Ophthalmic Surgery, Lasers and Imaging Retina

Case Report 

First Locally Acquired Congenital Zika Syndrome Case in the United States: Neonatal Clinical Manifestations

Camila V. Ventura, MD, PhD; Emmalee S. Bandstra, MD; Maria P. Fernandez, MD; Joshua M. Cooper, MD; Gaurav M. Saigal, MD; Charles R. Bauer, MD; Julie A. Hofheimer, PhD; Michelle D. Berkovits, PhD; Robert C. Fifer, PhD; Alyssa D. Pensirikul, MD; Ivan A. Gonzalez, MD; Christine L. Curry, MD; Samita Andreansky, PhD; Ramzi T. Younis, MD; Xue Z. Liu, MD, PhD; Tanuj P. Banker, MD; Sander R. Dubovy, MD; Samantha M. Langer, BS; Audina M. Berrocal, MD

Abstract

In the spring of 2017, a full-term infant with microcephaly was delivered in South Florida. During first trimester, the mother presented with fever, nausea, and vomiting. She reported no foreign travel for herself or her partner. The infant's neurologic, ophthalmologic, neuroradiologic, and audiologic findings were highly suggestive of congenital Zika syndrome (CZS), confirmed by IgM antibodies and plaque reduction neutralization test. New observations, including peripheral temporal retinal avascularity and peripapillary retinal nerve fiber layer thinning, are presented from this first known case of non-travel-associated CZS in the United States.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:e93–e98.]

Abstract

In the spring of 2017, a full-term infant with microcephaly was delivered in South Florida. During first trimester, the mother presented with fever, nausea, and vomiting. She reported no foreign travel for herself or her partner. The infant's neurologic, ophthalmologic, neuroradiologic, and audiologic findings were highly suggestive of congenital Zika syndrome (CZS), confirmed by IgM antibodies and plaque reduction neutralization test. New observations, including peripheral temporal retinal avascularity and peripapillary retinal nerve fiber layer thinning, are presented from this first known case of non-travel-associated CZS in the United States.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:e93–e98.]

Introduction

Congenital Zika syndrome (CZS) is characterized by a broad spectrum of neurological defects, ophthalmological findings, skeletal malformations, and hearing deficits.1 According to the Pan American Health Organization, as of November 16, 2017, 27 countries and territories in the Americas have reported confirmed CZS cases, including the United States.2

Through November 2017, 98 liveborn infants with Zika-associated birth defects were identified in the continental United States.3 Nevertheless, there is a lack of data describing the mode of virus transmission (travel-associated, local mosquito-borne transmission, or sexual transmission). Until now, the only case of CZS reported in the United States has been travel-associated, and the first was from Miami, Florida.4 Herein, we report the first locally transmitted case of CZS in the United States and contribute new ocular findings to the previously identified clinical spectrum of CZS.

Case Report

A 1-day-old female infant born to a 22-year-old African-American mother at 39 weeks gestational age (GA) via cesarean section in Miami was referred for ophthalmologic consultation with a high suspicion of CZS.

During the first trimester, the mother presented to the emergency department with a history of fever, nausea, and vomiting. Ultrasonography confirmed an intrauterine pregnancy at 8 weeks GA. She reported no foreign travel for herself and her partner and denied prenatal alcohol, tobacco, and drug use or having any other symptoms such as arthralgia, myalgia, rash, and / or conjunctivitis during pregnancy. Fetal ultrasonography at 22 weeks GA was normal. Follow-up ultrasound at 37 weeks GA disclosed an estimated fetal weight of 2,063 grams, less than tenth percentile; head circumference and biparietal diameter less than third percentile; and bilateral ventriculomegaly, suspected absence of the corpus callosum, and frontal lobe flattening.

Physical examination at birth revealed severe microcephaly with partially collapsed skull [head circumference: 27.5 cm (< first percentile); birth weight: 2,410 grams (third percentile); birth length: 45 cm (third percentile) (Figure 1A). The only other anomaly was bilateral postaxial polydactyly type 2B (familial). There was no other family history of congenital anomalies, developmental delay, or hearing loss.

Clinical features of full-term infant with congenital Zika syndrome. (A) Posterior view of excessive scalp folds. (B) Cranial ultrasound using a mastoid window demonstrating moderate ventriculomegaly (white arrows). (C) Axial T2-weighted magnetic resonance imaging of the brain demonstrating marked prominence of the extra axial spaces and ventriculomegaly consistent with severe atrophy of the brain and a simplified gyral pattern (short black arrows). Punctate hypointensities consistent with calcifications are also seen in the periventricular white matter (long white arrows).

Figure 1.

Clinical features of full-term infant with congenital Zika syndrome. (A) Posterior view of excessive scalp folds. (B) Cranial ultrasound using a mastoid window demonstrating moderate ventriculomegaly (white arrows). (C) Axial T2-weighted magnetic resonance imaging of the brain demonstrating marked prominence of the extra axial spaces and ventriculomegaly consistent with severe atrophy of the brain and a simplified gyral pattern (short black arrows). Punctate hypointensities consistent with calcifications are also seen in the periventricular white matter (long white arrows).

The newborn was admitted to the neonatal intensive care unit for microcephaly evaluation. Toxoplasmosis, rubella, cytomegalovirus, HIV, and syphilis were ruled out. Real-time transcription polymerase chain reaction assays (Trioplex real-time polymerase chain reaction [RT-PCR] assay) for Zika, dengue, and chikungunya viruses were negative in maternal serum and urine, and infant serum, urine, and cerebrospinal fluid (CSF). However, immunoglobulin M (IgM) testing for Zika antibodies (Centers for Disease Control and Prevention [CDC] Zika IgM ELISA assay [MAC-ELISA]) was positive in maternal and infant sera and infant CSF. Serum plaque reduction neutralization test was positive for Zika in maternal and infant sera. Placental tissue was positive for Zika virus-NS5 gene RT-PCR.

Cranial ultrasonography with a poor acoustic window showed moderate ventriculomegaly (Figure 1B). Brain magnetic resonance imaging demonstrated severe brain abnormalities (Figure 1C).

Comprehensive ophthalmic examination revealed normal anterior segment structures and pupil reaction to light with no afferent pupillary defect bilaterally. Funduscopy showed bilateral increased cup-to-disc ratio, pigment mottling, and sharply demarcated chorioretinal atrophy within the macular regions (Figure 2A). Axial lengths were approximately 16.5 mm in the right eye and 16.8 mm in the left. Fluorescein angiography disclosed a window defect in the macular region and peripheral avascularity of the temporal retina bilaterally (Figure 2B). Using spectral-domain optical coherence tomography (SD-OCT) (iVue; Optovue, Fremont, CA), average retinal nerve fiber layer (RNFL) thickness was 63 μm on the right and 59 μm on the left. Macular OCT images showed neurosensory retinal thinning with discontinuation of the ellipsoid zone, choroidal thinning, and hyperreflectivity underlying the retinal pigment epithelium (Figure 2C).

Ophthalmological findings in a full-term infant with congenital Zika syndrome. (A) Fundus montage of the left eye (OS) demonstrating increased optic nerve cupping, focal pigmentary changes, and well-defined chorioretinal atrophy within the macular region. (B) Fluorescein angiography montage of the OS showing a window defect in the macular region and peripheral avascularity of the temporal retina. (C) Macular optical coherence tomography of the right eye revealing retinal and choroidal thinning with discontinuation of the ellipsoid zone.

Figure 2.

Ophthalmological findings in a full-term infant with congenital Zika syndrome. (A) Fundus montage of the left eye (OS) demonstrating increased optic nerve cupping, focal pigmentary changes, and well-defined chorioretinal atrophy within the macular region. (B) Fluorescein angiography montage of the OS showing a window defect in the macular region and peripheral avascularity of the temporal retina. (C) Macular optical coherence tomography of the right eye revealing retinal and choroidal thinning with discontinuation of the ellipsoid zone.

Comprehensive audiology examination showed possible mild hearing loss in the mid-frequency region bilaterally (Table).

Auditory Brainstem Response Results

Table:

Auditory Brainstem Response Results

The infant was discharged on postnatal day 11 and was scheduled for ambulatory care and multidisciplinary subspecialty follow-up.

Discussion

The CDC characterizes CZS by five rare or unique features: severe microcephaly with partially collapsed skull; thin cerebral cortices with subcortical calcifications; macular scarring and focal pigmentary retinal mottling; congenital contractures; and marked early hypertonia and symptoms of extrapyramidal involvement.1 The neuroimaging findings of CZS detected in the present case such as severe microcephaly, subcortical calcifications, ventriculomegaly, and marked thinning of the corpus callosum reflecting severe central nervous system (CNS) damage have been reported previously.1,5

The observed chorioretinal scar and focal pigmentary changes as seen in the current case were first reported in 2016 by Ventura et al. in Brazilian infants and corroborated in cases from other South American countries.6–10 In this CZS case, macular OCT showed evidence of severe retinal and choroidal destruction similar to previous reports.10,11 Importantly, this is the first study of CZS to report results of RNFL thickness analysis quantifying diffuse bilateral RNFL thinning in the peripapillary region. According to Vajzovic et al., term babies have a RNFL thickness of approximately 170 μm at the parafoveal region.12 Taking into consideration that the RNFL measurement was performed in a different region, the current infant's RNFL can still be considered significantly thin (63 μm right and 59 μm left). In addition, diffuse RNFL thinning has been similarly observed in patients with hereditary optic neuropathies such as Leber's hereditary optic neuropathy and dominant optic atrophy.13,14 Therefore, we postulate that the observed RNFL thinning may correlate with the severe CNS and visual system damage caused by infection with Zika virus (ZIKV).1,15

Another interesting ocular finding identified was the bilateral peripheral retinal avascularity, which can be key to understanding the pathophysiology of the ocular manifestations in CZS. Mladinich et al. recently demonstrated that ZIKV infects persistently the primary human brain microvascular endothelial cells to serve as cellular reservoirs for ZIKV replication and enable viral spread across the blood-brain barrier into neuronal compartments.16 They hypothesized that the endothelial cells from other sites may also favor ZIKV to cross testicular, placental, and retinal tissues in affected patients. Clinically, these retinal vascular findings serve as an alert to possible progression such as neovascularization, traction, and/or complex retinal detachment as seen in retinopathy of prematurity, incontinentia pigmenti, and familial exudative vitreoretinopathy.17–19 Thus, close follow-up with comprehensive ophthalmological examination of the peripheral retina is vital.

The demonstrated early hearing sensitivity loss in the mid-frequencies on auditory brainstem response test raises concern for late-onset hearing loss requiring follow-up.20

To our knowledge, this is the first case of non-travel-associated, locally transmitted congenital Zika infection in the continental United States. The identification of this sentinel CZS case should heighten national and global awareness of ZIKV's reach. The current case emphasizes the importance of early Zika screening of pregnant women and their partners and multidisciplinary assessments and interventions for affected infants. This report also substantiates the urgent need for more effective mosquito-vector control measures and innovative vaccine and drug research to prevent and treat this potentially devastating infection.

References

  1. Moore CA, Staples JE, Dobyns WB, et al. Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatr. 2017;171(3):288–295. doi:10.1001/jamapediatrics.2016.3982 [CrossRef]
  2. Zika cases and congenital syndrome associated with Zika virus reported by countries and territories in the Americas, 2015–2017: Cumulative cases. Pan American Health Organization and World Health Organization. http://www.paho.org/hq/index.php?option=com_docman&task=doc_view&Itemid=270&gid=42925&lang=en. Updated November 16, 2017. Accessed November 26, 2017.
  3. Outcomes of pregnancies with laboratory evidence of possible Zika virus infection, 2015–2017. The Centers of Disease Control and Prevention. https://www.cdc.gov/pregnancy/zika/data/pregnancy-outcomes.html. Accessed November 26, 2017.
  4. Ventura CV, Fernandez MP, Gonzalez IA, et al. First travel-associated congenital Zika syndrome in the US: ocular and neurological findings in the absence of microcephaly. Ophthalmic Surg Lasers Imaging Retina. 2016;47(10):952–955. doi:10.3928/23258160-20161004-09 [CrossRef]
  5. de Fatima Vasco Aragao M, van der Linden V, Brainer-Lima AM, 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. doi:10.1136/bmj.i1901 [CrossRef]
  6. Ventura CV, Maia M, Bravo-Filho V, Góis AL, Belfort R Jr, . Zika virus in Brazil and macular atrophy in a child microcephaly. Lancet. 2016;387(10015):228. doi:10.1016/S0140-6736(16)00006-4 [CrossRef]
  7. Ventura CV, Maia M, Ventura BV, et al. Ophthalmological findings in infants with microcephaly and presumable intra-uterus Zika virus infection. Arq Bras Oftalmol. 2016;79(1):1–3. doi:10.5935/0004-2749.20160002 [CrossRef]
  8. de Paula Freitas B, de Oliveira Dias JR, Prazeres J, et al. Ocular findings in infants with microcephaly associated with presumed Zika virus congenital infection in Salvador, Brazil. JAMA Ophthalmol. 2016;134(5):529–535. doi:10.1001/jamaophthalmol.2016.0267 [CrossRef]
  9. Yepez JB, Murati FA, Pettito M, et al. Ophthalmic manifestations of congenital Zika syndrome in Colombia and Venezuela. JAMA Ophthalmol. 2017;135(5):440–445. doi:10.1001/jamaophthalmol.2017.0561 [CrossRef]
  10. de Oliveira Dias JR, Ventura CV, Borba PD, et al. Infants with congenital Zika syndrome and ocular findings from São Paulo, Brazil: spread of infection. Retin Cases Brief Rep. 2017;doi:. doi:10.1097/ICB.0000000000000518 [CrossRef]
  11. Ventura CV, Ventura LO, Bravo-Filho V, et al. Optical coherence tomography of retinal lesions in infants with congenital Zika syndrome. JAMA Ophthalmol. 2016;134(12):1420–1427. doi:10.1001/jamaophthalmol.2016.4283 [CrossRef]
  12. Vajzovic L, Hendrickson AE, O'Connell RV, et al. Maturation of the human fovea: correlation of spectral-domain optical coherence tomography findings with histology. Am J Ophthalmol. 2012;154(5):779–789.e2. doi:10.1016/j.ajo.2012.05.004 [CrossRef]
  13. Barboni P, Savini G, Valentino ML. Retinal nerve fiber layer evaluation by optical coherence tomography in Leber's hereditary optic neuropathy. Ophthalmology. 2005;112(1):120–126. doi:10.1016/j.ophtha.2004.06.034 [CrossRef]
  14. Barboni P, Savini G, Parisi V, et al. Retinal nerve fiber layer thickness in dominant optic atrophy measurements by optical coherence tomography and correlation with age. Ophthalmology. 2011;118(10):2076–2080. doi:10.1016/j.ophtha.2011.02.027 [CrossRef]
  15. van den Pol AN, Mao G, Yang Y, Ornaghi S, Davis JN. Zika virus targeting in the developing brain. J Neurosci. 2017;37(8):2161–2175. doi:10.1523/JNEUROSCI.3124-16.2017 [CrossRef]
  16. Mladinich MC, Schwedes J, Mackow ER. Zika virus persistently infects and is basolaterally released from primary human brain microvascular endothelial cells. MBio. 2017;8(4):e00952–17. doi:10.1128/mBio.00952-17 [CrossRef]
  17. John VJ, McClintic JI, Hess DJ, Berrocal AM. Retinopathy of prematurity versus familial exudative vitreoretinopathy: Report on clinical and angiographic findings. Ophthalmic Surg Lasers Imaging Retina. 2016;47(1):14–19. doi:10.3928/23258160-20151214-02 [CrossRef]
  18. Tzu JH, Murdock J, Parke DW 3rd, Warman R, Hess DJ, Berrocal AM. Use of fluorescein angiography in incontinentia pigmenti: A case report. Ophthalmic Surg Lasers Imaging Retina. 2013;44(1):91–93. doi:10.3928/23258160-20121221-20 [CrossRef]
  19. Watzke RC, Stevens TS, Carney RG Jr, . Retinal vascular changes of incontinentia pigmenti. Arch Ophthalmol. 1976;94(5):743–746. doi:10.1001/archopht.1976.03910030353001 [CrossRef]
  20. Mittal R, Fifer RC, Liu XZ. A possible association between hearing loss and Zika virus infections. JAMA Otolarngol Head Neck Surg. 2017;doi:. doi:10.1001/jamaoto.2017.1798 [CrossRef]

Auditory Brainstem Response Results

Right Ear Threshold (db nHL)Left Ear Threshold (db nHL)
Click70, 50, 30, 25, 20Click70, 50, 45, 40, 35, 30
1,000 Hz50, 40, 35, 301,000 Hz50, 45, 40
4,000 Hz40, 35, 30, 254,000 Hz60, 40, 35, 20, 25, 20

University of Miami Pediatric Zika Research Consortium Investigators

Department of Ophthalmology
  Audina M. Berrocal, MD
  Camila V. Ventura, MD, PhD
  Maria Paula Fernandez, MD
  Tanuj P. Banker, MD
  Sander R. Dubovy, MD
  Catherin I. Negron, MBA
  Brenda J. Fallas

Department of Pediatrics (Division of Neonatology)
  Emmalee S. Bandstra, MD
  Charles R. Bauer, MD
  Joshua M. Cooper, MD
  Michelle D. Berkovits, PhD
  Lihua Xue, MS
  Maritza Torres, MD
  Angelica A. Floren, MD
  Ana J. Rodriguez, RN
  Janet E. Mitchell, RN
  Samantha M. Langer, BS
  Alexandra Fernandez, MD
  Elizabeth Crep, BS
  Katherine Horan, MD, MPH

Department of Pediatrics (Division of Ambulatory Pediatric Care)
  Audrey Y. Ofir, MD

Department of Pediatrics (Division of Pediatric Infectious Diseases)
  Ivan A. Gonzalez, MD
  Raymond S. Vado, MD
  Zhanna Kozhekbaeva, PhD

Department of Pediatrics (Division of Pediatric Hematology-Oncology)
  Samita Andreansky, PhD

Department of Pediatrics (Division of Pediatric Nephrology)
  Chryso P. Katsoufis, MD

Department of Pediatrics (Division of Pediatric Cardiology)
  Juanita A. Hunter, MD

Department of Pediatrics (Division of Pediatric Audiology and Speech Pathology)
  Robert C. Fifer, PhD

Department of Pediatrics (Division of Pediatric Clinical Research)
  David A. Ludwig, PhD
  Sunil Mathew, BS
Department of Otolaryngology
  Ramzi T. Younis, MD
  Xue Zhong Liu, MD, PhD
  Rahul Mittal, PhD
  Si Chen, MD
  Megan Ballard, MD
  Maria Campos, BA
  Constanza H. Pelusso, FMG, CCRP
  Joaquin Jimenez, BS

Department of Radiology
  Gaurav M. Saigal, MD
  Varan Govind, PhD
  Robert Quencer, MD
  Gabriela de la Vega Muns, MD
  Fiama Reyes Avila, BA
  Shanchita Ghosh, MD
  Jessica Riotti

Department of Neurology (Division of Pediatric Neurology)
  Alyssa D. Pensirikul, MD

Department of Obstetrics and Gynecology
  Christine L. Curry, MD, PhD
  JoNell E. Potter, PhD

University of North Carolina — Department of Pediatrics, Division of Neonatology
  Julie Hofheimer, PhD

Florida Gulf Coast University — Department of Biological Sciences
  Scott Michael, PhD
  Sharon Isern, PhD
University of Miami Pediatric Zika Research Consortium InvestigatorsUniversity of Miami Pediatric Zika Research Consortium Investigators

Table A:

University of Miami Pediatric Zika Research Consortium Investigators

Authors

From the Department of Ophthalmology, Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami (CMV, MPF, TPB, SRD, AMB); the Department of Ophthalmology, Altino Ventura Foundation, Recife, Brazil (CMV); the Department of Pediatrics, Division of Neonatology, Jackson Memorial Hospital, Miller School of Medicine, University of Miami, Miami (ESB, JMC, CRB, MDB, SML); the Department of Radiology, Jackson Memorial Hospital, Miller School of Medicine, University of Miami, Miami (GMS); the Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (JAH); the Department of Pediatrics, Division of Audiology and Speech Pathology, Jackson Memorial Hospital, Miller School of Medicine, University of Miami, Miami (RCF); the Department of Neurology, Division of Pediatric Neurology, Miller School of Medicine, University of Miami, Miami (ADP); the Department of Pediatrics, Division of Pediatric Infectious Diseases, Jackson Memorial Hospital, Miller School of Medicine, University of Miami, Miami (IAG); the Department of Obstetrics and Gynecology, Miller School of Medicine, University of Miami, Miami (CLC); the Department of Pediatrics, Division of Pediatric Hematology and Oncology, Miller School of Medicine, University of Miami, Miami (SA); and the Department of Otolaryngology, Miller School of Medicine, University of Miami, Miami (RY, XL).

The authors report no relevant financial disclosures.

Drs. Ventura and Bandstra contributed equally to this manuscript.

*:

The authors would like to thank the University of Miami Pediatric Zika Research Consortium Investigators, the names of whom are listed at the end of this study. Special thanks to the participating mothers and their infants. They are also grateful for the contributions of the collaborators and staff at the Florida and Miami-Dade County Departments of Health (Danielle Stanek, DVM; Lea A. Heberlein-Larson, BS, MPH; Lillian Rivera, RN, MSN, PhD; Reynald Jean, MD, MPH, MSN, AGPCNP-BC; and Marie Ketty Etienne, RN, MPH), the Centers for Disease Prevention and Control, the Bascom Palmer Eye Institute, the Batchelor Children's Research Institute, the Florida Early Steps Program, the Mailman Center for Child Development, the Jackson Health Systems, and the Healthy Start Coalition of Miami-Dade County.

This work was supported by the Florida Department of Health Biomedical Research Program, Zika Research Initiative Awards 7ZK08 (Bandstra), 7ZK14 (Saigal), 7ZK20 (Younis), and 7ZK26 (Gonzalez).

Address correspondence to Audina M. Berrocal, MD, Bascom Palmer Eye Institute, 900 NW 17th Avenue, Miami, FL 33136; email: aberrocal@med.miami.edu.

Received: November 27, 2017
Accepted: February 27, 2018

10.3928/23258160-20180907-14

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