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Toxoplasma gondii Toxoplasma gondii is an obligate intracellular protozoan of

worldwide distribution.

T.gondii is one of the most common causes of chronicinfection with an intracellular organism in humans.

A chronically infected individual who develops defects in

cell-mediated immunity is at risk for reactivation of theinfection.

Toxoplasmosis in this setting manifests primarily astoxoplasmic encephalitis.

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. felines serve as definitive hosts and are infected by theconsumption of meat containing tissue cysts withbradyzoites.

The sexual development occurs within the smallintestine.Oocysts are formed after fusion of the micro- and macro-gametes, and are shed in the feces.The transmission to the intermediate host occurs by

ingestion of oocysts, normally in food or water.Infections can also occur via organ transplantation.The acute infection is characterized by fast-growingtachyzoites after invasion within any nucleated cell andsubsequent host-cell lysis and reinfection of more cells.

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Concurrent with the development of immunity, tachyzoitestransform into slow-growing bradyzoites, which reside

within cysts in the muscles and brain.

Around 10

20% of the infected individuals develop thesystematic form, but the majority of the cases (8090%) areasymptomatic.The chronic infection can persist for the life of the hosts.In immunodeficient hosts, bradyzoites reactivate, which

causes cerebral toxoplasmosis.When the primary infection occurs during pregnancy, theparasites can also infect the fetus by congenitaltransmission

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The introduction of HAART for the treatment of HIVinfection has resulted in dramatic reductions in morbidity,mortality and healthcareutilization.[97]Decreasing rates of opportunistic diseases, including

neurological infections, have been reported both indeveloped and developing countries with access to HAART.However, the impact of HAART seems to be lower indeveloping countries with access to HAART owing to

delayed diagnosis of HIV infection or lack of opportunitiesto start treatment in patients prior to diagnosis ofHIV.Cerebral toxoplasmosis is an HIV-indicative event in 35% ofpatients and an AIDS-defining event in 75% of cases.[60]

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Cerebral toxoplasmosis is usually the most commoncerebral opportunistic disease in both developed anddeveloping countries.[101,102] In some places, particularlyin Africa, cases of cerebral toxoplasmosis are onlyexceeded by cases of cryptococcalmeningoencephalitis. Globally, T. gondii causes themost common focal brain lesion in HIV-infectedpatients

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The incidence of toxoplasmosis varies by country anddepends on the prevalence ofT. gondii infection in thegeneral population. Differences in genotypes ofT.

gondii isolates, races and ethnicities and the mode oftransmission also seem to influence the occurrence of theinfection.[35] Data are available regarding infectionprevalence in different parts of the world. The data indicatethat around 25% of AIDS patients from Paris had cerebral

toxoplasmosis in the pre-HAART era compared with 10% insome cities from the USA.[104,105] The rate in the USA andUK was found to vary between 16 and 40%, in Spain it wasapproximately 60%, in Brazil 5080% and in France 7590%.[1

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The definitive diagnosis of cerebral toxoplasmosisrequires the presence of the tachyzoite form of theparasite in cerebral tissue to be directly demonstrated.In clinical practice, presumptive cerebraltoxoplasmosis diagnosis depends on an association ofserological, clinical and radiologicalinformation.[107] Diagnosis is confirmed with aresponse to empiric anti-Toxoplasma therapy. Afavorable clinical and radiological response is expectedwithin 1014 days of specific treatment

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There are no pathognomonic clinical or radiologicalfindings of cerebral toxoplasmosis. Thus, differentialdiagnosis of AIDS patients with extensive brain lesionsis essential and two factors should be alwaysconsidered: the local neuroepidemiology and thedegree of immunosuppression in thehost.[108] Differential diagnosis of expansive brain

lesions presents geographic particularities

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. In developed countries, primary lymphoma of theCNS constitutes the main differential diagnosis ofcerebral toxoplasmosis.[103] In developing countries,

focal forms of cerebral TB (tuberculomas and, lesslikely, tuberculous brain abscess) are the mainalternative diagnoses.[109] Primary lymphoma of theCNS usually presents with a CD4 cell count below 50cells/mm3, cerebral toxoplasmosis frequently below100 cells/mm3, and cerebral TB usually below 200cells/mm3.[60] Of these three etiologies, cerebral TB ismore likely to present with CD4 cell count above 200cells/mm3

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In addition to these more frequent neurologiccomplications, the differential diagnosis of expansive brainlesions in HIV-infected patients is broad and includes

other infections such as cryptococcosis, aspergillosis andChagas disease; AIDS- and non-AIDS-associated tumorssuch as metastases of disseminated lymphomas andglioblastoma multiform, respectively; and vasculardiseases. For these reason, more invasive approaches such

as stereotactic biopsy should be considered in all HIV-infected patient with expansive brain lesions empiricallytreated for cerebral toxoplasmosis that do not respond toantiparasitic treatment within 1014 days.

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However, at least 10% of cerebral toxoplasmosis casesdied despite what was thought to be adequatetreatment.[60] Molecular diagnosis using CSF orperipheral blood samples is a useful tool for early,minimally invasive diagnosis of cerebraltoxoplasmosis.[59,112,113] However, in clinical practice,results should always be interpreted in association

with serological, clinical and radiological information

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CNS Lymphoma in HIV

Mycobacterial infection (eg, tuberculous abscess,

tuberculoma) Fungal infection (eg, cryptococcosis, candidiasis)

Chagas disease

Bacterial abscess (eg,Nocardia)

Neurosyphilis

http://emedicine.medscape.com/article/1167482-overviewhttp://emedicine.medscape.com/article/1167389-overviewhttp://emedicine.medscape.com/article/214581-overviewhttp://emedicine.medscape.com/article/214581-overviewhttp://emedicine.medscape.com/article/214581-overviewhttp://emedicine.medscape.com/article/214581-overviewhttp://emedicine.medscape.com/article/1167389-overviewhttp://emedicine.medscape.com/article/1167482-overview

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Cardioembolic Stroke

Cytomegalovirus Encephalitis in HIV

Progressive Polyradiculopathy in HIVVacuolar Myelopathy in HIV

Progressive Multifocal Leukoencephalopathy

http://emedicine.medscape.com/article/1160370-overviewhttp://emedicine.medscape.com/article/1167229-overviewhttp://emedicine.medscape.com/article/1167145-overviewhttp://emedicine.medscape.com/article/1167064-overviewhttp://emedicine.medscape.com/article/1167145-overviewhttp://emedicine.medscape.com/article/1167145-overviewhttp://emedicine.medscape.com/article/1167145-overviewhttp://emedicine.medscape.com/article/1167064-overviewhttp://emedicine.medscape.com/article/1167064-overviewhttp://emedicine.medscape.com/article/1167064-overviewhttp://emedicine.medscape.com/article/1167064-overviewhttp://emedicine.medscape.com/article/1167064-overviewhttp://emedicine.medscape.com/article/1167145-overviewhttp://emedicine.medscape.com/article/1167145-overviewhttp://emedicine.medscape.com/article/1167145-overviewhttp://emedicine.medscape.com/article/1167145-overviewhttp://emedicine.medscape.com/article/1167229-overviewhttp://emedicine.medscape.com/article/1160370-overviewhttp://emedicine.medscape.com/article/1160370-overviewhttp://emedicine.medscape.com/article/1160370-overview

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The clinical manifestations depend on the location andnumber of lesions. More frequent complaints include:headache (4963%),fever (4168%),

focal deficits (2280%),

seizures (1929%),mental confusion (1552%),ataxia (1525%),lethargy (1244%),

cranial nerve alterations (12

19%) andvisual alterations (815%).Other manifestations include disarthria, cognitivedysfunction, intracranial pressure and involuntarymovements

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Imaging studies, either computed tomography (CT) orMRI, are essential for the presumptive diagnosis ofcerebral toxoplasmosis.[97,103] MRI is more sensitive,

particularly for identifying small lesions and thoselocated in the posterior fossa. Single lesions areobserved in approximately 30% of the patients by CT,but by MRI it is common to identify two or more

lesions. Radiological diagnosis can be classified astypical or atypical patterns

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Typical patterns are observed in around 80% of casesand include hypodense lesions with ring-enhancingand perilesional edema, and hypodense lesions with

nodular-enhancing and perilesional edema. Atypicalpatterns are shown in around 20% of cases and arehypodense lesions without contrast enhancing andwith expansive effect, CT without focal lesions and

MRI demonstrating focal lesions, and diffuse cerebralencephalitis without visible focal lesions.

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A highly suggestive image for toxoplasmosis, althoughunusual, is the 'eccentric target sign', which is a smallasymmetric nodule along the wall of the enhancing

ring. Figure 2 shows the main radiological features ofcerebral toxoplasmosis in HIV-infected patients

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Most patients have serological evidence of infection, usually withhigh titres of IgGwith high avidity, supporting the idea that thereactivation of the latent infection occurs in the secondaryimmune

response.As these antibodies are usually present in cerebral toxoplasmosis,some studies suggested that, statistically, high titers might beindicative of the active disease or a higher risk of developingit.

Thus, a negative serological result or low titers do not exclude apositive diagnosis for cerebral toxoplasmosis and must not delaythe start of empiric treatment of cerebral toxoplasmosis in AIDSpatients with compatible clinical and radiological findings

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ESAs constitute an excellent serological marker for thediagnosis of cerebral toxoplasmosis in HIV-infectedpatients as they are produced by tachyzoites, the form

responsible for disseminating the infection, whichplays an important role in stimulation of the humoraland cellular immune responses to controlinfection. Numerous tachyzoitesare released from the quiescent cysts and aconsiderable proportion of excreted/secreted antigensare released, eliciting the specific immune response toESAs.

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When ESAs are used as antigens in ELISA (ESA-ELISA) and in immunoblot it is possible to distinguishsera from patients with the active disease.

Normally, these sera are three times more reactivethan those from seropositiveindividuals.

Thus, anti-ESA antibodies were present principally inpatients with active disease, suggesting its importance,particularly in regions with high prevalence of latenttoxoplasmosis in the general population.

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The antiparasitic drug combination employed is keyfor effective treatment. However, therecommended drugs act primarily against the

tachyzoites, but do not eradicate the bradyzoites.

Cerebral toxoplasmosis therapy in AIDS patientsincludes acute treatment, secondary prophylaxis(treatment maintenance) and primary prophylaxis

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Three randomized double-blinded trials of cerebraltoxoplasmosis treatment have been publishedcomparing pyrimethamine plus sulfadiazine with

pyrimethamine plus clindamycin,[172,173] andpyrimethamine plus sulfadiazine withtrimethoprim/sulfamethoxazole.[174] In a recent reviewof these studies The Cochrane Collaboration did not

identify any superior regimen among these threecombinations for cerebral toxoplasmosis treatment

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The following regimens as first-choice initial therapyis treatment for 6 weeks with sulfadiazine (1.01.5 goral route [PO] every 6 h) associated with

pyrimethamine (100200 mg PO loading dose, then 50

PO daily) and folinic acid (1020 mg PO daily), whichreduces the likelihood of the hematologic toxicitiesassociated with pyrimethamine therapy

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The second association istrimethroprim/sulfamethoxazol (5/25 mg/kg PO orintravenous [IV] every 12 h for 46 weeks).[176,177] . An

alternative regimen for patients without tolerance tosulfa drugs is the combination for 6 weeks ofpyrimetamine (100200 mg PO loading dose, then 50PO daily), clindamycin (600900 PO or IV every 6 h)and folinic acid (1020 mg PO daily).[97] Longertreatment courses might be appropriate if the clinicalor radiologic diagnoses show that there has been anincomplete response or the degree of infection is stillextensive after 6 weeks.

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In the exceptional setting where none of the previousregimens can be administrated, the following optionsmight be considered. Treatment for 6 weeks with

pyrimethamine and folinic acid (as in first-choiceregimen) associated with azithromycin (1.21.5 g POdaily) or atovaquone (750 mg PO every 6 h).

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Complications such as expansive brain lesions with amass effect (e.g., deviation of the middle linestructures or imminent risk of cerebral herniation)

and cases with diffuse encephalitis should beadministered adjunctive corticosteroids (e.g.,dexamethasone). Anticonvulsivant agents should beadministrated in the occurrence of seizures. However,

the use of prophylactics should be discouraged.

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Primary prophylaxis against T. gondii in AIDS patientshas been shown to be effective in preventing cerebraltoxoplasmosis reactivation. For this reason, current

guidelines recommend the use of a double-strengthtablet daily dose of trimethroprim/sulfamethoxazolin Toxoplasma-seropositive patients who have aCD4+ T-cell count below 100 cells/mm3

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The combination of pyrimethamine (2550 mg/day)plus sulfadiazine (500 mg every 6 h) plus leucovorin(1020 mg/day) is highly effective as suppressive

therapy for patients with cerebral toxoplasmosis.When patients cannot take the sulfadiazine four timesa day regimen, an alternative is the use of the sametotal daily dose in a twice a day regimen.

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In patients who cannot tolerate sulfa drugs, analternative option is pyrimethamine plus clindamycin(600 mg clindamycin every 8 h is recommended.

trimethroprim/sulfamethoxazol seems to be areasonable alternative when the conventionalmaintenance therapy is not possible. In this scenario,we suggest trimethroprim/sulfamethoxazol 2.5/12.5

mg/kg PO every 12 h.

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Secondary prophylaxis can be safely discontinuedwhen HIV-infected patients receiving effective HAARTwith successfully completed initial therapy for cerebral

toxoplasmosis have a sustained increase of CD4+ T-cellcount above 200 cell/mm3 (e.g., after 6 months). Onthe other hand, the same prophylaxis should bereintroduced if the CD4 cell count decreases below

200 cells/mm3.

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Immune reconstitution inflammatory syndrome (IRIS) hasbeen reported in association with HAART in patients with

AIDS with several neurologic complications, particularly,tuberculous meningitis, cryptococcal meningitis andprogressive multifocal leukoencephalopathy. Despitecerebral toxoplasmosis being the most commonopportunistic neurologic disease in HIV-infected patients,there has been doubt regarding the existence of cerebral

toxoplasmosis-associated IRIS as a true disease entity.Recently, a neuropathologic-proven IRIS case in an AIDSpatient with cerebral toxoplasmosis waspublished.[183] Thus, cerebral toxoplasmosis-associatedIRIS exists but remains uncommon

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As cerebral toxoplasmosis persists to cause highmorbidity and mortality, particularly in developingcountries, the use of laboratorial tools, including ESA-

ELISA, immunoblot, cnPCR and qrtPCR, need to betested in different clinical settings. Thesemethodologies may be associated with clinicaldiagnosis and images (presumptive diagnosis).Identification ofT. gondii DNA in CSF or peripheralblood samples can contribute not only with the earlydiagnosis, but also with the differential diagnosis ofpatients with expansive brain lesions who also haveother opportunistic neurological diseases.

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. However, presumptive diagnosis calls for a promptstart to antiparasitic treatment. For acute cerebraltoxoplasmosis treatment we recommended

sulfadiazine with pyrimethamine and folinic acid ortrimethroprim/sulfamethoxazol. Maintenance therapycan be safely discontinued in patients with consistentimmune reconstitution