Week in Review: Number 32

Increased Risk of High Refractive Error in Children of Mothers with Diabetic Complications
A nationwide population-based cohort study comprised of more than 2.4 million individuals born in Denmark between 1977 and 2016, with follow-up spanning up to 25 years, found that mothers who have diabetes before or during their pregnancy were at an increased risk of having children who go on to develop high refractive error (RE). Including conditions such as myopia, hyperopia, and astigmatism, refractive errors collectively result in defocus of the retinal image and if the degree of refractive error is high enough, can contribute to visual impairment. Based on earlier studies showing links between refractive error and congenital eye defects, the researchers suspected that maternal hyperglycemia during pregnancy could lead to elevated fetal blood glucose levels, which in turn can damage the retina and optic nerve and lead to changes in the shape of the eyes that ultimately cause RE. The results indicate that among the study population, 2.3% were exposed to maternal diabetes, with 0.9% and 0.3% being type 1 and type 2 pre-gestational diabetes respectively, and 1.1% involving gestational diabetes. Exposure to maternal diabetes was associated with a 39% greater risk of high RE compared to unexposed offspring, with elevated risk observed in all three types of refractive error. There was also a difference between type 1 and type 2 diabetes; compared to unexposed offspring, rates of high RE were 32% higher in offspring of mothers with type 1 diabetes and 68% higher in offspring of mothers with type 2 diabetes. Most notably, offspring of mothers with complications arising from diabetes were twice as likely (200%) to have high RE, compared to 18% in unexposed offspring. All this being said, the actual numbers of incidence were low. For example, the authors report, "During up to 25 years of follow-up, 553 offspring of mothers with diabetes and 19,695 offspring of mothers without diabetes were diagnosed with high RE." Although 553 individuals is a tiny number in a sample size of 2,470,580, the authors stress the importance of early screening and prevention, stating, "[A]ny tiny improvement in this low-risk preventable factor will contribute to a huge reduction in absolute numbers of these eye conditions."

Case Report: Acute Vision Loss from IgG4-Related and Bacterial Rhinosinusitis after COVID-19
A recent case report involving a COVID-19 patient who experienced acute loss of vision in one eye provides insight into how SARS-CoV-2 infection could affect the immune system. Specifically, the patient was diagnosed with immunoglobulin G4-related disease (IgG4-RD) concurrent with bacterial rhinosinusitis, the first such case reported in the literature. The patient experienced complete resolution of symptoms after treatment with surgery, antibiotics, and corticosteroids; however, the unusual coinciding factors in this case, including a possible connection to preceding COVID-19 infection and ocular involvement, highlight its relevance for discussion. The male patient in his 70s initially presented to the emergency department with a headache for 2 weeks and vision loss in the right eye for 2 days; he reported no history of rhinosinusitis but did have rhinorrhea (a runny nose) 3 weeks prior and was diagnosed with COVID-19. Although he recovered from COVID-19, the patient developed a worsening right-sided headache 1 week later and right vision loss 2 days prior to presentation. The patient's right eye visual acuity at presentation was limited to hand-motion detection, with severe pain on ocular motion. CT scans revealed opacification with diffuse inflammation in all sinuses on the right side of his face, as well as erosion of the medial orbital apex bone. Emergency surgery and antibiotics were initiated. Bacterial cultures showed that this particular infection involved Streptococcus constellatus, which is associated with orbital invasion.

Histopathologic analysis of sinus samples showed dense infiltrate of IgG-containing plasma cells, with most being IgG4 positive; this finding was confirmed with elevated serum IgG4. IgG4-related rhinosinusitis was diagnosed and the patient was additionally prescribed prednisone and amoxicillin-clavulanate. At 3-week follow-up, the patient's vision had returned to baseline and his headaches had completely resolved. "Although rare, rheumatological workup for IgG4-RD in patients with severe rhinosinusitis and acute vision loss is critical because treatment of IgG4-RD differs from that of bacterial rhinosinusitis," the authors emphasize, "Hence, corticosteroids and antibiotics may be indicated in patients with severe rhinosinusitis until either IgG4-related or bacterial rhinosinusitis can be ruled out." They further state, "Importantly, this patient’s prior SARS-CoV-2 infection suggests a possible relationship between COVID-19 and IgG4-RD. Immunoglobulin G4-RD is mediated by cytotoxic CD4-positive T-cells, an atypical subset of helper T-cells with cytotoxic ability. Increased representation of cytotoxic CD4-positive T-cells was recently discovered in SARS-CoV-2 reactive T-cells, with higher levels associated with hospitalization. This finding signals a possible link between COVID-19 and IgG4-RD," although additional cases would be needed to differentiate between coincidence and connection between the two diseases.

Progress in Augmented Reality Contact Lenses
A start-up company, Mojo Vision, recently announced progress in the design of augmented reality (AR) displays embedded into contact lenses, adding a layer of information onto real world images. Although a long ways from clinical implementation or hitting the shelves, the Mojo Lens boasts features such as a hexagonal display less than a millimeter wide, with pixels each merely a quarter of the width of a red blood cell, and a "femtoprojector" that beams images directly onto the central retina. Electronic features include a camera that captures the outside world; a computer chip that processes imagery, controls the display, and communicates wirelessly with external devices; a motion tracker that incorporates accelerometer and gyroscope technology to compensate for eye movement, and a wirelessly charging battery. Current challenges include extending battery life and "making these things small enough to be socially acceptable," since social discomfort related to recording and sharing information were problems encountered by earlier AR systems such as the Google Glass eyeglasses. When asked why they chose contact lenses as an AR display technology, the start-up emphasizes that contact lenses are worn by 150 million people worldwide, they are lightweight and don't fog up, and AR technology on contact lenses would work even with the eyes closed. At this stage, the team reports that prototypes have passed toxicology tests and they have all the hardware and software components to start assembling fully featured prototypes.

Scientists Develop Brain Organoids with Optic Cups
Organoids are miniature organs grown from induced pluripotent stem cells (iPSCs) that share enough characteristics with the source organ to serve as models to study tissue and embryonic development, disease pathophysiology, and personalized therapies/therapeutics. Researchers studying the connection between the eyes and the brain have grown brain organoids that developed bilateral optic cups, the rudimentary structures that later become the eyes. Previous studies by other research teams had used human embryonic stem cells or alternatively iPSCs (which are derived from adult cells that have been genetically reprogrammed back into an embryonic-like pluripotent state) to generate the optic cup; these studies focused on generating only the retina. The present research instead seeks to study the interorgan interaction of optic cups as they are functionally integrated into brain organoids. Using cells from four iPSC donors, they developed 16 independent batches and generated 314 brain organoids, 72% of which formed optic cups (showing that the method is reproducible). Their lab protocol, such as adding retinol acetate to the culture medium to encourage eye development, produced brain organoids that formed optic cups as early as 30 days, with more mature visible structures appearing within 60 days, a time frame that parallels retinal development in human embryos. The optic cups matured enough to contain primitive corneal epithelial and lens-like cells, as well as retinal pigment epithelia, retinal progenitor cells, synapsin-1, CTIP-positive myelinated cortical neurons, microglia, and axon-like projections that formed electrically active neuronal networks. Furthermore, these organoids exhibited photosensitive response to various light intensities and connectivity to brain regions. Because the formation of optic cups within brain organoids is novel, the researchers report this being the first time observing nerve fibers of retinal ganglion cells reach out to connect with their brain targets in an in vitro system. The team is working on strategies to extend the viability of the organoids and hopes that these organoids will aid in the study of retinopathies, neurodevelopmental disorders, and tissue transplantation.

Blind People Understand Color Through Language
How we learn what we know—whether through direct sensory experience, talking with others, or reasoning through our own thoughts—is a puzzle for empirical philosophy, whose subject matter centers on the idea that to truly know something, one must experience it directly. Recent research sheds light on this question through comparing the understanding of visual phenomena, in this case color, between congenitally blind and sighted people, only the latter of whom have personally experienced color. Contrary to what was predicted by empiricist philosophers such as John Locke, who argued that although individuals who are born blind might grasp arbitrary color facts without an understanding of color, cognitive neuroscientists found that both congenitally blind and sighted individuals possess in-depth understanding of object color, often making similar generative inferences for novel objects and giving similar causal explanations, although they do not necessarily agree about arbitrary color facts. For example, both blind and sighted people can infer that two natural kinds, e.g., two bananas, are more likely to have the same color. Similarly, both blind and sighted people can infer that two objects with functional colors, e.g., two stops signs, are more likely to have the same color than two objects with nonfunctional colors, e.g., two cars. However, relative to sighted people, blind people are less likely to infer that bananas are yellow or that stop signs are red. Even more surprising, blind people can sometimes generate independent, coherent causal explanations for object color. For example, when asked to predict the color of a polar bear, while sighted individuals said that polar bears are white to camouflage with the snow, some blind individuals said that polar bears are black in order to absorb heat and stay warm. The intuitions applied to novel scenarios, independent of memory, such as when asked to predict the color of objects on an imaginary island. These examples revealed that people develop intuitive and inferentially rich “theories” of color regardless of visual experience, and in turn illustrates the effectiveness of linguistic exposure and communication with people who talk about color as sufficient for forming intuitive theories and understanding of color. The researchers next plan to study how and when color understanding develops in the brain among blind and sighted children.

In Other News
(1) Evolution of color vision in lampreys
(2) Bionic eye brings blind patient new sight
(3) Collaboration between optometry and computer science