Congenital Toxoplasmosis

Transmission to the fetus usually follows acquisition of infection by an immunologically normal mother during gestation. Congenital transmission from mothers infected before pregnancy is extremely rare except for immunocompromised women who are chronically infected. The incidence of congenital infection in the USA ranges from 1/1,000 to 1/8,000 live births. The incidence of infection among pregnant women depends on the general risk for infection in the specific locale and the proportion of the population that has not been infected previously.

Congenital Toxoplasmosis

When a mother acquires infection during gestation, organisms may disseminate hematogenously to the placenta. Infection may be transmitted to the fetus transplacentally or during vaginal delivery. Of untreated maternal infections acquired in the 1st trimester, approximately 17% of fetuses are infected, usually with severe disease. Of untreated maternal infection acquired in the 3rd trimester, approximately 65% of fetuses are infected, usually with disease that is mild or inapparent at birth. These different rates of transmission and outcomes are most likely related to placental blood flow, virulence, inoculum of T. gondii, and immunologic capacity of the mother to limit parasitemia.

Examination of the placenta of infected newborns may reveal chronic inflammation and cysts. Tachyzoites can be seen with Wright or Giemsa stains but are best demonstrated with immunoperoxidase technique. Tissue cysts stain well with periodic acid–Schiff and silver stains as well as with the immunoperoxidase technique. Gross or microscopic areas of necrosis may be present in many tissues, especially the CNS, choroid and retina, heart, lungs, skeletal muscle, liver, and spleen. Areas of calcification occur in the brain.

Almost all congenitally infected individuals who are not treated manifest signs or symptoms of infection, such as chorioretinitis, by adolescence. Some severely involved infants with congenital infection appear to have Toxoplasma antigen–specific cell-mediated anergy, which may be important in the pathogenesis of disease.

Acquired Toxoplasmosis

Immunocompetent children who acquire infection postnatally generally do not have clinically recognizable symptoms. When clinical manifestations are apparent, they may include almost any combination of fever, stiff neck, myalgia, arthralgia, maculopapular rash that spares the palms and soles, localized or generalized lymphadenopathy, hepatomegaly, hepatitis, reactive lymphocytosis, meningitis, brain abscess, encephalitis, confusion, malaise, pneumonia, polymyositis, pericarditis, pericardial effusion, and myocarditis. Chorioretinitis is usually unilateral and occurs in approximately 1% of cases in the USA. Half the cases of ocular toxoplasmosis in English children are due to acute acquired infection; the appearance does not distinguish acute vs. congenital infection. Symptoms may be present for a few days only or may persist many months. The most common manifestation is enlargement of 1 or a few cervical lymph nodes. Cases of Toxoplasma lymphadenopathy rarely resemble infectious mononucleosis, Hodgkin’s disease, or other lymphadenopathies (Chapter 484). In the pectoral area in older girls and women, enlarged nodes may be confused with breast neoplasms. Mediastinal, mesenteric, and retroperitoneal lymph nodes may be involved. Involvement of intra-abdominal lymph nodes may be associated with fever, mimicking appendicitis. Nodes may be tender but do not suppurate. Lymphadenopathy may wax and wane for as long as 1-2 yr.

Almost all patients with lymphadenopathy recover spontaneously without antimicrobial therapy. Significant organ involvement in immunologically normal persons is uncommon, although some individuals have suffered significant morbidity, including rare cases of encephalitis, brain abscesses, hepatitis, myocarditis, pericarditis, and polymyositis. In persons acquiring T. gondii in Guyana and along Amazon tributaries, a severe form of multivisceral involvement with fever has occurred.

Ocular Toxoplasmosis

In the USA and Western Europe, T. gondii is estimated to cause 35% of cases of chorioretinitis (Fig. 282-2). In Brazil, T. gondii retinal lesions are common. Clinical manifestations include blurred vision, visual floaters, photophobia, epiphora, and, with macular involvement, loss of central vision. Ocular findings of congenital toxoplasmosis also include strabismus, microphthalmia, microcornea, cataracts, anisometropia, nystagmus, glaucoma, optic neuritis, and optic atrophy. Episodic recurrences are common, but precipitating factors have not been defined.

Figure 282-2 Toxoplasmic chorioretinitis. A, Active acute lesion by indirect ophthalmoscopy. B, The healed foci of toxoplasmic chorioretinitis may resemble a coloboma (macular pseudocoloboma).

(B, Adapted from Desmonts G, Remington J: Congenital toxoplasmosis. In Remington JS, Klein JO, editors: Infectious diseases of the fetus and newborn infant, ed 5, Philadelphia, 2001, WB Saunders.)

Immunocompromised Persons

Disseminated T. gondii infection among older children who are immunocompromised by AIDS, malignancy, cytotoxic therapy or corticosteroids, or immunosuppressive drugs given for organ transplantation involves the CNS in 50% of cases and may also involve the heart, lungs, and gastrointestinal tract. Stem cell transplant recipients present a special problem, because active infection is particularly difficult to diagnose. After transplantation, T. gondii-specific antibody levels may remain the same, increase, or decrease and can even become undetectable. Most often immunoglobulin G (IgG) antibody is present; thus, toxoplasmosis in these patients almost always results from transplantation from a seropositive individual to a seronegative recipient. Active infection is often fulminant and rapidly fatal.

Congenital T. gondii infection in infants with HIV infection is rare and is often a severe and fulminant disease with substantial CNS involvement. Alternatively, it may be more indolent in presentation, with focal neurologic deficits or systemic manifestations such as pneumonitis.

From 25-50% of persons with T. gondii antibodies and HIV infection without antiretroviral treatment eventually experience toxoplasmic encephalitis, which is fatal if not treated. Highly active antiretroviral therapy and trimethoprim-sulfamethoxazole prophylaxis have diminished the incidence of toxoplasmosis in patients with HIV infection, but toxoplasmic encephalitis remains a presenting manifestation in 20% of adult patients with AIDS. Typical findings include fever, headache, altered mental status, psychosis, cognitive impairment, seizures, and focal neurologic defects, including hemiparesis, aphasia, ataxia, visual field loss, cranial nerve palsies, and dysmetria or movement disorders. In adult patients with AIDS, toxoplasmic retinal lesions are often large with diffuse necrosis and contain many organisms but little inflammatory cellular infiltrate. Diagnosis of presumptive toxoplasmic encephalitis based on neuroradiologic studies in patients with AIDS necessitates a prompt therapeutic trial of medications effective against T. gondii. Clear clinical improvement within 7-14 days and improvement of neuroradiologic findings within 3 wk makes the presumptive diagnosis almost certain.

Congenital Toxoplasmosis

Congenital toxoplasmosis usually occurs when a woman acquires primary infection while pregnant. Most often, maternal infection is asymptomatic or without specific symptoms or signs. As with other adults with acute toxoplasmosis, lymphadenopathy is the most common symptom.

In monozygotic twins the clinical pattern of involvement is most often similar, whereas in dizygotic twins the manifestations often differ, including cases of congenital infection in only 1 twin. The major histocompatibility complex class II gene DQ3 appears to be more frequent among HIV-infected persons seropositive for T. gondii who develop toxoplasmic encephalitis, and in children with congenital toxoplasmosis who develop hydrocephalus. These findings suggest that the presence of HLA-DQ3 is a risk factor for severity of toxoplasmosis. Other allelic variants of genes, including Col2A, ABC4r, P2X7r, Nalp1, TLR9, and ERAAP are also associated with susceptibility.

Congenital infection may present as a mild or severe neonatal disease or with sequelae or relapse of a previously undiagnosed and untreated infection later in infancy or even later in life. There is a wide variety of manifestations of congenital infection, ranging from hydrops fetalis and perinatal death to small size for gestational age, prematurity, peripheral retinal scars, persistent jaundice, mild thrombocytopenia, cerebrospinal fluid (CSF) pleocytosis, and the characteristic triad of chorioretinitis, hydrocephalus, and cerebral calcifications. More than 50% of congenitally infected infants are considered normal in the perinatal period, but almost all such children develop ocular involvement later in life if they are not treated during infancy. Neurologic signs such as convulsions, setting-sun sign with downward gaze, and hydrocephalus with increased head circumference may be associated with or without substantial cerebral damage or with relatively mild inflammation obstructing the aqueduct of Sylvius. If affected infants are treated promptly, signs and symptoms may resolve and development may be normal.

The spectrum and frequency of neonatal manifestations of 210 newborns with congenital Toxoplasma infection identified by a serologic screening program of pregnant women are presented in Table 282-1. In this study, 10% had severe congenital toxoplasmosis with CNS involvement, eye lesions, and general systemic manifestations; 34% had mild involvement with normal clinical examination results other than retinal scars or isolated intracranial calcifications; and 55% had no detectable manifestations. These numbers represent an underestimation of the incidence of severe congenital infection for several reasons: the most severe cases, including most of those individuals who died, were not referred; therapeutic abortion was often performed when acute acquired infection of the mother was diagnosed early during pregnancy; in utero spiramycin therapy may have diminished the severity of infection; and only 13 infants had brain CT and 23% did not have a CSF examination. Routine newborn examinations often yield normal findings for congenitally infected infants, but more careful evaluations may reveal significant abnormalities. In 1 study of 28 infants identified by a universal state-mandated serologic screening program for T. gondii–specific IgM, 26 had normal findings on routine newborn examination and 14 had significant abnormalities detected with more careful evaluation. The abnormalities included retinal scars (7 infants), active chorioretinitis (3 infants), and CNS abnormalities (8 infants). In Fiocruz, Belo Horizonte, Brazil, infection is common, occurring in 1/600 live births. Half of these infected infants have active chorioretinitis at birth.

Table 282-1 SIGNS AND SYMPTOMS IN 210 INFANTS WITH PROVED CONGENITAL TOXOPLASMA INFECTION*

* Infants were identified by prospective study of infants born to women who acquired Toxoplasma gondii infection during pregnancy.

Data adapted from Couvreur J, Desmonts G, Tournier G, et al: A homogeneous series of 210 cases of congenital toxoplasmosis in 0 to 11-month-old infants detected prospectively, Ann Pediatr (Paris) 31:815–819, 1984.

There is also a wide spectrum of symptoms of untreated congenital toxoplasmosis that presents later in the 1st yr of life (Table 282-2). More than 80% of these children have IQ scores of <70, and many have convulsions and severely impaired vision.

Table 282-2 SIGNS AND SYMPTOMS OCCURRING BEFORE DIAGNOSIS OR DURING THE COURSE OF UNTREATED ACUTE CONGENITAL TOXOPLASMOSIS IN 152 INFANTS (A) AND IN 101 OF THESE SAME CHILDREN AFTER THEY HAD BEEN FOLLOWED 4 YR OR MORE (B)

* Patients with otherwise undiagnosed central nervous system disease in the 1st yr of life.

^† Patients with otherwise undiagnosed non-neurologic diseases during the 1st 2 mo of life.

Adapted from Eichenwald H: A study of congenital toxoplasmosis. In Slim JC, editor: Human toxoplasmosis, Copenhagen, 1960, Munksgaard, pp 41–49. Study performed in 1947. The most severely involved institutionalized patients were not included in the later study of 101 children.

Skin

Cutaneous manifestations among newborn infants with congenital toxoplasmosis include rashes, petechiae, ecchymoses, and large hemorrhages secondary to thrombocytopenia. Rashes may be fine punctate, diffuse maculopapular, lenticular, deep blue-red, sharply defined macular, or diffuse blue and papular. Macular rashes involving the entire body including the palms and soles, exfoliative dermatitis, and cutaneous calcifications have been described. Jaundice with hepatic involvement and/or hemolysis, cyanosis due to interstitial pneumonitis from congenital infection, and edema secondary to myocarditis or nephrotic syndrome may be present. Jaundice and conjugated hyperbilirubinemia may persist for months.

Endocrine Abnormalities

Endocrine abnormalities may occur secondary to hypothalamic or pituitary involvement or end-organ involvement. Reported endocrinopathies include myxedema, persistent hypernatremia with vasopressin-sensitive diabetes insipidus without polyuria or polydipsia, sexual precocity, and partial anterior hypopituitarism.

Central Nervous System

Neurologic manifestations of congenital toxoplasmosis vary from massive acute encephalopathy to subtle neurologic syndromes. Toxoplasmosis should be considered as a potential cause of any undiagnosed neurologic disease in children <1 yr of age, especially if retinal lesions are present.

Hydrocephalus may be the sole clinical neurologic manifestation of congenital toxoplasmosis and may be compensated but most often requires shunt placement. Hydrocephalus may present prenatally and progress during the perinatal period, or, less commonly, may present later in life. Patterns of seizures are protean and have included focal motor seizures, petit and grand mal seizures, muscular twitching, opisthotonus, and hypsarrhythmia. Spinal or bulbar involvement may be manifested by paralysis of the extremities, difficulty swallowing, and respiratory distress. Microcephaly usually reflects severe brain damage, but some children with microcephaly caused by congenital toxoplasmosis who have been treated have normal or superior cognitive function. Untreated congenital toxoplasmosis that is symptomatic in the 1st yr of life can cause substantial diminution in cognitive function and developmental delay. Intellectual impairment also occurs in some children with subclinical infection without or despite treatment with pyrimethamine and sulfonamides. Seizures and focal motor defects may become apparent after the newborn period, even when infection is subclinical at birth.

CSF abnormalities occur in at least 30% of infants with congenital toxoplasmosis. A CSF protein level of >1 g/dL is characteristic of severe CNS toxoplasmosis and is usually accompanied by hydrocephalus. Local production of T. gondii–specific IgG and IgM antibodies may be demonstrated. CT of the brain is useful to detect calcifications, determine ventricular size, and demonstrate porencephalic cystic structures (Fig. 282-3). Calcifications occur throughout the brain, but there is a propensity for development of calcifications in the caudate nucleus and basal ganglia, choroid plexus, and subependyma. MRI and contrast-enhanced CT brain scans are useful for detecting active inflammatory lesions. MRIs that take only a brief time (<45 sec) for imaging or ultrasonography may be useful for following ventricular size. Treatment in utero and in the 1st yr of life results in improved neurologic outcomes.

Figure 282-3 Head CT scans of infants with congenital toxoplasmosis. A, CT scan at birth that shows areas of hypolucency, mildly dilated ventricles, and small calcifications. B, CT scan of the same child at 1 yr of age (after antimicrobial therapy for 1 yr). This scan is normal with the exception of 2 small calcifications. This child’s Mental Development Index (MDI) at 1 yr of age was 140 by the Bayley Scale of Infant Development. C, CT scan from a 1 yr old infant who was normal at birth. His meningoencephalitis became symptomatic in the 1st weeks of life but was not diagnosed correctly and remained untreated during his 1st 3 mo of life. At 3 mo of age, development of hydrocephalus and bilateral macular chorioretinitis led to the diagnosis of congenital toxoplasmosis, and antimicrobial therapy was initiated. This scan shows significant residual atrophy and calcifications. This child had substantial motor dysfunction, development delays, and visual impairment. D, CT scan obtained during the 1st mo of life of a microcephalic child. Note the numerous calcifications. This child’s IQ scores using the Stanford-Binet Intelligence Scale for children when she was 3 yr of age and the Wechsler Preschool and Primary Scale Intelligence when she was 5 yr of age were 100 and 102, respectively. She received antimicrobial therapy during her 1st yr of life. E, CT scan with hydrocephalus owing to aqueductal stenosis, before shunt. F, Scan from the same patient as the scan in E, after shunt. This child’s IQ scores using the Stanford-Binet Intelligence Scale for children were approximately 100 when she was 3 and 6 yr of age.

(Adapted from McAuley J, Boyer K, Patel D, et al: Early and longitudinal evaluations of treated infants and children and untreated historical patients with congenital toxoplasmosis: the Chicago Collaborative Treatment Trial, Clin Infect Dis 18:38–72, 1994.)

Eyes

Almost all untreated congenitally infected infants develop chorioretinal lesions by adulthood, and about 50% will have severe visual impairment. T. gondii causes a focal necrotizing retinitis in congenitally infected individuals (see Fig. 282-2). Retinal detachment may occur. Any part of the retina may be involved, either unilaterally or bilaterally, including the maculae. The optic nerve may be involved, and toxoplasmic lesions that involve projections of the visual pathways in the brain or the visual cortex also may lead to visual impairment. In association with retinal lesions and vitritis, the anterior uvea may be intensely inflamed, leading to erythema of the external eye. Other ocular findings include cells and protein in the anterior chamber, large keratic precipitates, posterior synechiae, nodules on the iris, and neovascular formation on the surface of the iris, sometimes with increased intraocular pressure and glaucoma. The extraocular musculature may also be involved directly. Other manifestations include strabismus, nystagmus, visual impairment, and microphthalmia. Enucleation has been required for a blind, phthisic, painful eye. The differential diagnosis of ocular toxoplasmosis includes congenital coloboma and inflammatory lesions caused by cytomegalovirus, Treponema pallidum, Mycobacterium tuberculosis, or vasculitis. Ocular toxoplasmosis may be a recurrent and progressive disease that requires multiple courses of therapy. Limited data suggest that occurrence of lesions in the early years of life may be prevented by instituting antimicrobial treatment with pyrimethamine and sulfonamides during the 1st yr of life and that treatment of the infected fetus in utero followed by treatment in the 1st yr of life with pyrimethamine, sulfadiazine, and leukovorin reduces the incidence and the severity of the retinal disease.

Ears

Sensorineural hearing loss, both mild and severe, may occur. It is not known whether this is a static or progressive disorder. Treatment in the 1st yr of life is associated with decreased frequency of hearing loss.

Culture

Organisms are isolated by inoculation of body fluids, leukocytes, or tissue specimens into mice or tissue cultures. Body fluids should be processed and inoculated immediately, but T. gondii has been isolated from tissues and blood that have been stored overnight or even for 4-5 days at 4°C. Freezing or treatment of specimens with formalin kills T. gondii. From 6 to 10 days after inoculation into mice, or earlier if mice die, peritoneal fluids should be examined for tachyzoites. If inoculated mice survive for 6 wk and seroconvert, definitive diagnosis is made by visualization of Toxoplasma cysts in mouse brain. If cysts are not seen, subinoculations of mouse tissue into other mice are performed.

Microscopic examination of tissue culture inoculated with T. gondii shows necrotic, heavily infected cells with numerous extracellular tachyzoites. Isolation of T. gondii from blood or body fluids reflects acute infection. Except in the fetus or neonate, it is usually not possible to distinguish acute from past infection by isolation of T. gondii from tissues such as skeletal muscle, lung, brain, or eye obtained by biopsy or at autopsy.

Diagnosis of acute infection can be established by demonstration of tachyzoites in biopsy tissue sections, bone marrow aspirate, or body fluids such as CSF or amniotic fluid. Immunofluorescent antibody and immunoperoxidase staining techniques may be necessary, because it is often difficult to distinguish the tachyzoite using ordinary stains. Tissue cysts are diagnostic of infection but do not differentiate between acute and chronic infection, although the presence of many cysts suggests recent acute infection. Cysts in the placenta or tissues of the newborn infant establish the diagnosis of congenital infection. Characteristic histologic features strongly suggest the diagnosis of toxoplasmic lymphadenitis.

Serologic Testing

Multiple serologic tests may be necessary to confirm the diagnosis of congenital or acutely acquired Toxoplasma infection. Each laboratory that reports serologic test results must have established values for their tests that diagnose infection in specific clinical settings, provide interpretation of their results, and ensure appropriate quality control before therapy is based on serologic test results. Serologic test results used as the basis for therapy should be confirmed in a reference laboratory.

The Sabin-Feldman dye test is sensitive and specific. It measures primarily IgG antibodies. Results should be expressed in international units (IU/mL), based on international standard reference sera available from the World Health Organization.

The IgG indirect fluorescent-antibody (IgG-IFA) test measures the same antibodies as the dye test, and the titers tend to be parallel. These antibodies usually appear 1-2 wk after infection, reach high titers (≥1 : 1,000) after 6-8 wk, and then decline over months to years. Low titers (1 : 4 to 1 : 64) usually persist for life. Antibody titer does not correlate with severity of illness. Approximately half of the commercially available IFA kits for T. gondii have been found to be improperly standardized and may yield significant numbers of false-positive and false-negative results.

An agglutination test (Bio-Mérieux, Lyon, France) that is available commercially in Europe uses formalin-preserved whole parasites to detect IgG antibodies. This test is accurate, simple to perform, and inexpensive.

The IgM-IFA test is useful for the diagnosis of acute infection with T. gondii in the older child because IgM antibodies appear earlier, often by 5 days after infection, and diminish more quickly than IgG antibodies. In most instances, IgM antibodies rise rapidly (1 : 50 to <1 : 1,000) and then fall to low titers (1 : 10 or 1 : 20) or disappear after weeks or months. However, some patients continue to have positive IgM results with low titers for several years. The IgM-IFA test detects Toxoplasma-specific IgM in only approximately 25% of congenitally infected infants at birth. IgM antibodies may not be present in sera of immunocompromised patients with acute toxoplasmosis or in patients with reactivation of ocular toxoplasmosis. The IgM-IFA test may yield false-positive results as a result of rheumatoid factor.

The double-sandwich IgM enzyme-linked immunosorbent assay (IgM-ELISA) is more sensitive and specific than the IgM-IFA test for detection of Toxoplasma IgM antibodies. In the older child, serum IgM-ELISA Toxoplasma antibodies of >2.0 (a value of 1 reference laboratory; each laboratory must establish its own value) indicates that Toxoplasma infection most likely has been acquired recently. The IgM-ELISA identifies approximately 50-75% of infants with congenital infection. IgM-ELISA avoids both the false-positive results from rheumatoid factor and the false-negative results from high levels of passively transferred maternal IgG antibody in fetal serum, as may occur in the IgM-IFA test. Results obtained with commercial kits must be interpreted with caution, because false-positive reactions are not infrequent. Care must also be taken to determine whether kits have been standardized for diagnosis of infection in specific clinical settings, such as in the newborn infant. The IgA-ELISA also is a sensitive test for detection of maternal and congenital infection, and results may be positive when those of the IgM-ELISA are not.

The immunosorbent agglutination assay (ISAGA) combines trapping of a patient’s IgM, IgA, or IgE to a solid surface and use of formalin-fixed organisms or antigen-coated latex particles. It is read as an agglutination test. There are no false-positive results from rheumatoid factor or antinuclear antibodies. The IgM-ISAGA is more sensitive than the IgM-ELISA and may detect specific IgM antibodies before and for longer periods than the IgM-ELISA.

At present, the IgM-ISAGA, the IgA-ISAGA, and the IgA-ELISA are the best tests for diagnosis of congenital infection in the newborn. The IgE-ELISA and IgE-ISAGA are also sometimes useful in establishing the diagnosis of congenital toxoplasmosis or acute acquired T. gondii infection. The presence of IgM antibodies in the older child or adult can never be used alone to diagnose acute acquired infection.

The differential agglutination test (HS/AC) compares antibody titers obtained with formalin-fixed tachyzoites (HS antigen) with titers obtained using acetone- or methanol-fixed tachyzoites (AC antigen) to differentiate recent and remote infections in adults and older children. This method may be particularly useful in differentiating remote infection in pregnant women, because levels of IgM and IgA antibodies detectable by ELISA or ISAGA may remain elevated for months to years in adults and older children.

The avidity test can be helpful to time infection. A high-avidity test result indicates that infection began >16 wk earlier, which is especially useful in determining time of acquisition of infection in the 1st or final 16 wk of gestation. A low-avidity test result may be present for many months and is not diagnostic of recent acquisition of infection.

A relatively higher level of Toxoplasma antibody in the aqueous humor or in CSF demonstrates local production of antibody during active ocular or CNS toxoplasmosis. This comparison is performed, and a coefficient [C] is calculated as follows:

Significant coefficients [C] are >8 for ocular infection, >4 for CNS for congenital infection, and >1 for CNS infection in patients with AIDS. If the serum dye test titer is >300 IU/mL, most often it is not possible to demonstrate significant local antibody production using this formula with either the dye test or the IgM-IFA test titer. IgM antibody may be detectable in CSF.

Comparative Western immunoblot tests of sera from a mother and infant may detect congenital infection. Infection is suspected when the mother’s serum and her infant’s serum contain antibodies that react with different Toxoplasma antigens.

The enzyme-linked immunofiltration assay (ELIFA) using micropore membranes permits simultaneous study of antibody specificity by immunoprecipitation and characterization of antibody isotypes by immunofiltration with enzyme-labeled antibodies. This method is capable of detecting 85% of cases of congenital infection in the 1st few days of life.

PCR is used to amplify the DNA of T. gondii, which then can be detected by using a DNA probe. Detection of repetitive T. gondii genes, the B1 or 529 bp, 300 copy gene, in amniotic fluid is the PCR target of choice for establishing the diagnosis of congenital Toxoplasma infection in the fetus. Sensitivity and specificity of this test in amniotic fluid obtained to diagnose infections acquired between 17 and 21 wk of gestation are approximately 95%. Before and after that time, PCR with the 529 bp, 300 copy repeat gene as the template is 92% sensitive and 100% specific for detection of congenital infection. PCR of vitreous or aqueous fluids also has been used to diagnose ocular toxoplasmosis. PCR of peripheral white blood cells, CSF, and urine has been used to detect congenital infection.

Lymphocyte blastogenesis to Toxoplasma antigens has been used to diagnose congenital toxoplasmosis when the diagnosis is uncertain and other test results are negative. However, a negative result does not exclude the diagnosis because many infected newborns do not respond to T. gondii antigens.

Acquired Toxoplasmosis

Recent infection is diagnosed by seroconversion from a negative to a positive IgG antibody titer (in the absence of transfusion); a 2 tube increase in Toxoplasma-specific IgG titer when serial sera are obtained 3 wk apart and tested in parallel; or the detection of Toxoplasma-specific IgM antibody in conjunction with other tests, but never alone.

Ocular Toxoplasmosis

IgG antibody titers of 1 : 4 to 1 : 64 are usual in older children with active Toxoplasma chorioretinitis. Presence of antibodies measurable only when serum is tested undiluted is helpful in establishing the diagnosis. The diagnosis is likely with characteristic retinal lesions and positive serologic tests. PCR of aqueous or vitreous fluid has been used to diagnose ocular toxoplasmosis but is infrequently performed because of risks associated with obtaining fluid.

Immunocompromised Persons

IgG antibody titers may be low, and Toxoplasma-specific IgM is often absent in immunocompromised stem cell transplant recipients, but not kidney or heart transplant recipients with toxoplasmosis. Demonstration of Toxoplasma antigens or DNA in serum, blood, and CSF may identify disseminated Toxoplasma infection in immunocompromised persons. Resolution of CNS lesions during a therapeutic trial of pyrimethamine and sulfadiazine has been useful to diagnose toxoplasmic encephalitis in patients with AIDS. Brain biopsy has been used to establish the diagnosis if there is no response to a therapeutic trial and to exclude other likely diagnoses such as CNS lymphoma.

Congenital Toxoplasmosis

Fetal ultrasound examination, performed every 2 wk during gestation, beginning at the time acute acquired infection is diagnosed in a pregnant woman, and PCR analysis of amniotic fluid are used for prenatal diagnosis. T. gondii may also be isolated from the placenta at delivery.

Serologic tests are also useful in establishing a diagnosis of congenital toxoplasmosis. Either persistent or rising titers in the dye test or IFA test, or a positive IgM-ELISA or IgM-ISAGA result is diagnostic of congenital toxoplasmosis. The half-life of IgM is about 2 days, so if there is a placental leak, the level of IgM antibodies in the infant’s serum decreases significantly, usually within 1 wk. Passively transferred maternal IgG antibodies may require many months to a year to disappear from the infant’s serum, depending on the magnitude of the original titer. Synthesis of Toxoplasma antibody is usually demonstrable by the 3rd mo of life if the infant is untreated. If the infant is treated, synthesis may be delayed for as long as the 9th mo of life and, infrequently, may not occur at all. When an infant begins to synthesize IgG antibody, infection may be documented serologically even without demonstration of IgM antibodies by an increase in the ratio of specific serum IgG antibody titer to the total IgG, whereas the ratio will decrease if the specific IgG antibody has been passively transferred from the mother.

Newborns suspected of having congenital toxoplasmosis should be evaluated by general, ophthalmologic, and neurologic examinations; head CT scan; attempt to isolate T. gondii from the placenta and infant’s leukocytes from peripheral blood buffy coat; measurement of serum Toxoplasma-specific IgG, IgM, IgA, and IgE antibodies, and the levels of total serum IgM and IgG; lumbar puncture including analysis of CSF for cells, glucose, protein, Toxoplasma-specific IgG and IgM antibodies, and level of total IgG; and testing of CSF for T. gondii by PCR and inoculation into mice. Presence of Toxoplasma-specific IgM in CSF that is not contaminated with blood or confirmation of local antibody production of Toxoplasma-specific IgG antibody in CSF establishes the diagnosis of congenital Toxoplasma infection.

Many manifestations of congenital toxoplasmosis occur in other perinatal infections, especially congenital cytomegalovirus infection. Neither cerebral calcification nor chorioretinitis is pathognomonic. The clinical picture in the newborn infant may also be compatible with sepsis, aseptic meningitis, syphilis, or hemolytic disease. Some children <5 yr of age with chorioretinitis have postnatally acquired T. gondii infection.

Acquired Toxoplasmosis

Patients with acquired toxoplasmosis and lymphadenopathy do not need specific treatment unless they have severe and persistent symptoms or evidence of damage to vital organs. If such signs and symptoms occur, treatment with pyrimethamine, sulfadiazine, and leukovorin should be initiated. Patients who appear to be immunocompetent but have severe and persistent symptoms or damage to vital organs (e.g., chorioretinitis, myocarditis) need specific therapy until these specific symptoms resolve, followed by therapy for an additional 2 wk. Therapy is usually administered for at least 4-6 wk. The optimal duration of therapy is unknown. A loading dose of pyrimethamine for older children is 2 mg/kg/day divided bid (maximum 50 mg/day), given for the 1st 2 days of treatment. The maintenance dose is 1 mg/kg/day (maximum 50 mg/day). Sulfadiazine is administered to children >1 yr of age at a dosage of 100 mg/kg/day divided bid (maximum 4 g/day). Leukovorin is administered orally at a dosage of 5-20 mg 3 times a week (or even daily depending on the leukocyte count).

Ocular Toxoplasmosis

Patients with ocular toxoplasmosis are usually treated with pyrimethamine, sulfadiazine, and leukovorin for approximately 1 wk after the lesion develops a quiescent appearance (i.e., sharp borders and associated inflammatory cells in the vitreous resolve), which usually occurs in 2-4 wk. Within 7-10 days the borders of the retinal lesions sharpen, and visual acuity usually returns to that noted before development of the acute lesion. Systemic corticosteroids have been administered concomitantly with antimicrobial treatment when lesions involve the macula, optic nerve head, or papillomacular bundle. Corticosteroids are never given alone and are begun after loading doses of pyrimethamine and sulfadiazine have been administered (2 days). Most new lesions appear contiguous to old ones. Very rarely, vitrectomy and removal of the lens are needed to restore visual acuity. Suppressive treatment has prevented frequent recurrences of vision-threatening lesions.

Immunocompromised Persons

Serologic evidence of acute infection in an immunocompromised patient, regardless of whether signs and symptoms of infection are present or tachyzoites are demonstrated in tissue, are indications for therapy similar to that described for immunocompetent persons with symptoms of organ injury. It is important to establish the diagnosis as rapidly as possible and institute treatment early. In immunocompromised patients other than those with AIDS, therapy should be continued for at least 4-6 wk beyond complete resolution of all signs and symptoms of active disease. Careful follow-up observation of these patients is imperative because relapse may occur, requiring prompt reinstitution of therapy. Relapse is frequent in patients with AIDS, and suppressive therapy with pyrimethamine and sulfonamides, or trimethoprim-sulfamethoxazole, traditionally has been continued for life. It is possible to discontinue maintenance therapy when the CD4 count remains at >200 cells/µL for 4-6 mo and all lesions have resolved. Therapy usually induces a beneficial response clinically, but it does not eradicate cysts. Treatment of T. gondii–seropositive patients with AIDS should be continued as long as CD4 counts remain at <200 cells/µL. Prophylactic treatment with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia significantly reduces the incidence of toxoplasmosis in patients with AIDS.

Congenital Toxoplasmosis

All newborns infected with T. gondii should be treated whether or not they have clinical manifestations of the infection because treatment may be effective in interrupting acute disease that damages vital organs. Infants should be treated for 1 yr with pyrimethamine (2 mg/kg/day divided bid for 2 days, then 1 mg/kg/day for 2 or 6 mo, and then 1 mg/kg given on Monday, Wednesday, and Friday [or more often], PO), sulfadiazine (100 mg/kg/day divided bid PO), and leukovorin (5-10 mg given on Monday, Wednesday, and Friday, or more often depending on neutrophil count, PO). The relative efficacy in reducing sequelae of infection and the safety of treatment with 2 vs 6 mo of the higher dosage of pyrimethamine are being compared in the U.S. National Collaborative Study. Updated information about this study and these regimens is available from Dr. Rima McLeod (773-834-4131). Pyrimethamine and sulfadiazine are available only in tablet form and can be prepared as suspensions. Prednisone (1 mg/kg/day divided bid PO) has been utilized in addition when active chorioretinitis involves the macula or otherwise threatens vision or the CSF protein is >1,000 mg/dL at birth, but the efficacy is not established. Prednisone is continued only for as long as the active inflammatory process in the posterior pole of the eye is vision threatening or CSF protein is >1,000 mg/dL and then tapered rapidly if the duration of treatment has been brief.

Pregnant Women with T. gondii Infection

The immunologically normal pregnant woman who acquired T. gondii before conception does not need treatment to prevent congenital infection of her fetus. Although data are not available to allow for a definitive time interval, if infection occurs during the 6 mo prior to conception, it is reasonable to evaluate the fetus by use of PCR with amniotic fluid and ultrasonography and treat to prevent congenital infection in the fetus in the same manner as described for the acutely infected pregnant patient.

Treatment of a pregnant woman who acquires infection at any time during pregnancy reduces the chance of congenital infection in her infant. Spiramycin (1 g every 8 hr PO without food) is recommended for prevention of fetal infection if the mother develops acute toxoplasmosis during pregnancy. Spiramycin is available in the USA through the Food and Drug Administration (301-796-1600, attn. Leo Chan) after the diagnosis of acute infection is confirmed in a reference laboratory (650-326-8120). Adverse reactions are infrequent and include paresthesias, rash, nausea, vomiting, and diarrhea. Pyrimethamine (50 mg once daily PO), sulfadiazine (1.5-2 g bid PO), and leukovorin (10 mg once daily PO) are recommended for treatment of the pregnant woman whose fetus has confirmed or probable fetal infection except in the 1st trimester. In the 1st trimester when there is definite infection, sulfadiazine alone is recommended because pyrimethamine is potentially teratogenic at that time. Spiramycin treatment is used early in gestation when it is uncertain whether there is fetal infection. Treatment of the mother of an infected fetus with pyrimethamine and sulfadiazine reduces infection in the placenta and the severity of disease in the newborn. Delay in maternal treatment during gestation results in greater brain and eye disease in the infant. Diagnostic amniocentesis should be performed at >17-18 wk of gestation in pregnancies when there is high suspicion of fetal infection. Overall sensitivity of PCR for amniotic fluid is at 85% between 17 and 21 wk of gestation. The sensitivity of PCR using amniotic fluid for diagnosis of fetal infection is 92% in early and late gestation when amniotic fluid is tested for presence of the 529 bp, 300 copy gene. After 24 weeks gestation, incidence of transmission is high and pregnant women who are infected acutely after that time are often treated with pyrimethamine and sulfadiazine to treat the fetus.

The approach in France to congenital toxoplasmosis includes systematic serologic screening of all women of childbearing age and again intrapartum each month during gestation, at term, and 1 mo after term. Mothers with acute infection are treated with spiramycin, which decreases the transmission from 60-23%. Ultrasonography and amniocentesis for PCR at approximately 18 wk of gestation are used for fetal diagnosis, which have 97% sensitivity and 100% specificity. Confidence intervals for sensitivity are largest early and late in gestation. Fetal infection is treated with pyrimethamine and sulfadiazine. Termination of pregnancy is very rare at present. Treatment with pyrimethamine and sulfadiazine during pregnancy usually has an excellent outcome, with normal development of children. Only 19% have subtle findings of congenital infection, including intracranial calcifications (13%) and chorioretinal scars (6%), although 39% have chorioretinal scars detected at follow-up observation during later childhood. Several studies have demonstrated improved outcomes with shorter times between diagnosis and initiation of treatment.

Chronically infected pregnant women who are immunocompromised have transmitted T. gondii to their fetuses. Such women should be treated with spiramycin throughout gestation. The optimal management for prevention of congenital toxoplasmosis in the fetus of a pregnant woman with HIV infection and inactive T. gondii infection is unknown. If the pregnancy is not terminated, some investigators suggest that the mother should be treated with spiramycin during the 1st 14 wk of gestation and thereafter with pyrimethamine and sulfadiazine until term. There are no accepted guidelines. In a study of adult patients with AIDS, pyrimethamine (75 mg once daily PO) combined with high dosages of intravenously administered clindamycin (1,200 mg every 6 hr IV) appeared equal in efficacy to sulfadiazine and pyrimethamine in the treatment of toxoplasmic encephalitis. Other experimental agents include the macrolides roxithromycin and azithromycin.

Active choroidal neovasular membranes due to toxoplasmic chorioretinitis have been treated successfully in children with intravitreal injection of antibody to VegF.