Corneal diseases affect all ages and impart significant disability to patients as the cornea, the eye’s window, is essential for clear sight and, due to its rich innervation, ocular comfort. Patients suffering corneal disease, as well as corneal injuries, have unmet clinical needs due to poor sight and ocular discomfort. The Corneal Research Group at the Save Sight Institute, The University of Sydney, has been looking for innovative ways to improve outcomes. Here Professor Stephanie Watson reports on recent research and findings.
THE SAVE SIGHT REGISTRIES: FIGHT CORNEAL BLINDNESS! PROJECT
The Save Sight Keratoconus Registry (SSKR) is a simple, yet powerful, web-based tool to collect data. Information, including patient reported outcome measures (PROMs), can be recorded from a patient visit in under 60 seconds. What started in 2014, now has over 35,000 patient visits. It has become the world’s largest keratoconus registry,1,2 providing real world evidence on keratoconus and its treatment.
The Save Sight Registry’s automatically generated reports allow clinicians to show patients their treatment journey
Having established the SSKR, and recognising a lack of real-world evidence for dry eye – the commonest eye disease with a burden for patients as severe as angina – we recently launched the Save Sight Dry Eye Registry (SSDR).
These two world-first, cross-disciplinary registries actively collect data from both optometrists and ophthalmologists. The Save Sight Registry’s automatically generated reports allow clinicians to show patients their treatment journey (Figure 1). They also allow clinicians to audit their practice (CPD accredited Royal Australian and New Zealand College of Ophthalmologists (RANZCO), Optometry Australia Institute of Excellence) and compare findings against benchmarks, driving improvements in care. Additionally, they enable outcomes research, with the ultimate intent of enhancing care for people living with keratoconus and dry eye.
Clinical practice has been informed over the past 12 months from the Registries’ publications, highlights of which include:
- Both standard and accelerated corneal crosslinking (CXL) were found to be similarly safe and effective in stabilising keratoconus at one-year post-surgery in the real-world setting. These findings supported the adoption of accelerated CXL for time and convenience.3
- During CXL, patients who had riboflavin induction for 30 or 15 minutes had similar results in terms of the flattest meridian keratometry (K2) and visual acuity (VA) at one year of follow-up. The 15-minute group had better outcomes in maximum anterior sagittal curvature (Kmax) and thinnest corneal thickness (TCT) but with higher rates of haze, without impact on the final VA.4 Shorter riboflavin induction times can be considered for CXL.
- A steeper Kmax and younger age were the most clinically useful baseline predictors of progression; they were associated with worsening of two clinical parameters.5 Indeed, every 1D steeper Kmax was associated with a 7% and 3% greater risk of worsening VA and thinning TCT, respectively. Additionally, each one year younger was associated with a 4% and 2% greater risk of steepening Kmax and thinning TCT, respectively.
- In keratoconus, Quality of Life scores (QoL, IVI scores) were worse than for retinal diseases, especially for emotional scores (Figure 2). The correlation between VA and QoL scores had low strength, although statistically significant, suggesting a complex relationship.6
Looking to the future, we found that item banks administered using a CAT system, along with the use of Rasch analysis to develop a PROM for ocular allergy, will provide tools to assess outcomes in clinical trials, healthcare and research.7,8
In 2022, the World Association of Eye Hospitals’ keratoconus outcomes is supporting the use of the Save Sight Keratoconus Registry, which includes a PROM and Keratoconus Outcomes Research Questionnaire. To join the registry, request access at frbresearch.org or email: firstname.lastname@example.org.
Globally, microbial keratitis remains a common cause of corneal blindness (Figure 3) and is considered a ‘neglected tropical disease’ (NTD).9 The classification as an NTD is needed to join political, social and economic forces together to eliminate avoidable blindness.
In the developed world, stromal scarring from herpes simplex keratitis (HSK) is a significant cause of unilateral blindness (Figure 4). The Herpetic Eye Disease Study Group made considerable recommendations for HSK treatment regimens in the 1990s. These recommendations have been poorly translated to clinical practice in Australia as they did not include topical aciclovir for epithelial HSK, which is easily accessible and commonly prescribed locally. Additionally, there were no recommendations made for keratouveitis or endothelial HSK.10
Our research over the last year found that:
- Microbial keratitis remains a severe disease for the elderly. Those with a history of topical corticosteroid use, corneal or ocular surface disease, are at risk of evisceration/ enucleation. For these reasons, the elderly should be made aware of the need for prompt hospital presentation and treatment of microbial keratitis to decrease the risk of losing the eye.11
- Gram-positive bacteria are the most common causal microbes of keratitis in Sydney. For resistant gram-positive bacteria, visual and clinical outcomes were significantly better for resistant Coagulase negative staphylococci than for resistant staphylococci aureus or Corynebacterium spp.12
- Patients with clinical presumed concomitant microbial and HSK face significant ocular morbidity and poor visual outcomes. In our setting, Grampositive bacteria were the most commonly associated organisms.13
- Late onset of microbial keratitis after LASIK should be managed similarly to non-LASIK keratitis, as they have a similar clinical course; there is no interface involvement and nontuberculous mycobacteria is not isolated.14
- Microbial keratitis post-CXL should be promptly identified and managed as it may lead to moderate-to-poor patient outcomes. After CXL, microbial keratitis was predominately associated with grampositive bacteria and, in some cases, delayed epithelialisation.15
- Clinical and visual outcomes varied with the type of HSK and prescribed therapies. Diverse initial anti-viral therapies were identified: and standardising them may improve outcomes.16
The implementation of the HSK treatment guideline, developed at the Sydney Eye Hospital (Figure 5), was found to lessen HSK recurrences in patients on HSK prophylaxis. Ongoing distribution of the guideline to new staff, and reminders to old staff, will be essential to maintain adherence to this guideline. Audits are warranted every two to three years to evaluate ongoing adherence to this guideline and outcomes.17
Antimicrobial resistance (AMR) is a global health threat recognised as having a significant potential impact on treatment outcomes. Surveillance programs of AMR are recommended by the World Health Organisation (WHO) Global Action Plan18 to underpin disease prevention and control strategies, and to inform guidelines. Patients with bacterial keratitis continue to lose sight while current Australian data is lacking on AMR. Our local surveillance programme, the Bacterial Ocular Surveillance System, has reported local data19 and will be going national with support from an Australian Vision Research Grant in 2022.
OCULAR SURFACE DISEASE
Critical to the health of the cornea is an intact epithelium – this is the first line of defence to the environment. Limbal (corneal) epithelial stem cells (LESC) maintain the epithelium and heal the cornea following disease, trauma, or surgical procedures. Limbal stem cell deficiency (LSCD) leads to vision loss and ocular discomfort (Figure 6). Stem cell therapies have the potential to treat many ocular conditions, but safe and effective treatments remain limited.
Over the last year we published that:
- Australian ophthalmologists were generally aware of ocular stem cell therapies for corneal disease, macular degeneration, and inherited retinal diseases. However, many felt they had insufficient knowledge to counsel patients. This highlighted the need for education to improve clinicians’ knowledge of ocular stem cells.20
- In the first systematic review, led by Professor Nick DiGirolamo at the University of New South Wales, we assessed the reporting quality and clinical translational relevance of animal models of LSCD. The models of LSCD had evolved over time, which led to variable reporting of the characteristics of animals, experimental procedures and adverse events. Validation of LSCD was mostly made using clinical tests; newer adjunctive techniques would enhance diagnostic validation. We recommended that as most studies sought to evaluate novel therapies for LSCD, animal models should ideally reproduce all the clinical features that we see in patients.21
For common ocular surface diseases, such as dry eye, many patients continue to suffer despite available treatments (Figure 7). We sought to find new solutions and evaluate existing treatments.
- One in eight women are diagnosed with breast cancer and Aromatase inhibitors (AI) are the first line of therapy. Our cross-sectional, observational study of postmenopausal women treated with AI, gathered clinical information from their treating clinician. Ocular and treatment symptoms were then assessed using validated questionnaires and clinical assessments were performed to assess for dry eye. Our study found increased tear osmolarity and meibomian gland drop out in women on AI therapy with symptomatic dry eye. Longer duration of AI therapy and higher tear osmolarity may increase the risk of developing dry eye and could be used to identify at-risk patients.22
- We also reviewed the role of N-acetylcysteine (NAC) in ocular therapeutics since its discovery as a mucolytic agent in 1960. The potent antioxidant, anti-inflammatory and mucolytic properties of NAC has led to its extensive topical use in the treatment of ocular pathology, for example in the treatment of corneal wounds, chemical injuries, keratitis, dry eye disease and meibomian gland dysfunction. The clinical benefits of NAC were evident over a wide range of concentrations, 5–10% topical NAC applied four times daily was used mostly commonly. Adverse effects, such as corneal necrosis are rare, but have been reported with higher doses. NAC also has potential applications in laser epithelial keratomileusis, diabetic eye disease, retinitis pigmentosa, senile nuclear cataracts, macular degeneration, and cigarette smoke-induced corneal damage. Recently, chitosan-NAC has been used as a nanocarrier for the topical administration of medications to the ocular surface.23
- We discovered the motilin receptor in the lacrimal and accessory lacrimal gland. Motilin may play a role in the muscarinic control of aqueous tear secretion; further research is needed to establish the significance of our finding.24
Ophthalmic trauma is a leading cause of preventable monocular blindness worldwide and often irreversibly damages the cornea (Figure 8). The International Globe and Adnexal Trauma Epidemiology Study (IGATES) is a clinical registry hosted on a secure web-based platform with user-friendly smart features, an integrated Ocular Trauma Score (OTS) prognosis calculator, efficient data collection points, and schematic graphical software. Thirty-seven participating centres around the world25 have furthered our understanding of how the prevalence of ophthalmic trauma varies considerably, based on geographic location, socio-economic status, age groups, occupation, and cultural practices such as firework celebrations. Findings from clinical registries are known to be valuable in guiding the diagnosis, management, and prognostication of complex diseases. For example, we now know that:
- Severe vision loss from fireworksrelated ocular trauma occurred during celebrations in a variety of countries and was associated with penetrating and/or lens injury and poor presenting vision.26
- In Open Globe Injuries (OGIs) from 13 hospitals, female gender, older age, zone III injury, eyelid injury, and IOFB were associated with higher risk of visual outcome or severe visual loss.27
- Paediatric ocular trauma occurred mostly in males from projectiles or being struck, with injuries commonly occurring from sporting equipment, toys and sticks. Vision was poorer with open globe injuries, as opposed to closed.28
- The Australian Trauma Model has clear guidelines for referral of trauma patients to ensure appropriate care of the severely injured. However, there are no clear guidelines for the integration of ophthalmology into trauma. To improve outcomes from ocular trauma, early referral to ophthalmology and streamlining of referral pathways of specialist care are needed.29
- To repair the cornea after trauma, Save Sight Institute has developed a laser activated wound sealant. In our large in vivo study, we found that the adhesive was able to seal penetrating corneal incisions and tolerated higher burst pressures than sutures or self-sealing wounds. The adhesive was biocompatible and there was a rapid gain in wound strength that was sustained over the study period (Figure 9).30 Furthermore, there were no ophthalmoscopically or histologically visible retinal changes in the in vivo model.31
PREGNANCY AND THE EYE
Lastly, in a review of the effects of pregnancy and the eye, led by Associate Professor Lyndell Lim, Centre for Eye Research, refractive changes were reported to be common and may persist in the postpartum in patients with keratoconus.32 If progression is noted in women planning pregnancy, CXL may be considered.
For glaucoma, limited use of topical and systemic glaucoma therapies is recommended as data on their safety is limited. There is a preference for selective laser trabeculoplasty as first line treatment in appropriate cases. The impact of pregnancy on diabetic retinopathy remains unclear and due to uncertainties over safety for the developing foetus, anti-vascular endothelial growth factor agents are best avoided in the first and second trimesters. Fortunately, non-infectious uveitis may become less active during pregnancy, which may allow systemic therapy to be tapered and local topical or injected corticosteroid treatment to be used for active disease as required.
Significant changes can occur to the eye during pregnancy, and further research is needed to inform practice to achieve the best balance to preserve the mother’s sight and the health of the developing foetus. For women with established ocular disease, multidisciplinary care is paramount and should involve preconception planning between the obstetrician, physician, eye care professional and paediatrician.
WHAT IS NEXT?
Corneal diseases remain a major cause of irreversible blindness globally and ocular surface disease burdens patients with discomfort that interrupts their daily living. The cornea provides an ideal model for understanding stem cell biology and developing therapies. In 2021, clinical practice was informed and improved, and new knowledge was generated for patients with corneal disease. In 2022, the work of the Corneal Research Group at the Save Sight Institute continues to meet the ongoing challenge of improving patient care for those with corneal disease.
To remain informed, visit mivision.com.au and www.linkedin.com/in/todd-tai-0624174 as well as Fight Corneal Blindness Save Sight Registries (Keratoconus, Dry Eye) steering committees and working groups (savesightregistries.org).
Follow us on Twitter: @profswatson @cornealresearch @kandelhimal @annette_hoskin @CabreraMarie Linked in www.linkedin.com/in/stephanie-watson-11b1a032.
You can also listen to reports presented on the Sydney Eye Podcast during the year: www.buzzsprout.com/1550734.
Thank you to the following contributors to this article:
Professor Nick Di Girolamo, Professor John Foster, Professor Monica Lahra, Professor Frank Lovicu; Dr Himal Kandel, Kornhauser Research Associate; Dr Maria Cabrera Aguas; Dr Jack Tan; Dr Pauline Khoo; Annette Hoskin; Dr Ken Ooi; Dr Alex Ferdi; and Dr Chris Bartimote.
Professor Stephanie Watson is Head of the Corneal Research Group at The University of Sydney Save Sight Institute. She is also Co-Deputy Director, Industry, Innovation and Commercialisation at Sydney Nano, and Head of the Corneal Unit at Sydney Eye Hospital. Professor Watson is Chair of Australian Vision Research (formerly Ophthalmic Research Institute of Australia) and Chair of the Advocacy and Outreach Committee, Association for Research in Vision and Ophthalmology.
- Watson S, Gunasekara G, Go C, Kerdraon Y, Males J, Daniell M, et al. Efficient capture of high-quality data on the outcomes of corneal cross-linking for keratoconus: The Fight Corneal Blindness! Project. Clin Exp Ophthalmol. 2015;43 (Suppl 1):48.
- Tan J, Ferdi A, Gillies M, Watson S. Clinical registries in ophthalmology. Ophthalmol. 2018;126(5):655-62.
- Kandel H, Nguyen V, Ferdi A, Gupta A, Abbondanza M, Sullivan L, et al. Comparative efficacy and safety of standard versus accelerated corneal cross-linking for keratoconus: one-year outcomes from the Save Sight Keratoconus Registry study. Cornea. 2021;40(12):1581-9.
- Benito-Pascual B, Kandel H, Abbondanza M, Mills R, Sullivan L, Watson S. Efficacy and safety of standard corneal cross-linking procedures performed with short vs standard riboflavin induction: A Save Sight Keratoconus Registry study. Cornea. Accepted 16.02.2022.
- Ferdi A, Nguyen V, Kandel H, Tan J, Arnalich-Montiel F, Abbondanza M, et al. Predictors of progression in untreated keratoconus: a Save Sight Keratoconus Registry study. Br J Ophthalmol. 2021.
- Kandel H, Nguyen V, Piermarocchi S, Ceklic L, Teo K, Arnalich-Montiel F, et al. Quality of life impact of eye diseases: a Save Sight Registries study. Clin Exp Ophthalmol. 2022.
- Kandel H, Khadka J, Watson S, Fenwick E, Pesudovs K. Item banks for measurement of refractive error-specific quality of life. Ophthalmic Physiol Opt. 2021;41(3):591-602.
- Kandel H, Watson S. Quality-of-life researchers in ocular allergy may benefit from the newer methods. J Allergy Clin Immunol Pract. 2021;9(1):595-6.
- Ung L, Acharya N, Agarwal T, Alfonso E, Bagga B, Bispo P, et al. Infectious corneal ulceration: a proposal for neglected tropical disease status. Bull World Health Org. 2019;97(12):854-6.
- Cabrera-Aguas M, Robaei D, McCluskey P, Watson S. Clinical translation of recommendations from randomized trials for management of herpes simplex virus keratitis. Clin Exp Ophthalmol. 2018;46(9):1008-16.
- Cabrera-Aguas M, Khoo P, Watson S. Presumed Microbial Keratitis Cases Resulting in Evisceration and Enucleation in Sydney, Australia. Ocul Immunol Inflamm. 2021:1-7.
- Cabrera-Aguas M, Khoo P, Watson SL. Outcomes of Microbial Keratitis Cases Resistant to Antimicrobials in Sydney, Australia. Cornea. 2021.
- Cabrera-Aguas M, Khoo P, George C, Lahra M, Watson S. Predisposing factors, microbiological features and outcomes of patients with clinical presumed concomitant microbial and herpes simplex keratitis. Eye. 2021;36(1):86-94.
- Garcerant D, Cabrera-Aguas M, Khoo P, Watson S. Late onset of microbial keratitis after laser in situ keratomileusis surgery: case series. J Cataract Refract Surg. 2021;47(8):1044-9.
- Khoo P, Cabrera-Aguas M, Watson S. Microbial Keratitis After Corneal Collagen Cross-Linking for Corneal Ectasia. Asia Pac J Ophthalmol (Phila). 2021;10(4):355-9.
- Cabrera-Aguas M, Kerdraon Y, Watson S. Clinical outcomes of herpes simplex keratitis: Two-year experience from a quaternary eye care centre in Sydney, Australia. Ophthalmic Physiol Opt. 2021;41(5):961-70.
- Cabrera-Aguas M, Kerdraon Y, Watson S. Outcomes of Patients with Herpes Simplex Keratitis Before and After the Implementation of a New Treatment Guideline in Sydney, Australia. Asia Pac J Ophthalmol (Phila). 2021;10(2):228-9.
- Global Action Plan on Antimicrobial Resistance. Geneva, Switzerland: World Health Organisation; 2015.
- Watson S, Gatus B, Cabrera Aguas M, Armstrong B, George C, Khoo P, et al. Bacterial Ocular Surveillance System (BOSS) Sydney, Australia 2017-2018. Commun Dis Intell (2018). 2020;44.
- Cabrera Aguas M, Downie L, Munsie M, Watson S. Stem cell therapies for eye conditions: A survey of Australian Ophthalmologists. Asia Pac J Ophthalmol (Phila). Accepted 29.10.2021.
- Delic NC, Cai JR, Watson SL, Downie LE, Di Girolamo N. Evaluating the clinical translational relevance of animal models for limbal stem cell deficiency: A systematic review. Ocul Surf. 2022;23:169-83.
- Khoo P, Groeneveld T, Boyle F, O’Neill S, Forster B, Watson S. Dry eye signs and symptoms in patients on aromatase inhibitor therapy. Eye. 2021;36(4):766-72.
- Eghtedari Y, Oh L, Girolamo N, Watson S. The role of topical N-acetylcysteine in ocular therapeutics. Surv Ophthalmol. 2022;67(2):608-22.
- Sadig R, Allende A, Hall G, Tran D, Madigan M, Watson S, et al. Motilin Receptor Expression Found in the Human Main and Accessory Lacrimal Glands. Ocul Immunol Inflamm. 2021:1-6.
- Ng S, Low R, Hoskin A, Rousselot A, Gunasekeran D, Natarajan S, et al. The application of clinical registries in ophthalmic trauma-the International Globe and Adnexal Trauma Epidemiology Study (IGATES). Graefes Arch Clin Exp Ophthalmol. 2022;260(4):1055-67.
- Hoskin A, Low R, de Faber J, Mishra C, Susvar P, Pradhan E, et al. Eye injuries from fireworks used during celebrations and associated vision loss. Graefes Arch Clin Exp Ophthalmol. 2021;260(1):371-83.
- Hoskin A, Low R, Sen P, Mishra C, Kamalden T, Woreta F, et al. Epidemiology and outcomes of open globe injuries, The International Globe and Trauma Epidemiology Study (IGATES). Graefes Arch Clin Exp Ophthalmol. 2021;259(11):3485-99.
- Liu Y, Hoskin A, Watson S. Epidemiology, aetiology and outcome of paediatric ocular trauma in Sydney. J Paediatr Child Health. 2021;57(9):1479-84.
- Bartimote C, Fraser C, Watson S. Integration of ophthalmology in ocular trauma to improve patient care: A narrative review. Trauma. 2021;24(1):3-13.
- Tan J, Foster L, Lovicu F, Watson S. New thin-film adhesive for sealing full-thickness corneal incisions in rabbits. J Cataract Refract Surg. 2022;48(3):355-62.
- Tan J, Foster L, Lovicu F, Watson S. Laser-activated corneal adhesive: Retinal safety in rabbit model. Transl Vis Sci Technol. 2021;10(27):1-8. 32. Khong E, Chan H, Watson S, Lim L. Pregnancy and the eye. Curr Opin Ophthalmol. 2021;32(6):527-35.