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Fig. 5.8 Toxoplasmic encephalitis. An area of necrosis with perivascular inflammatory infiltrate and clusters of intracellular tachyzoites (arrow). Extracellular tachyzoites are more difficult to distinguish from fragments of necrotic cells. Haematoxylin and eosin stain. Bar=50 ^m

Frenkel, 1973, 1988). In mice fed bradyzoites, the first step appears to be local invasion of the small intestinal epithelium. The bradyzoite and tachy-zoite are both capable of active invasion of many cell types, and replicate within a parasite-modified vacuole (Dubremetz, 1998; Lingelbach and Joiner, 1998; Schwab et al, 1994). Bradyzoites rapidly convert to tachyzoites in vivo. In vitro the formation of bradyzoite cysts can be stimulated by various maneuvers that stress the infected cells, including change of pH or temperature or various mitochondrial poisons (Dubey et al., 1998; Dubremetz, 1998; Soete et al., 1994). The key step in spreading the infection from the localized initial site is likely infection of circulating monocytes in the lamina propria; this cell subset has been shown to be permissive for T. gondii replication in both mice and humans, and may therefore be responsible for transport of the parasite widely throughout tissues (Fadul et al., 1995).

Tachyzoites are found in all organs in acute infection, most prominently in muscle, including heart, and in liver, spleen, lymph nodes and the central nervous system (Bertoli et al., 1995; Figures 5.8, 5.9). The initial pathological lesion is necrosis caused by death of parasitized cells, with a vigorous acute inflammatory reaction. As the disease progresses, more lymphocytic infiltration develops but true granulomas are not formed. If the host controls the replication of tachyzoites effectively, tissues are restored to

Fig. 5.9 Toxoplasmic myocarditis. Intracellular tachyzoites are within a myocardial muscle cell, which is surrounded by extensive edema and inflammatory infiltrate. Geimsa stain. Bar=50 ^m

anatomic integrity without scarring, and cysts containing the long-lived bradyzoites remain without sign of host reaction. The humoral immune response is rapid and may be capable of killing extracellular tachyzoites (and is of use diagnostically), but it is not protective in the mouse model (Frenkel, 1973). Control of the disease appears to depend on the elaboration of appropriate cytokines including IL-12 and IFNy (Suzuki et al., 1988a; Yap and Sher, 1999a), followed by a specific cell-mediated immunity, with CD8+ helper T cells apparently the most important subgroup (Suzuki, 1999; Yap and Sher, 1999a). In some experimental infections there is intense acute inflammation with few identifiable parasites and early death, which may be caused by an overly vigorous cytokine response to the infection (Khan et al., 1997).

CLINICAL SYNDROMES Acute Disease in Adults

Most individuals positive for T. gondii antibodies have no history of a clinical syndrome that was diagnosed as toxoplasmosis, leading to the supposition that most primary infections are asymptomatic or unrecognized. The most common recognized finding is cervical lymph-adenopathy, usually painless and sometimes accompanied by low-grade fever (McCabe et al., 1987a). Single or multiple enlarged nodes may persist at one site or there may be involvement of many scattered nodes. Toxoplas-mic lymphadenopathy may be evident for weeks, and may need to be distinguished from lymphoma (McCabe et al., 1987b). The other common presentation is a mononucleosis-like syndrome, which is characterized by fever, headache, malaise, lymphadenopathy, hepatosplenomegaly, myalgia and atypical lymphocytosis, and which develops within 1-3 weeks after exposure to infectious material (Krick and Remington, 1978; Remington, 1974; Remington et al., 1995). The symptomatic illness may persist for up to several months. The most severe manifestations of toxoplasmosis in persons with normal immune function are rare and include pneumonitis, myocarditis, meningoencephalitis, polymyositis and systemic disease leading to death (Evans and Schwartzman, 1991; Feldman, 1968a,b; Frenkel, 1985; Greenlee et al., 1975; Krick and Remington, 1978; Mawhorter et al., 1992; Wilder, 1952).

Congenital Disease

Toxoplasma may infect the maternal side of the placenta in the course of acute primary disease, and if the parasite penetrates to the fetal side, the fetus may become infected. The ability of the parasite to cross the placenta depends on the anatomic characteristics of the placenta, which change with the stage of gestation. Total maternal-fetal transmission is about 30% throughout all of gestation, but varies from 6% at 13 weeks to 72% at 36 weeks (Dunn et al., 1999). However, fetuses infected in early pregnancy are at a higher risk of manifesting clinical signs of infection. The two trends combine to give women who seroconvert at 24-30 weeks of gestation the highest risk (10%) of having a congenitally infected child with early clinical signs of infection, a child that is therefore at risk of long-term sequelae.

Congenital infection has been reported only rarely when the mother has antibody to T. gondii or symptoms of primary infection acquired before gestation (Vogel et al., 1996). Evidence of infection within months prior to pregnancy should be considered to carry a small risk of congenital infection. Immunosuppression of women (as with corticosteroid therapy) who have prior T. gondii infections may also lead, rarely, to transplacental transmission of infection. Acute infection is clinically apparent in the minority of infected pregnant women, but both symptomatic and asymptomatic infections can lead to transplacental transmission. The rate of transplacental transmission and the severity of disease varies with time of gestation. A large study of congenital toxoplasmosis in Norway (Jenum et al., 1998) showed that, in 35 940 pregnant women, 10.9% had evidence of infection preceding pregnancy and 0.17% showed evidence of primary infection during pregnancy. Congenital infection was detected in 11 infants and 13% occurred in the first, 29% in the second and 50% in the third trimester. After 1 year of follow-up, only one infant, born without gesta-tional treatment, was clinically affected, with unilateral chorioretinitis. Between 0.6% and 1.3% of women were falsely positive by a commercial IgM assay when tested from the beginning to the end of pregnancy. Of the women infected prior to pregnancy, 6.8% had persisting specific IgM. A positive specific-IgM result had a low predictive value for identifying primary T. gondii infection. Another large screening study found that 50% of positive cord-blood IgM assays were false positives, but of the true positives, 40% of infants had identifiable signs, but not symptoms, of infection (Guerina et al., 1994). These conclusions are in accordance with poor performance of other commercial IgM assays in detection of congenital disease (Wilson et al., 1997). Improvements in IgM assays are under development (Tuuminen et al., 1999), but the low-affinity IgM seen in infants makes serological diagnosis of congenital disease difficult.

The great majority (>75%) of infants born with toxoplasmosis are asymptomatic or have disease that is not detected by routine neonatal examination (Desmonts and Couvreur, 1974a,b; Guerina et al., 1994). Careful ophthalmological examination may reveal evidence of chorioretin-itis in otherwise asymptomatic infants (McAuley et al., 1994). The majority of congenitally infected infants will subsequently develop clinically apparent evidence of infection within months to years (Koppe et al., 1986; Koppe and Meenken, 1999; Wilson et al., 1980). Reactivation of congenital infection may be correlated with Th2-type cytokine responses, which have been noted, in experimental infection, to be associated with progressive disease (Kahi et al., 1999).

Infections in the first trimester and early second trimester may lead to spontaneous abortion, stillbirth or severe neonatal disease (Frenkel, 1974; Remington et al., 1995). The most severely affected organ is the brain, where focal necrosis and perivascular mononuclear inflammation is seen, with intracellular and extracellular tachy-zoites and early cysts. Resolving lesions may show microglial nodules and calcification. Large lesions may be associated with thrombosis of small and medium-sized vessels ofthe white and gray matter. Lesions are frequently periventricular and, when they involve the aqueduct of Sylvius, subsequent fibrosis may lead to hydrocephalus. Neurological sequelae include seizures, developmental delay, deafness, hydrocephalus, microcephalus and prominent intracerebral calcifications. Approximately 75% of clinically apparent congenital toxoplasmosis manifests as visual impairment caused by bilateral retinochoroiditis (Mets et al., 1997). Peripheral retinal lesions may be difficult to detect in infants without an examination under anesthesia. In infants severely affected with congenital toxoplasmosis, systemic manifestations, such as fever, hypothermia, jaundice, hepatosple-nomegaly, diarrhea, vomiting, lymphadenopathy, pneumonitis, myocarditis and petechial or purpu-ric rash, may be evident (McAuley et al., 1994). Laboratory findings may include anemia, throm-bocytopenia, elevated CSF protein and CSF pleocytosis (McAuley et al., 1994). The presence of symptoms and signs of systemic and CNS involvement may not guarantee a bad prognosis, however, in infants who are diagnosed and treated appropriately (McAuley et al., 1994). Factors correlating with poor outcomes include episodes of hypothermia, bradycardia and apnea or hypox-emia. Cerebral atrophy persisting after therapy for hydrocephalus, and CSF protein levels greater than 1 g/dl, have also been noted in infants who have had the worst outcomes in a longitudinal study (McAuley et al., 1994).

Ocular Disease

Involvement of the eye is commonly seen in congenital disease, but recent outbreaks in Canada and Brazil have demonstrated that retinochoroiditis is a more common result of acute primary infection in adults than has been previously appreciated (Bowie et al, 1997; Glasner et al., 1992). In these studies, the high incidence of ocular involvement was associated with infection contracted from food or water. Retinochoroiditis in children and teenagers is most frequently ascribed to congenital infection that was silent or undetected at birth (Mets et al., 1997; Pavesio and Lightman, 1996). Therapy for toxoplasmosis in gestation or in the first year of life may decrease the incidence and/or severity of retinochoroiditis (Peyron et al., 1996). Symptoms of acute retinochoroiditis include blurred vision, scotoma, photophobia and pain, without fever or other systemic manifestations. Funduscopic examination shows evidence of vitritis, with elevated pale, cotton-like patches in the retina, resembling a 'headlight in fog' (Montoya and Remington, 2000). The pathology of the lesions involves coagulative necrosis of the retina with inflammatory infiltrates and loose granulomas in the choroid (Roberts and McLeod, 1999). Healed scars are pale with distinct margins and prominent black pigment of choroidal epithelium (Roberts and McLeod, 1999) (Figure 5.10). Recurrent retinochoroiditis involving the macula may lead to blindness. Vascularization of scars from the choroid may predispose to retinal detachment, especially in those with myopia (Bosch-Driessen et al., 2000; Lafaut et al., 1999). Micro-ophthalmia, strabismus, cataracts, glaucoma and optic atrophy are long-term complications of severe retinochoroiditis.

Disease in Persons with Human Immunodeficiency Virus (HIV) and Other Causes of Immunodeficiency

Cell-mediated immunity is required for the continued control of T. gondii infection, and any disease process or therapeutic regimen that depresses cellular immunity may allow for reactivation of disease, leading to overwhelming

Fig. 5.10 Toxoplasmic retinochoroiditis in a patient with congenital infection. Courtesy of Dr Rima McLeod, University of Chicago infection. The most frequent condition predisposing to systemic toxoplasmosis is advanced HIV disease. Persons with persistently less than 100 CD4+ T cells/^l are at risk for reactivation of previous infection (Israelski et al., 1993; Ruskin and Remington, 1976). There is some evidence that CD8+ T cells are key effectors in long-term immunity to T. gondii (Parker et al., 1991) and the CD8 + cell count falls late in HIV disease. In populations that have a high incidence of inadequately treated opportunistic infections, such as in developing countries, toxoplasmosis may be less prevalent, since patients may die before the disease is manifested. Other immuno-suppressed persons at high risk are those treated for solid organ transplantation, especially those without T. gondii antibody who have been given organs from T. gondii-positive donors (Luft et al., 1983b). Hodgkin's disease and other lymphomas have also been found to predispose to serious Toxoplasma infections. Toxoplasmosis in AIDS is most frequently the result of reactivation of latent infection (Mariuz et al., 1994). The underlying incidence of T. gondii exposure of a population therefore affects the risk of reactiva tion, and patients from groups with high incidence of anti-Toxoplasma antibody are at higher risk. AIDS patients who lack evidence of T. gondii antibody may have symptomatic toxoplasmosis, but disease in the absence of an antibody response is rare, even in advanced immunosuppression. In one series of patients with toxoplasmic encephalitis, 16% of cases had no evidence of IgG antibody (Porter and Sande, 1992). Without chemoprophylaxis, the incidence of reactivation of latent T. gondii infection in AIDS is up to 30% (Mariuz et al., 1994) but the practice of Pneumocystis carinii prophylaxis, which suppresses T. gondii as well, has reduced this dramatically (Richards et al., 1995). There is preliminary evidence that persons who respond to HIV treatment with sustained immune reconstitution above 200 CD4+ T cells/^l of blood are at low risk for toxoplasmic encephalitis, and may be removed from anti-Toxoplasma prophylaxis (Furrer et al., 2000).

Although toxoplasmosis in immunosuppressed individuals can affect all organ systems, there is a remarkable predominance of toxoplasmic encephalitis seen in AIDS patients, which is not fully explained but is thought to be caused by the reactivation of latent cysts in the central nervous system. This disease is usually manifested by multiple necrotizing lesions in the cerebral corticomedullary regions or the basal ganglia, which may be detected by various imaging techniques (see below). Symptoms most frequently include a subacute presentation of fever, headache, altered mental state and/or a wide range of neuropsychiatric manifestations, focal neurological findings (including cranial nerve deficits, cerebellar deficits and movement disorders, weakness and sensory changes) and indications of generalized CNS dysfunction, such as seizures. Signs of meningeal irritation are not usually seen. Laboratory tests of CSF are frequently only minimally abnormal, with CSF protein being the most commonly elevated indicator. The course of disease can also be acute and rapidly fatal.

Other organs involved most frequently in immunosuppressed patients include the heart and lungs (Tschirhart and Klatt, 1988). Toxo-plasmic myocarditis is infrequently symptomatic but may cause arrhythmia and heart failure (Montoya and Remington, 2000). When symptomatic, it may be the predominant feature of disseminated disease (Figure 5.9). Dermal and skeletal myositis has also been described as a symptomatic feature of toxoplasmosis. Pulmonary toxoplasmosis is most frequently seen late in the course of AIDS, and clinically resembles pneumonitis caused by Pseumocystis carina, but is more rapidly progressive, with pulmonary infiltrates and respiratory decompensation. Virtually all other organ systems have been found to harbor tachyzoites in disseminated disease, but clinical symptoms attributable to individual organs other than the brain, heart, muscle and lung are unusual.

DIAGNOSIS Imaging Studies

Lesions in organs other than brain are nonspecific and cannot be distinguished from other infectious processes by imaging studies. In the central nervous system, computed tomography (CT) scans in typical cases of toxoplasmic encephalitis show multiple isodense or hypodense lesions, at the corticomedullary junction or in the basal ganglia, that are enhanced following the administration of intravenous contrast material (Figure 5.11A-C). Lesions may also be single, or the encephalitis may be poorly demarcated, involving the cerebrum diffusely and not producing typical CT or magnetic resonance (MR) images. MR findings typical of toxoplasmic encephalitis are ring enhancement around the lesions on T1-weighted images with gadolinium contrast material, and high signal lesions on T2-weighted images (Figures 5.11B,C). 'Bullseye' lesions may be seen, representing successive expansion and contraction of the necrotic focus with interruption of therapy. CT scans are less sensitive for detecting lesions, even with intravenous contrast (Figure 5.11A) (Knobel et al., 1995; Maschke et al., 1999). Response to therapy, as observed by imaging studies, is slower than the clinical response, taking up to 3 weeks to be evident. Complete resolution of lesions may take up to 6 months, and small residua may persist from large lesions. It is not possible to differentiate completely between the radiographic findings of toxoplasmic encephalitis and CNS lymphoma. Various newer imaging techniques, including positron emission tomography (PET), radionuclide uptake scans and MR proton spectroscopy, have been investigated to help in this differentiation, but none is established as a definitive diagnostic modality.

In cases of congenital infection, calcifications may be detected by plain X-ray or by CT and are suggestive of toxoplasmosis, especially when they are seen outlining a unilaterally or bilaterally enlarged ventricle (Figure 5.12A) (McAuley et al., 1994). Calcifications are more easily detected on CT images (Figure 5.12B).

Laboratory Diagnosis

Direct Detection and Isolation of Parasites

The list of conditions that must be distinguished from toxoplasmosis is large and varies with the clinical circumstances (Table 5.1). The diagnosis of toxoplasmosis may be established by several modalities, the most specific being the identification of tachyzoites within tissue. In most clinical

Fig. 5.11 Toxoplasmic encephalitis in a 31 year-old man with AIDS. The multiple lesions demonstrated by CT scan are better defined by MR scanning. (A) CT scan with intravenous contrast. (B) MR image, T1 weighted with gadolinium contrast. (C) MR scan, T2 weighted. Courtesy of Dr Laurence D. Cromwell, Dartmouth-Hitchcock Medical Center

Fig. 5.11 Toxoplasmic encephalitis in a 31 year-old man with AIDS. The multiple lesions demonstrated by CT scan are better defined by MR scanning. (A) CT scan with intravenous contrast. (B) MR image, T1 weighted with gadolinium contrast. (C) MR scan, T2 weighted. Courtesy of Dr Laurence D. Cromwell, Dartmouth-Hitchcock Medical Center circumstances this is not necessary, and serolo-gical tests may be used to establish the diagnosis and rule out other conditions.

Tissue biopsies may demonstrate tachyzoites or cysts, which stain with hematoxylin and eosin in routine histopathological preparations. The Romanovsky stains, such as Geimsa and Wright's, also demonstrate T. gondii forms well (Figure 5.13). The parasite is most easily seen as clusters of slightly elongate to oblate 5.7 x 2.3 ^ nucleated bodies, within a vacuole inside infected cells. The parasite can be found in various cell types, including endothelial cells, fibroblasts, hepatocytes, myocytes, macrophages and various cells of the central nervous system. This characteristic differentiates T. gondii from other intracellular parasites, which infect only a single cell type. Yeast such as Histoplasma capsulatum, which may be found in macrophages, may have a similar appearance but are usually smaller and more abundant than T. gondii and may demonstrate budding division. The hemoflagellates, such as Leishmania and Trypanosoma cruzi, demonstrate both nuclei and deeply staining kinetoplasts within individual organisms. Extracellular T. gondii tachyzoites are easily seen by

Fig. 5.12 Congenital toxoplasmosis. Periventricular calcifications are demonstrated in the brain of a 7 month-old boy by plain films and CT scan. (A) Plain film (B) CT scan without contrast. The calcifications are prominent white areas surrounding the dilated ventricles. Courtesy of Dr Laurence D Cromwell, Dartmouth-Hitchcock Medical Center

Fig. 5.12 Congenital toxoplasmosis. Periventricular calcifications are demonstrated in the brain of a 7 month-old boy by plain films and CT scan. (A) Plain film (B) CT scan without contrast. The calcifications are prominent white areas surrounding the dilated ventricles. Courtesy of Dr Laurence D Cromwell, Dartmouth-Hitchcock Medical Center standard stains, but may be obscured in necrotic areas that have abundant cell debris and inflammatory infiltrate. Specific immunological staining may demonstrate T. gondii antigen in such necrotic lesions. Cytocentrifuge preparations of cerebrospinal fluid, amniotic fluid or broncho-alveolar lavage fluid may also demonstrate tachyzoites. None of these morphological techniques is sensitive, and many lesions attributable to T. gondii infection have no identifiable parasites. Toxoplasmic lymphadenitis is characterized by reactive follicular hyperplasia, irregular infiltrates of large histiocytes ('epi-theloid cells') at the germinal center margin and scattered islands of monocytic and apoptotic cells in distended sinuses. Cysts may be stained by the periodic acid-Schiff (PAS) protocol, which stains both the cyst wall of the mature cyst and the intracellular amylopectin of individual brady-zoites, or by argyrophilic stains, which stain cyst walls. Finding cysts does not establish the diagnosis of acute disease in the absence of necrosis and inflammation, since they may be stable for years.

Alternatives to morphological identification of tachyzoites are tissue culture, animal inoculation and detection of specific T. gondii DNA by amplification techniques. Culture of live parasites definitively establishes the etiology of infection in tissues, but it is relatively insensitive and slow, taking up to several weeks. Many tissue culture lines may be used, but human fibroblasts are the most easily observed for evidence of parasite growth. Peritoneal inoculation of mice is a more sensitive technique, especially for strains of genetic type I, which may kill mice with a single infective parasite. Some strains of T. gondii may not elicit clinical disease in mice, however, and the infection may have to be detected by serology of mouse blood, or by examination of brains for cysts after 4-6 weeks (Dubey and Beattie, 1998). No culture approaches are readily available in clinical laboratories, but may be available from the Toxoplasma Reference Laboratories. PCR amplification of parasite DNA from tissue, CSF, amniotic fluid or blood is a sensitive method for detection of infection, and several potential amplification targets have been described. The B1 gene, which is present in all T. gondii strains in 35 copies, has been the most frequently used target (Grover et al, 1990) but SAG1, the major surface antigen gene, and ribosomal gene targets have also been described (Contini et al., 1999). PCR is available from several reference laboratories and is the preferred test for establishment of infection during gestation, by assay of amniotic fluid (Foulon et al., 1999a; Grover et al., 1990).

Table 5.1 Differential diagnoses for toxoplasmosis in various circumstances

Clinical setting

Possible alternative etiological agents Distinguishing points

Tissue biopsy or aspirate with intracellular organisms seen morphologically

Mononucleosis syndrome


Congenital infection

Retinochoroiditis in immunocompetent individuals

Retinochoroiditis in AIDS

CNS lesions in AIDS

Histoplasma capsulatum Leishmania spp. Trypanosoma cruzi Other intracellular yeast EBC CMV

Acute HIV

African trypanosomiasis

South American trypanosomiasis

Cat scratch disease







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