A 37-year-old homosexual man who has been active with multiple partners without taking precautions begins to experience fever and persistent headaches. Over the next two weeks, he develops mild nausea with occasional vomiting. He then starts to hallucinate and exhibit irrational behavior, at which point his friends bring him to the ER. Vital signs are normal, except for a mild fever (38.5ºC). The man is confused and disoriented. His visual fields appear to be reduced, he has a number of movement disorders, particularly on the left, and he is displaying signs of aphasia.

Question 10.1: What tests should you do?

The man's history of sexual activity raises the possibility of a sexually transmitted disease, especially AIDS, so tests for HIV infection should be performed. In regard to the neurological symptoms, a cerebral CT scan or MRI would be most helpful. A lumbar puncture could be helpful as well, but is justified only if it reasonably certain the intracranial pressure is not overly elevated.

Test Results:

The patient's CD4+ lymphocyte count is 57 cells/microliter, and his CD4+/CD8+ cell ratio is 0.05. The level of HIV-1 RNA copies is 51,500/mL. HIV tests (both ELISA and Western blot assays) are positive as well. The CT scan reveals the presence of multiple bright intracranial mass lesions in the right hemisphere, especially in the basal ganglia and corticomedullary junction.

Question 10.2: What is your diagnosis?

The man is clearly in an advanced stage of AIDS. The mass lesions are characteristic of cerebral toxoplasmosis, which usually develops only in immunocompromised individuals. However, the lesions could also be result of a CNS lymphoma, about 40% of which are multifocal.

Question 10.3: How is the diagnosis confirmed?

In patients with AIDS, the presence of IgG antibodies (detected by ELISA and other methods) in serum and radiologic findings consistent with toxoplasmosis are grounds for a presumptive diagnosis, in which case therapy should be started immediately. Definitive diagnosis of toxoplasmosis requires demonstration of the causative agent, Toxoplasma gondii, as trophozoites and cysts in tissues or body fluids. Biopsy specimens from lymph nodes, brain, myocardium, or other suspected tissues, as well as body fluids, including CSF and amniotic fluid can be examined directly for the organisms. Newer monoclonal antibody-based fluorescent stains can facilitate the direct detection of T. gondii in tissue. PCR-based methods are currently under development and might a rapid and sensitive method for detection of the organism in fluids in the near future.

Question 10.4: What is the pathogen's life cycle?

Cats and other felines are the essential reservoir hosts for T. gondii. The protozoan develops in the intestinal cells of the cat, as well as during an extraintestinal cycle with passage to the tissues via the bloodstream. The organisms from the intestinal cycle are passed in cat feces and mature into infective cysts within 3-4 days in the external environment. The infected oocysts may be ingested by other animals, after which they can produce acute or chronic infections. A wide range of animals, including humans and birds, can be infected with T. gondii. These terminal hosts can also be infected by consuming animal tissues that are infected with cysts that contain bradyzoites or sporulated oocysts.

In non-feline hosts, bradyzoites or sporozoites (released when cysts are digested by gastric acid) enter the small-intestinal epithelium and transform into rapidly dividing tachyzoites. The tachyzoites then migrate through the bloodstream to various tissues, where they replicate as intracellular parasites that destroy the host cells. The organism has a particular predilection for cells of the CNS, lungs, heart, and lymphoid organs. Most tachyzoites are eliminated by the host's humoral and cell-mediated immune responses. Tissue cysts containing many bradyzoites develop 7 to 10 days after the systemic tachyzoite infection. Although the cysts can occur in a variety of organs, they especially tend to persist within the CNS and muscle. Development of this chronic stage of infection completes the non feline portion of the T. gondii life cycle.

Question 10.5: How is this disease transmitted?

Transmission to humans is usually by the oral route, either by ingestion of the sporulated oocysts from soil contaminated with feline feces or by ingestion of undercooked meat that contains tissue cysts and bradyzoites (see above). Direct transmission of the parasite by blood or organ products is also possible, but rare. Transplancental transmission during pregnancy is also possible; in fact, about one-third of all women who become infected with T. gondii during pregnancy transmit the parasite to the fetus.

Question 10.6: How did the man's disease develop?

He was probably infected many years earlier, before he become immunocompromised. Most T. gondii infections in otherwise healthy individuals are benign and asymptomatic, so the individual never knows they were infected. Persistence of infection with cysts containing bradyzoites (see above) is common in immunocompetent hosts, but this lifelong infection usually remains asymptomatic and, like the initial infection, goes unnoticed. Bradyzoites are in a slow metabolic state, but cysts do degenerate and rupture within the CNS. This degenerative process, with the development of new cysts, is the most likely source of recrudescent infection in immunocompromised hosts. The reduced immune responses in these hosts are unable to control the infection, so it develops into an acute form of the disease. In AIDS victims, encephalitis typically develops when the CD4+ cell count falls below 100/microliter.

Question 10.7: How should you treat this case?

In an immunocompromised individual, cerebral toxoplasmosis can be rapidly fatal if untreated. The patient in this case should be given initial high doses of pyrimethamine and sulfadiazine, followed by lower doses of both drugs for an indefinite period of time. Toxicity of this drug combination (rash and bone marrow suppression) may necessitate a change to alternative agents. The best studied alternative is clindamycin plus pyrimethamine. Of course, this patient must also be started on aggressive antiretroviral therapy, in hopes of controlling the HIV infection.