Toxoplasmosis is the commonest central nervous system (CNS) infection in patients with HIV/AIDS who are not on appropriate prophylaxis. The usual manifestation of cerebral toxoplasmosis is typically one or more CNS mass lesions. Other opportunistic conditions seen in AIDS that may present with mass like lesions include primary CNS lymphoma (typically associated with the Epstein-Barr virus) and progressive multifocal leukoencephalopathy (PML) which is caused by JC polyomavirus. 
The causative agent is Toxoplasma gondii, an exclusively intracellular, coccidian protozoan parasite with worldwide distribution. Transmission occurs following ingestion of infectious oocysts from contaminated meat, other food, or water. The oocysts are abundant in the soil, cat litter contaminated with feline feces or undercooked meat from an infected animal (especially felines). Felines are the only animals in which T. gondii can complete its reproductive cycle. After ingestion, the organisms encyst in nucleated cells and can lie dormant within the tissues for the life of the host (latent infection). In most scenarios, disease occurs following reactivation of latent infection because of progressive loss of cellular immunity. This can occur in the setting of advanced HIV, following solid or stem cell transplant, prolonged steroids, use of monoclonal antibodies, or chemotherapy.
The incidence of toxoplasmosis infection depends on the seropositivity of Toxoplasma gondii in the population. In the United States, the seropositivity of T. gondii is approximately 10% of the adult population. Seropositivity is higher in Africa and Europe where it can reach up to 80%, and toxoplasma encephalitis could be as high as 25% to 50% of susceptible hosts. The seropositivity in the HIV population mirrors that of the general population.
Even though cats and related felines have traditionally been associated with toxoplasmosis, the prevalence of infection is not related to owning a cat. In the HIV Toxoplasma-seropositive patients with CD4 less than 100 who are not on appropriate prophylaxis, the probability of developing reactivated toxoplasmosis is as high as 30%.
Apart from oral transmission, toxoplasmosis can also be transmitted via the placenta from mother to fetus or through transplantation of an infected organ.
After ingestion of the infective forms, the organism invades the intestinal epithelium and subsequently disseminates throughout the body. At the tissues, which often is the brain but can affect any tissue, they then encyst and lie dormant until immunity wanes. The dormant forms are called bradyzoites while the actively replicating forms are called tachyzoites. Primary toxoplasmosis is often subclinical but could rarely present symptomatically in an immunocompromised seronegative person who became recently exposed to the infective forms. In this scenario, IgM to a toxoplasma is often positive, but IgG is not, unlike most reactivation cases, when IgG is the only positive serology test. As previously outlined, in most situations, clinical toxoplasmosis in the HIV patient is due to reactivation of latent infection as immunity wanes.
The histology usually reveals diffuse encephalitis, cyst-containing lesions, microglial nodules and a lymphocytic vasculitis.
Cerebral toxoplasmosis (toxoplasmic encephalitis), usually with one or more ring-enhancing brain lesions is the typical presentation in HIV patients. Symptoms are often subacute, ranging from a few days to a month. Common symptoms include a headache, confusion, and lethargy. Fever may be present but often absent. There is some suggestion that chronic Toxoplasma infection state may not be completely asymptomatic and in some patients, behavioral changes and neuropsychiatric disorders are possible. Seizures and focal neurologic deficits are also common occurring in up to 30% and 70% of patients respectively. Mental status changes could range from dull affect to stupor and coma often secondary to global encephalitis and/or increased intracranial pressure. On the other hand, the latent/dormant phase is often asymptomatic.
Extracerebral involvement is typically less common than CNS infection. These include pneumonitis, chorioretinitis and less commonly gut, liver, heart, bladder, spinal cord, bone marrow, and testes. Rarely toxoplasmosis may present as a disseminated disease.
There are no routine laboratory findings that are specific for toxoplasmosis. Lactate dehydrogenase (LDH) can be increased markedly in patients with disseminated toxoplasmosis and pulmonary disease.
A presumptive diagnosis of cerebral toxoplasmosis in the HIV patient can be made as follows:
If the above criteria are present, there is at least a 90% probability the diagnosis will be cerebral toxoplasmosis.
It is important to note however that a positive serology does not confirm the diagnosis and a negative serology implies the diagnosis is not likely (though not impossible) to be cerebral toxoplasmosis.
The brain imaging often shows multiple (67%) or single (33%) ring-enhancing brain lesions often associated with edema (See figure). There is a predilection for involvement of the basal ganglia, corticomedullary junction or brain white matter.
A more definitive diagnosis can be made by obtaining lumbar puncture. Cerebrospinal fluid (CSF) analysis will often show mononuclear pleocytosis, elevated protein and sometimes, reduced CSF glucose. Polymerase chain reaction (PCR) testing for T. gondii in CSF is 100% specific but only 44% to 65% sensitive. This suggests a positive CSF PCR result establishes the diagnosis of cerebral toxoplasmosis but a negative one does not rule it out.
When the diagnosis is in doubt and alternative diagnoses considered, brain biopsy can be obtained. Findings in cerebral toxoplasmosis may show necrotic abscesses with blood vessel thrombosis and necrosis. Cysts containing bradyzoites may often be found coexisting with numerous active tachyzoites. In most cases, brain biopsy is not required for diagnosis.
The treatment of toxoplasmosis in HIV-infected patients includes:
Pyrimethamine and sulfadiazine are most commonly employed in treatment. Both agents synergistically and sequentially block folic acid metabolism which is necessary for the development of the parasite. Folinic acid (leucovorin) is often added to replace folate stores which are non-selectively depleted. Initial treatment is typically for six weeks.
Initial therapy is followed by secondary prophylaxis or maintenance therapy which is continued until CD4 plus T-lymphocyte counts are over 200 cells/microliters for more than three months. In addition to awaiting immune recovery, secondary prophylaxis provides continuous therapy against dormant cystic forms which may rupture and reinitiate the infectious process at any time. Maintenance therapy, therefore, is necessary to prevent relapse.
In patients who are allergic to sulfonamides, treatment options include any of the following: clindamycin; trimethoprim/sulfamethoxazole; pyrimethamine plus atovaquone plus folinic acid; pyrimethamine plus azithromycin plus folinic acid; and atovaquone alone (if unable to tolerate sulfur drugs or pyrimethamine).
Spiramycin is the drug of choice in the first trimester of pregnancy as pyrimethamine may be teratogenic.
Most clinicians often employ the use of steroids (when edema is present), but studies have shown its use to be neither beneficial or harmful. The use of steroids in cerebral toxoplasmosis should probably be limited to impending brain herniation as the diagnosis may be clouded once steroid is started before a definitive diagnosis is made.
Treatment course is often dramatic with half the cases showing neurological improvement by day three and in most cases by day seven of treatment commencement. If there is no significant improvement or worsening symptoms by days ten to 14 of therapy, repeat imaging and possibly brain biopsy should be considered. Persistent neurologic sequelae may remain in 37% of survivors and death rate at one year could vary from 10% to 60%.
An integral part of therapy is starting antiretroviral (ART) agents as soon as feasible, usually within 2 weeks of starting anti-toxoplasma therapy. Immune reconstitution inflammatory syndrome (IRIS) which can present as paradoxical worsening of symptoms as immunity recovers is rarer with toxoplasmosis compared to mycobacterial and cryptococcal infections. Even though there are no studies about the optimal timing of ART in toxoplasmosis, early ART has clear benefits and should not necessarily be delayed beyond 2 weeks. 
Once antibiotic treatment has started, improvement is gradual and may take several weeks. Imaging studies need to be repeated in 4-6 weeks to determine if the lesion is decreasing in size.
Long-term therapy is continued at low doses. If the CD4 count improves and the lesion is resolving then one may consider discontinuing the therapy.
Prophylaxis against reactivation of T. gondii in seropositive patients with CD4 lymphocyte counts less than 100 cells/microliter is recommended. Mostly used is trimethoprim/sulfamethoxazole. Other options include dapsone plus pyrimethamine and folinic acid or atovaquone with or without pyrimethamine/leucovorin.
In conclusion, toxoplasmosis should always be included in the differential diagnosis of CNS lesions in advanced HIV/AIDS. Diagnosis is a combination of clinical symptoms and signs, serology and imaging. CSF may further support the diagnosis. Brain biopsy is often reserved for difficult cases. Treatment is often dramatic, and most patients have a favorable clinical outcome.
Besides physicians, the role of the nurse and pharmacist as part of the interprofessional healthcare team cannot be overemphasized in the management of HIV patients with CNS toxoplasmosis. The nurse should emphasize safe sex practices and counsel both partners on sex education. Washing hands after contact with cat litter is highly recommended. In addition, walking bare feet in contaminated soil is not recommended. Patients should be cautioned against the use of intravenous drugs. One should wash hands after coming into contact with raw meat and wear gloves when gardening. Because these patients are on many medications including HAART, the pharmacist is in the ideal position to encourage compliance and oversee the regimen. HIV patients with CNS toxoplasmosis require life long prophylaxis with trimethoprim-sulfamethoxazole and the pharmacist should educate the patient on potential complications if one does not comply with therapy. Finally, these individuals should be told to avoid travel to areas where toxoplasmosis is endemic. Only through an established, integrative, interprofessional team approach can the morbidity and mortality of CNS toxoplasmosis be lowered in HIV patients. [Level 5]
The prognosis of CNS toxoplasmosis in HIV is guarded. Relapses are very common if the treatment is discontinued. Ongoing treatment can lower the risk of recurrent infection. If the disorder is not treated adequately, complications like deafness, seizures, and blindness can occur. Infants with congenitally acquired toxoplasmosis generally have a better outcome than HIV adults. (level V)
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