If the patient is discharged home on IV antibiotics then they will need home health and frequent complete blood count (CBC) if on pyrimethamine.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None needed prior to discharge except for physical and occupational therapy with home safety evaluation.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

CBC twice a week if the patient is discharged on pyrimethamine.

E. Placement Considerations.

These are variable, depending on neurologic status and comorbidities.

F. Prognosis and Patient Counseling.

As relapse occurs in up to 80% of patients, it is important to stress the importance of treatment and follow-up compliance

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

There are no Joint Commission core measures applicable to this diagnosis.

It is important to document neurologic examination daily and response to treatment

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

  • Secondary prophylaxis: discussed above.

  • Deep venous thrombosis (DVT) prophylaxis: intermediate risk for DVT.

  • Glycemic control if patient on corticosteroids.

  • Initiation of HAART as per ID recommendation.

  • Depending on CD4 count: consider other appropriate primary or secondary prophylaxis that may be necessary.

VI. What's the evidence?

Meira, C, Costa-Silva, T. “Use of the serum reactivity against excreted-secreted antigens in cerebral toxoplasmosis diagnosis in human immunodeficiency virus-infected patients”. . vol. 57. 2008. pp. 845-850.

Dedicoat, M, Livesley, N. “Management of Toxoplasmic encephalitis in HIV-infected adults (with an emphasis on resource-poor settings)”. . 2006. pp. CD005420

Correia, C, Melo, H, Costa, V. “Influence of neurotoxoplasmosis characteristics on real-time PCR sensitivity among AIDS patients in Brazil”. T. vol. 104. 2010. pp. 24-28.

Portegies, P, Solod, L. “Guidelines for the diagnosis and management of neurological complications of HIV infection”. . vol. 11. 2004. pp. 297-304.

Hoffmann, C, Meyer, M. “Evolving characteristics of toxoplasmosis in patients infected with human immunodeficiency virus-1: clinical course and -specific immune responses”. . vol. 13. 2007. pp. 510-515.

Contini, C. “Clinical and diagnostic management of toxoplasmosis in the immunocompromised patient”. . vol. 50. 2008. pp. 45-50.

Meroni, V, Genco, F. “Toxoplasmosis in pregnancy: evaluation of diagnostic methods”. . vol. 50. 2008. pp. 51-53.

Nohui, F, Mattas, S. “Neurotoxoplasmosis diagnosis for HIV-1 patients by real-time PCR of cerebrospinal fluid”. . vol. 13. 2009. pp. 18-23.

Pereira-Chioccola, V, Vidal, J, Su, C. ” infection and cerebral toxoplasmosis in HIV-infected patients”. . vol. 4. 2009. pp. 1363-1379.

Mandell, G, Bennett, J, Dolin, R. “”. 2010.

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