Abstract
Zika virus (ZIKV) infection acquired during pregnancy is associated with congenital microcephaly. We describe 2 cases of ZIKV infection in women in their 36th week of pregnancy whose fetuses had preserved head circumference at birth and findings of subependymal cysts and lenticulostriate vasculopathy in postnatal imaging. These represent the first signs of congenital brain injury acquired due to ZIKV in the third trimester.
Zika virus (ZIKV) infection is generally benign. The most common symptoms last from 2 to 7 days and include maculopapular rash, fever, arthralgia, and conjunctivitis. Myalgia, headache, retro-orbital pain, edema, vomiting, pruritus, dizziness, mucosal ulcers, diarrhea, and constipation can also occur [1].
Recent evidence shows that infection acquired during pregnancy can cause congenital microcephaly associated with brain atrophy, ventriculomegaly, calcifications, and dysgenesis of the corpus callosum and cerebellar vermis [2, 3]. In October 2015, the Brazilian Health Ministry announced an increase in the prevalence of infants with microcephaly in northeastern Brazil where a ZIKV outbreak had occurred earlier that year [2]. Reports were subsequently published that demonstrated the isolation of genetic material of ZIKV in amniotic fluid [4], in the conceptus postmortem including in the brain [5, 6], and in material from miscarriages of microcephalic fetuses of mothers with confirmed maternal viremia [2, 5].
Both miscarriages and congenital microcephaly seem to be more common when the ZIKV infection occurs in the first trimester [3, 7, 8]; to date, morphological brain changes have not been described in newborns whose mothers acquired the infection in the third trimester.
This article describes 2 cases of ZIKV infection that occurred in the 36th week of gestation, with the newborns showing no abnormalities at birth. However, findings showing congenital infection were identified by imaging the central nervous system.
CASE 1
Neonatal transfontanellar ultrasound showing multiple small subependymal/intraventricular cysts in coronal (A) and sagittal views (B), and hyperechogenicity (mineralization) of lenticulostriate vessels in the sagittal plane at the thalamus (C), with vascular flow confirmed by color Doppler (D).
CASE 2
In a 16-year-old primigravida patient with history of pulmonary valvular disease without hemodynamic repercussion, routine screening in the first trimester showed the presence of immunoglobulin M and immunoglobulin G antibodies against toxoplasmosis in maternal serum at the ninth and 18th gestational weeks. Avidity assay was not performed, and we cannot estimate the date of maternal toxoplasmosis infection. The patient did not give permission to amniocentesis and the fetal diagnosis of toxoplasmosis by PCR was not performed; therefore, only the triple-drug therapy (sulfadiazine, pyrimethamine and folinic acid) was maintained until birth. At 36 weeks and 3 days of gestation, she presented with rash, fever, headache, and arthralgia lasting for 3 days. Infectious diseases were routinely investigated and were negative for CMV, rubella, syphilis, herpes, and dengue. However, a urine sample was positive for ZIKV by qPCR [9]. Ultrasounds performed during the prenatal period identified no abnormalities. A female neonate was born in the 39th week of pregnancy weighing 3462 g and with a head circumference of 35.5 cm (Capurro newborn gestational age, 38 weeks and 4 days); head circumference was at the 90th percentile as shown on the Fenton growth chart [10]. The 1-minute and 5-minute Apgar scores were 8 and 10, respectively. The ocular fundus examination was normal for age. The results of tests of the newborn in respect to toxoplasmosis, including computed tomography, were negative. However, a transfontanellar ultrasound identified subependymal cysts; no other abnormalities were identified by brain MRI. Investigations of ZIKV in samples of the infant's urine and blood from the umbilical cord by PCR were negative. The newborn had normal neural development for age as of the first postnatal month; follow-up was then referred to another service by request.
DISCUSSION
We present 2 cases of pregnant women who became infected with ZIKV at 36 gestational weeks as confirmed by qPCR of maternal urine samples. Both babies were born at term with preserved head circumference, that is, without microcephaly, but with lesions identified by transfontanellar ultrasound in the early neonatal period.
Brasil et al 2016 [8] reported on a pregnant women who was infected by ZIKV in the 35th week of pregnancy with restricted intrauterine growth that was not confirmed at birth and nonspecific electroencephalographic changes. The monitoring of our cases did not evidence signs of placental insufficiency.
Two specific changes were found in the transfontanellar ultrasounds of the newborns: subependymal cysts and lenticulostriate vasculopathy. The former are pseudocysts located below the external angles of the frontal horns of the lateral ventricles and fourth ventricle or in the region of the foramen of Monro. The underlying pathological process for the development of these cysts is not well understood. Neurotropic congenital infections such as CMV and rubella have been correlated with these cysts, probably as these infections cause lysis of undifferentiated cells in the subependymal periventricular germinal matrix that are susceptible to high mitotic activity. The cysts can also result from intrauterine aggression resulting from a vascular event, such as hemorrhage or infarction, in particular in preterm babies, or due to chromosomal abnormalities or cocaine abuse by the mother [11, 12]. The long-term neurodevelopment of affected newborns depends on the underlying pathology. The data described so far show that neurodevelopmental changes are more frequent when they are associated with intrauterine growth restriction, chromosomal aberrations, and congenital infections, especially by CMV. The neurodevelopment usually remains preserved when this change is an isolated finding [11, 13].
Lenticulostriate vasculopathy, on the other hand, is an echodensity of lenticulostriate branches of the middle cerebral artery in the region of the basal ganglia or thalamus. It is a nonspecific marker of previous injury to the developing brain [14]. This vasculopathy has been associated with congenital infections such as toxoplasmosis, rubella, CMV, herpes, and human immunodeficiency virus and also with chromosomal abnormalities including perinatal asphyxia, nonimmune fetal hydrops, twin-to-twin transfusion syndrome, congenital heart disease, and metabolic disorders such as congenital hypothyroidism [13, 15, 16]. The long-term clinical significance and neurological development are unclear. Mild to moderate forms in isolation generally have good prognoses, whereas the prognosis of lenticulostriate vasculopathy associated with other injuries depends on the severity of the other lesions [8, 14, 17].
Lenticulostriate vasculopathy associated with microcephaly, cerebral atrophy, calcifications, and dysgenesis of the corpus callosum and cerebellar vermis was described in a case of congenital ZIKV infection by Oliveira Melo et al [4]. The mother had a history of fever associated with rash in the first trimester of pregnancy when the virus was detected in amniotic fluid.
The central nervous system is under continuous development during intrauterine and early postnatal life. It is expected that a breach of this development may have different consequences depending on the time that it occurs; this has been described in cases of congenital CMV infection. When the disruption occurs before the 18th week, there is a loss of neurons and glial cells, manifesting as lissencephaly, thin cortex, cerebellar hypoplasia, and ventriculomegaly. Impaired myelination and periventricular calcification can also be seen. A breach happening at the end of the second trimester (18–24 weeks) can result in abnormalities of neuronal migration, such as polymicrogyria, cerebellar hypoplasia, and, occasionally, schizencephaly. Ventriculomegaly can occur, although less severely than in fetuses infected earlier in gestation. Infection in the third trimester (>26 weeks) can result in deficient myelination, demyelination, and changes to the white matter. Periventricular calcifications are common and intracranial hemorrhage may occur. The gyri have a normal appearance as the growth and neuronal migration are already complete at the time of infection [15].
In the cases described in this article, ZIKV infection occurred late in the third trimester, and the findings may represent the first signs of viral congenital brain injury during this period.
In the adult, ZIKV remains in the blood for less than a week after the onset of infection [1]; however, the fetal period of viremia is not known. The delivery of the first case occurred 13 days after maternal infection, and the genetic material of ZIKV was identified in the newborn's urine. In the second case, the birth took place 18 days after maternal infection, and qPCR of both umbilical cord blood and the newborn's urine were negative.
Examinations of the newborns showed no apparent neurological disorders at birth, but subependymal cysts and lenticulostriate vasculopathy were found in postnatal imaging. These findings have been associated with other congenital infectious syndromes and may represent the first signs of congenital brain injury acquired after ZIKV infection in the third trimester.
Transfontanellar ultrasound in the neonatal period of children exposed to ZIKV infection in intrauterine life may show minor changes not detected by prenatal ultrasound. Clinical and ultrasound follow-ups of these children will elucidate the importance of these findings and ascertain whether there is real neurodevelopmental significance in the long run.
Notes
Acknowledgments. The authors thank David Hewitt for his help with the English manuscript.
Disclaimer. The opinions, assumptions, and conclusions or recommendations expressed in this material are the responsibility of the authors and do not necessarily reflect the views of the São Paulo Research Foundation (FAPESP).
Financial support. This work was supported by the São Paulo Research Foundation (FAPESP numbers 2013/21719-3 to M. L. N.; 2015/12295-0 to A. C. B. T.; and 2016/05115-9 to L. C. M.). M. L. N. is supported by a CNPq Fellowship.
Potential conflicts of interest. All authors: No potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
