Research in Ophthalmology


Vision is arguably one of humanity’s most important senses. It is the only sensory modality with nationally and internationally recommended and (depending on the country) legislated thresholds of quality to permit activities such as driving (1–3), civil and military aviation (4), and heavy machinery operation (5). Located in the occipital lobe, the visual cortex in most humans contains approximately 15-20% of the 30 billion neurons that comprise both cerebral hemispheres (6). This is larger and more complex than our primate relatives (7) which is likely attributable to the range of needs that our vision serves, from functional acuity and spatial, motion and colour perception necessary for day to day tasks, to the numerous interactions between vision and thought, memory (and learning) and emotion, which has led to more research on vision and its interactions than on any other traditional sensory modality (8).


Consequently, the loss of vision can have devastating effects for individuals at all stages of life. Population-based surveys indicate that individuals rank the threat of vision impairment (usually termed “sight loss”) greater than the loss of other traditional senses such as hearing, touch and taste (9,10). It is estimated up to 340 million people worldwide live with some form of vision impairment (11), which is associated with increased risks of developmental delays in children (12,13), increased burdens of educational attainment in young-working age adults (14), and poorer indices of quality of life, mood, confidence and social interaction in all ages (15–17). In older adults who are at greatest risk of eye disease, vision impairment has been linked with increased risks of cognitive decline, loss of independence as well as increased risks of mortality (18–21). There is a significant financial and societal burden associated with vision impairment as well, compounded by the reduced earning potential of individuals with vision impairment which is disproportionately worse in less economically developed countries (22,23).


The field of ophthalmology seeks to understand, and stabilise, reverse, and/or prevent vision impairment, as well as promote awareness of eye disease in the general public. Eyes have complex interactions with many other body systems, and while ophthalmologists primarily treat and monitor eye-specific disorders such as age-related macular degeneration (AMD), glaucoma and cataracts, we are often called upon to assess individuals who have eye manifestations of other systemic diseases, such as diabetes, thyroid and rheumatological issues, and neurological disorders such as strokes, Parkinson’s disease and multiple sclerosis. Advances in medical imaging and therapeutics in the preceding few decades have revolutionised many aspects of ophthalmology – from the introduction of phacoemulsification techniques for cataract surgery in the 1960s, to the increasing availability of high resolution imaging such as optical coherence tomography (OCT) since the 1990s allowing microscopic visualisation and monitoring of eye disease (Figure 1), to the introduction of novel anti-vascular endothelial growth factor (anti-VEGF) drugs in the 2000s that finally offered a chance for patients with wet AMD to recover lost vision and prevent the progression of their disease.



Figure 1 - Left Eye Optical Coherence Tomogram. The image on the Left is the back of the eye rendered in black and white under an infra-red beam, while the image on the Right is a cross-sectional representation of the retina at the back of the eye. This particular patient has an area of disruption to the retina (yellow arrow) caused by a disorder called “Acute Macular Outer Retinopathy”


Underpinning all of these changes has been evidence gathered from clinical research – broadly defined as research that furthers our understanding, prevention or treatment of illness, and promotes health in humans. Clinical research is broad in scope and encompasses analysis of population-based epidemiological trends in human health, to lab-based experimental animal models to better understand disease processes, to in-human trials evaluating the impact of novel medications, surgical procedures, or educational and behavioural tools.


There have been a number of exciting recent trends in ophthalmic research in recent years, partly driven by real-world pressures. For example, increasing emphasis has been placed on highlighting inequities in health access and delivery on national and global scales, with eye health forming one of the key sustainability development goals (SDGs) for the World Health Organisation moving forward from 2020 (24).


In terms of clinical research, our team at King’s is primarily focused on retinal research and the application of advanced imaging and surgical techniques to clinical practice. For example, advances in imaging have meant we can reliably, simply and non-invasively assess and monitor the retina and optic nerve at the back of eye with a high degree of accuracy using technologies such as OCT and OCT-angiography which visually maps blood vessels by detecting the movement of red blood cells (25) (Figure 2).




Figure 2 - An Optical Coherence Tomography Angiography (OCT-A) image of the Right eye. The white lines you see are the blood vessels at the back of the eye with the fovea (the absolute center of vision where your colour vision and perception is clearest) being normally absent of blood vessels. The shape and distribution of blood vessels can diminish in diseases like diabetes, and traditionally the only way to see these vessels was by injecting a dye into a patient’s arm – but OCT-A can map the blood vessels simply by detecting the movement of your red blood cells in the vessel.

These structures in turn give an excellent representation of the microvascular system (in the form of the retina) and brain (in the form of the optic nerve) which has led to recent research by our team and others into whether changes in these structures detected with these highly sensitive devices can be used to detect and predict the onset of blood vessel disorders such as diabetes, or neurodegenerative diseases such as dementia or Parkinson’s (26–28). Furthermore, the increasing volume of ophthalmic images and curation of high quality databases have also opened doors to applying machine learning to automatically detect, quantify and determine an individual’s risk for eye diseases such as diabetic retinopathy, macular degeneration and glaucoma (29–32), which is the PhD focus of one of our team members (Dr Paul Nderitu). We are also the coordinating research unit for two large, active, multicentre research studies called the STAR study (ISRCTN12884465; https://starstudy.org.uk/) which investigates the efficacy of stereotactic radiotherapy in the treatment of wet AMD; and the TIGER study (NCT04663750; https://tigerstudy.org.uk/) which investigates the efficacy of surgery and alteplase (a clot busting drug) injected underneath the retina to treat big bleeds at the back of the eye secondary to wet AMD.


Other exciting avenues of ophthalmology research currently being developed by numerous teams around the world include restoring sight to individuals with established vision loss, through the use of prostheses that replace function (such as photovoltaic cell-based retinal implants; see Argus II and POLYRETINA implants) or stem-cell derived cells to replace corneal, retinal, or neural tissue (33–35). Gene therapy has also found its way into ophthalmic practice, with the first in-human Food and Drug Administration (FDA) approved gene treatment LUXTURNATM (an in-eye injection treatment for RPE65-mutation associated eye disease such as Retinitis Pigmentosa and Leber’s Congenital Amaurosis) coming onto the market in 2017 at a whopping $850,000/£613,410 for a single one-off treatment (36). Further research is underway into therapies for other inherited eye disorders such as Leber’s Hereditary Optic Neuropathy, a maternally inherited mitochondrial gene disorder, with the RESCUE and REVERSE trials being the first in-human, phase 3 mitochondrial gene therapy studies to show promising results (37). Devices are also increasingly being implemented in ophthalmic practice, with an ever-growing number of implants to help reduce eye pressure in glaucoma, as well as newer intraocular lenses (implanted after the removal of cataracts to help focus light and improve vision) that aim to improve one’s depth of focus and restore an element of near vision (38,39).


In summary, ophthalmology is an exciting and varied specialty, incorporating advanced technology in the diagnosis and treatment of eye disease to reverse and prevent blindness. It is my vision that all individuals have the right to sight, and my hope that we will someday see a future free from blindness.


Acknowledgments

This article was kindly reviewed and critiqued by Dr George Murphy


References


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