Toxoplasma gondii

Toxoplasma gondii is an obligate intracellular protozoan of

worldwide distribution. T.gondii is one of the most common causes of chronic infection with an intracellular organism in humans. A chronically infected individual who develops defects in cell-mediated immunity is at risk for reactivation of the infection. Toxoplasmosis in this setting manifests primarily as toxoplasmic encephalitis.

felines serve as definitive hosts and are infected by the consumption of meat containing tissue cysts with bradyzoites. The sexual development occurs within the small intestine. Oocysts are formed after fusion of the micro- and macrogametes, 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-growing tachyzoites after invasion within any nucleated cell and subsequent host-cell lysis and reinfection of more cells.

 Concurrent with the development of immunity, tachyzoites

transform into slow-growing bradyzoites, which reside within cysts in the muscles and brain. Around 1020% of the infected individuals develop the systematic form, but the majority of the cases (8090%) are asymptomatic. 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, the parasites can also infect the fetus by congenital transmission

 The introduction of HAART for the treatment of HIV

infection has resulted in dramatic reductions in morbidity, mortality and healthcare utilization.[97] Decreasing rates of opportunistic diseases, including neurological infections, have been reported both in developed and developing countries with access to HAART. However, the impact of HAART seems to be lower in developing countries with access to HAART owing to delayed diagnosis of HIV infection or lack of opportunities to start treatment in patients prior to diagnosis of HIV. Cerebral toxoplasmosis is an HIV-indicative event in 35% of patients and an AIDS-defining event in 75% of cases.[60]

 Cerebral toxoplasmosis is usually the most common

cerebral opportunistic disease in both developed and developing countries.[101,102] In some places, particularly in Africa, cases of cerebral toxoplasmosis are only exceeded by cases of cryptococcal meningoencephalitis. Globally, T. gondii causes the most common focal brain lesion in HIV-infected patients

 The incidence of toxoplasmosis varies by country and

depends on the prevalence ofT. gondii infection in the general population. Differences in genotypes of T. gondii isolates, races and ethnicities and the mode of transmission also seem to influence the occurrence of the infection.[35] Data are available regarding infection prevalence in different parts of the world. The data indicate that around 25% of AIDS patients from Paris had cerebral toxoplasmosis in the pre-HAART era compared with 10% in some cities from the USA.[104,105] The rate in the USA and UK was found to vary between 16 and 40%, in Spain it was approximately 60%, in Brazil 5080% and in France 75 90%.[1

 The definitive diagnosis of cerebral toxoplasmosis

requires the presence of the tachyzoite form of the parasite in cerebral tissue to be directly demonstrated. In clinical practice, presumptive cerebral toxoplasmosis diagnosis depends on an association of serological, clinical and radiological information.[107] Diagnosis is confirmed with a response to empiric anti-Toxoplasma therapy. A favorable clinical and radiological response is expected within 1014 days of specific treatment

 There are no pathognomonic clinical or radiological

findings of cerebral toxoplasmosis. Thus, differential diagnosis of AIDS patients with extensive brain lesions is essential and two factors should be always considered: the local neuroepidemiology and the degree of immunosuppression in the host.[108] Differential diagnosis of expansive brain lesions presents geographic particularities

 . In developed countries, primary lymphoma of the

CNS constitutes the main differential diagnosis of cerebral toxoplasmosis.[103] In developing countries, focal forms of cerebral TB (tuberculomas and, less likely, tuberculous brain abscess) are the main alternative diagnoses.[109] Primary lymphoma of the CNS usually presents with a CD4 cell count below 50 cells/mm3, cerebral toxoplasmosis frequently below 100 cells/mm3, and cerebral TB usually below 200 cells/mm3.[60] Of these three etiologies, cerebral TB is more likely to present with CD4 cell count above 200 cells/mm3

 In addition to these more frequent neurologic

complications, the differential diagnosis of expansive brain lesions in HIV-infected patients is broad and includes other infections such as cryptococcosis, aspergillosis and Chagas disease; AIDS- and non-AIDS-associated tumors such as metastases of disseminated lymphomas and glioblastoma multiform, respectively; and vascular diseases. For these reason, more invasive approaches such as stereotactic biopsy should be considered in all HIVinfected patient with expansive brain lesions empirically treated for cerebral toxoplasmosis that do not respond to antiparasitic treatment within 1014 days.

 However, at least 10% of cerebral toxoplasmosis cases

died despite what was thought to be adequate treatment.[60] Molecular diagnosis using CSF or peripheral blood samples is a useful tool for early, minimally invasive diagnosis of cerebral toxoplasmosis.[59,112,113] However, in clinical practice, results should always be interpreted in association with serological, clinical and radiological information

 CNS Lymphoma in HIV

Mycobacterial infection (eg, tuberculous abscess,

tuberculoma) Fungal infection (eg, cryptococcosis, candidiasis) Chagas disease Bacterial abscess (eg, Nocardia) Neurosyphilis

 Cardioembolic Stroke
Cytomegalovirus Encephalitis in HIV Progressive Polyradiculopathy in HIV

Vacuolar Myelopathy in HIV

Progressive Multifocal Leukoencephalopathy

 The clinical manifestations depend on the location and

number 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 (1219%) and visual alterations (815%). Other manifestations include disarthria, cognitive dysfunction, intracranial pressure and involuntary movements

 Imaging studies, either computed tomography (CT) or

MRI, are essential for the presumptive diagnosis of cerebral toxoplasmosis.[97,103] MRI is more sensitive, particularly for identifying small lesions and those located in the posterior fossa. Single lesions are observed 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 as typical or atypical patterns

 Typical patterns are observed in around 80% of cases

and include hypodense lesions with ring-enhancing and perilesional edema, and hypodense lesions with nodular-enhancing and perilesional edema. Atypical patterns are shown in around 20% of cases and are hypodense lesions without contrast enhancing and with expansive effect, CT without focal lesions and MRI demonstrating focal lesions, and diffuse cerebral encephalitis without visible focal lesions.

 A highly suggestive image for toxoplasmosis, although

unusual, is the 'eccentric target sign', which is a small asymmetric nodule along the wall of the enhancing ring. Figure 2 shows the main radiological features of cerebral toxoplasmosis in HIV-infected patients

 Most patients have serological evidence of infection, usually with

high titres of IgG with high avidity, supporting the idea that the reactivation of the latent infection occurs in the secondary immune response. As these antibodies are usually present in cerebral toxoplasmosis, some studies suggested that, statistically, high titers might be indicative of the active disease or a higher risk of developing it. Thus, a negative serological result or low titers do not exclude a positive diagnosis for cerebral toxoplasmosis and must not delay the start of empiric treatment of cerebral toxoplasmosis in AIDS patients with compatible clinical and radiological findings

 ESAs constitute an excellent serological marker for the

diagnosis of cerebral toxoplasmosis in HIV-infected patients as they are produced by tachyzoites, the form responsible for disseminating the infection, which plays an important role in stimulation of the humoral and cellular immune responses to control infection. Numerous tachyzoites are released from the quiescent cysts and a considerable proportion of excreted/secreted antigens are released, eliciting the specific immune response to ESAs.

 When ESAs are used as antigens in ELISA (ESA-

ELISA) and in immunoblot it is possible to distinguish sera from patients with the active disease. Normally, these sera are three times more reactive than those from seropositive individuals. Thus, anti-ESA antibodies were present principally in patients with active disease, suggesting its importance, particularly in regions with high prevalence of latent toxoplasmosis in the general population.

 The antiparasitic drug combination employed is key

for effective treatment. However, the recommended drugs act primarily against the tachyzoites, but do not eradicate the bradyzoites. Cerebral toxoplasmosis therapy in AIDS patients includes acute treatment, secondary prophylaxis (treatment maintenance) and primary prophylaxis

 Three randomized double-blinded trials of cerebral

toxoplasmosis treatment have been published comparing pyrimethamine plus sulfadiazine with pyrimethamine plus clindamycin,[172,173] and pyrimethamine plus sulfadiazine with trimethoprim/sulfamethoxazole.[174] In a recent review of these studies The Cochrane Collaboration did not identify any superior regimen among these three combinations for cerebral toxoplasmosis treatment

 The following regimens as first-choice initial therapy

is treatment for 6 weeks with sulfadiazine (1.01.5 g oral route [PO] every 6 h) associated with pyrimethamine (100200 mg PO loading dose, then 50 PO daily) and folinic acid (1020 mg PO daily), which reduces the likelihood of the hematologic toxicities associated with pyrimethamine therapy

 The second association is

trimethroprim/sulfamethoxazol (5/25 mg/kg PO or intravenous [IV] every 12 h for 46 weeks).[176,177] . An alternative regimen for patients without tolerance to sulfa drugs is the combination for 6 weeks of pyrimetamine (100200 mg PO loading dose, then 50 PO daily), clindamycin (600900 PO or IV every 6 h) and folinic acid (1020 mg PO daily).[97] Longer treatment courses might be appropriate if the clinical or radiologic diagnoses show that there has been an incomplete response or the degree of infection is still extensive after 6 weeks.

 In the exceptional setting where none of the previous

regimens can be administrated, the following options might be considered. Treatment for 6 weeks with pyrimethamine and folinic acid (as in first-choice regimen) associated with azithromycin (1.21.5 g PO daily) or atovaquone (750 mg PO every 6 h).

 Complications such as expansive brain lesions with a

mass effect (e.g., deviation of the middle line structures or imminent risk of cerebral herniation) and cases with diffuse encephalitis should be administered adjunctive corticosteroids (e.g., dexamethasone). Anticonvulsivant agents should be administrated in the occurrence of seizures. However, the use of prophylactics should be discouraged.

 Primary prophylaxis against T. gondii in AIDS patients

has been shown to be effective in preventing cerebral toxoplasmosis reactivation. For this reason, current guidelines recommend the use of a double-strength tablet daily dose of trimethroprim/sulfamethoxazol in Toxoplasma-seropositive patients who have a CD4+ T-cell count below 100 cells/mm3

 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 times a day regimen, an alternative is the use of the same total daily dose in a twice a day regimen.

 In patients who cannot tolerate sulfa drugs, an

alternative option is pyrimethamine plus clindamycin (600 mg clindamycin every 8 h is recommended. trimethroprim/sulfamethoxazol seems to be a reasonable alternative when the conventional maintenance therapy is not possible. In this scenario, we suggest trimethroprim/sulfamethoxazol 2.5/12.5 mg/kg PO every 12 h.

 Secondary prophylaxis can be safely discontinued

when HIV-infected patients receiving effective HAART with successfully completed initial therapy for cerebral toxoplasmosis have a sustained increase of CD4+ T-cell count above 200 cell/mm3 (e.g., after 6 months). On the other hand, the same prophylaxis should be reintroduced if the CD4 cell count decreases below 200 cells/mm3.

 Immune reconstitution inflammatory syndrome (IRIS) has

been reported in association with HAART in patients with AIDS with several neurologic complications, particularly, tuberculous meningitis, cryptococcal meningitis and progressive multifocal leukoencephalopathy. Despite cerebral toxoplasmosis being the most common opportunistic 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 AIDS patient with cerebral toxoplasmosis was published.[183] Thus, cerebral toxoplasmosis-associated IRIS exists but remains uncommon

 As cerebral toxoplasmosis persists to cause high

morbidity and mortality, particularly in developing countries, the use of laboratorial tools, including ESAELISA, immunoblot, cnPCR and qrtPCR, need to be tested in different clinical settings. These methodologies may be associated with clinical diagnosis and images (presumptive diagnosis). Identification of T. gondii DNA in CSF or peripheral blood samples can contribute not only with the early diagnosis, but also with the differential diagnosis of patients with expansive brain lesions who also have other opportunistic neurological diseases.

 . However, presumptive diagnosis calls for a prompt

start to antiparasitic treatment. For acute cerebral toxoplasmosis treatment we recommended sulfadiazine with pyrimethamine and folinic acid or trimethroprim/sulfamethoxazol. Maintenance therapy can be safely discontinued in patients with consistent immune reconstitution