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Congenital toxoplasmosis
Handbook of Clinical Neurology, Vol. 112 (3rd series) Pediatric Neurology Part II O. Dulac, M. Lassonde, and H.B. Sarnat, Editors © 2013 Elsevier B.V. All rights reserved
Chapter 112
Congenital toxoplasmosis FRANC¸OIS KIEFFER1* AND MARTINE WALLON2 Neonatal Intensive Care Unit, Armand Trousseau Hospital, Paris, France
1
2
Department of Parasitology, Hoˆpital de la Croix Rousse, Lyon, France
EPIDEMIOLOGY OF TOXOPLASMA INFECTION Congenital Toxoplasma infection results from the transplacental transmission of Toxoplasma gondii after maternal primary infection during pregnancy. The three stages of this intracellular parasite are: the oocyst which is present in cat feces and remains infectious in the soil for over 1 year; the tachyzoite which replicates rapidly and destroys infected cells before being transformed into the bradyzoite under the pressure of the host immune system; and the tissue cyst that contains bradyzoites and remains permanently within skeletal and heart muscles, brain, retina, and lymph nodes. Human infection route is oral by ingestion of the cyst stage from undercooked or raw meat (mainly pork and lamb) or the oocyst stage from contact with cat feces or contaminated food or soil. Seroprevalence in pregnant women varies greatly among countries possibly in relation to climate, lifestyle, and diet and increases with age. Seroprevalence has fallen in numerous countries over a number of decades (Montoya and Liesenfeld, 2004). Seroprevalence among French women at delivery decreased from 54% in 1995 to 44% in 2003. Main risk factors are consumption or manipulation of raw or undercooked meat or unwashed vegetables, contact with soil or cat litter, and poor hand hygiene. Three genotypes (I, II, III) of T. gondii have been isolated. Type II is responsible for 80% of congenital infections in Europe and in the USA, from benign and subclinical to severe, lethal forms. Type I is usually responsible for severe cases.
CONGENITAL INFECTION Acute maternal infection may lead to the hematogenous propagation of T. gondii through the placenta. Overall
risk of transmission is 30% and increases with the date of maternal infection, from less than 15% at 13 weeks of gestation to almost 71% at 36 weeks (Fig. 112.1). Prevalence of congenital infection ranges from 0.1 to 0.3 per 1000 live births. Potential damage to the nervous system of the fetus includes multifocal and diffuse parenchymal necrosis that can transform into calcification, and microglial nodules. Hydrocephalus can occur as the result of sloughing of periventricular necrotic tissues and the obstruction of the aqueduct of Sylvius and/or the foramen of Monro. Microcephalus, which is less frequent, is the consequence of loss of brain tissue. Retinochoroiditis, the most frequent ocular lesion, is due to necrosis in the retinal tissue and inflammation extending into the choroid plexi. Infections in early gestation can result in severe disseminated fetal infection with cerebral calcifications, cerebral abscess, hydrocephalus, or microcephalus and ascitis, leading to death in utero. Fetal infections in the third trimester are usually subclinical at birth. A recent European study (Syrocot, 2007) estimated the incidence of brain lesions to be 30% after maternal infection at 5 weeks of gestation, 10% at 20 weeks of gestation, and less than 5% after third trimester infection (Fig. 112.2). Neurological and intellectual sequelae can develop postnatally in the absence of treatment even in children who were asymptomatic at birth. Of 13 children followed over a mean 7½ years (range 2.8–10), one had microcephalus associated with seizures and severe psychomotor retardation, four moderate neurological sequelae, and eight normal development but mean IQ of 89 (Wilson et al., 1980). In children treated for 12 months postnatally for subclinical or pauci- symptomatic infections, neurological development appeared satisfactory but available evidence is based on small series or on a parent survey and needs to be confirmed through large long-term studies.
*Correspondence to: Franc¸ois Kieffer, Neonatal Intensive Care Unit, Armand Trousseau Hospital, 26 Avenue du Dr Arnold Netter, 75012 Paris, France. Tel: þ33 1 71 73 86 43, Fax: þ33 1 44 73 68 92, E-mail: [email protected]
1100
F. KIEFFER AND M. WALLON risk of congenital infection
90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
0
5
10
15
20
25
30
35
40
gestational age at maternal seroconversion (weeks)
Fig. 112.1. Risk of congenital infection by date of maternal infection. Modified from SYROCOT (2007).
50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% 0
5
10
15
20
25
30
35
40
gestational age at maternal seroconversion (weeks)
Fig. 112.2. Risk of cerebral lesions (solid line) and eye lesions (dashed line) by date of maternal infection. Adapted from Syrocot (2007).
Retinochoroiditis is the most frequent consequence of congenital toxoplasmosis. New lesions or reactivation of scarred lesions can occur anytime in childhood and early adulthood and can be associated with poor visual acuity if the macula is involved. Ocular lesions have been reported in as many as 80% of untreated, congenitally infected adolescents, with almost 50% having uni- or bilateral blindness (Wilson et al., 1980). In a recent study of 327 children treated pre- and postnatally, retinal lesion was detected at 1 year of age in 12%, 2 years in 14%, 5 years in 18%, and 10 years of age in 23%. Thirteen percent of those with retinochoroiditis had unilateral blindness (Wallon et al., 2004). Cerebral calcifications at birth are the main risk factor for retinochoroiditis while gestational age at maternal infection has little impact (Syrocot, 2007) (see Fig. 112.2).
ANTENATAL DIAGNOSIS As Toxoplasma infection is often asymptomatic, prenatal screening with repeated serological testing for nonimmune pregnant women is performed in several countries
or regions to prospectively identify maternal seroconversions. The biological diagnosis of fetal infection is performed on amniotic fluid sampled after 18 weeks of gestation and at least 4 weeks after the date of maternal infection. Polymerase chain reaction assays for the detection of T. gondii DNA are 100% specific. Current real-time techniques are associated with more than 90% sensitivity and can predict unfavorable prognosis in early infections when parasite quantification is above 100/mL. Antenatal ultrasound scans do not show any abnormalities in two-thirds of fetuses. Symptomatic forms result mainly from infection in the first half of pregnancy. Symmetrical cerebral ventricular dilatation, typically of unfavorable prognosis, and cerebral calcifications are the most common and specific lesions. Less specific signs such as hepatomegaly, ascitis, pericardial effusion, hyperechogenic fetal bowel, and placental thickness can also be observed. In severe cases, termination of pregnancy is justified. Prenatal treatment is expected to reduce the risks of infection and of sensorineural impairment in infected children. Spiramycin is prescribed to prevent motherto-child transmission but is only parasitostatic. The pyrimethamine-sulphonamide association is highly parasiticidal and is offered to reduce the risk of clinical manifestation and/or reduce transmission. Observational studies revealed that a shorter delay between maternal infection and treatment initiation (<3–8 weeks) was associated with lower risk of transmission and clinical manifestations (Syrocot, 2007), but well conducted randomized trials are necessary to determine the exact benefit of prenatal treatment.
POSTNATAL DIAGNOSIS AND MANAGEMENT Clinical examination is most frequently normal or can reveal nonspecific signs of evolving (hepatomegaly, splenomegaly, icterus, thrombocytopenic purpura, anemia) or not fetopathy (hydro- or microcephalus, seizures). Indirect ophthalmoscopy should ideally be used to disclose retinochoroiditis. Imaging of the brain relies on ultrasound or computed tomography to detect nodular or curvilinear calcifications, or hydrocephalus (Fig. 112.3). Magnetic resonance has not been well-studied in this context. Positive biological diagnosis relies on the detection of specific IgM and/or IgA, IgG being the only ones to cross the placenta. Sensitivity depends on the tests used and increases from 40% in the first trimester to 70% in the third. Specificity reaches 100% if tests are performed on peripheral-blood rather than cord-blood. Mother– infant immunological profiles can also be compared to identify IgG, IgM, and IgA neo-synthesized by the neonate. Sensitivity of these comparative methods
CONGENITAL TOXOPLASMOSIS
1101
pyrimethamine-sulfadiazine, reported in 50% of children over the course of a 12-month treatment (McAuley et al., 1994). They are much less frequent with pyrimethamine/sulfadoxine. Minor cutaneous allergic reactions to sulphonamides, such as rash or urticaria, are observed in 1 to 2% of children.
Fig. 112.3. Neonatal longitudinal cerebral ultrasound scan: right parietal calcification.
is higher than the standard serological tests but their interpretation may be difficult. Analysis of CSF is of limited value. Two situations can be defined based on the results of the pre- and postnatal tests: ●
●
No proof of infection at birth (maternal seroconversion with negative prenatal diagnosis, normal clinical, ophthalmological and imaging findings, and no detection of specific IgM and IgA): no treatment is necessary. Serological tests should be repeated every 2 months until IgG drop under undetectable levels. If serological testing indicates congenital infection, the child must ideally be treated as indicated in the next paragraph. Proven congenital infection (diagnosed during pregnancy, at birth or postnatally): postnatal treatment is expected to reduce the risk and severity of long-term sequelae. Two protocols are used: one based on the association of pyrimethamine (1 mg/kg/day for 2 months and then 0.5 mg/kg/day for 10 months) with sulfadiazine (100 mg/kg/day in two separate doses for 12 months); and the other based on the combination of pyrimethamine (1.25 mg/kg every 10 days) with sulfadoxine (25 mg/kg every 10 days) (Fansidar®). A sulfadoxine half-life of 120 to 195 hours allows a simpler administration but longacting sulphonamides expose the patients to higher risks in case of allergies. Folinic acid must be administered (50 mg every 7 days) over the whole treatment period to reduce hematological toxicity. Reversible neutropenia is the main side-effect with
IgG levels decrease during therapy, sometimes below detectable levels. This is of no consequence and should not be taken as a sign of noninfection. After treatment has been stopped, clinical and ophthalmological examination and serological testing should be performed every 3 months during the second year of life, every 6 months during the third year, and yearly, thereafter, indefinitely. There is no reason to resume treatment unless active ocular lesions are detected. In this case, treatment should be resumed for 3 months and scaring of the lesions should be confirmed. Treatment is not necessary in the event of a serological rebound with normal or stable fundus oculi.
CONCLUSION Despite the lack of evidence regarding the effectiveness of treatment for congenital Toxoplasma infection, early diagnosis and treatment have improved its long-term prognosis. Long-term follow-up of infected children remains necessary because of the risk of late ocular lesions.
REFERENCES McAuley J, Boyer KM, Patel D et al. (1994). 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. Montoya JG, Liesenfeld O (2004). Toxoplasmosis. Lancet 363: 1965–1976. SYROCOT (Systematic Review on Congenital Toxoplasmosis) Study Group (2007). Effectiveness of prenatal treatment for congenital toxoplasmosis: a metaanalysis of individual patients’ data. Lancet 369: 115–122. Wallon M, Kodjikian L, Binquet C et al. (2004). Long-term ocular prognosis in 327 children with congenital toxoplasmosis. Pediatrics 113: 1567–1572. Wilson CB, Remington JS, Stagno S et al. (1980). Development of adverse sequelae in children born with subclinical congenital Toxoplasma infection. Pediatrics 66: 767–774.
Chapter 112
Congenital toxoplasmosis FRANC¸OIS KIEFFER1* AND MARTINE WALLON2 Neonatal Intensive Care Unit, Armand Trousseau Hospital, Paris, France
1
2
Department of Parasitology, Hoˆpital de la Croix Rousse, Lyon, France
EPIDEMIOLOGY OF TOXOPLASMA INFECTION Congenital Toxoplasma infection results from the transplacental transmission of Toxoplasma gondii after maternal primary infection during pregnancy. The three stages of this intracellular parasite are: the oocyst which is present in cat feces and remains infectious in the soil for over 1 year; the tachyzoite which replicates rapidly and destroys infected cells before being transformed into the bradyzoite under the pressure of the host immune system; and the tissue cyst that contains bradyzoites and remains permanently within skeletal and heart muscles, brain, retina, and lymph nodes. Human infection route is oral by ingestion of the cyst stage from undercooked or raw meat (mainly pork and lamb) or the oocyst stage from contact with cat feces or contaminated food or soil. Seroprevalence in pregnant women varies greatly among countries possibly in relation to climate, lifestyle, and diet and increases with age. Seroprevalence has fallen in numerous countries over a number of decades (Montoya and Liesenfeld, 2004). Seroprevalence among French women at delivery decreased from 54% in 1995 to 44% in 2003. Main risk factors are consumption or manipulation of raw or undercooked meat or unwashed vegetables, contact with soil or cat litter, and poor hand hygiene. Three genotypes (I, II, III) of T. gondii have been isolated. Type II is responsible for 80% of congenital infections in Europe and in the USA, from benign and subclinical to severe, lethal forms. Type I is usually responsible for severe cases.
CONGENITAL INFECTION Acute maternal infection may lead to the hematogenous propagation of T. gondii through the placenta. Overall
risk of transmission is 30% and increases with the date of maternal infection, from less than 15% at 13 weeks of gestation to almost 71% at 36 weeks (Fig. 112.1). Prevalence of congenital infection ranges from 0.1 to 0.3 per 1000 live births. Potential damage to the nervous system of the fetus includes multifocal and diffuse parenchymal necrosis that can transform into calcification, and microglial nodules. Hydrocephalus can occur as the result of sloughing of periventricular necrotic tissues and the obstruction of the aqueduct of Sylvius and/or the foramen of Monro. Microcephalus, which is less frequent, is the consequence of loss of brain tissue. Retinochoroiditis, the most frequent ocular lesion, is due to necrosis in the retinal tissue and inflammation extending into the choroid plexi. Infections in early gestation can result in severe disseminated fetal infection with cerebral calcifications, cerebral abscess, hydrocephalus, or microcephalus and ascitis, leading to death in utero. Fetal infections in the third trimester are usually subclinical at birth. A recent European study (Syrocot, 2007) estimated the incidence of brain lesions to be 30% after maternal infection at 5 weeks of gestation, 10% at 20 weeks of gestation, and less than 5% after third trimester infection (Fig. 112.2). Neurological and intellectual sequelae can develop postnatally in the absence of treatment even in children who were asymptomatic at birth. Of 13 children followed over a mean 7½ years (range 2.8–10), one had microcephalus associated with seizures and severe psychomotor retardation, four moderate neurological sequelae, and eight normal development but mean IQ of 89 (Wilson et al., 1980). In children treated for 12 months postnatally for subclinical or pauci- symptomatic infections, neurological development appeared satisfactory but available evidence is based on small series or on a parent survey and needs to be confirmed through large long-term studies.
*Correspondence to: Franc¸ois Kieffer, Neonatal Intensive Care Unit, Armand Trousseau Hospital, 26 Avenue du Dr Arnold Netter, 75012 Paris, France. Tel: þ33 1 71 73 86 43, Fax: þ33 1 44 73 68 92, E-mail: [email protected]
1100
F. KIEFFER AND M. WALLON risk of congenital infection
90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
0
5
10
15
20
25
30
35
40
gestational age at maternal seroconversion (weeks)
Fig. 112.1. Risk of congenital infection by date of maternal infection. Modified from SYROCOT (2007).
50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% 0
5
10
15
20
25
30
35
40
gestational age at maternal seroconversion (weeks)
Fig. 112.2. Risk of cerebral lesions (solid line) and eye lesions (dashed line) by date of maternal infection. Adapted from Syrocot (2007).
Retinochoroiditis is the most frequent consequence of congenital toxoplasmosis. New lesions or reactivation of scarred lesions can occur anytime in childhood and early adulthood and can be associated with poor visual acuity if the macula is involved. Ocular lesions have been reported in as many as 80% of untreated, congenitally infected adolescents, with almost 50% having uni- or bilateral blindness (Wilson et al., 1980). In a recent study of 327 children treated pre- and postnatally, retinal lesion was detected at 1 year of age in 12%, 2 years in 14%, 5 years in 18%, and 10 years of age in 23%. Thirteen percent of those with retinochoroiditis had unilateral blindness (Wallon et al., 2004). Cerebral calcifications at birth are the main risk factor for retinochoroiditis while gestational age at maternal infection has little impact (Syrocot, 2007) (see Fig. 112.2).
ANTENATAL DIAGNOSIS As Toxoplasma infection is often asymptomatic, prenatal screening with repeated serological testing for nonimmune pregnant women is performed in several countries
or regions to prospectively identify maternal seroconversions. The biological diagnosis of fetal infection is performed on amniotic fluid sampled after 18 weeks of gestation and at least 4 weeks after the date of maternal infection. Polymerase chain reaction assays for the detection of T. gondii DNA are 100% specific. Current real-time techniques are associated with more than 90% sensitivity and can predict unfavorable prognosis in early infections when parasite quantification is above 100/mL. Antenatal ultrasound scans do not show any abnormalities in two-thirds of fetuses. Symptomatic forms result mainly from infection in the first half of pregnancy. Symmetrical cerebral ventricular dilatation, typically of unfavorable prognosis, and cerebral calcifications are the most common and specific lesions. Less specific signs such as hepatomegaly, ascitis, pericardial effusion, hyperechogenic fetal bowel, and placental thickness can also be observed. In severe cases, termination of pregnancy is justified. Prenatal treatment is expected to reduce the risks of infection and of sensorineural impairment in infected children. Spiramycin is prescribed to prevent motherto-child transmission but is only parasitostatic. The pyrimethamine-sulphonamide association is highly parasiticidal and is offered to reduce the risk of clinical manifestation and/or reduce transmission. Observational studies revealed that a shorter delay between maternal infection and treatment initiation (<3–8 weeks) was associated with lower risk of transmission and clinical manifestations (Syrocot, 2007), but well conducted randomized trials are necessary to determine the exact benefit of prenatal treatment.
POSTNATAL DIAGNOSIS AND MANAGEMENT Clinical examination is most frequently normal or can reveal nonspecific signs of evolving (hepatomegaly, splenomegaly, icterus, thrombocytopenic purpura, anemia) or not fetopathy (hydro- or microcephalus, seizures). Indirect ophthalmoscopy should ideally be used to disclose retinochoroiditis. Imaging of the brain relies on ultrasound or computed tomography to detect nodular or curvilinear calcifications, or hydrocephalus (Fig. 112.3). Magnetic resonance has not been well-studied in this context. Positive biological diagnosis relies on the detection of specific IgM and/or IgA, IgG being the only ones to cross the placenta. Sensitivity depends on the tests used and increases from 40% in the first trimester to 70% in the third. Specificity reaches 100% if tests are performed on peripheral-blood rather than cord-blood. Mother– infant immunological profiles can also be compared to identify IgG, IgM, and IgA neo-synthesized by the neonate. Sensitivity of these comparative methods
CONGENITAL TOXOPLASMOSIS
1101
pyrimethamine-sulfadiazine, reported in 50% of children over the course of a 12-month treatment (McAuley et al., 1994). They are much less frequent with pyrimethamine/sulfadoxine. Minor cutaneous allergic reactions to sulphonamides, such as rash or urticaria, are observed in 1 to 2% of children.
Fig. 112.3. Neonatal longitudinal cerebral ultrasound scan: right parietal calcification.
is higher than the standard serological tests but their interpretation may be difficult. Analysis of CSF is of limited value. Two situations can be defined based on the results of the pre- and postnatal tests: ●
●
No proof of infection at birth (maternal seroconversion with negative prenatal diagnosis, normal clinical, ophthalmological and imaging findings, and no detection of specific IgM and IgA): no treatment is necessary. Serological tests should be repeated every 2 months until IgG drop under undetectable levels. If serological testing indicates congenital infection, the child must ideally be treated as indicated in the next paragraph. Proven congenital infection (diagnosed during pregnancy, at birth or postnatally): postnatal treatment is expected to reduce the risk and severity of long-term sequelae. Two protocols are used: one based on the association of pyrimethamine (1 mg/kg/day for 2 months and then 0.5 mg/kg/day for 10 months) with sulfadiazine (100 mg/kg/day in two separate doses for 12 months); and the other based on the combination of pyrimethamine (1.25 mg/kg every 10 days) with sulfadoxine (25 mg/kg every 10 days) (Fansidar®). A sulfadoxine half-life of 120 to 195 hours allows a simpler administration but longacting sulphonamides expose the patients to higher risks in case of allergies. Folinic acid must be administered (50 mg every 7 days) over the whole treatment period to reduce hematological toxicity. Reversible neutropenia is the main side-effect with
IgG levels decrease during therapy, sometimes below detectable levels. This is of no consequence and should not be taken as a sign of noninfection. After treatment has been stopped, clinical and ophthalmological examination and serological testing should be performed every 3 months during the second year of life, every 6 months during the third year, and yearly, thereafter, indefinitely. There is no reason to resume treatment unless active ocular lesions are detected. In this case, treatment should be resumed for 3 months and scaring of the lesions should be confirmed. Treatment is not necessary in the event of a serological rebound with normal or stable fundus oculi.
CONCLUSION Despite the lack of evidence regarding the effectiveness of treatment for congenital Toxoplasma infection, early diagnosis and treatment have improved its long-term prognosis. Long-term follow-up of infected children remains necessary because of the risk of late ocular lesions.
REFERENCES McAuley J, Boyer KM, Patel D et al. (1994). 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. Montoya JG, Liesenfeld O (2004). Toxoplasmosis. Lancet 363: 1965–1976. SYROCOT (Systematic Review on Congenital Toxoplasmosis) Study Group (2007). Effectiveness of prenatal treatment for congenital toxoplasmosis: a metaanalysis of individual patients’ data. Lancet 369: 115–122. Wallon M, Kodjikian L, Binquet C et al. (2004). Long-term ocular prognosis in 327 children with congenital toxoplasmosis. Pediatrics 113: 1567–1572. Wilson CB, Remington JS, Stagno S et al. (1980). Development of adverse sequelae in children born with subclinical congenital Toxoplasma infection. Pediatrics 66: 767–774.