Cerebral toxoplasmosis

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.

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.