Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Fluorescein Angiography Findings in Children With Congenital Zika Syndrome

Camila V. Ventura, MD, PhD; Adriana L. Gois, MD; Bárbara O. Freire, MD; Danielle C. de Almeida, MD; Leslie D. MacKeen, BSc, CRA; Marcelo C. Ventura Filho, MD; Audina M. Berrocal, MD; R.V. Paul Chan, MD; Rubens Belfort Jr., MD, PhD; Mauricio Maia, MD, PhD; Liana O. Ventura, MD, PhD

Abstract

BACKGROUND AND OBJECTIVE:

To evaluate the retinal and vasculature changes in infants with congenital Zika syndrome (CZS) using fluorescein angiography (FA).

PATIENTS AND METHODS:

This consecutive case series included six infants with CZS. FA and color fundus imaging were performed under general anesthesia in both eyes of all infants using a contact widefield digital imaging system. All color fundus images were obtained using a 130° field of view lens, and the FA images were captured using either a 130° or 80° field of view lens. The immunoglobulin M antibody capture enzyme-linked immunosorbent assay was positive for Zika virus in the cerebrospinal fluid samples of all infants. Other congenital infections were ruled out.

RESULTS:

The mean ± standard deviation age of the infants at the time of examination was 1.4 years ± 0.1 years (range: 1.3 years to 1.5 years). Contact fundus photographs showed macular abnormalities in seven eyes (58%) and retinal vasculature changes in two eyes (17%). FA detected macular abnormalities in all 12 eyes (100%) and retinal vasculature changes in five eyes (42%). The main retinal vasculature changes were peripheral avascularity in five eyes (42%) and microvasculature abnormalities in three eyes (25%).

CONCLUSION:

FA may be an important tool for detecting subtle macular and retinal vasculature changes in CZS.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:702–708.]

Abstract

BACKGROUND AND OBJECTIVE:

To evaluate the retinal and vasculature changes in infants with congenital Zika syndrome (CZS) using fluorescein angiography (FA).

PATIENTS AND METHODS:

This consecutive case series included six infants with CZS. FA and color fundus imaging were performed under general anesthesia in both eyes of all infants using a contact widefield digital imaging system. All color fundus images were obtained using a 130° field of view lens, and the FA images were captured using either a 130° or 80° field of view lens. The immunoglobulin M antibody capture enzyme-linked immunosorbent assay was positive for Zika virus in the cerebrospinal fluid samples of all infants. Other congenital infections were ruled out.

RESULTS:

The mean ± standard deviation age of the infants at the time of examination was 1.4 years ± 0.1 years (range: 1.3 years to 1.5 years). Contact fundus photographs showed macular abnormalities in seven eyes (58%) and retinal vasculature changes in two eyes (17%). FA detected macular abnormalities in all 12 eyes (100%) and retinal vasculature changes in five eyes (42%). The main retinal vasculature changes were peripheral avascularity in five eyes (42%) and microvasculature abnormalities in three eyes (25%).

CONCLUSION:

FA may be an important tool for detecting subtle macular and retinal vasculature changes in CZS.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:702–708.]

Introduction

The Zika virus (ZIKV) has been studied extensively during the last 3 years after an increased prevalence of microcephaly was reported in Brazilian newborns.1,2 Its rapid spread throughout 45 countries in the Americas lead the World Health Organization to consider the ZIKV outbreak a public health emergency of international concern for 8 months in 2016.3,4

After proving an association between microcephaly and vertical transmission of ZIKV, investigators focused on describing the wide array of clinical malformations caused by ZIKV.1 The broad spectrum of unique abnormalities including brain and cranial malformations, ocular findings, hearing deficits, and congenital contractures were later compiled into a new entity referred to congenital Zika syndrome (CZS).5

In January 2016, our research team was the first to report the ocular involvement in the CZS, which included chorioretinal atrophy and focal pigment mottling in affected children.6,7 Subsequent studies corroborated with these initial reports and revealed additional ophthalmic findings associated with CZS such as optic nerve abnormalities, retinal vessel changes, congenital glaucoma, microphthalmia, congenital cataract, lens subluxation, and iris coloboma.8–12

The broad spectrum of ocular manifestations of CZS has raised curiosity among scientists to try to explain its physiopathology. So far, researchers have described two possible mechanisms: 1) Axonal transportation: ZIKV infects the visual system in the brain and migrates axonally to the eye; 2) blood-retinal barrier (BRB) Break: ZIKV breaks both outer and inner BRB, which enables its retinal spread.13–15 In fact, a recent histopathologic study suggested that these two mechanisms could be occurring simultaneously.15

Curiously, a recent study by Mladinich et al.16 revealed that the ZIKV persistently infects the primary microvascular endothelial cells in the human brain that serves as cellular reservoirs for ZIKV replication and enables its spread across the blood-brain barrier (BBB). In this study, authors hypothesized that the endothelial cells from other sites including the retinal tissue could be involved in a similar process.16 Despite these experimental model studies, little is known about the retinal vascular changes that may occur in children with CZS. Therefore, in the current study we aim to gain a better understanding of the potential retinal vascular changes in CZS and describe the retinal vasculature findings in six infants with CZS using fluorescein angiography (FA).

Patients and Methods

The institutional review board of the Altino Ventura Foundation (FAV), Recife, Brazil, where the study was conducted, and the Federal University of São Paulo (Unifesp) approved this prospective case series study (protocols 2.557.262 and 2.608.308), which followed the tenets of the Declaration of Helsinki. The patients' parents provided informed consent before study enrollment.

The inclusion criteria were positive serology for the ZIKV using the antibody-capture enzyme-linked immunosorbent assay performed on cerebrospinal fluid samples; and negative serology for toxoplasmosis, rubella, cytomegalovirus, herpes simplex, syphilis (TORCHS), and human immunodeficiency virus.

The fundus examination was performed prior to color fundus and FA imaging by two retina experts using binocular indirect ophthalmoscopy. Retinal photography was performed by a certified ophthalmic imaging specialist with the children under general anesthesia. The color fundus and FA images of the posterior pole and periphery were obtained using the RetCam 3 digital imaging system (Natus Medical, Pleasanton, CA). The color fundus images were obtained using a 130° field of view lens and the FA images using either a 130° or 80° field of view lens. A 20% solution of fluorescein (Ophthalmos S.A., São Paulo, Brazil) was intravenously administered as a bolus of 7.7 mg/kg, followed by an isotonic saline flush. Systane Gel (Alcon, Fort Worth, TX) was applied as a coupling gel between the contact camera lens and the eye. Scleral depression was performed to better visualize vascular patterns out to the ora serrata during FA.

Results

This consecutive case series included six infants with a mean ± standard deviation age at examination of 1.4 years ± 0.1 years (range: 1.3 years to 1.5 years), from which four (67%) were male (Table A, available at www.healio.com/OSLIRetina). Five mothers (83%) reported cutaneous rash during pregnancy and microcephaly was detected at birth in the six children (100%), from which five (83%) were classified as severe (Table B, available at www.healio.com/OSLIRetina). The fundus evaluation and wide-angle color images fundus photography revealed retinal findings in seven eyes (58%) and abnormal retinal vasculature findings in two eyes (17%). The FA examination alone showed abnormal retinal findings in all eyes (100%) and abnormal retinal vasculature findings in five eyes (42%) (Table C, available at www.healio.com/OSLIRetina). According to Table C, the FA showed window defects in additional three eyes (25%) that were otherwise deemed normal on clinical examination. In the other eyes, the chorioretinal atrophy was quite prominent clinically and the FA evidenced the presence of window defects. The FA did not show any activity of the retinal lesions. In three eyes (25%), the FA revealed peripheral retinal vasculature changes that were not detected by fundus examination and wide-angle imaging.

Demographic Profile of Children With Congenital Zika Syndrome

Table A:

Demographic Profile of Children With Congenital Zika Syndrome

Brain Computerized Tomography Scan Findings and Mothers' Symptoms During Pregnancy of Children Born With Congenital Zika Syndrome

Table B:

Brain Computerized Tomography Scan Findings and Mothers' Symptoms During Pregnancy of Children Born With Congenital Zika Syndrome

Fundus Examination Associated With Wide-Angle Fundus Images Findings Versus Fluorescein Angiography Findings in Children Born With Congenital Zika Syndrome

Table C:

Fundus Examination Associated With Wide-Angle Fundus Images Findings Versus Fluorescein Angiography Findings in Children Born With Congenital Zika Syndrome

Patient 1

A 1.4-year-old female infant was born at term with microcephaly. The fundus examination and fundus imaging description of the right eye (OD) were unremarkable (Figure 1A) and the findings in the left eye (OS) included optic nerve hypoplasia, increased disc cupping, and a colobomatous chorioretinal atrophy in the macula.

Patient 1. Wide-angle fundus and fluorescein angiography images obtained from an infant with congenital Zika syndrome. (A) Unremarkable fundus in the right eye (OD). (B) Window defects in the macula OD.

Figure 1.

Patient 1. Wide-angle fundus and fluorescein angiography images obtained from an infant with congenital Zika syndrome. (A) Unremarkable fundus in the right eye (OD). (B) Window defects in the macula OD.

The FA showed discrete window defects in the macula OD (Figure 1B). In OS, the FA enhanced the colobomatous atrophy and showed discrete window defects on the superior nasal border of the colobomatous atrophy. FA did not show staining or leakage of the retinal vessels nor abnormal peripheral findings in both eyes (OU).

Patient 2

A 1.5-year-old male infant was born at term with severe microcephaly. The fundus examination and imaging showed temporal hyperpigmentation of the optic nerve and pigment mottling in the macula OD and an unremarkable fundus OS (Figure 2A).

Patient 2. Wide-angle fundus and fluorescein angiography images obtained from an infant with congenital Zika syndrome. (A) Unremarkable fundus in the left eye (OS). (B) Areas of window defects in the macula OS.

Figure 2.

Patient 2. Wide-angle fundus and fluorescein angiography images obtained from an infant with congenital Zika syndrome. (A) Unremarkable fundus in the left eye (OS). (B) Areas of window defects in the macula OS.

FA showed areas of window defects and hypofluorescent dots at the site of the pigment mottling in the macula OD; and discrete areas of window defects in the macula OS (Figure 2B). FA did not show staining, leakage or any evidence of peripheral neovascularization OU.

Patient 3

A 1.3-year-old male infant was born at term with severe microcephaly. The fundus examination and imaging revealed optic nerve pallor and hypoplasia, increased disc cupping, two large chorioretinal atrophies, one small satellite chorioretinal atrophy, and pigment mottling in the macular region, a vascular tuft inferior to the optic nerve, and diffuse peripheral avascularity in the four quadrants OD. The OS presented with optic nerve hypoplasia, increased disc cupping, one chorioretinal atrophy in the macula, and diffuse vascular attenuation in the four quadrants (Figures 3A and 3B).

Patient 3. Wide-angle fundus and fluorescein angiography images obtained from an infant with congenital Zika syndrome. (A) Optic nerve pallor and hypoplasia, increased disc cupping, chorioretinal atrophy and pigment mottling in the macula, vascular tuft inferior to the optic nerve, and diffuse avascularity in the right eye (OD). (B) Optic nerve hypoplasia, increased disc cupping, chorioretinal atrophy in the macula, and vascular attenuation in the four quadrants in the left eye (OS). (C) Leakage inferior to the nerve and diffuse peripheral avascularity of the retina in OD. (D) Retinal vessels attenuation and diffuse peripheral avascularity of the retina in OS.

Figure 3.

Patient 3. Wide-angle fundus and fluorescein angiography images obtained from an infant with congenital Zika syndrome. (A) Optic nerve pallor and hypoplasia, increased disc cupping, chorioretinal atrophy and pigment mottling in the macula, vascular tuft inferior to the optic nerve, and diffuse avascularity in the right eye (OD). (B) Optic nerve hypoplasia, increased disc cupping, chorioretinal atrophy in the macula, and vascular attenuation in the four quadrants in the left eye (OS). (C) Leakage inferior to the nerve and diffuse peripheral avascularity of the retina in OD. (D) Retinal vessels attenuation and diffuse peripheral avascularity of the retina in OS.

The FA showed a chorioretinal atrophy and hypofluorescent dots at the site of the pigment mottling in the macula, a leakage inferior to the nerve, and diffuse avascularity of the peripheral retina OD. FA enhanced the chorioretinal atrophy OS and showed retinal vessels rectification, vascular attenuation, and 360° of peripheral avascularity (Figures 3C and 3D). The FA did not reveal any evidence of peripheral neovascularization OS.

Patient 4

A 1.3-year-old male infant was born at term with severe microcephaly. The fundus examination and imaging showed optic nerve hypoplasia, colobomatous chorioretinal atrophy, and pigment mottling in the macula OU.

FA showed optic nerve hypoplasia, chorioretinal atrophy, hypofluorescent dots at site of the pigment mottling in the macula OU. FA did not show any staining, leakage, or avascularity, nor was there any evidence of neovascularization of the retina in OU.

Patient 5

A 1.4-year-old male infant was born at term with severe microcephaly. The fundus examination and imaging were unremarkable in OD and showed a chorioretinal atrophy in the macula OS.

FA showed discrete window defects in the macula, microvasculature changes, retinal vessel staining, abnormal arteriovenous shunts in the periphery, and peripheral avascularity of the retina in the four quadrants OD (Figures 4A and 4B). The FA OS showed a chorioretinal atrophy, microvasculature changes, retinal vessel staining, abnormal arteriovenous shunts in the periphery, and peripheral avascularity of the retina in the four quadrants. FA did not show leakage or any evidence of neovascularization OU (Figure 4C).

Patient 5. Fluorescein angiography images obtained from an infant with congenital Zika syndrome. (A) Discrete window defects in the macula in the right eye (OD). (B) Image montage showing peripheral avascularity of the retina in OD. (C) Image montage showing peripheral avascularity of the retina in the left eye.

Figure 4.

Patient 5. Fluorescein angiography images obtained from an infant with congenital Zika syndrome. (A) Discrete window defects in the macula in the right eye (OD). (B) Image montage showing peripheral avascularity of the retina in OD. (C) Image montage showing peripheral avascularity of the retina in the left eye.

Patient 6

A 1.4-year-old female infant was born preterm with severe microcephaly. The fundus examination and imaging showed colobomatous chorioretinal atrophy in the macula OU.

FA enhanced the colobomatous chorioretinal atrophy OU and showed microvasculature changes and peripheral avascularity of the retina in the four quadrants OD (Figure 5A). FA did not show staining, leakage or any evidence of neovascularization OU.

Patient 6. Fluorescein angiography images obtained from an infant with congenital Zika syndrome. (A) Microvasculature changes and peripheral avascularity of the retina in the right eye.

Figure 5.

Patient 6. Fluorescein angiography images obtained from an infant with congenital Zika syndrome. (A) Microvasculature changes and peripheral avascularity of the retina in the right eye.

Discussion

According to the literature, ocular manifestations may be identified in up to 55% of newborns with the CZS.8,11,17,18 Despite retinal and optic nerve manifestations being the most common findings in the CZS, vascular alterations including abnormal termination of the vessels in the periphery and avascularity of the peripheral retina were previously described.9,10 The current study not only corroborates with the studies by Miranda et al.9 and Ventura et al.,10 it further investigates the eyes of six children with the CZS using FA and detected additional macular and retinal vasculature changes not observed on routine exam with indirect ophthalmoscopy nor with wide-angle color fundus images.

This case series was conceptualized to better understand the retinal vasculature features in the eyes of children with the CZS. However, in addition to the vascular findings, FA was useful for detecting discrete retinal pigment epithelial (RPE) changes that were not identified during fundus examination and wide-angle color fundus imaging. One of the most common retinal abnormalities detected by FA and previously unidentified by fundus examination and wide-angle imaging were the window defects in the macular region that were seen in six eyes (50%); these defects also are seen in other diseases that affect the RPE, such as rubella retinitis, choroideremia, and thioridazine toxicity.19 The histopathological analysis of human eyes showed that the window defects corresponded to areas in which the RPE cells were thin, fewer in number, had loss of pigment granules, and were associated with partial loss of the photoreceptors and choriocapillaris. According to Keno and Green,19 the choriocapillaris changes occur first followed by RPE and photoreceptor cellular loss, which suggests damage to the BRB and consequently damage to the outer retinal layers.

Previous studies by Singh et al.19 and Zhao et al.20 have shown that the RPE is highly susceptible to the ZIKV in an animal model and in vivo experiments and suggested that the ZIKV damages the retina by disrupting the BRB.19,20 In addition, the histopathological study by Fernandez et al.15 isolated the ZIKV in several ocular tissues, including the retina and choroid, and suggested that the ZIKV gains access to the fetal circulation, thus allowing access to the inner and outer BRB. By identifying window defects in the eyes of children with the CZS, the current study supports the notion that the ZIKV can disrupt the outer BRB.

Regarding the inner BRB, the current study showed a variety of retinal vasculature changes such as avascularity of the peripheral retina in 42% of the eyes and capillary changes in 25% of eyes. We speculated that these retinal vascular findings may occur in response to the direct aggression of the ZIKV on the retinal vessels, based on a recent study by Mladinich et al.16 that showed the ZIKV not only crosses the BBB but also uses the microvascular endothelial cells in the brain for replication. Nevertheless, a recent study by Caires-Júnior et al.21 identified a 9.2-fold decrease of LHX2 mRNA, an early neural marker that regulates neural differentiation by attenuating the Wnt signaling. Since Wnt pathway is an important regulatory pathway in embryonic and vascular development we have to consider that it may also play an important role in the pathophysiology of the vascular findings identified in the current study.22

The main limitation of this study was the small sample size. Thus, we could not estimate the prevalence rates of the vascular and retinal findings in this study. Despite providing information about the FA findings in CZS, these retinal and vascular findings are not unique to the CZS. Peripheral avascularity of the retina, arteriovenous shunts, and capillary changes in seen on FA images have been described in pediatric retinal diseases such as retinopathy of prematurity, Coats' disease, incontinentia pigmenti, familial exudative vitreoretinopathy, and in normal children.24–28

It is important to emphasize that these are initial FA findings in children with CZS and that to determine the progression of these retinal vasculature findings and need for treatment, clinical assessment and FA follow-up are necessary.

FA may provide a better assessment of children with the CZS by identifying both subtle macular lesions and additional vascular manifestations. Larger studies with longer follow-up are needed to better understand the potential progression of the macular and retinal vasculature alterations identified in the current study.

References

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Demographic Profile of Children With Congenital Zika Syndrome

PatientSexAge at Examination (Years)Gestational Age at Birth (Weeks)Head Circumference at Birth (cm)
1F1.43930
2M1.53828*
3M1.33929*
4M1.341.530*
5M1.43729*
6F1.434.625*

Brain Computerized Tomography Scan Findings and Mothers' Symptoms During Pregnancy of Children Born With Congenital Zika Syndrome

PatientBrain CT FindingsMother SymptomsTrimester of Symptoms
1Calcifications, volume reduction, lissencephaly, ventriculomegaly, and agenesis of the corpus callosumCutaneous rash, fever, arthralgia, and headacheNot informed*
2Calcifications, volume reduction, and ventriculomegalyCutaneous rash, itchiness, and arthralgia1st
3Calcifications, ventriculomegaly, and lissencephalyNo symptoms
4Calcifications, volume reduction, pachygyria, and ventriculomegalyCutaneous rash1st
5Calcifications, volume reduction, lissencephaly, and ventriculomegalyCutaneous rash, fever, arthralgia, and ocular hyperemia3rd
6Calcifications and ventriculomegalyCutaneous rash and feverNot informed*

Fundus Examination Associated With Wide-Angle Fundus Images Findings Versus Fluorescein Angiography Findings in Children Born With Congenital Zika Syndrome

Fundus Examination and Wide-angle Image FindingsFluorescein Angiography Findings
PatientEyeRetinaRetinal VasculatureRetinaRetinal Vasculature
1ODUnremarkableUnremarkableWindow defectsUnremarkable
OSColobomatous chorioretinal atrophyUnremarkableWindow defects on the superior nasal border of the colobomatous atrophyUnremarkable
2ODPigment mottlingUnremarkableWindow defects and hypofluorescent dotsUnremarkable
OSUnremarkableUnremarkableDiscrete areas of window defectsUnremarkable
3ODTwo large chorioretinal atrophy, a small satellite chorioretinal atrophy, and pigment mottlingVascular tuft inferior to the optic nerve and diffuse avascularityChorioretinal atrophy, hypofluorescent dotsLeakage inferior to the nerve and diffuse avascularity of the periphery
OSChorioretinal atrophyDiffuse vascular attenuationChorioretinal atrophyRectification, attenuation, and diffuse avascularity of the periphery
4ODColobomatous chorioretinal atrophy and pigment mottlingUnremarkableColobomatous chorioretinal atrophy and pigment mottlingUnremarkable
OSColobomatous chorioretinal atrophy and pigment mottlingUnremarkableColobomatous chorioretinal atrophy and pigment mottlingUnremarkable
5ODUnremarkableUnremarkableWindow defectsMicrovasculature changes, abnormal AV shunts in the periphery, and diffuse avascularity of the periphery
OSChorioretinal atrophyUnremarkableChorioretinal atrophyMicrovasculature changes, abnormal AV shunts in the periphery, and diffuse avascularity of the periphery.
6ODColobomatous chorioretinal atrophyUnremarkableColobomatous chorioretinal atrophyAbnormal distribution, microvasculature changes, and diffuse avascularity of the periphery.
OSColobomatous chorioretinal atrophyUnremarkableColobomatous chorioretinal atrophy and window defectsUnremarkable
Authors

From the Department of Ophthalmology, Altino Ventura Foundation, Recife, PE, Brazil (CVV, ALG, BOF, DCA, MCVF, LOV); the Department of Ophthalmology, HOPE Eye Hospital, Recife, PE, Brazil (CVV, ALG, LOV); the Department of Ophthalmology and Visual Sciences, Paulista School of Medicine, Federal University of São Paulo, São Paulo, SP, Brazil (CVV, RB, MM); the Department of Ophthalmology and Visual Sciences, Hospital for Sick Children, Toronto, Canada (LDM); the Department of Ophthalmology, Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami (AMB); and the Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago (RVPC).

Supported by P30 EY001792 from the National Institute of Health, Bethesda, Maryland (RVPC), an Unrestricted Departmental Grant from Research to Prevent Blindness, New York, NY (RVPC), and a Blind Children's Center Research Grant.

Dr. Chan is on the Scientific Advisory Board for Visunex Medical Systems, Fremont, California. The remaining authors report no relevant financial disclosures.

The authors would like to acknowledge Natus Medical Inc. for leasing the RetCam III for this study.

Address correspondence to Camila V. Ventura, MD, PhD, Fundação Altino Ventura, Rua da Soledade, 170, Recife, PE, Brazil 50070-040; email: camilaventuramd@gmail.com.

Received: November 09, 2018
Accepted: March 25, 2019

10.3928/23258160-20191031-05

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