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

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 PARTICIPANTSThis 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 MEASURESThe 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 CongenitalZika 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.

Ophthalmologic Manifestations Associated With Zika Virus Infection

“…To corroborate Zhao et al's 31 findings, in a most recent study, Aleman et al 32 provided the first in vivo evidence in humans showing a thinning of the ganglion cell layer, which suggests an in utero depletion of this neuronal population as a consequence of ZIKV infection.…”

Ocular Manifestations of Emerging Flaviviruses and the Blood-Retinal Barrier

“…The virus could reach the fetal circulation from the placenta and infect the RPE, retinal endothelial cells, and the retina [ 94 ]. The other possible pathway would be through axonal transport into the eye along the optic nerve [ 95 , 96 ], leading to ganglion cell layer (GCL) loss, foveal maldevelopment, and central chorioretinal abnormalities [ 97 ]. How ZIKV and other flaviviruses enter the eye in vivo remains to be determined.…”

“…For example, Singh et al have recently reported that retinal cell types lining the BRB are susceptible to ZIKV infection and cause cell death by activating Caspase 3 [ 94 ]. Zhao et al and Aleman et al have independently shown the Muller glia cells to be the primary target of ZIKV infection leading to decreased neurotropic functions and increased pro-inflammatory cytokines post infection with the help of murine models [ 96 , 98 ]. ZIKV infection in RPE was shown to disrupt its cell to cell adhesion and barrier properties [ 99 ].…”

RDH12Mutations Cause a Severe Retinal Degeneration With Relatively Spared Rod Function

“…A separate imaging analysis software (http://imagej.nih.gov/ij/links.html, available in the public domain) was used to generate longitudinal reflectivity profiles from exported images and help supervise and correct automatic segmentation errors. [18][19][20] ''Retinal thickness'' was defined as the distance between the signal peak at the vitreoretinal interface (the internal limiting membrane [ILM]) and the posterior boundary of the major signal peak that corresponds to the basal retinal pigment epithelium/Bruch's membrane complex (RPE/BrM). In normal subjects, the RPE/BrM is the last reflectivity within the 4-6 signals that are identifiable in the outer retina.…”