Abstract
Prompt diagnosis and rapid initiation of medical treatment are critical for the best outcomes in infants with congenital toxoplasmosis. This is important for pregnant women, fetuses, and infants, including those with active retinitis and choroidal neovascular membranes. For hydrocephalus, prompt placement of a ventriculoperitoneal shunt is key for improved outcomes. Pyrimethamine and Sulfadiazine with Leucovorin are first-line medicines. For later recurrences of active retinitis, Azithromycin or Clindamycin are sometimes substituted for Sulfadiazine as second-line treatments, given with Pyramethamine. Following resolution of active retinitis, these medicines may be useful without Pyrimethamine for suppression and avoid the risk of hypersensitivity from Trimethoprim/Sulfamethoxazole. Antibody to VEGF, in conjunction with antimicrobial therapy, results in resolution of choroidal neovascular membranes. Serologic screening of seronegative pregnant women to detect primary infection during gestation, and facilitating medicine administration and thereby preventing or treating fetal infection, is an optimal, apparently cost-effective, means to reduce disease. Definitively curative medicines currently being developed likely will improve future management and outcomes of this disease.
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Introduction
In 1939, Wolf and Cowen reported the first case of congenital toxoplasmosis attributed to Toxoplasma gondii [1]. This infected infant presented with ultimately fatal encephalitis [1] and was diagnosed with T. gondii infection by Sabin [2]. Other cases were described in the following years. Understanding of clinical manifestations, pathogenesis, pathology, and development of current approaches to optimal management evolved over the next decades [3, 4, 5•, 6–16, 17••, 18–21, 22••, 23–34, 35••, 36, 37•, 38–41, 42••, 43–47, 48•, 49–62, 63•, 64–67, 68•, 69. 70•, 71–78, 79••, 80••, 81••, 82•, 83, 84•, 85•, 86, 87•, 88–90, 91•, 92, 93, 94••, 95, 96, 97•, 98••, 99–111, 112•, 113•114–118, 119•, 207]. In the 1950s and 1960s, the severity of infection was recognized to be inversely correlated with gestational age at the time of infection. Transmission rates were low early in gestation but were associated with more severe clinical disease, while transmission occurred more frequently later in gestation but was frequently subclinical [23–30, 36–40, 43, 44, 63•, 64]. Prognosis was guarded for those infants with substantial manifestations of active disease at birth in the absence of subsequent treatment [43, 44]. Untreated subclinical infections were noted to harm children later in life, particularly causing cognitive decline and recurrent retinal disease [63•, 64]. The presence of meningitis or retinal disease was noted in up to 50 % of infants whose infection went unnoticed with standard newborn examinations. In France, Austria, and Germany, gestational serologic screening programs were developed to detect acquisition of infection during fetal life [21, 28, 31, 49, 61, 62, 115, 117, 118]. Treatment to prevent infection and disease in the fetus and infant was optimized (Fig. 1; [21, 28, 31, 49, 61, 62, 69, 70•, 71–78, 79••, 80••, 81••, 107, 115–118], 119•, 120••, 121••, 207). In a phase 1 study and in a phase 2 randomized trial of a higher and lower dosage of Pyrimethamine treatment of infants compared with untreated historical controls (Fig. 2), and treated children with recurrent eye disease had improved outcomes [35, 69, 70•, 71–78, 79••, 80••, 81••, 92, 93, 114, 121••, 207]. Effective treatments in infancy and through the first year of life were defined in the USA, and this work changed the approach to management of the disease in the next decades in the USA [69, 70•, 71–78, 79••, 80••, 81••, 121••, 207], as well as in France, Austria, Germany, and other countries [3, 69, 70•, 71–78, 79••, 80••, 81••, 90, 207]. Mathematical analyses suggest that such serologic screening will be cost-effective in the USA, and these methods of analysis are also being applied in other countries such as Brazil and Panama. Adjunctive treatments such as prompt ventriculoperitoneal shunt procedures resulted in favorable outcomes for some infants with hydrocephalus. Without such medical and neurosurgical interventions, prognosis is guarded (96, 119, Hutson, McLeod, et al. in preparation). Herein, we present practical approaches to manage this infection to optimize the quality of life for infected individuals and their families [78, 79••]. The more rapidly the diagnosis is made, with prompt initiation of treatment, the better the observed outcome.
Gestational screening and treatment to improve outcomes. a Serologic screening for T. gondii infection during pregnancy an algorithm for early diagnosis of acquisition of T. gondii infection. For boxes shaded with blue, consult with high-risk maternal-fetal medicine. Adapted with permission from McLeod et al. [206, 207]. b Screening for toxoplasmosis throughout pregnancy. Diagram indicating when and how screening for T. gondii infection should occur, prenatally and 1 month after birth. Adapted with permission from McLeod et al. [206, 207]. c Amniocentesis to Detect Congenital T. gondii Infection. Relationship between percentage of pregnant women undergoing amniocentesis (open bars) and those with fetuses with congenital toxoplasmosis (filled bars) as a function of the gestational age at seroconversion. The inserted table indicates the sensitivity, specificity, and positive and negative predictive values of PCR analysis of samples obtained via amniocentesis as a function of trimester. Adapted with permission from Wallon et al. [119]. d Gestational age and its relationship to parasitemia. Relationship between the gestational age at the time of maternal infection with T. gondii and the magnitude of parasitemia (parasites/mL). Note early infection is correlated with more severe disease. Empty bars are indicative of subclinical infection, while filled bars represent symptomatic infection. Adapted with permission from Romand et al. [103]. e French algorithm and its impact on outcomes in congenital toxoplasmosis. Summary of outcomes for congenitally infected individuals. Adapted with permission from Mehta et al. [208]. f Impact of the french approach on likelihood of congenital infection with T. gondii. Impact of utilization of French algorithm on probability of fetal infection following gestational infection as a function of gestational age. In the Lyon Cohort, this approach to early screening/treatment was implemented in 1992, and, at that time, probability of fetal infection decreased. Accompanying table indicates both reduction in the risk of infection and of clinical signs of congenital Toxoplasma infection following changes in screening policy in 1992 and prenatal diagnosis and treatment in 1995. Adapted with permission from Wallon et al. [120]. g Impact of early detection/treatment on frequency of eye disease at 3 years of age. Kaplan–Meier plot depicting the impact of early diagnosis and treatment on the fraction of patients without eye disease. In patients with less than 4 weeks of delay between gestational infection and initiation of treatment (solid line) and with between four and 8 weeks of delay (dashed line), eye disease is much less common than for those patients with an interval of greater than eight weeks between infection and treatment (dotted line). Adapted with permission from Kieffer et al. [62]. h Conclusions regarding the outcomes of T. gondii infection in those infants with prenatal screening, diagnosis, and treatment. Adapted with permission from and McLeod et al. [207]. (I)—A Time and Treatment of T. gondii Infection Adapted with permission from McLeod et al. [206, 207]. (I)—B Effect of treatment on quality of life in congenital T. gondii infection impact of treatment within a study cohort on various measures of quality of life. Adapted with permission from McLeod et al. [206, 207]. (I)—C. Frequency of ophthalmologic and neurologic manifestations of congenital toxoplasmosis. Frequency of symptoms, especially ophthalmologic and neurologic symptoms, within a study cohort of patients with congenital T. gondii infection. Adapted with permission from McLeod et al. [206, 207]
Manifestations of congenital toxoplasmosis in infancy. a A1-Percentage of patients with specific manifestations of congenital T. gondii infection with several images of some of these manifestations. These include blueberry muffin rash (in this case, with congenital infection with cytomegalovirus, though the manifestation is the same in congenital toxoplasmosis), petechiae secondary to thrombocytopenia, and an infant born, prematurely, as a result of T. gondii infection. Adapted with permission from McLeod et al. [206, 207]. Data from McAuley et al. [71]. Image from Mehta et al. [208] and from http://www.nhlbi.nih.gov/health/health-topics/topics/itp/ with permission. A2-Approach and samples for the diagnosis of congenital T. gondii Infection. Diagnostic approaches to congenital toxoplasmosis in a newborn, including specific instructions regarding samples, shipment, and diagnostic procedures. Adapted with permission from McLeod et al. [206, 207]. b Ordering serologic testing for T. gondii from the U.S. Reference laboratory. An example of a completed order form for serological testing from a typical reference laboratory in order to diagnose a patient with suspected congenital infection with T. gondii. Adapted with permission from McLeod et al. [206, 207]. c Diagnostic testing for T. gondii Infection organized by sample type. Examples of the types of testing that can be used to diagnose congenital toxoplasmosis as a function of sample type. Adapted with permission from McLeod et al. [206, 207]. d Geography, genetic diversity, and disease manifestations in the U.S. T. gondii Population. Relationship between geography, genetic diversity, and disease manifestation in T. gondii in the Uni. Note the prevalence of different serotypes depending upon region, as well as the impact of genotype on severity. Genotype also shows some co-association with a variety of epidemiological factors. Adapted with permission from McLeod et al. [79]
Prevention, Diagnosis, and Treatment of Congenital Toxoplasmosis During Gestation
Optimal management of congenital T. gondii infection begins with prenatal diagnosis, prevention of transmission to the fetus, and treatment of the fetus as soon after acquisition as possible [3, 4, 5•, 6–16, 17••, 18–21, 22••, 23–34, 35••, 36, 37•, 38–41, 42••, 43–47, 48•, 49–62, 63•, 64–67, 68•, 69. 70•, 71–78, 79••, 80••, 81••, 82•, 83, 84•, 85•, 86, 87•, 88–90, 91•, 92, 93, 94••, 95, 96, 97•, 98••, 99–111, 112•, 113•114–118, 119•, 120••, 207]. This approach was developed in France (Fig. 1) and is currently the gold standard of care for all pregnant women in that country. Preconception or serologic screening by 11 weeks identifies seronegative women who undergo monthly serologic screening for T. gondii IgG and IgM beginning at 11 weeks’ gestation and continuing through the first postpartum month. This approach identifies gestational infection in the previously seronegative pregnant woman by detecting the presence of new T. gondii-specific serum antibody. When a pregnant woman seroconverts, treatment with Spiramycin, which is concentrated in the placenta, can block transmission to the fetus up to 50 % of the time [95]. This approach is used for maternal infection prior to the 17th week of gestation without known transmission to the fetus. Further therapy is stratified based on the presence or absence of fetal infection; amniocentesis with PCR for T. gondii DNA is utilized to diagnose fetal infection and prompt fetal treatment via Pyrimethamine, Sulfadiazine, and Leucovorin (PSL) administered to the pregnant woman. Infection may be detected by amniotic fluid PCR of the 20 copy T. gondii B1 gene or the more sensitive 300 copy repeat gene of unknown function [115] at 17 weeks or later in gestation. PSL maternal therapy is administered to the pregnant women after the 11th week in T. gondii PCR-positive pregnancies; Sulfadiazine is used alone before that time. Findings compatible with toxoplasmosis in the fetus of an acutely infected pregnant woman should also prompt treatment. Pyrimethamine is not used in the first trimester due to possible teratogenic effects. An alternate approach of treating all acutely infected pregnant women with Pyrimethamine, Sulfadiazine, and Leucovorin, again withholding Pyrimethamine in the first trimester, was developed in Austria [118]. This appears to be equally effective in promoting favorable outcomes in the newborn infant and subsequently, later in life, for the congenitally infected person [81••, 118]. Treatment of the fetus is followed by treatment of the infant throughout the first year of life for congenital toxoplasmosis with Pyrimethamine, Sulfadiazine, and Leucovorin [69, 70•, 71–78, 79••, 80••, 81••] (see below). Most patients whose infection is detected and treated during fetal life are doing well as young adults as demonstrated in longitudinal studies in Lyon, France (Fig. 1). The more rapid the diagnosis (Table 1; Fig. 2) and consequent rapid initiation of treatment (Table 2; Fig. 3), the better the outcomes (69, 70•, 71–78, 79••, 80••, 81••, 207; Figs. 1, 4).
Treatment of congenital toxoplasmosis. a Instructions for the preparation, administration, and storage of Pyrimethamine, Sulfadiazine, and Leucovorin. Adapted with permission from McLeod et al. [206, 207]. b Administration of these medicines in management of congenital T. gondii infection in the first year of life. Adapted with permission from McLeod et al. [206, 207]. c Pyrimethamine: pharmacokinetics and consequences of its use pharmacokinetics of Pyrimethamine, as well as potential toxic effects of the medicine. Hypersensitivity secondary to Sulfadiazine. Adapted with permission from McLeod et al. [206, 207]
Manifestations of congenital toxoplasmosis and outcomes of treatment. a Neurologic manifestations of congenital toxoplasmosis and response to treatment. Brain CT images depicting the impact of proper shunt placement and treatment of congenital toxoplasmosis on the course of hydrocephalus secondary to T. gondii infection. Adapted with permission from McLeod et al. [207]. b Congenital toxoplasmosis, its impact on the retina, and the effect of treatment on eye lesions. Effect of treatment on the recurrence of eye lesions secondary to T. gondii infection, with increased frequency of occurrence at entrance into school and at adolescence. c Response of active eye lesions to treatment. Treatment of eye lesions leads to resolution of overlying vitritis, hazy margins and sharp demarcation and hyperpigmented lesions. d Choroidal neovascular lesions and their response to anti-T.gondii treatment and antibody to VEGF. The first image is a patient with choroidal neovascular membrane and the resultant resolution with treatment. Note the presence of blood and subretinal fluid, which decreases following treatment with appropriate therapy. Adapted with permission from Benevento, McLeod et al. [206, 207]. Additional choroidal neovascular membranes and their response to treatment in additional patients. The impact of prompt, appropriate treatment of choroidal neovascular membranes in a series of patients. Evidence of bleeding decreases, as does the presence of subretinal fluid in these patients. Adapted with permission from Benevento, McLeod et al. [206]. e Literature outcomes in congenital toxoplasmosis and outcomes in the NCCCTS cohort. A comparison of frequency of outcomes as reported by literature and within the National Collaborative Chicago-based Congenital Toxoplasmosis Study cohort. Note the dramatic decreases in the frequency of outcomes in this particular cohort relative to literature sources. This is true for many outcomes, including IQ, motor function, retinal lesions, and central nervous system manifestations. Adapted with permission from McLeod et al. [206, 207]. f The treatment of congenital toxoplasmosis, in utero, and outcomes due to this early treatment. The impact of treatment, in utero, on the frequency of disease manifestation in congenital T. gondii infection. Note the increased frequency of most disease manifestations without the initiation of treatment, in utero. Adapted with permission from and McLeod et al. [207]. g Parasite serotype and its relationship to treatment efficacy. Tabular representation of the impact of parasite type on outcomes in treated patients. Postnatal treatment was effective (i.e., improved outcomes) in both type II and type NE-II parasites, indicating that both respond to treatment. Adapted with permission from and McLeod et al. [207]. h Outcomes in NCCCTS cohort compared to the literature. Data indicating improved outcomes in treated patients over preexisting literature data on pre-established endpoints, including neurologic outcomes, reductions in IQ, worsened vision, new retinal lesions, and hearing loss. Adapted with permission from McLeod et al. [206, 207]. (I) Dosage of Pyrimethamine and its Impact on Treatment Outcomes. Kaplan–Meier plots indicating no significant differences in outcomes between two treatment arms receiving higher doses of Pyrimethamine versus lower doses. In practice, infants with less severe manifestations often receive the lower dose of Pyrimethamine, though with severe disease often are still treated with higher doses. Adapted with permission from McLeod et al. [206, 207]
Diagnosis of the Newborn Infant
This can be accomplished by recognition of clinical findings compatible with the congenital infection in the infant of an acutely infected mother (Table 1, Fig. 2). Typical clinical findings include prematurity, intrauterine growth retardation, being small for gestational age, “rule out sepsis,” blueberry muffin rash, petechiae, hepatitis, splenomegaly, hepatomegaly, anemia, leukopenia, thrombocytopenia, abnormal cerebrospinal fluid cells, protein, or glucose, IgM specific for T. gondii or cerebrospinal fluid with T. gondii-specific DNA present demonstrated by PCR, intracerebral calcifications, microcephalus, hydrocephalus, chorioretinal scars or choroiditis and vitritis, vitreal veils, uveitis, and cataracts. Diagnosis may be confirmed by isolation of T. gondii from placenta or peripheral blood buffy coat [95], demonstration of T. gondii by PCR of placenta, or serologic testing with the demonstration of T. gondii-specific IgM or IgA. These antibodies are present in only approximately 70 % of infected babies. Images depicting some of these findings, and their improvement with treatment, are shown in Figs. 2, 3, 4. In general, disease manifestations among untreated infants are more severe when infection is acquired earlier in pregnancy and less severe when acquired later in gestation, although parasite and host genetics play a major role in outcomes as well [77, 121••,122, 123••, 124–128, 129•, 130•, 131, 132, 133••, 134••, 135•, 136•, 137–140, 141•, 142–147]. There appear to be four primary genetic parasite types in the USA. Type 2 parasites, similar to those in Europe, also are present in the USA. There is less severe disease and risk of prematurity in those with Type 2 infection, although there is not a complete correlation between parasite type and severity of congenital infection. The inoculum size of ingested parasites, including acquisition of oocysts and contaminated meat in epidemic settings, likely also play a role in outcomes [148] Obstructive hydrocephalus due to obstruction of the Aqueduct of Sylvius results in third ventricular dilatation. This pattern of hydrocephalus may be associated with cerebrospinal fluid protein levels of >1 g/dL. Obstruction of the Foramen of Monroe can lead to unilateral or bilateral ventricular dilatation. Hydrocephalus can also occur without anatomic obstruction of CSF circulation. For example, communicating hydrocephalus, which may be due to loss of brain parenchyma, or hydrocephalus associated with poor reabsorption of cerebrospinal fluid, presumably due to a fibrotic process, can occur. This latter pathogenesis is apparently similar to that seen in normal pressure hydrocephalus in adults. All patterns of hydrocephalus can benefit from shunt placement (Hutson, McLeod, McLone, Frim, et al., in preparation 2014);the prognosis is guarded if a shunt is not placed or placement is delayed when necessary.
Treatment of the Infant from Birth to 1 year of Age with Pyrimethamine, Sulfadiazine, and Leucovorin
Treatment with Pyrimethamine (1 mg/kg/day, beginning on the third day following a loading dose of 1 mg/kg b.i.d. for 2 days), Sulfadiazine (50 mg/kg b.i.d.), and Leucovorin (5–10 mg per dose daily or Monday, Wednesday, Friday depending on weight and neutrophil count) from birth to 1 year of age appears to result in much more favorable outcomes than reported for untreated infants earlier [52, 69, 70•, 71–78, 79••, 80••, 81••, 121••, 207]. Typical presenting signs and symptoms, preparation, administration, and monitoring of this treatment and outcomes are summarized in Figs. 2 and 3. Infants are weighed weekly and medications, made fresh each week, are dosed based on increasing weight each week. Signs of active infection and neurologic outcomes appear to be improved relative to those reported in earlier decades without treatment. Signs of active infection appear to resolve early (in weeks) during treatment. Neutrophil counts should be measured via heel prick with only 0.3 mL of blood collected in a tube for a pediatric complete blood count each Monday and Thursday while taking Pyrimethamine and in the week after this regimen is discontinued. See Table 1 and Fig. 3. Most children have an absolute neutrophil count ~900–1,200 neutrophils/mm3 during this year of treatment. Leucovorin can be increased to 10–20 mg daily if needed. Pyrimethamine is changed from daily administration to Monday, Wednesday, and Friday dosing after 2 or 6 months. A randomized study did not demonstrate different outcomes with these two dosing schedules for children followed to 15 years of age [74]. Thus, with milder infections, 2 months of daily treatment is often utilized. In cases with more severe initial disease, 6 months of daily treatment is utilized. Leucovorin is continued for a week after Pyrimethamine is discontinued due to the long half-life of Pyrimethamine with its attendant myelosuppressive effects. Care is taken to make certain that the baby’s teeth are cleaned after medicine administration because of the sugar-suspending agents leading to the development of dental carries. When neutrophil count is less than 1000 neutrophils/mm3, a manual differential counting 500 white blood cells is performed to improve accuracy. With neutrophil counts less than 700-1000 neutrophils/mm3, Leucovorin dosage may be increased to a maximum of 20 mg per day. With less than or equal to 600 neutrophils/mm3, Pyramethamine and Sulfadiazine are withheld, and Leucovorin continued. These medicines are held until neutrophil count is greater than 1000 neutrophils/mm3.
Steroid Treatment
Based on early data from France, Prednisone (1 mg/kg/day) is given for a short time with end points being until active vitritis threatening the posterior pole (fovea and optic nerve) of the eye resolves, or when CSF protein declines below 1 g/dL if it is initially >1 g/dL. Steroids are begun after loading doses of Pyrimethamine with Sulfadiazine have been administered. There have been no randomized controlled studies to demonstrate whether such treatment with Prednisone improves outcomes.
Approach to Cerebral Ventricular Enlargement
Hydrocephalus due to congenital toxoplasmosis is treated with ventriculoperitoneal shunting. It is not clear from initial neuroimaging studies which children will benefit most from aggressive CSF drainage. This question is further confounded by the observation that despite progressive ventricular dilatation and cortical compression, measured CSF pressures may remain low (Hutson, McLeod, McLone, Frim, et al. in preparation, 96). Thus, it is imperative to proceed as though all children with hydrocephalus would benefit from CSF shunting as early drainage can promote cortical reconstitution and remarkably good functional outcomes. One recent advance in neuroimaging for following hydrocephalus and/or shunt function is a two sequence, 45-s magnetic resonance imaging (MRI) study of the brain, which does not require sedation or contrast administration. This can be used to follow the progress of ventricular dilatation or the correction of hydrocephalus in a manner that is easy and comfortable for both parent and child. There are two sequences, collectively referred to as “brain shunt hydrocephalus screen” in some US hospitals. These two sequences are T2 axial and coronal single shots with images at 3-mm intervals.
Delays in shunt placement have been associated with less favorable outcomes [96]. Endoscopic third ventriculocisternostomy (ETV) frequently fails as a treatment for aqueductal obstruction causing hydrocephalus in this disease [96] and should not be used [96]. A possible cause of this failure of ETV is entry of inflammatory CSF into the subarachnoid space, resulting in adhesions and inadequate CSF absorption. It is not uncommon for children to have cortical expansion and restoration of normal ventricular volume and neurologic function (Fig. 4). High CSF protein and diabetes insipidus have been linked to less favorable outcomes, but this is not absolute.
Seizures and other Neurologic Findings Early in Infancy and Later
Seizures due to T. gondii have been treated effectively with Levetiracetam (Keppra®). In contrast to Phenobarbital, this anti-epileptic does not induce hepatic enzymes that degrade Pyrimethamine. It does not displace Sulfadiazine binding from albumin, as Phenytoin (Dilantin®) does, nor does it trigger the bone marrow toxicity associated with Carbamazepine (Tegretol®). It has less sedative hypnotic type effects than certain other anti-epileptic medicines. In some cases, intractable myoclonic seizures associated with recurrent central nervous system disease responded to ketogenic diet therapy (McLeod, Swisher, Hood, Heydemann, et al. in preparation). In some cases, treatment of the acute encephalitic findings caused by active T. gondii in the perinatal period, with Pyrimethamine and Sulfadiazine, has made it possible to discontinue anti-epileptic medicine without recurrence of seizures upon their discontinuation. It is not common to develop progressive and/or recrudescent central nervous system disease in treated children, but it can occur and may present as new seizures (McLeod et al., in preparation, 2014). Serum, CSF, neuroimaging, and biomarkers indicate that this is secondary to active central nervous system disease and parasite proliferation (McLeod et al. in preparation 2014).
Earlier studies [4, 64, 65] suggested recurrent and/or progressive disease occurred in untreated children. To date, relapsing central nervous system infection is uncommon in treated children in the National Collaborative Chicago-Based Congenital Toxoplasmosis Study (NCCCTS), which encompassed most of the clinical experience based on direct observation in a single center longitudinal study in North America from 1981 to the present. The incidence and extent of unrecognized CNS sequelae [148, 149••, 150••, 151, 152••, 153–157, 158•, 159–161] in postnatally or congenitally infected children remain to be determined.
Recrudescent Eye Disease and Management of Active Retinitis After the First Year of Life
Retinal disease due to T. gondii becomes quiescent with treatment in the first year of life [162–164, 165••, 166••, 167, 168], with fewer recurrences in promptly treated children than for those referred after the first year of life (Fig. 4). Recurrence occurs most frequently at the age of school entry, in puberty and adolescence (Fig. 4), and in the presence of substantial stress (e.g., bereavement, surgery, or trauma). Pyrimethamine, Sulfadiazine, and Leucovorin are used in retreatment (Table 2). Active infection in all parts of the retina require therapy; prompt therapy is associated with more rapid lesion resolution. Treatment is continued for several weeks after the borders of the lesions become sharply demarcated and the edges pigmented (Fig. 4). This often occurs within a few weeks after initiating treatment. If there is hypersensitivity to sulfonamides, Azithromycin is offered instead of Sulfadiazine. Azithromycin suppressive therapy has been utilized successfully in patients with recurrent chorioretinitis following resolution of active disease, particularly when recurrence of lesions is vision threatening. Although TMP–SMX successfully suppressed recurrences in a series in Sao Paulo, Brazil [168], it had an unacceptably high incidence of hypersensitivity. TMP/SMX suppression may lead to sulfonamide hypersensitivity and appears to be less efficacious than Pyrimethamine plus Sulfadiazine treatment, likely due to suboptimal TMP/SMX dose ratios and lesser efficacy of TMP than Pyrimethamine and SMX than Sulfadiazine. The optimal duration of prophylaxis to prevent the loss of vision or frequently recurring retinal disease has not been determined.
Choroidal Neovascular Membranes
Choroidal neovascular membranes (CNVM) [169, 170, 171•] occur rarely as a complication of chorioretinal disease due to T. gondii infection. Diagnosis is determined by clinical examination with the findings of subretinal blood or fluid, leaky vasculature visualized by fluorescein angiography and ocular coherence tomography (OCT). Infection with T. gondii drives increased expression of hypoxia-inducible factor 1-α (HIF1-α), which leads to increased levels of vascular endothelial growth factor (VEGF) transcription. VEGF promotes the growth of new blood vessels. Infiltration of vasculature arising from the choroid disrupts Bruch’s membrane, causing retinal scars. Fluid accumulates in the subretinal space. Hemorrhage can result from new, leaky blood vessels with resultant sudden loss of vision. This pathologic process can be abrogated by antibodies against VEGF. Ranibizumab (Lucentis®), in conjunction with standard anti-parasitic therapies, has been used. Bevacizumab (Avastin®) treated persons also had improved outcomes with CNVM due to toxoplasmosis. These α-VEGF medicines are injected intravitreally. Dosages can be found in Table 2. Infants have received α-VEGF safely for retinopathy of prematurity, but we are unaware of their use for CNVM due to T. gondii [170]. The recommended form of management for this complication is α-VEGF, in combination with anti-parasitic medications. This regimen has been effective in persons with CNVM due to T. gondii. Photodynamic therapy has also been reported to have efficacy [169, 170, 171•].
Implications of Congenital Infection for Family Members and Those who Share Risk Factors for Acquisition of Infection
Acquisition of T. gondii infection by multiple family members due to common exposures is not infrequent. Thus, it is reasonable to determine whether other family members were also acutely infected at the time a pregnant woman has acquired infection or a congenitally infected baby is born. Because retinal disease may occur in up to 10 % of mothers of infected babies and may occur in family members who could benefit from treatment, it may be prudent to also test other family members of infected babies [172, 173].
Prognosis
Many children born with congenital toxoplasmosis who are treated in utero and throughout the first year of life have normal cognitive development and function well, being able to continue on to university and having families of their own. There is more retinal disease among children born in the USA who missed being treated in utero and appears to occur more often in those who were not diagnosed and treated in the first year of life. There is a gradation in outcomes from severe impairment to completely functional children and young adults, both with and without treatment in the first year of life. It appears that outcomes with treatment for those who are born with moderate or severe involvement at birth are markedly better than that reported in the older literature for those who were not treated or treated for only 1 month [43, 44, 62, 64, 65, 69, 81••]. Approximately 70 % of children who had generalized systemic or neurologic manifestations and thus would have been expected to have severe disability have done well. Interestingly, for treated children, intracerebral calcifications may resolve partially or completely during the first year of life [90]. However, there may also be significant impairment. Severe involvement may impact quality of life when treatment is started too late to effect a markedly improved outcome [174].
The Future
At the present time, there is a substantial need for less toxic, improved medicines for tachyzoites and medicines effective against encysted bradyzoites [175–180, 181••, 182–184, 185••, 186•, 187–189], as well as an effective vaccine [190•, 191•, 192•, 193•, 194, 195, 205]. There are robust efforts to develop such agents, with recent successes in developing compounds that eliminate bradyzoites and reduce toxicity of treatment of the active infection. These advances are likely to lead to improved approaches to treatments and outcomes for this infection in the near future. Prenatal screening [61, 62, 95, 107] is another significant advance that likely will occur in the USA during the next decade and result in decreased congenital toxoplasmosis and reduce costs for care [120••, 202•]. Additional insights into pathogenesis are also arising from new genetic studies and associations of ocular disease with unusual parasite types [200•, 201•, 202•, 203•]. Live vaccines can now prevent infections in animal models [203•] and translation of the protective mechanisms to non-live reagents and to clinical use through immuno-sense [194], approaches may offer substantial advances. Whether there is clear cause and effect for congenital toxoplasmosis leading to other neurobehavioral diseases remains to be determined [196, 197, 198•, 199•, 201•]; although it is not evident in the US cohort of families followed from 1981 to the present.
Conclusions
Effective management requires recognition of infection early during its pathogenesis to lessen the significant impact of congenital toxoplasmosis on long-term health. Prevention through detection of T. gondii infection in the pregnant woman facilitates treatment and is critical for optimal management. Treatment is initiated following detection of acute T. gondii infection in the pregnant woman through serologic testing or in the fetus due to clinical findings and confirmed by amniocentesis. Spiramycin is used to prevent infection early in fetal development. Later in development, in infancy, or in patients with recurrent eye disease, treatment is with Pyrimethamine with Leucovorin and Sulfadiazine. The earlier the treatment is offered in each clinical setting, the more likely disease will be arrested and outcomes improved. This approach to early treatment also applies to ventricular shunting for hydrocephalus. Seizures respond to anti-parasitic and anti-epileptic medications. Choroidal neovascular membranes secondary to T. gondii infection respond to treatment with α-VEGF and anti-parasitic medicines. New medicines with less toxicity and hypersensitivity, and improved efficacy by targeting the latent stage of the parasite, will change the management of this disease markedly in the future. For the first time, there appear to be promising candidate compounds in development with these properties. Similarly, there is promise in recent work for vaccine development. Neither new medicines nor vaccines are in clinical trials at this time.
References
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Acknowledgments
We gratefully acknowledge the support of NIH R01 DMID AI 27530, the Mann and Cornwell Family, the Morel Family, the Rooney Alden Family, The Engel family, The Samuel family and friends, The Pritzker family, The Harris family, The Mussilami Family, and the Hyatt Hotels Foundation. We are grateful for the many patients and physicians who have worked with us in the NCCCTS and have helped us to learn how to manage this infection.
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McLeod, R., Lykins, J., Gwendolyn Noble, A. et al. Management of Congenital Toxoplasmosis. Curr Pediatr Rep 2, 166–194 (2014). https://doi.org/10.1007/s40124-014-0055-7
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DOI: https://doi.org/10.1007/s40124-014-0055-7