VII.  Neuropathology of T. gondii

The neuropathology of schizophrenia is subtle, with mild atrophy and dilated ventricles. The brain regions of greatest interest have been the prefrontal cortex, hippocampus, and association cortex, which includes the superior temporal gyrus and inferior parietal lobule; other areas, such as the cingulate, basal ganglia, thalamus, and cerebellum, are also thought to be involved. Abnormalities have been described in both neurons and glia.

The neuropathology of congenital toxoplasmosis has been well described. It consists of periaqueductal and periventricular vasculitis with necrosis. Obstruction of the aqueduct may produce hydrocephalis and the necrotic tissue may calcify (Frenkel JK, Pathology and pathogenesis of congenital toxoplasmosis, Bull NY Acad Med 1974;50;182–191).

The neuropathology of T. gondii infection acquired after birth has been less completely described except for cases of immunosuppression, such as AIDS. In one of the few cases reported, a 6-year-old boy died from acute toxoplasma encephalitis and was autopsied one hour after death. According to the report, “there was no gross pathologic change . . . [and] the paucity of microscopic abnormalities was equally surprising.” The author concluded: “It is also remarkable how the observations in this case differ from the extensive, gross and microscopic changes which have been observed in the one proved case of ‘congenital’ encephalitis due to toxoplasma (Sabin AB, Toxoplasmic encephalitis in children, JAMA 1941;116:801–807). Other case reports have also noted the paucity of CNS findings in adult toxoplasmosis; however, one study reported widespread pathological findings in other organs, including the liver and spleen (Callahan WP, Russell WO, Smith MG, Human toxoplasmosis: a clinicopathologic study with presentation of five cases and review of the literature, Medicine 1946;25:343–397). There are scattered case reports of CNS pathology in adult toxoplasmosis in immunocompetent hosts, such as meningoencephalitis (Kaushik RM, Mahajan SK, Sharma A et al., Toxoplasmic meningoencephalitis in an immunocompetent host Trans R Soc Trop Med Hyg 2005;99:874–878) and brain abscess (Silva LA, Vieira RS, Serafini LN et al., [Toxoplasmosis of the central nervous system in a patient without immunosuppression: case report], Rev Soc Bras Med Trop 2001;34:487–490); however, such reports appear to be rare.

T. gondii is known to be highly neurotropic and to infect both neurons and astrocytes (Halonen SK, Lyman WD, Chiu FC, Growth and development of Toxoplasma gondii in human neurons and astrocytes, J Neuropath Exp Neurol 1996;55:1150–1156; Cruzet C, Robert F, Roisin MP et al., Neurons in primary culture are less efficiently infected by Toxoplasma gondii than glial cells, Parasitol Res 1998;84:25–30). In non-immunosuppressed individuals who are diagnosed with acute toxoplasmic encephalitis, the CSF shows moderately elevated protein, normal glucose levels, and T. gondii “is rarely isolated from the CSF.” Necrosis and an intense inflammatory reaction are seen on autopsy (Post MJD, Chan JC, Hensley GT, Toxoplasma encephalitis in Haitian adults with acquired immunodeficiency syndrome: a clinical-pathologic-CT correlation, Am J Roentgenol 1983;140:861–868). In immunosuppressed individuals, T. gondii may cause an acute necrotizing encephalitis that is most severe in the frontal and parietal lobes, basal ganglia, and thalamus (Shankar SK, Mahadevan A, Satishchandra P et al., Neuropathology of HIV/AIDS with an overview of the Indian scene, Indian J Med Res 2005;121:468–488; Dellacasa-Lindberg I, Hitziger N, Barragan A, Localized recrudescence of Toxoplasma infections in the central nervous system of immunocompromised mice assessed by in vivo bioluminescence imaging, Microbes Infect 2007;9:1291–1298).

Less information is available on the neuropathology of individuals chronically infected with T. gondii with bradyzoites. A study of 46 postmortem cases of AIDS patients with T. gondii infection reported “one case with intact tissue cysts in the parietal white matter as the only histopathologically identifiable lesion” (Strittmatter C, Lang W, Wiestler OD et al., The changing pattern of human immunodeficiency virus-associated cerebral toxoplasmosis: a study of 46 postmortem cases, Acta Neuropathol 1992;83:475–481).

     Neuropath studies of T. gondii in schizophrenia

One study has been carried out. Conejero-Goldberg studied the orbital frontal cortex of  postmortem specimens from 14 individuals with schizophrenia, 11 with other psychiatric   diagnoses, and 26 normal controls. The primers “were designed to amplify a conserved region in the parasitic genome and a fragment of the hsp/Bag1gene (a bradyzoite-expressed gene)” using a nested polymerase chain reaction. All specimens were negative (Conejero-Goldberg C, Torrey EF, Yolken RH, Herpesviruses and Toxoplasma gondii in orbital frontal cortex of psychiatric patients, Schizophr Res 2003;60:65–69).

Recent research, not yet published, suggests that the methods used for fixing and freezing postmortem brain tissue may destroy the T. gondii cysts; if this is true, then it may be virtually impossible to find cysts in human postmortem brain tissue using currently available methods. Other studies of mice have suggested that the number of cysts in the brain decreases over time (Blackwell JM, Roberts CW, Alexander J, Influence of genes within the MHC on mortality and brain cyst development in mice infected with Toxoplasma gondii: kinetics of immune regulation in BALB H-2 congenic mice, Parasite Immunol 1993;15:317–324; Hunter CA, Roberts CW, Alexander J, Kinetics of cytokine mRNA production in the brains of mice with progressive toxoplasmic encephalitis, Eur J Immunol 1992;22:2317–2322); this would also make it difficult to find cysts in older tissue.

     Other means of identifying T. gondii in brain tissue

In addition to neuropathological studies, it is also possible to identify the presence of T. gondii in brain tissue by inoculating the brain tissue into mice known to be uninfected and then looking for evidence of infection. A 1965 study that did this with brain autopsy tissue from 44 individuals known to have serological antibodies to T. gondii reported that the mice became antibody-positive in 4 of the 44 cases. In other cases, in addition to the 44, the mice became antibody-positive after being injected with muscle tissue (Remington JS, Cavanaugh AB, Isolation of the encysted form of Toxoplasma gondii from human skeletal muscle and brain, N Engl J Med 1965;273:1308–1310).