Cerebral Toxoplasmosis

in HIV-Infected Patients
Introduction
 Toxoplasmosis:
– An infection with worldwide distribution.
– Caused by the intracellular protozoan parasite,
Toxoplasma gondii.
– Immunocompetent persons with primary
infection are usually asymptomatic.
– Latent infection can persist for the life of the
host.
– In immunosuppressed patients, especially with
AIDS, the parasite can reactivate and cause
disease.
 Usually occurs when the CD4 count falls below 100.
Epidemiology
 Seroprevalence rates of toxoplasmosis vary
significantly among countries.
 The rate is approximately 15% in the US.
 It is over 50% in some European countries.
 The rate in HIV-infected patients is similar
to that of the general population.
Epidemiology
 AIDS patients:
– The incidence of infection in cat owners is equal
to that in non-cat owners.
– In those with CD4 <100, who are seropositive,
there is a 30% probability of developing
reactivated toxoplasmosis if effective prophylaxis
is not taken.
– The introduction of anti-toxoplasma prophylaxis
and HAART has decreased the occurrence.
Clinical Presentation
 When T. gondii reactivates in an AIDS
patient, it usually does so in the CNS,
leading to cerebral abscesses.
 The most common presenting symptom is
headache.
 Other common symptoms include:
– Confusion
– Fever
– Focal neurologic deficits
– Seizures
Clinical Presentation

 Patients may also present with:

– Dull affect:
 May be due to global encephalitis.
– Profound mental status changes:
 Usually indicate elevated intracranial
pressure, especially when accompanied by
nausea or vomiting.
Diagnosis
 The majority of patients are seropositive for
anti-toxoplasma IgG antibodies.
 Anti-toxoplasma IgM antibodies are usually
absent.
 Quantitative IgG titers are not helpful.
 The absence of antibodies makes the
diagnosis less likely, but does not exclude
the possibility of it.
Diagnosis
 Most patients with AIDS will have
multiple, ring-enhancing brain lesions
often associated with edema.
 There is a predilection for involvement
of the basal ganglia and periventricular
white matter of the brain.
 MRI is more sensitive than CT for
identifying lesions.
Diagnosis
 Head CT (left) and MRI (right) both with contrast of the same
patient with new seizures, focal weakness, and HIV infection.
Multiple ring-enhancing lesions are seen in the periventricular
white matter, consistent with Toxoplasma encephalitis. The
images point out the enhanced sensitivity of MRI over CT.
Diagnosis
 Neither MRI nor CT can differentiate among
the multiple possible etiologies of brain
lesions in AIDS patients.
 The differential diagnosis includes:
– Cryptococcosis
– Histoplasmosis
– Aspergillosis
– Tuberculosis
– Trypanosomiasis
– CNS lymphoma
Diagnosis

 Toxoplasmosis and CNS lymphoma are

the two most common entities.
 Toxoplasmosis accounts for 50% of
cases.
 CNS lymphoma accounts for 30% of
cases.
Diagnosis
 Contrast-enhancing
lesions in the
frontal lobes
bilaterally. The
largest lesion is
located within the
right frontal lobe
and is surrounded
by significant
edema.
Diagnosis
 Two contrast-
enhancing mass
lesions, one in the
right thalamic region
and the other in the
corticomedullary
junction in the right
parietal region, with
significant surrounding
edema and midline
shift.
Diagnosis
 Right temporal
contrast-enhancing
lesion, associated
with mild mass
effect, and similar
lesions in the left
thalamus and
midbrain.
Diagnosis
Diagnosis
 SPECT and PET imaging:
– SPECT - thallium single photon emission
computed tomography.
– PET - positron emission tomography.
– Can be useful in distinguishing toxoplasmosis or
other infections from CNS lymphoma.
– Lymphoma has greater thallium uptake on
SPECT and greater glucose and methionine
metabolism on PET than neurotoxoplasmosis or
other infections.
Diagnosis
 Brain biopsy:
– Definitive diagnosis is made by pathologic
examination of brain tissue obtained by
open or stereotactic brain biopsy.
– Organisms are demonstrated on
hematoxylin and eosin stains.
– Some laboratories also use
immunoperoxidase staining which can
increase diagnostic sensitivity.
Diagnosis

 Brain biopsy:
– There is associated morbidity and
mortality.
– Morbidity rates range from 3-12%.
– Mortality rates are around 2%.
– Due to such risk, it is common practice to
presumptively diagnose and treat patients
in whom clinical suspicion is high.
Diagnosis

 A presumptive diagnosis can be made

if the patient has a CD4 count <100
and:
– Is seropositive for T. gondii IgG antibody.
– Has not been receiving effective
prophylaxis.
– Has typical findings on brain imaging,
such as multiple ring-enhancing lesions.
Diagnosis
 If these criteria are met, there is a
90% probability of the diagnosis.
 Therefore, it is common to treat
empirically.
 If only one brain lesion is detected on
imaging, CNS lymphoma rises on the
differential diagnosis list, despite
positive toxoplasma serology.
Diagnosis

 When to perform brain biopsy or

another diagnostic test:
– If all three of the criteria are not met.
– If there is no clinical or radiographic
response to empiric therapy.
Diagnosis
 In patients with focal brain lesions already
receiving prophylaxis or who are
seronegative to T. gondii, PCR testing for
other pathogens should be considered,
including:
– EBV
– JC virus
– Mycobacterium tuberculosis
– Cryptococcus neoformans
Diagnosis

 Lumbar puncture may be performed to

analyze CSF, which:
– May have mild mononuclear pelocytosis
and elevated protein.
– With DNA amplification, can detect T.
gondii in most patients.
– When cytocentrifuged and stained with
Giemsa, can sometimes show tachyzoites.
Treatment
 Many therapies are available.
 Cerebral toxoplasmosis usually responds promptly
to treatment.
 Lack of clinical or radiographic improvement within
10 to 14 days of empiric therapy should raise the
possibility of an alternate diagnosis.
 The current treatment guidelines have been
recommended by the:
– The Centers for Disease Control and Prevention (CDC)
– National Institutes of Health (NIH)
– Infectious Diseases Society of America (IDSA)
Treatment
 First-line therapy:
– Pyrimethamine 200 mg po loading dose followed
by 75 mg/day plus sulfadiazine 6 to 8 g/day po
divided qid, or
– For sulfa allergic patients, pyrimethamine 200
mg po loading dose followed by 75 mg/day plus
clindamycin 600 to 1200 mg IV or 450 mg po
qid.
– All pyrimethamine regimens should include
folinic acid to prevent drug-induced hematologic
toxicity (10 to 25 mg/day po).
Treatment

 Pyrimethamine plus sulfadiazine:

– Has a higher incidence of cutaneous
hypersensitivity reactions.
– May have a lower incidence of relapse.
– Does not require additional TMP-SMX for
PCP prophylaxis.
– Is the same treatment used in pregnant
females.
Treatment

 Alternative regimens:
– Used in patients unable to tolerate other
medications:
 Pyrimethamine plus azithromycin (1200 to
1500 mg po qd)
 Pyrimethamine plus atovaquone (750 mg po
qid)
 Sulfadiazine (1500 mg po qid) plus
atovaquone (1500 mg po bid)
Treatment

 Atovaquone:
– Significant variation in drug absorption
among patients.
– Measuring plasma levels may be helpful.
– Higher plasma levels are associated with
better outcomes.
Treatment
 Trimethoprim-sulfamethoxazole:
– May be an effective alternative treatment
regimen, particularly in resource-poor settings.
– No statistically significant difference in a
multicenter, randomized prospective trial when
compared to standard therapy with
pyrimethamine-sulfadiazine.
– In critically ill patients, IV TMP 10 mg/kg/d and
SMX 50 mg/kg/d, can be considered, but is less
effective.
Treatment

 Anticonvulsants:
– Should be given to patients with a history
of seizures.
– Should not be given routinely for seizure
prophylaxis to all patients with cerebral
toxoplasmosis.
Duration of Therapy
 If a patient is not responding to therapy, the
diagnosis should be reconsidered.
 For patients who respond, the duration of
therapy is typically six weeks at the
recommended doses.
 After treatment is complete, the dose of
medication can be decreased for secondary
prophylaxis.
Steroids
 Adjunctive corticosteroids should be used
for patients with:
– Radiographic evidence of midline shift.
– Signs of critically elevated intracranial pressure.
– Clinical deterioration within the first 48 hours of
therapy.
 Dexamethasone:
– Used most commonly
– Dosed at 4 mg q6hrs
– Tapered over several days
Steroids
 May cause rapid improvement in symptoms
making the clinical response to antibiotics
difficult to assess.
 Reduce the intensity of ring-enhancement
and the amount of surrounding edema.
 Require that patients are carefully
monitored for the development of other
opportunistic infections.
Monitoring of Therapy

 Careful clinical evaluations

 Serial brain imaging
 Assessment of adverse effects of
therapy
 No value to serial assessment of IgG
toxoplasma antibody titers
Side Effects of Therapy
 Pyrimethamine:
– Rash
– Nausea
– Bone marrow suppression
 Clindamycin:
– Rash
– Fever
– Nausea
– Diarrhea
– Clostridium difficile
Side Effects of Therapy
 Sulfadiazine:
– Rash
– Fever
– Leukopenia
– Hepatitis
– Nausea
– Vomiting
– Diarrhea
– Crystalluria
Response to Therapy
 Clinical improvement usually precedes radiographic
improvement.
 During the first two weeks of treatment, a careful
daily neurologic exam is more important than
radiographic studies to assess the response to
therapy.
 Radiographic reassessment should be deferred for
2-3 weeks unless there has been clinical worsening
or lack of improvement.
 About 80% of patients show both clinical and
radiologic responses to therapy.
Prophylaxis

 Patients seropositive for T. gondii

should receive prophylaxis according
to the guidelines of the:
– Centers for Disease Control (CDC)
– United States Public Health Service
(USPHS)
– Infectious Diseases Society of America
(IDSA)
Primary Prophylaxis
 Indicated for patients with HIV and CD4
counts <100 who are T. gondii IgG positive.
 TMP/SMX in the doses given for PCP
prophylaxis is the usual choice in order to
prevent both opportunistic infections.
 Patients with negative toxoplasma serology
should be counseled to:
– Avoid eating undercooked meat.
– Not to avoid household cats entirely.
– Use gloves when carefully cleaning cat litter
boxes.
Primary Prophylaxis

 If the CD4 count rises above 200 for

three months, primary prophylaxis can
be safely discontinued.
 If the CD4 drops below 200,
prophylaxis should be reinitiated.
Secondary Prophylaxis
 Also known as chronic suppressive therapy:
– Following six weeks of therapy for treatment of
cerebral toxoplasmosis, patients can receive
lower doses of medication.
 First choice for treatment:
– Sulfadiazine 2-4 gm/day divided qid plus
pyrimethamine 25-50 mg/day.
– Folinic acid 10-25 mg/day is given concurrently.
Secondary Prophylaxis
 Alternative regimens:
– Clindamycin 300 mg po tid or 450 mg po tid plus
pyrimethamine 25-50 mg/day plus folinic acid
10-25 mg/day.
– Atovaquone 750 mg po bid-qid plus
pyrimethamine 25 mg/day plus folinic acid 10
mg/day.
– Atovaquone monotherapy of 750 mg po qid for
patients who cannot tolerate pyrimethamine,
with a one year relapse rate of 26%.
Secondary Prophylaxis
 There is low risk for recurrence of cerebral
toxoplasmosis if patients:
– Have completed therapy
– Remain asymptomatic
– Have a sustained increase in their CD4 counts
>200 for over six months:
 If so, secondary prophylaxis can be discontinued.
 If the CD4 count drops below 200, prophylaxis should
be reinitiated.
Summary
 Seroprevalence to T. gondii depends more
on the part of the world in which the patient
was born and has lived than on their HIV
status.
 Cerebral toxoplasmosis is the most common
presentation of toxoplasmosis as an
opportunistic infection among AIDS patients
and occurs most often if the CD4 count is
below 100.
Summary
 Prophylaxis against PCP and the widespread
use of HAART in developed countries has
greatly decreased the incidence of infection.
 The diagnosis of cerebral toxoplasmosis is
usually made presumptively in an AIDS
patient with a CD4 count <100, the
presence of T. gondii IgG antibodies, no
recent prophylaxis against toxoplasmosis,
and multiple ring-enhancing lesions on brain
imaging.
Summary
 Brain biopsy can yield the diagnosis in
patients who don’t meet diagnostic criteria
or fail to respond to presumptive therapy.
 First-line therapies for cerebral
toxoplasmosis include pyrimethamine and
sulfadiazine or pyrimethamine and
clindamycin.
 Alternatives include pyrimethamine and
azithromycin, pyrimethamine and
atovaquone, sulfadiazine and atovaquone,
or TMP/SMX as a last resort.
Summary
 Folinic acid must always accompany
pyrimethamine therapy.
 Corticosteroids are often administered in
conjunction with antibiotics in patients with
signs of significant increased intracranial
pressure.
 The doses of pyrimethamine and
sulfadiazine or pyrimethamine and
clindamycin are lowered for secondary
prophylaxis after six weeks of treatment.
Summary
 Primary prophylaxis against toxoplasmosis is
usually given to patients with CD4 counts
<200 who are T. gondii antibody positive.
 TMP/SMX in the doses given for PCP
prophylaxis is the usual choice for primary
prophylaxis in order to prevent both
opportunistic infections.
 Both primary and secondary prophylaxis can
be discontinued in patients who achieve
CD4 counts >200 with HAART therapy, for
three and six months, respectively.
References
 Bertschy, S. Discontinuation of maintenance therapy against
toxoplasma encephalitis in AIDS patients with sustained
response to anti-retroviral therapy. Clin Microbiol Infect 2006;
12: 666-671.
 Corr, Peter. Imaging of neuro-AIDS. Journal of
Psychosomatic Research 61 (2006) 295-299.
 Heller, Howard M. Toxoplasmosis in HIV-infected patients.
UpToDate 2007.
 Smego, Raymond A; Orlovic, Dragana; Wadula, Jeanette. An
algorithmic approach to intracranial mass lesions in HIV/AIDS.
International Journal of STD & AIDS; 17: 271-276.
 Tang, Hung-Jen. Opportunistic infections in adults with
acquired immunodeficiency syndrome: a comparison of
clinical and autopsy findings. J Microbiol Immunol Infect
2006;39:310-315.