First Autopsy of a Newborn with Congenital Zika Syndrome in Puerto Rico.
Numerous cases of congenital Zika syndrome (CZS) have been reported in Brazil, with similar cases now emerging in Puerto Rico. This new syndrome involves a pattern of birth defects found in fetuses and infants exposed to the ZV in utero. These birth defects include, but are not limited to, microcephaly, decreased brain tissue and atrophy, abnormally formed or absent brain structures, hydrocephalus, congenital contractures, and ophthalmologic abnormalities (2). Specific differences have been described in the clinical manifestations seen in babies affected by the ZV versus the manifestations linked to other congenital infections (3). Calcifications within the gray matter-white matter junction (an unusual location for the calcifications that are seen in other congenital infections), for example, are particular to the ZV (4). Severe cortical malformations, ventriculomegaly, cerebellar hypoplasia, and abnormal hypodensity of the white matter are other distinctive characteristics (3).
For this reason Puerto Rico's Department of Health has focused on ZV prevention, especially during pregnancy. As of August 2017, there have been 3,923 pregnant women with laboratory confirmation of ZV infection in Puerto Rico. Of these, 1,927 (49%) were symptomatic and 1,996 (51%) were asymptomatic. Further, of the live births in Puerto Rico (from 2016 up till week 29 of 2017), 47 of the neonates were found to have the congenital syndrome associated with ZV infection (5). There has been a lack of autopsy cases of fetuses and/or newborns with the pattern of birth defects mentioned.
We present the findings of the first autopsy performed on a neonate born with CZS in Puerto Rico.
A small-for-gestational-age neonate was born (delivered by cesarean section) at 39 weeks gestational age (wGA) to an 18-year-old mother (G1P0A0) with symptomatic, serologically confirmed (at 8 weeks, by RT-PCR) ZV infection; the mother was negative for dengue and chikungunya. Symptoms included rash and generalized arthralgia. The mother had a history of hypothyroidism treated with levothyroxine, was negative for HIV, hepatitis B, toxoplasmosis IGM and IGG, and cytomegalovirus IGM and IGG; VDRL was negative as well and she tested immune for rubella in her prenatal screening test. The patient had a normal alpha-fetoprotein level (her entire quad screen was negative). A prenatal sonographic evaluation at 30 weeks revealed a fetus with intrauterine growth restriction, microcephaly (>3 standard deviations below the mean), bilateral asymmetric ventriculomegaly, a decreased amount of cerebral parenchyma with a very thin cerebral cortex, and multiple cerebral calcifications in the cerebral cortex and periventricular areas. Other anomalies described included micrognathia, scissoring of the legs, and rocker bottom foot. Amniocentesis showed a normal male karyotype (46,XY). The mother was referred to the University District Hospital of Puerto Rico's high-risk clinics for her remaining prenatal care and childbirth.
At birth, the neonate required neonatal resuscitation and intubation. He presented micrognathia, multiple contractures of the joints (arthrogryposis), rocker bottom feet, clenched hands and scissor legs. He had a head circumference of 32.5 cm, only 1.5 standard deviations below the mean, thus, not meeting the criteria for microcephaly. The head sonogram revealed severe asymmetric ventriculomegaly of the lateral ventricles (Figure 1) with associated compression and thinning of the cerebral cortex. The apparent absence of the septum pellucidum and corpus callosum was also revealed. Echocardiography disclosed a ventricular septal defect (VSD) and severe pulmonary hypertension. The patient remained critically ill and expired 2 days after his birth. A TORCH screen of the neonate was not performed nor were his ZV titers determined.
The autopsy confirmed the multiple external anomalies previously mentioned (Figures 2 & 3). Body measurements and weights were below expected norms (Table 1). The heart presented a large perimembranous VSD, seen on echocardiography. On microscopy the lungs revealed acute pneumonia with hyaline membranes, focal hemorrhages, and hypertensive vascular changes. The brain weighed 150g after fixation, far below that expected (362g) for gestational age, and was grossly small and had a simplified gyral pattern. The infant's brain presented with a subarachnoid hemorrhage. On sectioning, the cerebrum disclosed poor differentiation between the gray and white matter. The ventricular system was markedly dilated, with ventricular lining granularities. Sections of the brainstem and cerebellum disclosed marked degeneration. On microscopy, there was severe encephalic degeneration with numerous dystrophic calcifications, subarachnoid, perivascular, and interstitial hemorrhages, microglial nodules, vascular proliferation, perivascular cuffing, and incomplete migration (Figure 4). These central nervous system findings are consistent with congenital Zika encephalopathy. A pathologic exam of the placenta revealed focal villous stromal edema and reactive amnion with pigment-laden macrophages.
The numerous anomalies found in this neonate were most likely secondary to maternal ZV infection (at 8 wGA). The cerebral and physical abnormalities have been well described in recent research studies of CZS.
In Ceara, part of northeastern Brazil, Sousa et al. performed postmortem examinations of 7 neonates with CZS. As was the case with the mother of our patient, the mothers of these babies had contracted ZV infection during the first trimester of pregnancy, with 5 of them presenting symptoms of infection. Brain weight was decreased in all 7 neonates, with evidence also of ventriculomegaly, dystrophic calcification, and severe cortical neuronal depletion. Six of these neonates had arthrogryposis. One neonate did not have microcephaly but did have significant intracranial pathology, similar that of to our patient (6). The discrepancy between the prenatal finding of fetal microcephaly and the postnatal findings may be explained by the early development of hydrocephalus. Sousa's autopsy findings are in accordance with our autopsy findings and with the diagnosis of CZS.
Furthermore, Vasco et al., through brain imaging, disclosed the prevalence of a simplified gyral pattern, malformations of cortical development, abnormalities of the corpus callosum, decreased brain volume, ventriculomegaly, and hypoplasia of the cerebellum or brainstem in neonates affected by the ZV (7). Soares et al. also documented congenital brain abnormalities in ZV-infected fetuses, with a prevalence of ventriculomegaly, abnormalities of the corpus callosum, cortical migration abnormalities, and intracranial calcifications, most commonly at the gray-white matter junction (4). Many of these findings, such as the degeneration of the brainstem and cerebellum, incomplete migration, intracranial calcifications, ventriculomegaly, and severe encephalic degeneration, were noted in the autopsy presented herein.
After reviewing the recent literature and comparing what it describes with our autopsy findings, we believe the diagnosis of CZS is highly likely. This reinforces the importance of continued research on the effects of ZV on the fetus. Furthermore, although at birth he did not fulfill microcephaly criteria, prenatally he consistently had a head circumference more than 3 standard deviations below the mean. This illustrates the need to reassess the definition of microcephaly as it applies to patients prenatally exposed to the ZV.
(1.) Cotello AN, Dua TA, Duran PA, Gulmezoglu ME, Oladapo OL, Perea WI, et al. Defining the syndrome associated with congenital Zika virus infection. Bull World Health Organ 2016;94:406-406A. Available at: Url: http://www.who.int/bulletin/volumes/94/6/16-176990.pdf. Accessed July 11, 2017.
(2.) Centers for Disease Control Prevention. Zika Virus [CDC website]. June 29, 2017. Available at: Url: https://www.cdc.gov/zika/index.html. Accessed July 10, 2017.
(3.) Franca GV, Schuler-Faccini L, Oliveira WK, Henriques CM, Carmo EH, Pedi VD, et al. Congenital Zika virus syndrome in Brazil: a case series of the first 1501 live births with complete investigation. Lancet 2016;388:891-897.
(4.) Soares de Oliveira-Szejnfeld P, Levine D, Melo AS, Amorim MM, Batista AG, Chimelli L, et al. Congenital Brain Abnormalities and Zika Virus: What the Radiologist Can Expect to See Prenatally and Postnatally. Radiology 2016;281;203-218.
(5.) Departamento de Salud de Puerto Rico. Informe Semanal de Enfermedades Arbovirales (Arbo V) Departamento de Salud de Puerto Rico, Semana 29 (16 al 22 de Julio de 2017). San Juan, PR: Departamento de Salud de Puerto Rico; 2017. Available at: Url: www.salud.gov.pr/Estadisticas- Registros-y-Publicaciones/informes%20Arbovirales/Reporte%20 ArboV%20semana%2029-2017.pdf. Accessed August 8, 2017.
(6.) Sousa AQ, Cavalcante DIM, Franco LM, Araujo FMC, Sousa ET, Valenca-Junior JT, et al. Postmortem Findings for 7 Neonates with Congenital Zika Virus Infection. Emerg Infect Dis 2017;23:1164-1167.
(7.) de Fatima Vasco Aragao M, van der Linden V, Brainer-Lima AM, Coeli RR, Rocha MA, Sobral da Silva P, et al. Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly retrospective case series study. BMJ 2016; 353: i1901.
Nicolle M. Davila-Castrodad, MD *; Zayhara Reyes-Bou, MD ([dagger]); Maria Correa-Rivas, MD ([double dagger]); Juan L. Perez-Berenguer, MD ([section]); Lorena Di-Pasquale, MD ([paragraph]); Ines Garcia-Garcia, MD **
* Neonatal-perinatal medicine resident, Neonatology Section, Department of Pediatrics, University of Puerto Rico Medical Sciences Campus, San Juan, PR; ([dagger]) Professor, Neonatology Section, Department of Pediatrics, University of Puerto Rico Medical Sciences Campus, San Juan, PR; ([double dagger]) Professor, Department of Pathology and Laboratory Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, PR; ([section]) Adjunct professor, Department of Pathology and Laboratory Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, PR; ([paragraph]) Pathology resident, Department of Pathology and Laboratory Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, PR; ** Professor, Neonatology Section, Department of Pediatrics, University of Puerto Rico Medical Sciences Campus, San Juan, PR
The author/s has/have no conflict/s of interest to disclose.
Address correspondence to: Ines Garcia-Garcia, Department of Pediatrics, Neonatology Section, School of Medicine, University of Puerto Rico, Medical Sciences Campus, P.O. Box 365067, San Juan, PR 00936-5067. Email: Ines.email@example.com
Caption: Figure 1. Head sonogram: right coronal view with evidence of severe dilatation of the lateral ventricles, more pronounced on the right.
Caption: Figure 2. External anomalies of the head, including micrognathia and low set, posteriorly rotated ears.
Caption: Figure 3. External anomalies of the extremities: rocker bottom feet, scissor legs, clenched and hyperflexed hands, and multiple contractures (arthrogryposis).
Caption: Figure 4. A: Dystrophic calcifications, 10x; B: Perivascular cuffing, 10x; C: Microglial nodule, 10x; D: subependymal nodules, 10x; E: Subarachnoid Hemorrhage, 4x; F: Incomplete neuronal migration.
Table 1. Organ measurements and weights Observed Expected (g [+ or -] cm) (g [+ or -] cm) Body weight 2100 2789 [+ or -] 520 Crown to heel 45 46.7 [+ or -] 4.4 Crown to rump 30 34.3 [+ or -] 1.9 Toe to heel 7.5 7.5 [+ or -] 0.5 Liver 60 121.3 [+ or -] 39.2 Spleen 8 10.1 [+ or -] 3.5 Adrenal glands 3 7.4 [+ or -] 2.5 Thymus 14 9.4 [+ or -] 2.5 Kidneys 20 26.1 [+ or -] 4.9 Lungs 25 42.6 [+ or -] 14.9 Heart 9 19.1 [+ or -] 2.8 Brain 150 362 Expected measurements and weights from Women and Infants Hospital, Providence, RI, USA, for a 39-week gestational age, liveborn baby.