Zika virus infection is caused by Zika virus (ZIKV), a single-stranded RNA virus belonging to the genus Flavivirus in the family Flaviviridae. It was first isolated in 1947 from a rhesus monkey in Uganda 1).
Zika virus is primarily transmitted to humans through the bite of infected Aedes aegypti and Aedes albopictus mosquitoes. Humans and non-human primates are considered the main hosts of the virus. In addition to mosquito-borne transmission, infection can occur through sexual contact, blood transfusion, and transplacental transmission from a pregnant woman to her fetus1).
Mosquito-borne transmission has been confirmed in over 86 countries. The 2015–2016 epidemic, centered in Brazil, revealed an association with congenital brain and eye disorders. Multiple outbreaks have been reported in India, including the 2021 Kanpur outbreak1).
Approximately 10% of fetuses of mothers infected with Zika virus during the perinatal period develop congenital Zika syndrome (CZS)1).
In adults, infection is often asymptomatic. When symptoms do occur, they are mild, such as fever, joint pain, rash, and non-purulent conjunctivitis, and resolve spontaneously within about a week. However, Guillain-Barré syndrome (GBS) has been reported in approximately 1 in 4,000 people, and monitoring for optic neuritis may be necessary.
The ophthalmological findings of Zika virus infection differ greatly between congenital (CZS) and non-congenital (infants, children, and adults) cases.
Infants with CZS develop visual impairment due to chorioretinal atrophy and optic nerve abnormalities. Cortical visual impairment is the main cause of reduced vision, but structural damage to the retina and optic nerve further worsens vision 2). In infants with visual impairment, nystagmus and strabismus may also be observed.
In older children and adults, the following subjective symptoms have been reported.
Symptoms are usually mild and last for several days to one week.
The spectrum of ocular abnormalities in CZS is broad. Up to 55% of infants have some ocular signs.
Retinal and Macular Lesions
Chorioretinal atrophy: Forms well-defined atrophic lesions centered on the macula. The most characteristic finding of CZS.
Pigment mottling: Focal pigment aggregation and depigmentation changes. Commonly occurs in the macula.
Extramacular lesions: Pigment aggregation and chorioretinal atrophy may extend beyond the macula.
Retinal vascular abnormalities: Abnormal cessation, focal dilation, tortuosity, and narrowing of vessels have been reported.
Optic nerve and other ocular findings
Optic nerve hypoplasia: Optic disc hypoplasia. One of the common optic nerve abnormalities in CZS.
Enlarged and pale optic disc cupping: A finding reflecting optic nerve damage.
Microphthalmia and congenital glaucoma: Rare but severe ocular malformations.
Others: Iris coloboma, cataract, lens subluxation, intraocular calcification, strabismus, and nystagmus have also been reported.
Color fundus photography with high magnification (80° lens) is useful for detecting subtle macular changes that cannot be detected with a wide-angle lens (130°) 2). In a study of 4 infants with CZS by Ventura et al., in all cases where unilateral findings were observed with a 130° lens, high-magnification lens newly detected subtle macular changes in the contralateral eye, which were confirmed by fluorescein angiography (FA) 2).
In adult case reports, the following diverse ophthalmic findings have been described.
Approximately 42% of children with CZS may not present with neurological symptoms such as microcephaly, and ocular abnormalities can exist even when neurological findings are normal. Since ocular findings also contribute to cortical visual impairment, a comprehensive ophthalmologic examination within the first month after birth is recommended regardless of neurological findings.
Zika virus has an affinity for neural progenitor cells. Regarding the mechanism of infection in the fetal eye and brain, animal studies have shown that the virus crosses the blood-retinal barrier and blood-brain barrier, infecting cells in the choroid and retinal layers, leading to inflammatory responses and cell death.
Human iris pigment epithelial cells have moderate susceptibility to ZIKV and exhibit a strong antiviral response (IFN-β) after infection.
In fetuses born to women infected with Zika virus in the first trimester, neurological abnormalities (microcephaly, ventriculomegaly, subcortical calcifications, gyral abnormalities) may become apparent in the third trimester1). Regular ultrasound surveillance is important.
Clinical suspicion is based on maternal risk factors (travel to affected areas, sexual contact with a partner at risk) and clinical signs and symptoms. Laboratory testing is required for definitive diagnosis.
| Test | Specimen | Method |
|---|---|---|
| RNA nucleic acid amplification test (NAT) | Serum, urine, CSF | RT-PCR |
| IgM antibody test | Serum | ELISA |
| Neutralizing antibody test | Serum | PRNT |
Since Zika viremia persists for less than one week after onset, RT-PCR may be ineffective. Confirmation of IgM positivity by PRNT is a more specific diagnostic method. Histopathological examination and immunohistochemical staining of the placenta and umbilical cord are also useful.
The CDC recommends a comprehensive eye examination within the first month of life for the following infants:
Examination includes visual acuity assessment (e.g., Teller acuity cards), pupillary light reflex, slit-lamp biomicroscopy, intraocular pressure measurement, and dilated fundus examination.
Optical coherence tomography (OCT) in congenital Zika syndrome shows the following:
Wide-angle lenses (130°) alone may miss subtle macular lesions. Color fundus photography using an 80° high-magnification lens can noninvasively detect subtle macular changes confirmed by FA in all cases 2). Fluorescein angiography (FA) is the gold standard for confirming subtle pigment epithelial changes as window defects, but requires sedation in children. High-magnification fundus photography is a less invasive and less costly alternative to FA 2).
Diagnosis is based on travel history, exposure to endemic areas, and clinical symptoms. Characteristic symptoms include acute fever with maculopapular rash, arthralgia, and conjunctivitis lasting several days to one week.
It may not be sufficient. In a study by Ventura et al., subtle macular changes were detected with 80° high-magnification lenses in all contralateral eyes that had no findings with 130° wide-field lenses. These were confirmed by FA, and adding high-magnification imaging may prevent oversight.
Currently, there is no established treatment to prevent or reduce congenital Zika virus infection. Management is primarily supportive care based on CDC interim guidance.
There is no specific antiviral drug. Treatment is primarily symptomatic, including rest, hydration, analgesics, and antipyretics.
For ocular lesions, the following management has been reported.
Zika virus has an affinity for neural progenitor cells and induces apoptosis of infected cells 1). For the fetal eye, it is thought that the virus crosses the blood-retinal barrier and directly infects cells of the choroid and retinal layers, causing an inflammatory response and cell death.
Ocular histopathology in four fetuses who died from CZS confirmed the following:
Immunostaining has confirmed the expression of ZIKV antigens in the iris, neural retina, choroid, and optic nerve.
In studies of ZIKV-infected mice, only the superficial retinal vessels developed, and vascular density was significantly reduced. CD45 antibody staining revealed abundant infiltration of inflammatory cells. These findings suggest that ZIKV suppresses retinal vascular growth and enhances the inflammatory response.
Visual impairment in CZS is multifactorial2).
Ventura et al. studied 119 children with CZS and showed that the majority had visual impairment regardless of the presence or absence of fundus findings2). This supports CVI as the main cause.
In adult infection, the virus is thought to enter the eye (aqueous humor and vitreous body) and cause uveitis. Since Zika virus can cause neurological abnormalities such as Guillain-Barré syndrome, monitoring for optic neuritis is also important.
Ventura et al. (2021) demonstrated that in 4 infants with CZS, color fundus photography using an 80° high-magnification lens noninvasively detected subtle macular changes confirmed by FA in all cases2). Subtle changes in the contralateral eye that were not detectable with conventional wide-angle lenses (130°) were visualized at high magnification. Previous studies reported fundus findings in 55% of cases, but high-magnification photography suggests the actual prevalence may be higher.
Currently, no vaccine against Zika virus has been put into practical use. Research is ongoing using multiple platforms, including mRNA vaccines, but none have reached the stage of clinical application.
In cases of infection during the first trimester, even if ultrasound findings are normal at 12, 16, and 20 weeks of gestation, abnormalities may first become apparent after 28 weeks 1). Case reports have emphasized the importance of regular ultrasound surveillance throughout pregnancy, and the establishment of more precise monitoring protocols is needed.
Singh D, Kaur L. Maternal Zika virus infection in the first trimester and fetal stigmata in the third trimester. Indian J Radiol Imaging. 2023;33:400-402.
Ventura CV, Aragão I, Ventura LO. Color fundus imaging using a high-magnification lens for detecting subtle macular changes in infants with congenital Zika syndrome. J VitreoRetinal Dis. 2021;5(5):425-430.
Labib BA, Chigbu DI. Pathogenesis and Manifestations of Zika Virus-Associated Ocular Diseases. Trop Med Infect Dis. 2022;7(6). PMID: 35736984.
