INTRODUCTION

Congenital toxoplasmosis (CT) is a disease caused by T. gondii, a protozoan parasite that represents a public health problem still neglected in several countries, including Peru ¹; being a preventable cause of neurological damage and congenital blindness ^{1 , 2}.

More than one third of the world’s population is estimated to be infected by this parasite; however, if infection occurs during pregnancy, it can cause damage to the newborn’s central nervous system ³. Worldwide, the estimated incidence of congenital infection is 400 to 4,000 new cases each year ⁴, and the disease burden of CT in disability-adjusted life years (DALYs) is 1.20 million per year ⁵. Some reports indicate that CT cases are more severe in Latin American countries, due to a probable exposure to more virulent strains (type I) ⁶.

In Peru, reports on CT are scarce and isolated ⁷. Therefore, the aim of this study was to describe the epidemiological, clinical and therapeutic characteristics of patients diagnosed with CT with encephalic, ocular and/or auditory involvement in a national pediatric referral institute in Lima, Peru.

THE STUDY

FINDINGS

During the study period, 79 patients with positive IgM results for T. gondii were identified at INSNSB, of which 33 were patients under 1 year of age (CT cases), 21 (63.6%) of them were included because they showed clinical manifestations of CT with severe neurological disease. The main epidemiological and clinical characteristics are detailed in Table 1, and the images of the most representative brain lesions of the cases are shown in Figure 1.

Figure 1 Abnormal findings in images of the cases. A). hydrocephalus and intracranial calcifications in cross-sectional brain computerized tomography. B). Decreased brain parenchymal volume with ventricular dilatation, microcephaly and intracranial calcifications in cross section of brain computerized tomography. C). Cerebellar hypoplasia in sagittal section of brain MRI. D). Intracranial calcifications in sagittal section of cerebral computerized tomography. E). Dysgenesis of the corpus callosum in sagittal section of brain MRI. F). Hepatic calcifications in abdominal ultrasound. 

The median age at diagnosis was 3.1 months (IQR: 1.7-7.3), and only 3/21 were diagnosed during the first month of life. None of the mothers were aware of the CT diagnosis or received treatment during gestation. Of the patients, 19.1% were from Lima (4/21), while 81% were from provinces (total 17/21; Ancash (3), Ayacucho (2), Piura (2), Huánuco (2), Amazonas (1), Arequipa (1), Cusco (1), Huancavelica (1), Junín (1), Lambayeque (1), San Martín (1) and Ucayali (1)). The comorbidities found in 10/21 patients were: congenital heart disease (5), spina bifida (2), myelomeningocele (1), esophageal atresia (1) and bronchopulmonary dysplasia (1). In addition, 19.1% (4/21) presented visceromegaly, and the presence of hepatic calcifications was identified in one case by ultrasound (Figure 1).

Laboratory tests showed the following results (median and IQR): hemoglobin: 11.4 g/dL (IQR: 9.8-12.4), platelet count: 293,000 (IQR: 212,000-536,000), eosinophils: 290 (IQR: 120-520), alanine aminotransferase: (ALT) 28 U/L (IQR: 14-44), total bilirubin: 2.095 mg/dL (IQR: 0.2-5). The cytochemical analysis of cerebrospinal fluid (CSF) carried out in 9/21 patients showed the following: mean cell count 30.2 (SD: 19.2) cells/mm³ (polymorphonuclear: 21.5, SD: 17.9; mononuclear: 78.5, SD: 17.9), glycorrhachia: 29.3 mg/dL (SD: 17.4), CSF protein: 484 mg/dL (IQR: 109-589), and adenosine deaminase: (ADA) 484 U/L (IQR: 109-589). Antiparasitic treatment was used in 13/21 patients and only three received the combination of pyrimethamine plus sulfadiazine, other details of the treatment are shown in Table 2.

DISCUSSION

This study shows a high percentage of CT cases with severe neurological disease (64%), describes the largest number of patients with this diagnosis, and was carried out in a single institution in Peru over a period of five years. However, there are few and isolated published reports of CT with severe neurological disease in Peru ⁷, despite the existence of high seroprevalence of toxoplasmosis in pregnant women, which varies between 32.5% and 94.5% ⁹.

Different routes of transmission of CT have been reported: 1) primary infection during or shortly before pregnancy; 2) reactivation of T. gondii in an HIV-infected or otherwise immune-compromised mother, and 3) secondary to infection by an atypical genotype of T. gondii in a pregnant woman immune to a typical genotype ¹⁰. Most CT cases are asymptomatic, the severity of fetal damage by T. gondii occurs mainly when the maternal infection occurs early in pregnancy (during the first trimester); however, the permeability of the placental barrier that allows the passage of T. gondii to the fetus is lower in the first trimester (equivalent to 10%), while during the second and third trimester permeability reaches 30 and 70%, respectively, in these cases the risk of fetal infection is higher, but with less possibility of causing neurological damage ¹¹.

On the other hand, it has been previously reported that the risk of CT with severe neurological disease, with clinical manifestations included in the classic Sabin and Pinkerton triad (hydrocephalus or microcephaly, intracranial calcifications and chorioretinitis), is higher in South American countries (according to data from Brazil and Colombia) compared to European countries, with a comparative risk in ocular lesions of 47% versus 14%, and for intracranial lesions of 53% versus 9% ¹². Likewise, Olariu et al. identified that 85% of the cases with clinical suspicion and laboratory confirmation of CT showed signs of severe neurological disease in the United States ¹³, while that figure was 64% in our study; it is worth mentioning that the INSNSB is a referral hospital that receives patients with diseases requiring neurosurgical management (such as hydrocephalus). Another series of CT cases in Peru reported 16 cases over a period of 15 years, two patients presented hydrocephalus (12.5%), four had microcephaly (25%) and none showed intracranial calcifications or ocular involvement ¹⁴. In addition, few cases of central diabetes insipidus secondary to CT have been reported in the literature; in our study we found two patients with this condition involving the hypothalamic-pituitary axis ¹⁵. Sensorineural hearing loss associated with CT is another clinical manifestation that should be evaluated, its prevalence varies and can reach up to 26% of cases, therefore monitoring and periodic audiometric evaluations are necessary and recommended in those patients diagnosed with CT ¹⁶.

Treatment for CT includes a prenatal approach, with the purpose of preventing infection of the fetus, and in case of infection, offering early treatment during gestation; the postnatal approach focuses on treating the infection and preventing sequelae ¹⁷. The treatment of choice for postnatal CT is based on the combination of pyrimethamine and sulfadiazine for a period of 12 months, both drugs have antiparasitic action against the tachyzoite forms of T. gondii; however, these drugs have not shown effectiveness in eliminating the cystic forms (bradyzoite) of the parasite, especially in the central nervous system and ocular system ^{17 , 18}. The use of other drugs, alone or in combination with pyrimethamine, such as sulfadoxine, clindamycin, cotrimoxazole, atovaquone and azithromycin, have also been described as treatment alternatives ¹⁷, due to the lack of availability and access to pyrimethamine and sulfadiazine. Adjuvant corticosteroid therapy is used in cases with active ocular involvement, such as chorioretinitis, and in cases with CSF proteins greater than 1 g/dL ¹⁹.

When it comes to prevention, it is important to strengthen public education, especially for pregnant women; information must be detailed and practical in order to allow clear communication between the physician and the patient, with the purpose of improving adherence to measures and habits, fundamentally hygiene, which reduces exposure to T. gondii ^{1 , 4}. In addition, countries such as France have an effective gestational screening and early treatment program that has been shown to reduce the prevalence and severity of CT; however, other countries with sociodemographic characteristics similar to ours, such as Morocco and Colombia, do screen pregnant women for CT, but have shown difficulties in the follow-up and treatment of diagnosed cases ²⁰.

A limitation of the study was that the cases were selected from only one institution; and therefore, the results may not reflect the real situation of CT in the country. Likewise, only patients with severe neurological disease and with postnatal diagnosis were included, because INSNSB, being a reference health facility, is focused on the management of surgical pathologies in pediatric patients and does not provide care to pregnant women.

In conclusion, our study reports a high percentage of CT cases with severe neurological disease mainly hydrocephalus, intracranial calcifications, microcephaly, and chorioretinitis. Most cases were diagnosed after one month of age and received alternative treatment. It is important to mention that in Peru congenital CT and other congenital infections are underreported and can therefore be considered as neglected. Therefore, national surveillance and research are required in order to identify the real implications and repercussions of CT in the Peruvian population, allowing the development of guidelines with appropriate strategies for prevention, early diagnosis and timely treatment during gestation and for the newborn, with access and availability of diagnostic methods and medications of choice.