By Emma Wells
Scheie Vision Annual Report 2017
The 2015-2016 Zika epidemic in the Americas brought to light the virus’s potential to cause devastating birth defects. A recent collaborative study spearheaded by Dr. Tomas S. Aleman has provided new insight into Zika’s effect on retinal development in infants exposed to the disease in utero.
The mosquito-born Zika virus is usually benign in adults, but babies born to infected mothers are at risk for neurological disorders. The most well-known of these birth defects is microcephaly, in which the infant experiences serious malformation of the brain, but Zika can also cause a number of other neurodevelopmental abnormalities. Congenital Zika Syndrome (CZS) encompasses the unique pattern of birth defects associated with Zika, including microcephaly and, of particular interest to Dr. Aleman, retinal abnormalities that can impair a child’s vision.
At the outset of the study, Zika researchers understood that CZS caused retinal damage, but the mechanism through which the virus enters the retina and causes a problem remained a topic of debate. One idea held that the infection causes inflammation in the retina, leading to damage. Another hypothesis proposed that infection and death of neuronal progenitors in-utero is behind the devastating malformations.
Dr. Aleman had been following the research of his colleagues in Brazil who study the retinal changes associated with CZS. While looking over the images they published, Dr. Aleman had a realization. “I noticed that the changes were very reminiscent of a condition that is caused by a genetic problem of Vitamin B12 metabolism called cobalamin C (cblC) deficiency, where we have postulated a malformation of the central retina as a possible disease mechanism,” he said.
Although cblC deficiency and CZS do not have a common etiology, both conditions are associated with very similar retinal lesions. Dr. Aleman was curious if comparing the two conditions could help assess whether Zika, like cblC deficiency, is associated with damage to specific areas of the retina.
Intrigued, Dr. Aleman approached the Brazilian team of researchers, and they agreed to collaborate on a study comparing the microstructural changes of the retina in CZS and cblC deficiency. In contrast to prior studies on retinal damage in CZS, Dr. Aleman was interested in examining areas of the retina unaffected by scarring. “Rather than looking at the atrophic scarred retina, we looked away from that area and went to areas that clinically would look normal or nearly normal,” said Dr. Aleman.
The study enrolled eight infants with CZS and nine individuals with cblC deficiency. All patients underwent ophthalmologic evaluation and spectral-domain optical coherence tomography (SD-OCT) imaging in at least one eye.
Dr. Aleman was surprised by the results. “What we found was that the predilection of both diseases is to affect the inner retina, especially a layer called the ganglion cells, which connects the retina to the brain,” he said. “The implication of the finding is that Zika may reach the retina through the axons of the ganglion cells and the surrounding tissue.” These results provide the first in vivo evidence in humans for retinal ganglion cell loss in CZS.
The researchers found a spectrum of problems from the inner retina to the outer retina in both diseases, casting doubt on the inflammation hypothesis. “There is more of a problem in the superficial layers of the retina than there is in the deeper layers,” said Dr. Aleman. “And that is new.” Since the publication, studies in mice have been consistent with the findings in Dr. Aleman’s work.
These findings have implications for future treatment of CZS. “If retinal damage from CZS resulted from spread from the retinal circulation, then the expectation would be a predilection for regions and cells that follow the path and territories served by those blood vessels,” said Dr. Aleman. This study suggests instead that the infection may spread through the neurons themselves or through their supportive tissue or glia, which may then be better (or additional) targets of treatments. “Ideally we would modify the ability of the virus to enter the neuronal progenitor cells or the supportive glia,” said Dr. Aleman.
The study results could also revolutionize the way clinicians monitor children who were exposed to Zika in utero. The researchers discovered that a retina damaged by CZS may appear normal in routine ophthalmic assessments. The study’s findings support the use of SD-OCT when monitoring patients at risk for CZS as a way to catch developmental abnormalities early and provide support during post-natal development. “We could use these kinds of quantitative measures as biomarkers of whether we have to worry about their development, not only visually but neurologically, in otherwise asymptomatic but Zika-exposed infants,” said Dr. Aleman.
There is hope for children who have sustained retinal damage from CZS. “The retina remains malleable and in development until later in life, and we may still have an opportunity to favorably modify the final visual outcome,” said Dr. Aleman. Early detection and closer monitoring of retinal damage in children exposed to CZS could improve their neurologic and visual outcomes for these children.