Cortical Visual Impairment in Congenital Cytomegalovirus Infection.

PURPOSE: To describe the presentation, evolution, and long-term outcome of cortical visual impairment (CVI) in patients with symptomatic congenital cytomegalovirus (CMV) infection, and to identify risk factors for the development of CVI in patients with symptomatic congenital CMV. METHODS: Retrospective subanalysis of a long-term prospective cohort study with data gathered from 1982 to 2013. RESULTS: Eleven of 77 (14.3%) patients with symptomatic CMV, 0 of 109 with asymptomatic CMV, and 51 control patients had CVI. Overall, patients with symptomatic CMV had worse vision than patients with asymptomatic CMV, who in turn had worse vision than control patients. Microcephaly, intracranial calcification, dilatation of ventricles, encephalomalacia, seizure at birth, optic atrophy, chorioretinitis/retinal scars, strabismus, and neonatal onset of sensorineural hearing loss were risk factors associated with CVI. CONCLUSIONS: CVI may result from symptomatic congenital CMV infection. The relationship of CVI and its risk factors in patients with CMV suggests the potential to predict the development of CVI through predictive modeling in future research. Early screening of CVI in children born with symptomatic congenital CMV can facilitate educational, social, and developmental interventions. [J Pediatr Ophthalmol Strabismus. 2019;56(3):194-202.].

Zika and the Eye: Pieces of a Puzzle.

Zika virus (ZIKV) is an arbovirus mainly transmitted to humans by mosquitoes from Aedes genus. Other ways of transmission include the perinatal and sexual routes, blood transfusion, and laboratory exposure. Although the first human cases were registered in 1952 in African countries, outbreaks were only reported since 2007, when entire Pacific islands were affected. In March 2015, the first cases of ZIKV acute infection were notified in Brazil and, to date, 48 countries and territories in the Americas have confirmed local mosquito-borne transmission of ZIKV. Until 2015, ZIKV infection was thought to only cause asymptomatic or mild exanthematous febrile infections. However, after explosive ZIKV outbreaks in Polynesia and Latin American countries, it was confirmed that ZIKV could also lead to Guillain-Barré syndrome and congenital birth abnormalities. These abnormalities, which can include neurologic, ophthalmologic, audiologic, and skeletal findings, are now considered congenital Zika syndrome (CZS). Brain abnormalities in CZS include cerebral calcifications, malformations of cortical development, ventriculomegaly, lissencephaly, hypoplasia of the cerebellum and brainstem. The ocular findings, which are present in up to 70% of infants with CZS, include iris coloboma, lens subluxation, cataract, congenital glaucoma, and especially posterior segment findings. Loss of retinal pigment epithelium, the presence of a thin choroid, a perivascular choroidal inflammatory infiltrate, and atrophic changes within the optic nerve were seen in histologic analyses of eyes from deceased fetuses. To date, there is no ZIKV licensed vaccines or antiviral therapies are available for treatment. Preventive measures include individual protection from mosquito bites, control of mosquito populations and the use of barriers measures such as condoms during sexual intercourse or sexual abstinence for couples either at risk or after confirmed infection. A literature review based on studies that analyzed ocular findings in mothers and infants with CZS, with or without microcephaly, was conducted and a theoretical pathophysiologic explanation for ZIKV-ocular abnormalities was formulated.

Ocular Histopathologic Features of Congenital Zika Syndrome.

Importance: Congenital Zika syndrome (CZS) is known to be associated with severe malformations in newborns. Although microcephaly is the hallmark of this disease, the ocular findings are important given the severe visual impairment that has been observed in these patients. Regardless of the increased number of CZS cases reported, to date, no studies have described the ocular histopathologic findings of this entity. Objectives: To evaluate the presence of Zika virus (ZIKV) antigens and describe the associated ocular histopathologic features of 4 cases of CZS. Design, Setting, and Participants: In this observational case series performed from June 19, 2015, through April 30, 2017, ocular tissue samples from 4 deceased fetuses with a diagnosis of CZS from the National Institute of Health in Colombia were sent to the Florida Lions Ocular Pathology Laboratory for evaluation. Main Outcomes and Measures: The microscopic features of each specimen were described, and immunostaining was performed using a ZIKV NS2B protein antibody. Results: Ocular tissue samples from the 4 deceased fetuses (2 female, 2 male) ranging from 21.5 to 29 weeks' gestation with a diagnosis of CZS were studied. The 4 eyes manifested with pupillary membranes, immature anterior chamber angles, loss of pigment and thinning of the retinal pigment epithelium, choroidal thinning, undifferentiated nuclear layers of the retina, and a perivascular inflammatory infiltrate within the choroid. The optic nerve, present in 2 of the eyes, demonstrated atrophy. Expression of ZIKV antigen was present in the iris in cases 1, 3, and 4; the neural retina and choroid in case 1; and in the optic nerve in case 4. Conclusions and Relevance: Loss of retinal pigment epithelium, the presence of a thin choroid, a perivascular choroidal inflammatory infiltrate, and atrophic changes within the optic nerve were consistently present. These findings may be attributed to ZIKV infection and warrant further study.

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.

Long-term Visual and Ocular Sequelae in Patients With Congenital Cytomegalovirus Infection.

BACKGROUND: Cytomegalovirus (CMV) is the most common congenital viral infection in the United States. Visual and ocular sequelae in adolescents and adults who are congenitally infected with CMV have not been well studied. Better understanding of the long-term visual and ocular sequelae can help with early detection, intervention and appropriate educational accommodations. METHODS: This study evaluated 237 patients (77 symptomatic, 109 asymptomatic and 51 control) who underwent a series of age-appropriate ophthalmologic, audiologic and neurodevelopmental examinations from 1982 to 2013. The frequency and etiology of visual impairment and other nonophthalmologic findings were recorded for each patient. Ophthalmologic findings were tabulated, and risk factors for abnormalities were analyzed. RESULTS: Fourteen of the 77 (18.2%) symptomatic and none of the asymptomatic and control subjects had severe visual impairments (P ≤ 0.006). Moderate visual impairment did not differ between symptomatic and asymptomatic subjects. Three asymptomatic subjects had retinal scars. The most common visual or ocular sequelae in the symptomatic group were strabismus (23.4%), chorioretinal scars (19.5%), cortical visual impairment (14.3%), nystagmus (14.3%) and optic nerve atrophy (11.7%). Three symptomatic patients had delayed visual deterioration because of later occurring retinal disorders: peripheral retinal scar, rhegmatogenous retinal detachment and Coats' disease. CONCLUSION: Symptomatic CMV patients experienced more ophthalmologic sequelae and significantly worse visual outcomes than asymptomatic CMV and control patients. Later occurring retinal disorders were found in symptomatic patients, and there is no clear evidence that CMV can reactivate in the retinas of children who were congenitally infected. Major risk factors for severe visual impairment included symptomatic status, optic nerve atrophy, chorioretinitis, cortical visual impairment and sensorineural hearing loss.

[Ocular manifestations of Zika virus: What we do and do not know]. / Manifestations oculaires du virus Zika : où en sommes-nous ?

Zika virus (ZIKV) disease outbreak, which was declared by the end of 2015 in Brazil, has become the largest one to date. Being reported in the Americas and in certain islands of the Pacific, it has the potential to spread worldwide. Although ZIKV infections are mostly self-limiting and/or asymptomatic in the healthy adult, they are responsible for devastating congenital neurologic malformations ZIKV (mainly microcephaly) when contracted during the first months of pregnancy. Ocular manifestations during the acute adult infection include conjunctivitis and more rarely ocular inflammation. Congenital infection is associated with chorioretinal atrophy pigment mottling of the retina retinal vasculature abnormalities and optic nerve atrophy. Therefore, complete ophthalmological evaluation is recommended for suspected congenital infections.

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.

Risk Factors Associated With the Ophthalmoscopic Findings Identified in Infants With Presumed Zika Virus Congenital Infection.

IMPORTANCE: The Zika virus (ZIKV) might cause microcephaly and ophthalmoscopic findings in infants of mothers infected during pregnancy. OBJECTIVE: To assess and identify possible risk factors for ophthalmoscopic findings in infants born with microcephaly and a presumed clinical diagnosis of ZIKV intrauterine infection. DESIGN, SETTING, AND PARTICIPANTS: We conducted a cross-sectional study at the Altino Ventura Foundation in Recife, Brazil, that included 40 infants with microcephaly born in Pernambuco state, Brazil, between May and December 2015. Toxoplasmosis, rubella, cytomegalovirus, syphilis, and human immunodeficiency virus were ruled out in all of them. Testing of cerebrospinal fluid for ZIKV using IgM antibody-capture enzyme-linked immunosorbent assay was performed in 24 of 40 infants (60.0%). The infants and mothers underwent ocular examinations. The infants were divided into 2 groups, those with and without ophthalmoscopic alterations, for comparison. MAIN OUTCOMES AND MEASURES: Identification of risk factors for ophthalmoscopic findings in infants born with microcephaly and ZIKV intrauterine infection. RESULTS: Among the 40 infants, the mean (SD) age was 2.2 (1.2) months (range, 0.1-7.3 months). Of the 24 infants tested, 100% had positive results for ZIKV infection: 14 of 22 infants (63.6%) from the group with ophthalmoscopic findings and 10 of 18 infants (55.6%) from the group without ophthalmoscopic findings. The major symptoms reported in both groups were rash by 26 mothers (65.0%), fever by 9 mothers (22.5%), headache by 9 mothers (22.5%), and arthralgia by 8 mothers (20.0%). No mothers reported conjunctivitis or other ocular symptoms during pregnancy or presented signs of uveitis at the time of examination. Thirty-seven eyes (46.3%) of 22 infants (55.0%) had ophthalmoscopic alterations. Ten mothers (71.4%) of infants with ocular findings reported symptoms during the first trimester (frequency, 0.48; 95% CI, 0.02-0.67; P = .04). A difference was also observed between the groups of infants with and without ocular findings regarding the cephalic perimeter: mean (SD) of 28.8 (1.7) and 30.3 (1.5), respectively (frequency, -1.50; 95% CI, -2.56 to -0.51; P = .004). CONCLUSIONS AND RELEVANCE: Ocular involvement in infants with presumed ZIKV congenital infection were more often seen in infants with smaller cephalic diameter at birth and in infants whose mothers reported symptoms during the first trimester.

Bilateral macular scars following intrauterine herpes simplex virus type 2 infection.

Neonatal herpetic infection is uncommon, with an estimated incidence of 1 in 3000 to 20,000 births. Ocular involvement most commonly consists of blepharoconjunctivitis or keratitis. We present a further manifestation of congenital herpes simplex virus (HSV) 2 infection.

Maternal intrauterine herpes simplex virus infection leading to persistent fetal vasculature.

Herpes simplex virus can cause serious ocular and systemic disease in the neonate. The mode of transmission to the neonate is usually from the maternal birth canal to the fetus intrapartum; but much more rarely, hematogenous transplacental infection can affect the developing fetus months prior to birth. Persistent fetal vasculature occurs when there is persistence of the fetal ocular vasculature, which normally regresses prior to birth. To our knowledge, we report the first case of serologically proven intrauterine herpes simplex virus infection associated with bilateral persistent fetal vasculature in a surviving term infant. Arch Ophthalmol. 2000;118:837-840

Congenital diffuse necrotizing herpetic retinitis.

Neonatal Herpes simplex infections are usually contracted from the birth canal, and the systemic lesions develop several days to weeks after delivery. We present the clinicopathologic findings in a newborn with a prenatal diagnosis of hydrocephalus who died at 1 day of age. Severe liquefaction necrosis and foci of calcification were present in the brain, adrenal glands, and retina. Cowdry type A intranuclear inclusions were present in the adrenal glands and retina. There was no clinical evidence of genital herpes in either parent. This is the first documented case of in utero transmission of Herpes simplex infection, confirmed by the polymerase chain reaction, and causing fulminant necrotizing retinitis and encephalitis.

The ocular manifestations of congenital rubella syndrome.

Congenital Rubella affects the eye in many ways. Ocular effects can be found in the lens, retina, ciliary body and cornea. Ocular manifestations of the Congenital Rubella Syndrome are congenital cataracts, microphthalmos, pigmentary retinopathy, strabismus, and glaucoma. While surgical and medical treatment is utilized for these conditions, the need for prevention is considered critical. The responsibility of health care providers to educate the public remains the key.

Ocular manifestations of the congenital varicella-zoster syndrome.

The congenital varicella syndrome is a rare disorder in which affected infants developed characteristic ocular and systemic manifestations. We present an infant who showed this syndrome, following maternal varicella during pregnancy. The infant had low birth weight, cicatricial skin lesions, limb contractures, hypotonia, areflexia and chorioretinal scarring. Fetal infection was demonstrated with the presence of varicella-zoster-specific IgM in the baby.