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 hydrocephalous and the necrotic tissue may calcify.1

Except for T. gondii infection in immunosuppressed individuals such as those with AIDS, the neuropathology of adult-acquired toxoplasmosis stands in sharp contrast to congenital toxoplasmosis and is unimpressive. The first case of autopsied adult toxo was published in 19402 and showed no macroscopic and very few microscopic (“rare focal collections of neutrophils and small round cells”) changes, although there was pathology in the heart and liver. In 1942 Paige, et al, commented on this case and two others: “In the three adults, the neural lesions were few and small”, contrasting the minimal brain findings in adults with the extensive brain pathology in the infant cases.3 In another case, 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.4 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.5There are scattered case reports of CNS pathology in adult toxoplasmosis in immunocompetent hosts, such as meningoencephalitis6  and brain abscess7; however, such reports appear to be rare.

Toxoplasma gondii is known to be highly neurotropic and to infect both neurons and astrocytes.8-9 Studies are underway to better understand how the parasite infects neurons.10 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.11

In individuals who are immunocompromised such as AIDS patients, toxoplasmosis is a common opportunistic infection.  Although one would not expect to see the same histopathology in such individuals as one necessarily finds in immunocompetent individuals, it is nevertheless interesting to see the effects of T. gondii on the immunocompromised brain.

  • The distribution of T. gondii lesions in the AIDS patients is quite consistent in different studies.  Among 35 cases the cerebral hemispheres were involved in 31; basal ganglia in 27; brain stem in 13; and spinal cord in 3.12   In a study of 68 cases necrosis was seen “mainly of periventricular areas of basal ganglia” and “cortical-subcortical border”.13 In a study of 15 cases the changes “were preferentially located in the subcortical or periventricular white matter of the cerebral hemisphere, the basal ganglia, or the cerebellum”.14  Among 28 cases abscesses- “were localized most often in the cerebral hemisphere with a preponderance in the basal ganglia”15.  A review of 6 cases localized abscesses “around the ventricles in basal ganglia and thalamus and peripherally in the cortex—white matter junction”.16
  • Histologically the case series emphasize the variability of the lesions.  Among 35 cases, 26 had multiple abscesses; 4 had exclusively “multiple microglial nodules with scattered encysted bradyzoites and a few tachyzoites within or in the immediate vicinity of microglial modules; and 5 had ill-defined areas of necrosis “accompanied by a weak inflammatory response.”17  Among 15 cases extensive necrosis was seen, described as follows: “In addition to multiple encysted bradysoites, numerous free or intracytoplasmic tachysoites were visualized immunohistochemically at the periphery of the lesions and within adjacent neutrophils, occasionally attacked by macrophages.  In the surrounding tissue some glial nodules were observed, occasionally containing a single pseudocyst”.18

The study of 28 cases also reported “numerous cysts and free trachyzoites” on the periphery of areas of necrosis (Zelman IB and Mossakaowski MJ. Opportunistic infections of the central nervous system in the course of acquired immune deficiency syndrome (AIDS). Folia Neuropathol. 1998; 36:129-144).  Another review emphasized atypical non-necrotic cases “ with microglial nodules, astrocytic gliosis, and proliferation of microglial cells”.19T. gondii is said to be visible with H & E or Giemsa stains but easier to find with a peroxidase-antiperoxidease staining procedure.20  Another study also emphasizes the use of “immunohistochemical techniques and electron microcrospy.”21

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”.22

Neuropath studies of T. gondii  in schizophrenia

In an MRI study of 44 individuals with schizophrenia, it was shown that patients who were seropositive forT. gondii  antibodies had more gray matter reduction than patients who were seronegative.23  Two histological studies have been done. 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.24  In another study, S.K. Halonen et al. used RT-PCR to look for evidence of T. gondii  in the brain (frontal, parietal and temporal samples) of an individual with schizophrenia who was seropositive; no evidence of T. gondii  was found.25

Multiple studies have been carried out in rodents to ascertain the location of the T. gondii brain cysts.  In fact, the cysts are widely distributed and may be found in all areas.  Some but not all studies have reported the highest number of cysts in the frontal cortex and amygdala.26-27

Recent research 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 time28-29;  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.30

Another approach to the neuropathology of T. gondii infection is to examine the effects of T. gondii on inflammatory and immune markers in mouse models.  One study reported that the T. gondii produced changes similar to the effects which have been reported in schizophrenia, including the effects on C-reactive protein; interleukin-1 beta; interferon gamma; and other measures.31 Another approach that should be pursued is more research on the brain cyst stage of toxoplasmosis.  Until recently it was assumed that the brain cysts are dormant; however imaging research has shown that they are not dormant.32

T. gondii and the Intestine

Until recently it was widely assumed that whatever effort T. gondii had on human behavior, including on diseases such as schizophrenia, were a consequence of its direct effect on the brain.  Recent research, however, has suggested that the parasite may also increase susceptibility to brain diseases through immune activation involving the gastrointestinal mucosa.33 For example, one study reported that in a mouse model infection with T. gondii increased antibodies to wheat gluten, thus offering a plausible mechanism tying the gastrointestinal tract to brain dysfunction.34   For a good review of this see reference #35.

T. gondii and the Eye

In addition to going to muscle tissue and the brain, T. gondii often also goes to the eye, especially the retina which is really an extension of the brain.  Whether or not T. gondii goes to the eye appears to depend on several factors including the strain (atypical strains found in South America are more likely to); the route of infection (more common in congenital infections);36 and probably genetic factors.

Regarding the connection between toxoplasmosis and schizophrenia, what is of interest is that both diseases have similar eye symptoms in some patients, specifically nystagmus, strabismus, and impaired visual acuity, and retinal anomalies. 37,38 One small study (n=34) to find ocular toxoplasmosis in patients with schizophrenia was negative.39


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