Pattern-Reversal Visual Evoked Potential in Children With Congenital Zika Syndrome.

PURPOSE: To objectively evaluate the visual function in children with congenital Zika syndrome using pattern-reversal visual evoked potential (PR-VEP). METHODS: This was a cross-sectional study composed of two patient groups: children aged between 18 and 24 months who were positive for the Zika virus (congenital Zika syndrome group) and age-matched healthy children (control group). All patients underwent a comprehensive ophthalmologic examination and PR-VEP was performed binocularly in a room with constant dim illumination. The P100 peak time in the 60' arc stimuli was used, and the results were correlated with visual acuity, cephalic perimeter at birth, and funduscopic findings. RESULTS: Thirty-seven children were included in the congenital Zika syndrome group and 15 in the control group. The mean age was 18.5 ± 0.9 months (range: 17 to 20 months) in the congenital Zika syndrome group and 24.3 ± 1.6 months (range: 21 to 28 months) in the control group. The P100 response was normal in 7 patients (18.9%) with congenital Zika syndrome, borderline in 2 (5.4%), abnormal with prolonged latency in 18 (48.6%), and abnormal with no response in 10 (27.0%). A significant correlation between the visual acuity and P100 peak time was observed (P < .001). The P100 values were not correlated significantly with the cephalic perimeter at birth (P = .412) or the funduscopic findings (P = .510). PR-VEP in children with congenital Zika syndrome and no funduscopic findings was significantly worse than in the control group (P = .001). CONCLUSIONS: Children with congenital Zika syndrome have characteristically abnormal PR-VEPs regardless of the funduscopic findings and severe microcephaly. The PR-VEP findings supported the diagnosis of cortical visual impairment in these children. [J Pediatr Ophthalmol Strabismus. 2021;58(2):78-83.].

Zika-related adverse outcomes in a cohort of pregnant women with rash in Pernambuco, Brazil.

BACKGROUND: While Zika virus (ZIKV) is now widely recognized as a teratogen, the frequency and full spectrum of adverse outcomes of congenital ZIKV infection remains incompletely understood. METHODS: Participants in the MERG cohort of pregnant women with rash, recruited from the surveillance system from December/2015-June/2017. Exposure definition was based on a combination of longitudinal data from molecular, serologic (IgM and IgG3) and plaque reduction neutralization tests for ZIKV. Children were evaluated by a team of clinical specialists and by transfontanelle ultrasound and were classified as having microcephaly and/or other signs/symptoms consistent with congenital Zika syndrome (CZS). Risks of adverse outcomes were quantified according to the relative evidence of a ZIKV infection in pregnancy. FINDINGS: 376 women had confirmed and suspected exposure to ZIKV. Among evaluable children born to these mothers, 20% presented with an adverse outcome compatible with exposure to ZIKV during pregnancy. The absolute risk of microcephaly was 2.9% (11/376), of calcifications and/or ventriculomegaly was 7.2% (13/180), of additional neurologic alterations was 5.3% (13/245), of ophthalmologic abnormalities was 7% (15/214), and of dysphagia was 1.8% (4/226). Less than 1% of the children experienced abnormalities across all of the domains simultaneously. Interpretation: Although approximately one-fifth of children with confirmed and suspected exposure to ZIKV in pregnancy presented with at least one abnormality compatible with CZS, the manifestations presented more frequently in isolation than in combination. Due to the rare nature of some outcomes and the possibility of later manifestations, large scale individual participant data meta-analysis and the long-term evaluation of children are imperative to identify the full spectrum of this syndrome and to plan actions to reduce damages.

Congenital Zika Syndrome: Surgical and Visual Outcomes After Surgery for Infantile Strabismus.

PURPOSE: To evaluate the surgical and functional outcomes in children with congenital Zika syndrome who underwent strabismus surgery. METHODS: This prospective case series included children with congenital Zika syndrome who presented with horizontal infantile strabismus and underwent strabismus surgery. Ocular motility and visual fields were assessed preoperatively and postoperatively. Visual fields were considered normal if they exceeded 70 degrees in the temporal meridian. Postoperatively, parents and caregivers answered a questionnaire that assessed their child's behavioral improvements. A final ocular alignment within ±10 prism diopters (PD) and expansion of the visual fields were considered satisfactory motor surgical results at 6 months postoperatively. RESULTS: Five children (3 girls [60%]) with congenital Zika syndrome (age: 36.4 ± 0.9 months) were included in this study. All children (100%) presented with moderate to severe visual impairment and 4 (80%) presented with funduscopic abnormalities. Preoperatively, 4 children (80%) had infantile esotropia (mean preoperative angle of deviation: 41.3 ± 6.3 PD) and 1 (20%) had infantile exotropia measuring 65 PD. The postoperative outcomes demonstrated ocular alignment in 4 children (80%) at the 6-month follow-up visit. Expansion of the temporal visual field was observed in 7 eyes (70%) of 4 children (80%). Four caregivers (80%) reported behavioral improvement in daily activities, and all caregivers (100%) reported improved peripheral target detection and socialization skills. CONCLUSIONS: Strabismus surgery can be an effective procedure for treating horizontal strabismus in children with congenital Zika syndrome because it can improve ocular alignment, expand the visual field, and improve the child's social, functional, and behavioral skills. [J Pediatr Ophthalmol Strabismus. 2020;57(3):169-175.].

Fluorescein Angiography Findings in Children With Congenital Zika Syndrome.

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.].

Visual impairment evaluation in 119 children with congenital Zika syndrome.

PURPOSE: To assess visual impairment in a large sample of infants with congenital Zika syndrome (CZS) and to compare with a control group using the same assessment protocol. METHODS: The study group was composed of infants with confirmed diagnosis of CZS. Controls were healthy infants matched for age, sex, and socioeconomic status. All infants underwent comprehensive ophthalmologic evaluation including visual acuity, visual function assessment, and visual developmental milestones. RESULTS: The CZS group included 119 infants; the control group, 85 infants. At examination, the mean age of the CZS group was 8.5 ± 1.2 months (range, 6-13 months); of the controls, 8.4 ± 1.8 months (range, 5-12 months; P = 0.598). Binocular Teller Acuity Card (TAC) testing was abnormal in 107 CZS infants and in 4 controls (89.9% versus 5% [P < 0.001]). In the study group, abnormal monocular TAC results were more frequent in eyes with funduscopic alterations (P = 0.008); however, 104 of 123 structurally normal eyes (84.6%) also presented abnormal TAC results. Binocular contrast sensitivity was reduced in 87 of 107 CZS infants and in 8 of 80 controls (81.3% versus 10% [P < 0.001]). The visual development milestones were less achieved by infants with CZS compared to controls (P < 0.001). CONCLUSIONS: Infants with CZS present with severe visual impairment. A protocol for assessment of the ocular findings, visual acuity, and visual developmental milestones tested against age-matched controls is suggested.

Response to correction of refractive errors and hypoaccommodation in children with congenital Zika syndrome.

PURPOSE: To describe the immediate response to correction of refractive errors and hypoaccommodation in children with congenital Zika syndrome (CZS). METHODS: Children born between May and December 2015 with a confirmed diagnosis of CZS and enrolled in a multidisciplinary early intervention program were included in this study. All children received a comprehensive ophthalmic examination, including dynamic retinoscopy and cycloplegic refraction. Children were prescribed their full correction if they met the criteria for refractive error, and additional plus 3.00 overcorrection for strabismus, accommodative dysfunction, and/or low vision. Monocular and binocular visual responses to Lea Grating Test at 30 cm, with and without eyeglasses, were measured on day 1 of glasses wear. RESULTS: A total of 60 children were evaluated (mean age at evaluation, 11.5 ± 1.1 months; range, 9.0-16.0 months). Lea Grating Test responses were abnormal in all children prior to spectacle correction. Hypoaccommodation was present in 17 of 21 children (81%). Overcorrection was prescribed for all children. Visual responses were subnormal even with glasses use; however, immediate improvement in binocular vision was found in 37 children (62%) and in 74 of 119 eyes (62.2%). For the monocular visual improvement, 27 of 115 eyes (23.5%) had structural abnormalities, and 44 of 115 eyes (38.3%) were structurally normal. There was a statistical difference between the cycloplegic refraction of the children in August and in November, including emmetropia (P = 0.001), hyperopia (P = 0.000), myopia (P = 0.007), and astigmatism (P = 0.004). CONCLUSIONS: Eyeglasses can improve visual acuity in children with CZS. Significant changes in their refractive status over time requires periodic updates.

Quantitative Assessment of Microstructural Changes of the Retina in Infants With Congenital Zika Syndrome.

Importance: A better pathophysiologic understanding of the neurodevelopmental abnormalities observed in neonates exposed in utero to Zika virus (ZIKV) is needed to develop treatments. The retina as an extension of the diencephalon accessible to in vivo microcopy with spectral-domain optical coherence tomography (SD-OCT) can provide an insight into the pathophysiology of congenital Zika syndrome (CZS). Objective: To quantify the microstructural changes of the retina in CZS and compare these changes with those of cobalamin C (cblC) deficiency, a disease with potential retinal maldevelopment. Design, Setting, and Participants: This case series included 8 infants with CZS and 8 individuals with cblC deficiency. All patients underwent ophthalmologic evaluation at 2 university teaching hospitals and SD-OCT imaging in at least 1 eye. Patients with cblC deficiency were homozygous or compound heterozygotes for mutations in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. Data were collected from January 1 to March 17, 2016, for patients with CZS and from May 4, 2015, to April 23, 2016, for patients with cblC deficiency. Main Outcomes and Measures: The SD-OCT cross-sections were segmented using automatic segmentation algorithms embedded in the SD-OCT systems. Each retinal layer thickness was measured at critical eccentricities using the position of the signal peaks and troughs on longitudinal reflectivity profiles. Results: Eight infants with CZS (5 girls and 3 boys; age range, 3-5 months) and 8 patients with cblC deficiency (3 girls and 5 boys; age range, 4 months to 15 years) were included in the analysis. All 8 patients with CZS had foveal abnormalities in the analyzed eyes (8 eyes), including discontinuities of the ellipsoid zone, thinning of the central retina with increased backscatter, and severe structural disorganization, with 3 eyes showing macular pseudocolobomas. Pericentral retina with normal lamination showed a thinned (<30% of normal thickness) ganglion cell layer (GCL) that colocalized in 7 of 8 eyes with a normal photoreceptor layer. The inner nuclear layer was normal or had borderline thinning. The central retinal degeneration was similar to that of cblC deficiency. Conclusions and Relevance: Congenital Zika syndrome showed a central retinal degeneration with severe GCL loss, borderline inner nuclear layer thinning, and less prominent photoreceptor loss. The findings provide the first, to date, in vivo evidence in humans for possible retinal maldevelopment with a predilection for retinal GCL loss in CZS, consistent with a murine model of the disease and suggestive of in utero depletion of this neuronal population as a consequence of Zika virus infection.

Visual impairment in children with congenital Zika syndrome.

PURPOSE: To describe the visual impairment associated with ocular and neurological abnormalities in a cohort of children with congenital Zika syndrome (CZS). METHODS: This cross-sectional study included infants with microcephaly born in Pernambuco, Brazil, from May to December 2015. Immunoglobulin M antibody capture enzyme-linked immunosorbent assay for the Zika virus on the cerebrospinal fluid samples was positive for all infants. Clinical evaluation consisted of comprehensive ophthalmologic examination including visual acuity, visual function assessment, visual developmental milestone, neurologic examination, and neuroimaging. RESULTS: A total of 32 infants (18 males [56%]) were included. Mean age at examination was 5.7 ± 0.9 months (range, 4-7 months). Visual function and visual developmental milestone could not be tested in 1 child (3%). Visual impairment was detected in 32 infants (100%). Retinal and/or optic nerve findings were observed in 14 patients (44%). There was no statistical difference between the patients with ocular findings and those without (P = 0.180). All patients (100%) demonstrated neurological and neuroimaging abnormalities; 3 (9%) presented with late-onset of microcephaly. CONCLUSIONS: Children with CZS demonstrated visual impairment regardless of retina and/or optic nerve abnormalities. This finding suggests that cortical/cerebral visual impairment may be the most common cause of blindness identified in children with CZS.

Optical Coherence Tomography of Retinal Lesions in Infants With Congenital Zika Syndrome.

IMPORTANCE: Zika virus (ZIKV) can cause severe changes in the retina and choroid that may result in marked visual impairment in infants with congenital Zika syndrome (CZS), the term created for a variety of anomalies associated with intrauterine ZIKV infection. OBJECTIVE: To evaluate the affected retinal layers in infants with CZS and associated retinal abnormalities using optical coherence tomography (OCT). DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, consecutive case series included 8 infants (age range, 3.0-5.1 months) with CZS. Optical coherence tomographic images were obtained in the affected eyes of 7 infants with CZS who had undergone previous ophthalmologic examinations on March 17, 2016, and in 1 infant on January 1, 2016. An IgM antibody-capture enzyme-linked immunosorbent assay for ZIKV was performed on the cerebrospinal fluid samples of 7 of the 8 infants (88%), and other congenital infections were ruled out. MAIN OUTCOMES AND MEASURES: Observation of retinal and choroidal findings in the OCT images. RESULTS: Among the 8 infants included in the study (3 male; 5 female; mean [SD] age at examination, 4.1 [0.7] months), 7 who underwent cerebrospinal fluid analysis for ZIKV had positive findings for IgM antibodies. Eleven of the 16 eyes (69%) of the 8 infants had retinal alterations and OCT imaging was performed in 9 (82%) of them. Optical coherence tomography was also performed in 1 unaffected eye. The main OCT findings in the affected eyes included discontinuation of the ellipsoid zone and hyperreflectivity underlying the retinal pigment epithelium in 9 eyes (100%), retinal thinning in 8 eyes (89%), choroidal thinning in 7 eyes (78%), and colobomatouslike excavation involving the neurosensory retina, retinal pigment epithelium, and choroid in 4 eyes (44%). CONCLUSIONS AND RELEVANCE: Zika virus can cause severe damage to the retina, including the internal and external layers, and the choroid. The colobomatouslike finding seen in the OCT images relate to the excavated chorioretinal scar observed clinically.