Characterization of Visual Pathway Abnormalities in Infants With Congenital Zika Syndrome Using Computed Tomography and Magnetic Resonance Imaging

Severe visual impairment is present in nearly all infants with congenital Zika syndrome (CZS); however, ocular abnormalities are present only in a subset of these infants. The purpose of this study was to characterize the visual pathway abnormalities seen on computed tomogra- phy (CT) and MRI scans in infants with CZS

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Characterization of Visual Pathway Abnormalities in Infants With Congenital Zika Syndrome Using Computed Tomography and Magnetic Resonance Imaging Amanda D. Henderson, MD, Camila V. Ventura, MD, PhD, Thierry A. G. M. Huisman, MD, Avner Meoded, MD, Adriano N. Hazin, MD, Vanessa van der Linden, MD, Natacha C. de Lima Petribu, MD, William N. May, MD Background: Severe visual impairment is present in nearly all infants with congenital Zika syndrome (CZS); however, ocular abnormalities are present only in a subset of these infants. The purpose of this study was to characterize the visual pathway abnormalities seen on computed tomography (CT) and MRI scans in infants with CZS. Methods: Preliminary neuroimaging information was obtained from a referred sample of 105 infants with clinical and epidemiologic data consistent with CZS in the Pernambuco state of Brazil. Subjects were excluded if Zika virus infection was not confirmed by serologic or cerebrospinal fluid studies or if images were nondiagnostic. Of the 105 subjects initially screened, head CT images adequate for interpretation were available for 54, and brain MRI images adequate for interpretation were available for 20. Four patients had both CT and MRI images. Magnetic resonance imaging and CT scans from infants with CZS were systematically reviewed for globe malformations, optic nerve and chiasmal atrophy, occipital cortical volume loss, white matter abnormalities, ventriculomegaly, and calcifications. Neuroimaging findings were correlated with measures of Division of Neuro-Ophthalmology (ADH), Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland; Department of Ophthalmology (CVV), Altino Ventura Foundation, Recife, Brazil; Department of Ophthalmology (CVV), HOPE Eye Hospital, Recife, Brazil; Division of Pediatric Radiology and Pediatric Neuroradiology (TAGMH, AM), the Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, Maryland; Edward B. Singleton Department of Radiology (TAGMH, AM), Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas; Instituto de Medicina Integral Professor Fernando Figueira (ANH, NCLP), Recife, Brazil; Departments of Pediatric Neurology (VL) and Radiology (NCLP), Barão de Lucena Hospital, Recife, Brazil; and Division of Comprehensive Ophthalmology (WNM), Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland. The authors report no conflicts of interest. Address correspondence to Amanda D. Henderson, MD, Division of Neuro-Ophthalmology, Wilmer Eye Institute, The Johns Hopkins School of Medicine, 600 N. Wolfe Street, Wilmer 233, Baltimore, MD 21287; E-mail: [e-mail] e598 visual function and with ocular examinations in these infants. Results: Thirty-three males and 37 females were included in the analysis. The mean age of the infants at the time of neuroimaging was 16.0 weeks (range 0 days–15.5 months), and the mean gestational age at the time of birth was 38 weeks. All patients were from the Pernambuco state of Brazil. Overall, 70 of 74 (95%) scans showed occipital volume loss, whereas 9 (12%) showed optic nerve atrophy, 3 (4%) showed chiasmal atrophy, and 1 (1%) showed an ocular calcification. Sixty-two of the infants underwent ophthalmologic examinations. A total of 34 (55%) infants had at least one documented structural ocular abnormality, and 26 (42%) had at least one structural ocular abnormality documented in both eyes. Of those with available visual acuity data, all had visual impairment. Among those with visual impairment and normal eye examinations, 100% had visual pathway abnormalities on neuroimaging, including 100% with occipital cortical volume loss, 8% with optic nerve atrophy, and 8% with chiasmal atrophy. Conclusion: Our results suggest that cortical visual impairment related to structural abnormalities of the occipital cortex is likely an important cause of visual impairment in children with CZS with normal eye examinations. Journal of Neuro-Ophthalmology 2021;41:e598–e605 doi: 10.1097/WNO.0000000000001127 © 2020 by North American Neuro-Ophthalmology Society T he Zika virus (ZIKV) is a flavivirus transmitted by Aedes aegypti, Aedes albopictus, and Aedes africanus mosquitoes. The ZIKV originally was isolated from a rhesus macaque (Macaca mulatta) in the Zika forest in Uganda in 1947 (1) and was first isolated outside of Africa in Malaysian A. aegypti mosquitoes in 1966 (2). The emergence of ZIKV in the Americas was first recognized in the Pernambuco state, located in the northeast of Brazil, in 2015, after a high incidence of microcephaly was reported in newborns (3). Later, an Henderson et al: J Neuro-Ophthalmol 2021; 41: e598-e605 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution children with CZS may present with cranial deformities, craniofacial disproportion, and brain abnormalities including both disruptive/malformative and destructive lesions with neuronal migration abnormalities, cortical malformations, global volume loss, cortical thinning, cortical and subcortical calcifications, ventriculomegaly, and hypoplasia or absence of the corpus callosum (4–7). In the eyes, ZIKV most commonly affects the posterior segment (retina, optic nerve, and retinal vasculature) (8–11). The prevalence of these structural ocular abnormalities varies among studies between 21.4% and 55% (12). Nevertheless, severe visual impairment has been demonstrated in almost all infants with CZS (10,13). Ventura et al, reported that visual impairment is more common when ocular abnormalities are present; however, 85% of children affected with CZS who have normal ocular examinations still have visual impairment (10). This discordance between ocular findings and visual impairment suggests the presence of abnormalities more posteriorly along the visual pathways. This study aims to identify these visual pathway abnormalities and characterize them using computed tomography (CT) and MRI and correlate the neuroimaging findings with visual outcomes. FIG. 1. Axial computed tomography from a 4-month-old boy demonstrates marked occipital atrophy. association between ZIKV and microcephaly was established, along with other birth defects including central nervous system (CNS) abnormalities, ophthalmological manifestations, skeletal findings, and hearing loss, which characterized a new entity called congenital Zika syndrome (CZS) (4). Because of its neurotropism, ZIKV mainly affects the brains of fetuses. Therefore, in addition to microcephaly, METHODS Ethics committee and institutional review board approvals were obtained from participating institutions (AACD Protocol #2.090.386, FAV Protocol #3.784.427, JHU SOM IRB201861). The research adhered to the tenets of the Declaration of Helsinki. Sample Selection One hundred five infants, all from the Pernambuco state of Brazil, were initially selected for study inclusion. All infants had a diagnosis of CZS based on clinical and epidemiologic FIG. 2. Axial computed tomography from a 5-week-old girl (A) soft-tissue window and (B) bone algorithm, demonstrates punctate occipital cortical and subcortical band-like hyperdense calcifications. Henderson et al: J Neuro-Ophthalmol 2021; 41: e598-e605 e599 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Brain Imaging Evaluation We reviewed these 54 CT scans and 20 MRI scans from 70 infants, particularly evaluating for abnormalities in the globes, optic nerves, optic chiasm, and occipital cortex. Each scan was reviewed by a pediatric neuroradiologist (T.A.G.M.H.), a neuro-ophthalmologist (A.D.H.), and a comprehensive ophthalmologist (W.N.M.). The visual pathways were evaluated systematically by subjective assessment for globe malformations, optic nerve and chiasmal atrophy, occipital cortical volume loss, white matter abnormalities, ventriculomegaly, and calcifications. Neuroimaging abnormalities typically were severe, as demonstrated in the figures. In the few cases in which there initially was disagreement among the scan reviewers, a consensus was reached before classification of the abnormalities. Neuroimaging findings were correlated with measures of visual function and with ocular examinations in these infants. Medical Records Data Collection FIG. 3. Axial T1-weighted MRI from a 3-month-old girl demonstrates occipital volume loss. data. Children without serologic or cerebrospinal fluid confirmation of CZS were excluded. CTs and MRIs were obtained as part of the patients’ clinical care in Brazil between July 2015 and February 2017. As neuroimaging was obtained for clinical purposes, the scanning protocols varied among individual patients and were not specifically tailored for evaluation of the visual pathways. Head CT images adequate for interpretation were available for 54, and brain MRI images adequate for interpretation were available for 20. Four patients had both CT and MRI images. The data collected from patients’ medical records included demographics, pregnancy and clinical history, and ophthalmological evaluation. The ophthalmological data included visual acuity measures and structural ocular findings. The bestcorrected visual acuity was performed using Teller Acuity Cards in cycles/centimeter and was categorized into the range of visual loss using the visual acuity ranges adopted by the International Council of Ophthalmology (14–16). The funduscopic evaluation was performed by a retina specialist through indirect binocular ophthalmoscopy, and fundus imaging was performed in all cases using a wide-angle digital fundus camera (RetCam Shuttle, Natus Medical Inc, Pleasanton, CA). Data Analysis Data analysis was performed using Microsoft Excel. Continuous variables were expressed as the mean ± SD and categorical variables by their absolute and relative frequencies. FIG. 4. Magnetic resonance imaging from a 4-month-old boy demonstrates severe occipital volume loss with a small cerebellum in the adjacent posterior fossa, as shown on (A) sagittal, T2-weighted imaging and (B) axial, T1-weighted imaging. e600 Henderson et al: J Neuro-Ophthalmol 2021; 41: e598-e605 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 5. Axial fluid-attenuated inversion recovery image MRI from a 12-month-old girl demonstrates bilateral optic nerve atrophy. RESULTS All 70 infants included in the analysis were from the Pernambuco State in Brazil. Thirty-seven (53%) were female. The mean age at the time of neuroimaging was 16.0 ± 19.8 weeks (range 0 days–15.5 months). The mean gestational age at the time of birth was 38 ± 2 weeks (range 31–41 weeks). Sixty-five infants had positive ZIKV titers in cerebrospinal fluid, and 5 had positive serologies. Fifty-one of 54 (95%) CT scans demonstrated occipital volume loss (Fig. 1). Six (11%) showed optic atrophy, 2 (4%) showed chiasmal thinning, and 1 (2%) had an ocular calcification in 1 eye. Fifty CTs (93%) had intracranial calcifications, with 31 (57%) showing calcifications specifically located in the occipital cortex (Fig. 2). Thirty-seven CTs (69%) showed ventriculomegaly. Notably, the scan with the ocular calcification did not have any occipital volume loss. Nineteen of the 20 MRIs (95%) showed occipital volume loss (Figs. 3 and 4). Three MRIs (15%) showed bilateral optic atrophy (Fig. 5), 1 (5%) chiasmal atrophy, and 7 (35%) white matter edema and/or dysmyelination as evaluated on T2 and fluid-attenuated inversion recovery image sequences. Six MRIs (30%) demonstrated calcifications (Fig. 6), and 18 (90%) had ventriculomegaly. Regarding the visual pathways, overall, 95% of scans showed occipital volume loss, whereas 12% showed optic atrophy, 4% showed chiasmal atrophy, and 1.4% showed a globe abnormality. Sixty-two of the infants underwent structural ophthalmologic examinations. The mean age at time of initial ophthalmologic examination was 21.4 ± 16.4 weeks (median 17.9, range 3.9–91.7 weeks). Seven (12.7%) of 55 with available data had nystagmus. Among the infants, none presented with anterior segment findings such as microphthalmia or cataracts. Fundus findings were detected in 60 eyes (48%) of 34 infants (55%). Optic nerve findings were seen in 43 eyes of 24 infants (39%) and retinal findings in 45 eyes of 30 infants (48%). The optic nerves were classified as small in 3 (5%) and large in 2 (3%) of 62 infants. Seventeen (27%) of 62 infants FIG. 6. Axial susceptibility weighted imaging and axial T1-weighted MR imaging show susceptibility weighted imaging -hypointense punctuate calcifications (short arrows) within both occipital lobes partially following the cortical ribbon, partially following the lateral ventricles. On the T1-weighted imaging the calcifications appear partially T1-hyperintense (large arrows). Henderson et al: J Neuro-Ophthalmol 2021; 41: e598-e605 e601 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution nerve atrophy, and 8% with chiasmal atrophy. Table 2 summarizes the degree of visual impairment and associated visual pathway abnormalities seen on neuroimaging among children with CZS, available visual acuity data, and normal eye examinations. Developmental outcomes paralleled visual outcomes. Of the 47 children from whom data were available, all had severe cognitive impairment, with a mean cognitive equivalent age of 2 months when their mean chronological age was 31.9 months. TABLE 1. Ranges of vision loss according the classification system adopted by the International Council of Ophthalmology (15) Classification Visual Acuity Normal vision Mild visual impairment Moderate visual impairment Severe visual impairment Profound visual impairment Near blindness Blindness $0.8 ,0.8 and $0.3 ,0.3 and $0.125 ,0.125 and $0.05 ,0.05 and $0.02 ,0.02 and $NLP NLP DISCUSSION had at least one pale optic nerve. Fourteen (23%) of 61 infants had increased optic disc cupping. Regarding the retina examination, 18 (30%) had pigmentary abnormalities, 17 (27%) had chorioretinal scarring, and 12 (19%) had hypopigmented lesions. A total of 34 (55%) infants had at least one documented structural ocular abnormality, and a total of 26 (42%) had at least one structural ocular abnormality documented in both eyes. Forty-five percent of infants had a normal eye examination. Twenty-five children had follow-up examinations with visual acuity data. The mean age at time of most recent examination was 3.5 ± 2 years (median 3.4 years, range 3.3– 3.9 years). Hundred percentages of children with data had visual impairment. Two (7%) had mild visual impairment, 5 (19%) moderate visual impairment, 7 (27%) severe visual impairment, 3 (12%) profound visual impairment, 7 (27%) near blindness, and 1 (4%) blindness, according the classification system adopted by the International Council of Ophthalmology (16). Table 1 shows the ranges of the visual acuity associated with each classification. Among those with visual impairment and normal eye examinations, 100% had visual pathway abnormalities on neuroimaging, including 100% with occipital cortical volume loss, 8% with optic Ocular abnormalities, including microphthalmia; macular pigmentary mottling; chorioretinal atrophy in the macula and elsewhere; retinal vascular changes; optic nerve abnormalities including optic disc pallor, optic atrophy, and increased cup-to-disc ratio; iris coloboma; posterior embryotoxon; lens subluxation; and congenital glaucoma, occur frequently in association with CZS, with a prevalence of severe ocular abnormalities estimated in up to 55% of infants with CZS (Table 3) (8,9,11,12,17–24). Ocular abnormalities contribute to visual disability in some cases; however, Ventura et al, previously reported that 85% of children affected with CZS who have normal ocular examinations still have visual impairment (10). Our findings suggest that the cause for this visual impairment is a structural occipital cortical abnormality. Several studies have evaluated brain findings in patients affected by CZS, but, to the best of our knowledge, none has focused specifically on the visual system. Previous neuroimaging studies, including CT and MRI, have reported intracranial calcifications present in 93%–100%, ventriculomegaly in 72%–100%, abnormal gyral patterns in 36%–100%, cerebellar and/or brainstem hypoplasia in 17%–78%, and an abnormal corpus callosum in 10%–84% TABLE 2. Visual impairment classification and associated visual pathway abnormalities seen on neuroimaging among children with congenital Zika syndrome and normal eye examinations Visual Pathway Abnormalities on Neuroimaging Case Visual Impairment Classification 1 2 3 4 5 6 7 8 9 10 11 12 Total Severe Mild Moderate Near blindness Severe Near blindness Severe Mild Severe Severe Moderate Near blindness e602 Optic Atrophy Chiasmal Atrophy X X 1 1 Occipital Cortical Volume Loss X X X X X X X X X X X X 12 Henderson et al: J Neuro-Ophthalmol 2021; 41: e598-e605 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Ocular findings in congenital Zika syndrome Macular pigmentary mottling (9,11,12,17–21,23,24) Chorioretinal atrophy/scarring (9,11,17–24) Retinal vascular abnormalities (19) Macular coloboma (12,17) Optic disc pallor (9,12,21,24) Increased cup-to-disc ratio (9,11,12,20) Optic nerve hypoplasia (9,11,12,20,21) Posterior embryotoxon (20) Iris coloboma (11) Lens subluxation (11) Congenital glaucoma (20,21) Microphthalmia (12) (6,7,17,25,26). Individual study findings are summarized in Table 4. Prenatal examination with fetal ultrasound has demonstrated cortical atrophy; ventriculomegaly; intracranial calcifications affecting the white matter; corpus callosum, brainstem, and cerebellar dysgenesis; and enlargement of the cisterna magna (27–30). Interestingly, Calheiros et al, reported that intracranial calcifications diminish in the first year of life in affected infants, without associated clinical improvement (31). In a neuropathological study of 10 infants affected with CZS, Chimelli et al, described 3 distinct patterns of CNS damage: (1) severe ventriculomegaly with midbrain damage and aqueductal stenosis, (2) decreased brain size with resultant exvacuo ventriculomegaly, and (3) less severe brain abnormality with mild intracranial calcification (32). Of note, they described one case in which the ventriculomegaly was most marked in the occipital region, leading to “collapse” of the occipital lobe. Of the 70 infants whose neuroimaging we evaluated, 95% had occipital volume loss. Although 55% of the children in our study had some structural abnormality in at least one eye, many of these abnormalities would not account for the level of vision impairment. In addition, the remaining 45% of children in our study presented with structurally normal eyes. Nevertheless, all children in our sample with available acuity data had visual impairment, and all of those with normal eye examinations showed occipital cortical volume loss on neuroimaging. These results correlate well with the previous findings of Ventura et al, in which 90% of 119 infants with CZS had abnormal visual acuity, including 85% of infants with normal eye examinations (10). Our data suggest that occipital cortical pathology can explain the visual impairment in these children with CZS with visual impairment and normal eye exams. A previous report of optical coherence tomography characteristics in CZS is also consistent with our findings. Aleman et al, reported optical coherence tomography findings from 8 infants with CZS, in which all 8 had severe thinning of the ganglion cell layer, out of proportion to thinning of inner nuclear and photoreceptor layers (33). In addition, all of these infants had cortical volume loss on their brain imaging. The finding of severe ganglion cell layer thinning along with cortical volume loss could represent trans-synaptic retrograde degeneration leading to ganglion cell loss because of the cortical pathology; alternatively, these findings may represent 2 manifestations of a single process of neurodevelopmental disruption. Either of these explanations could be consistent with our findings. TABLE 4. Previously reported neuroimaging abnormalities in the congenital Zika syndrome Study de Fatima Vasco Aragao (6) Del Campo (25) Hazin (7) Meneses (17) Soares de Oliveira-Szejnfeld (26) Study de Fatima Vasco Aragao (6) Del Campo (25) Hazin (7) Meneses (17) Soares de Oliveira-Szejnfeld (26) Scan Type Number of Cases Intracranial Calcifications (%) VentriculoMegaly (%) Abnormal Gyral Patterns (%) 16 8 87 23 81 45 100 100 93 100 99 100 91 100 72 100 94 96 — 75 36 100 82 98 CT MRI CT and MRI CT CT CT, prenatal and postnatal MRI Cerebellar/Brainstem Hypoplasia (%) Enlarged Cisterna Magna (%) Delayed Myelination (%) Abnormal Corpus Callosum (%) 50 — 17 74 52 78 — 88 — — — — — 88 — — — — — 75 10 — — 84 —, not reported; CT, computed tomography. Henderson et al: J Neuro-Ophthalmol 2021; 41: e598-e605 e603 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Our study is limited by its retrospective nature and the variable quality of the neuroimaging scans. As the neuroimaging was not performed specifically for evaluation of the visual system, the scans were not contrast enhanced. Fatsaturated orbital MRI sequences were not available, and, because of thick scan slices, the optic chiasm and optic tracts frequently were not optimally visualized. In addition, highresolution MRI sequences were not available. Scan variability prevented quantified volumetric measurements of the visual pathways. In addition, most scans in our study were CT rather than MRI. As MRI is the preferred imaging modality to evaluate the anterior visual pathways, it is possible that subtle abnormalities in the optic nerves, optic chiasm, and optic tracts would not have been detected on CT. However, despite these limitations, abnormalities of the occipital cortex were identified, which would account for the visual dysfunction in these infants. In conclusion, patients with CZS are likely to have severe visual impairment, even in the absence of ocular abnormalities. Based on the high rate of volume loss in the occipital cortex demonstrated in infants affected by CZS, and specifically in those with visual impairment and normal eye examinations, the visual impairment likely is related to cortical blindness, specifically because of structural abnormalities in the occipital cortex. Further study examining correlations between the degree of occipital abnormality and visual outcomes is needed and may have the potential to guide development of visual rehabilitative programs for children affected with CZS. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. D. Henderson, C. V. Ventura, T. A. G. M. Huisman, and W. N. May; b. Acquisition of data: A. D. Henderson, C. V. Ventura, T. A. G. M. Huisman, A. N. Hazin, V. van der Linden, LCdLP, and W. N. May; c. Analysis and interpretation of data: A. D. Henderson, C. V. Ventura, T. A. G. M. Huisman, A. Meoded, A. N. Hazin, V. van der Linden, LCdLP, and W. N. May. Category 2: a. Drafting the manuscript: A. D. Henderson and C. V. Ventura; b. Revising it for intellectual content: A. D. Henderson, C. V. Ventura, T. A. G. M. Huisman, A. Meoded, A. N. Hazin, V. van der Linden, LCdLP, and W. N. May. Category 3: a. Final approval of the completed manuscript: A. D. Henderson, C. V. Ventura, T. A. G. M. Huisman, A. Meoded, A. N. Hazin, V. van der Linden, LCdLP, and W. N. May. ACKNOWLEDGMENTS The authors thank the patients and their families for their participation in this study. REFERENCES 1. Dick GW, Kitchen SF, Haddow AJ. Zika virus. I. Isolations and serological specificity. Trans R Soc Trop Med Hyg. 1952;46:509–520. 2. Marchette NJ, Garcia R, Rudnick A. Isolation of Zika virus from Aedes aegypti mosquitoes in Malaysia. Am J Trop Med Hyg. 1969;18:411–415. e604 3. Kleber de Oliveira W, Cortez-Escalante J, De Oliveira WT, Carmo GM, Henriques CM, Coelho GE, de França GV. Increase in reported prevalence of microcephaly in infants born to women living in areas with confirmed Zika virus transmission during the first trimester of pregnancy—Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016;65:242–247. 4. Moore CA, Staples JE, Dobyns WB, Pessoa A, Ventura CV, Fonseca EB, Ribeiro EM, Ventura LO, Neto NN, Arena JF, Rasmussen SA. Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatr. 2017;171:288. 5. de Fatima Vasco Aragao M, Brainer-Lima AM, Holanda AC, van der Linden V, Aragão LV, Silva ML Jr, Sarteschi C, Petribu NCL, Valença MM. Spectrum of spinal cord, spinal root, and brain MRI abnormalities in congenital Zika syndrome with and without arthrogryposis. AJNR Am J Neuroradiol. 2017;38:1045–1053. 6. de Fatima Vasco Aragao M, van der Linden V, Brainer-Lima AM, da Silva PS, Linden A, Valenca MM. 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. 7. Hazin AN, Poretti A, Di Cavalcanti Souza Cruz D, Tenorio M, van der Linden A, Pena LJ, Brito C, Gil LH, de Barros Miranda-Filho D, Marques ET, Turchi Martelli CM, Alves JG, Huisman TA. Computed tomographic findings in microcephaly associated with Zika virus. N Engl J Med. 2016;374:2193–2195. 8. de Paula Freitas B, Ventura CV, Maia M, Belfort R Jr. Zika virus and the eye. Curr Opin Ophthalmol. 2017;28:595–599. 9. Ventura CV, Maia M, Ventura BV, Linden VV, Araújo EB, Ramos RC, Rocha MA, Carvalho MD, Belfort R, Ventura LO. Ophthalmological findings in infants with microcephaly and presumable intra-uterus Zika virus infection. Arq Bras Oftalmol. 2016;79:1–3. 10. Ventura LO, Ventura CV, Dias NC, Vilar IG, Gois AL, Arantes TE, Fernandes LC, Chiang MF, Miller MT, Lawrence L. Visual impairment evaluation in 119 children with congenital Zika syndrome. J AAPOS. 2018;22:218–222.e1. 11. de Paula Freitas B, de Oliveira Dias JR, Prazeres J, Sacramento GA, Ko AI, Maia M, Belfort R Jr. Ocular findings in infants with microcephaly associated with presumed Zika virus congenital infection in Salvador, Brazil. JAMA Ophthalmol. 2016;134:529–535. 12. Zin AA, Tsui I, Rossetto J, Vasconcelos Z, Adachi K, Valderramos S, Halai UA, Pone MVDS, Pone SM, Silveira Filho JCB, Aibe MS, da Costa AC, Zin OA, Belfort R, Brasil P, NielsenSaines K, Moreira ME. Screening criteria for ophthalmic manifestations of congenital Zika virus infection. JAMA Pediatr. 2017;171:847–854. 13. Ventura LO, Ventura CV, Lawrence L, van der Linden V, van der Linden A, Gois AL, Cavalcanti MM, Barros EA, Dias NC, Berrocal AM, Miller MT. Visual impairment in children with congenital Zika syndrome. J AAPOS. 2017;21:295–299.e2. 14. Teller DY, McDonald MA, Preston K, Sebris SL, Dobson V. Assessment of visual acuity in infants and children: the acuity card procedure. Dev Med Child Neurol. 1986;28:779–789. 15. International Council of Ophthalmology (ICO). Visual Standards, Aspects and Ranges of Vision Loss With Emphasis on Population Surveys. Available at: http://www.icoph.org/ standards. Accessed May 10, 2015. 16. Colenbrander A. Aspects of vision loss–visual functions and functional vision. Vis Impair Res. 2003;5:115–136. 17. Meneses JD, Ishigami AC, de Mello LM, de Albuquerque LL, de Brito CA, Cordeiro MT, Pena LJ. Lessons learned at the epicenter of Brazil’s congenital Zika epidemic: evidence from 87 confirmed cases. Clin Infect Dis. 2017;64:1302–1308. 18. Ventura CV, Maia M, Bravo-Filho V, Góis AL, Belfort R. Zika virus in Brazil and macular atrophy in a child with microcephaly. Lancet. 2016;387:228. 19. Miranda HA II, Costa MC, Frazao MA, Simao N, Franchischini S, Moshfeghi DM. Expanded spectrum of congenital ocular findings in microcephaly with presumed Zika infection. Ophthalmology. 2016;123:1788–1794. Henderson et al: J Neuro-Ophthalmol 2021; 41: e598-e605 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 20. de Paula Freitas B, Ko AI, Khouri R, Mayoral M, Henriques DF, Maia M, Belfort R Jr. Glaucoma and congenital Zika syndrome. Ophthalmology. 2017;124:407–408. 21. Yepez JB, Murati FA, Pettito M, Peñaranda CF, de Yepez J, Maestre G, Arevalo JF. Ophthalmic manifestations of congenital Zika syndrome in Colombia and Venezuela. JAMA Ophthalmol. 2017;135:440–445. 22. Ventura CV, Maia M, Dias N, Ventura LO, Belfort R. Zika: neurological and ocular findings in infant without microcephaly. Lancet. 2016;387:2502. 23. de Oliveira Dias JR, Ventura CV, Borba PD, de Paula Freitas B, Pierroti LC, do Nascimento AP, de Moraes NS, Maia M, Belfort R Jr. Infants with congenital Zika syndrome and ocular findings from Sao Paulo, Brazil: spread of infection. Retin Cases Brief Rep. 2018;12:382–386. 24. Verçosa I, Carneiro P, Verçosa R, Girão R, Ribeiro EM, Pessoa A, Almeida NG, Verçosa P, Tartarella MB. The visual system in infants with microcephaly related to presumed congenital Zika syndrome. J AAPOS. 2017;21:300–304.e1. 25. Del Campo M, Feitosa IM, Ribeiro EM, Horovitz DD, Pessoa AL, França GV, García-Alix A, Doriqui MJ, Wanderley HY, Sanseverino MV, Neri JI, Pina-Neto JM, Santos ES, Verçosa I, Mirlene CSPC. The phenotypic spectrum of congenital Zika syndrome. Am J Med Genet A. 2017;173:841–857. 26. Soares de Oliveira-Szejnfeld P, Levine D, Oliveira Melo AS, Amorim MM, Batista AG, Chimelli L, Tanuri A, Aguiar RS, Malinger G, Ximenes R, Robertson R, Szejnfeld J, Tovar-Moll F. Congenital brain abnormalities and Zika virus: what the radiologist can expect to see prenatally and postnatally. Radiology. 2016;281:203–218. 27. Oliveira Melo AS, Malinger G, Ximenes R, Szejnfeld PO, Alves Sampaio S, Bispo de Filippis AM. Zika virus intrauterine Henderson et al: J Neuro-Ophthalmol 2021; 41: e598-e605 28. 29. 30. 31. 32. 33. infection causes fetal brain abnormality and microcephaly: tip of the iceberg? Ultrasound Obstet Gynecol. 2016;47:6–7. ak-Prijatelj M, Mraz J, Mlakar J, Korva M, Tul N, Popovi c M, Poljs Kolenc M, Resman Rus K, Vesnaver Vipotnik T, Fabjan ek V, Vizjak A, Pi zem J, Petrovec M, Av si c Zupanc Vodus T. Zika virus associated with microcephaly. N Engl J Med. 2016;374:951–958. Sarno M, Sacramento GA, Khouri R, do Rosário MS, Costa F, Archanjo G, Santos LA, Nery N, Vasilakis N, Ko AI, de Almeida AR. Zika virus infection and stillbirths: a case of hydrops fetalis, hydranencephaly and fetal demise. PLoS Negl Trop Dis. 2016;10:e0004517. Guillemette-Artur P, Besnard M, Eyrolle-Guignot D, Jouannic JM, Garel C. Prenatal brain MRI of fetuses with Zika virus infection. Pediatr Radiol. 2016;46:1032–1039. Calheiros de Lima Petribu N, Vieira Fernandes AC, de Brito Abath M, Araújo LC, de Queiroz FR, de Miranda Araújo J, de Carvalho GB, van der Linden V. Common findings on head computed tomography in neonates with confirmed congenital Zika syndrome. Radiologia Brasileira. 2018;51:366–371. Chimelli L, Melo ASO, Avvad-Portari E, Wiley CA, Camacho AH, Lopes VS, Machado HN, Andrade CV, Dock DC, Moreira ME, Tovar-Moll F, Oliveira-Szejnfeld PS, Carvalho AC, Ugarte ON, Batista AG, Amorim MM, Melo FO, Ferreira TA, Marinho JR, Azevedo GS, Leal JI, da Costa RF, Rehen S, Arruda MB, Brindeiro RM, Delvechio R, Aguiar RS, Tanuri A. The spectrum of neuropathological changes associated with congenital Zika virus infection. Acta Neuropathol. 2017;133:983–999. Aleman TS, Ventura CV, Cavalcanti MM, Serrano LW, Traband A, Nti AA, Gois AL, Bravo-Filho V, Martins TT, Nichols CW, Maia M, Belfort R. Quantitative assessment of microstructural changes of the retina in infants with congenital Zika syndrome. JAMA Ophthalmol. 2017;135:1069–1076. e605 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.