ABSTRACT
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.
Subject(s)
Eye Infections, Viral/diagnosis , Pregnancy Complications, Infectious , Retinal Degeneration/diagnosis , Retinal Ganglion Cells/pathology , Zika Virus Infection/diagnosis , Adolescent , Antibodies, Viral/blood , Child , Child, Preschool , Eye Infections, Viral/congenital , Eye Infections, Viral/virology , Female , Humans , Infant , Male , Photoreceptor Cells, Vertebrate/pathology , Pregnancy , Retinal Degeneration/congenital , Retinal Degeneration/virology , Retinal Ganglion Cells/virology , Retrospective Studies , Tomography, Optical Coherence , Visual Acuity , Vitamin B 12 Deficiency/diagnosis , Zika Virus/immunology , Zika Virus Infection/congenital , Zika Virus Infection/virologyABSTRACT
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.
