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Case 3: Discussion - Toxoplasma Encephalitis

The patient in this case had a presumptive diagnosis of Toxoplasma encephalitis and received empiric therapy with pyrimethamine (Daraprim) plus sulfadiazine. The patient underwent an MRI at the time therapy was started and a follow-up brain MRI scan done 14 days later showed significant improvement. Toxoplasma encephalitis is the most common cause of focal central nervous system (CNS) mass lesions among patients with AIDS. Disease occurs as a result of reactivation of the parasite Toxoplasma gondii in patients with advanced immune suppression. The epidemiology, transmission, and primary prevention of Toxoplasma encephalitis are discussed in Case 2 in the section Opportunistic Infections: Prophylaxis. The following discussion will focus on the clinical features, diagnosis, and treatment of Toxoplasma encephalitis.

Clinical Manifestations of Toxoplasma Encephalitis

Most HIV-infected patients who develop Toxoplasma encephalitis have a CD4 cell count less than 100 cells/mm3[1], with the median CD4 count of approximately 50 cells/mm3 at the time of diagnosis[2]. Patients with a CD4 count less than 100 cells/mm3 who are seropositive for T. gondii have approximately a 30% risk of developing Toxoplasma encephalitis if they do not receive effective prophylaxis[1]. The central nervous system is by far the most common site for development of toxoplasmosis. Extracerebral disease, such as pulmonary or ocular involvement, occurs in about 1-2% of AIDS patients with toxoplasmosis[3]. Patients with AIDS and Toxoplasma encephalitis characteristically present with symptoms of headache, confusion, fever, and focal neurologic deficits (Figure 1 and Figure 2)[2]. Approximately 30% of patients develop seizures, and those with severe disease may present with more profound mental status changes, nausea, and vomiting. Abnormal findings on physical examination may include fever, hemiparesis, ataxia, altered consciousness, and cranial nerve palsies.

Diagnosis of Toxoplasma Encephalitis

Among persons with acute Toxoplasma encephalitis, approximately 95% have detectable anti-Toxoplasma IgG antibodies using an enzyme-linked immunosorbent assay (ELISA), and approximately 85% have detectable antibodies using an indirect immunofluorescence assay (IFA) with a cut-off of greater than or equal to 1:16[2]. Measuring anti-Toxoplasma IgM is of minimal value in HIV-infected patients suspected to have acute Toxoplasma encephalitis. Neuroimaging plays a critical role in the evaluation of patients with suspected Toxoplasma encephalitis. Contrast brain CT scan shows enhancing lesions in approximately 90% of patients with acute Toxoplasma encephalitis[2]. Patients with Toxoplasma encephalitis generally have multiple enhancing lesions (Figure 3) that often involve the basal ganglia. The contrast brain MRI (Figure 4) is more sensitive than contrast CT, often showing multiple lesions in patients whose CT scan demonstrated a solitary lesion[1]. Thus, MRI scans should be performed on patients who have a solitary lesion found on CT scan. In addition, since MRI is the more sensitive test, it is ideal to perform an initial MRI and use this test to follow response to therapy. Clinicians should avoid comparing a CT scan with an MRI scan when determining the response to therapy. If a patient can safely undergo lumbar puncture, analysis of the cerebrospinal fluid (CSF) can provide useful information, particularly for investigating causes other than Toxoplasma encephalitis. Because clinical and radiographic findings of primary central nervous system lymphoma can mimic those of Toxoplasma encephalitis, CSF studies should include cytology and Epstein-Barr virus polymerase chain reaction (PCR). The EBV PCR test has high sensitivity and specificity for central nervous system lymphoma[4]. Several groups have reported CSF T. gondii PCR may sometimes provide useful information, but this test suffers from poor sensitivity[5]. In addition, several reports involving small numbers of patients have suggested that Thallium single photon emission computed tomography (SPECT) scans can help differentiate Toxoplasma encephalitis from central nervous system lymphoma[6].

Approach with Suspected Toxoplasma Encephalitis

Factors that suggest Toxoplasma encephalitis include a positive IgG serology for T. gondii, non-use of Toxoplasma prophylaxis, the presences of multiple enhancing brain lesions, and a positive CSF PCR for T. gondii. Factors that suggest a diagnosis of primary central nervous system lymphoma include Toxoplasma seronegative status, current use of effective Toxoplasma prophylaxis, solitary brain lesion seen on MRI, and positive CSF PCR for Epstein-Barr virus. Most experts would recommend empiric therapy for Toxoplasma encephalitis in patients who are Toxoplasma seropositive and have multiple enhancing brain lesions. Brain biopsy carries significant risk and should generally be reserved for patients who have failed to have clinical or radiographic improvement after 10-14 days of anti-Toxoplasma therapy, or in selected cases when clinical, laboratory, and radiographic indicators strongly point to a diagnosis of lymphoma.

Initial Therapy for Toxoplasma Encephalitis

Patients with suspected Toxoplasma encephalitis should immediately receive intensive high-dose initial anti-Toxoplasma therapy (Figure 5). The combination of pyrimethamine (Daraprim) plus sulfadiazine is the best studied and is the preferred therapy[7,8,9]. Although this regimen is associated with excellent response rates, many patients develop dose-limiting side effects, including pyrimethamine-associated effects (nausea, leukopenia, and thrombocytopenia) and sulfadiazine-associated effects (rash, Stevens-Johnson syndrome, and crystal-induced reversible renal failure)[9,10]. If nausea becomes intolerable, the patient can split the once daily dose of pyrimethamine into two doses spaced 12 hours apart. Patients taking pyrimethamine should take leucovorin to minimize hematologic adverse effects. Laboratory monitoring for toxicity should include a CBC, platelets, BUN, and creatinine. Clindamycin (Cleocin) is considered an acceptable alternative for persons intolerant of sulfadiazine, but relapse of disease occurs at a higher rate with pyrimethamine plus clindamycin than with pyrimethamine plus sulfadiazine[8,9]. In vitro studies suggest that atovaquone (Mepron), azithromycin (Zithromax), and clarithromycin (Biaxin) all have significant activity against T. gondii, but clinical data with these drugs for the treatment of Toxoplasma encephalitis remains limited[11,12,13,14,15,16]. Accordingly, these drugs should be considered as an alternative only for use in a patient intolerant of sulfadiazine and pyrimethamine. In addition, it is not clear whether adding pyrimethamine to atovaquone, azithromycin, or clarithromycin would provide enhanced efficacy, but it would seem reasonable to add pyrimethamine in this setting whenever possible. For patients with presumed Toxoplasma encephalitis, use of adjunctive corticosteroids should generally be limited to patients with radiographic evidence of mass effect or midline shift, or in the situation when a patient deteriorates clinically. Use of corticosteroids complicates assessment of clinical response to therapy, since corticosteroids would also be expected to reduce edema cause by lymphoma. In addition, use of corticosteroids may alter the appearance of lymphoma on brain biopsy specimens, potentially complicating the diagnosis.

Response to Initial Therapy for Toxoplasma Encephalitis

Overall, more than 70% of patients respond to initial therapy with clinical and radiographic improvement[1,2]. In one retrospective study, among patients who eventually responded to anti-Toxoplasma therapy, 86% had improvement by day 7 and 91% had improvement (with respect to at least half of baseline abnormalities) by day 14 (Figure 6)[17]. If by day 14 the patient has not responded to therapy, the clinician should strongly consider a diagnosis other than Toxoplasma encephalitis and further studies should be performed in an attempt to make a definitive diagnosis. For patients who are seronegative for Toxoplasma, who have atypical radiographic features, or who worsen on appropriate therapy, a more rapid evaluation should be undertaken if an early favorable response does not occur. In most cases, the next step in the diagnostic evaluation is stereotactic brain biopsy, primarily to rule out primary central nervous system lymphoma. Patients who improve with anti-Toxoplasma therapy have presumed Toxoplasma encephalitis and should receive a minimum of 6 weeks of induction therapy prior to changing to a maintenance regimen. Many experts would recommend a follow-up neuroimaging study to document whether active disease has resolved prior to changing to maintenance therapy.

Maintenance Therapy for Toxoplasma Encephalitis

The change to maintenance therapy consists of reduced doses of the same medications used for induction therapy (Figure 5). The combination of pyrimethamine plus sulfadiazine is preferred, and pyrimethamine plus clindamycin is the best alternative regimen[8]. Patients who do not take maintenance therapy have a high risk of relapse. Patients taking sulfadiazine as part of the maintenance regimen have a low risk of developing Pneumocystis pneumonia and thus do not need additional agents for Pneumocystis prophylaxis[19].

Discontinuing Maintenance Therapy for Toxoplasma Encephalitis

Prior to the HAART era maintenance therapy for Toxoplasma encephalitis was recommended for life. But in the 2002 USPHS/IDSA Guidelines for Preventing Opportunistic Infections, a new recommendation stated that discontinuation of long-term maintenance therapy could be considered in patients on highly active antiretroviral therapy who experience a sustained increase in CD4 count (level greater than 200 cells/mm3 for at least 6 months) if they had completed initial therapy for Toxoplasma encephalitis and had no signs or symptoms suggestive of active Toxoplasma encephalitis. Data on discontinuation of maintenance therapy are limited[20]. Accordingly, some experts would recommend obtaining a brain MRI scan prior to discontinuation of maintenance therapy for Toxoplasma encephalitis.

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    Figure 1. Symptoms of Patients with Acute <em>Toxoplasma</em> Encephalitis

    Frequency of symptoms present in 115 patients with Toxoplasma encephalitis seen at San Francisco General Hospital during the years 1981-1990. Data from Porter SB, Sande MA. Toxoplasmosis of the central nervous system in the acquired immunodeficiency syndrome. N Engl J Med. 1992;327:1643-8.


    Figure 1
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    Figure 2. Signs of Patients with Acute <em>Toxoplasma</em> Encephalitis

    Frequency of signs present in 115 patients with Toxoplasma encephalitis seen at San Francisco General Hospital during the years 1981-1990. Focal signs consisted of hemiparesis (39%), ataxia (30%), cranial-nerve palsies (28%), sensory deficits (12%), aphasia (8%), and hemianopia (7%). Fever was defined at a temperature greater than 38.4°C. Data from Porter SB, Sande MA. Toxoplasmosis of the central nervous system in the acquired immunodeficiency syndrome. N Engl J Med. 1992;327:1643-8.


    Figure 2
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    Figure 3. Contrast Brain CT Scan in Patient with <em>Toxoplasma</em> Encephalitis

    The scan shows multiple ring-enhancing lesions with surrounding vasogenic edema.


    Figure 3
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    Figure 4. Brain MRI Scan in Patient with <em>Toxoplasma</em> Encephalitis

    This scan shows multiple enhancing lesions.


    Figure 4
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    Figure 5. Therapy for <em>Toxoplasma</em> Encephalitis

    Abbreviations: IV = intravenous; qd = once daily; bid = twice daily

    The maintenance section of this table is adapted from Kaplan JE, Masur H, Holmes KK; USPHS; Infectious Disease Society of America. Guidelines for preventing opportunistic infections among HIV-infected persons—2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR Recomm Rep. 2002;51(RR-8):1-52.


    Figure 5
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    Figure 6. Time to Neurologic Response in Patients with <em>Toxoplasma</em> Encephalitis

    The time to neurologic response was determined in 35 patients with Toxoplasma encephalitis. The investigators defined neurologic response as improvement in 50% of abnormalities present at baseline. The graph shows the percentage of patients that responded over time. Overall, the median time to response was 5 days. This graph is reproduced from Luft BJ, Hafner R, Korzun AH, et al. Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome. Members of the ACTG 077p/ANRS 009 Study Team. N Engl J Med. 1993;329:995-1000. Reproduced with permission from the Massachusetts Medical Society. Copyright © 1993 Massachusetts Medical Society. All rights reserved.


    Figure 6