Corneal blindness remains an important cause of avoidable blindness and affects all ages. We need to know more about this ocular condition and develop new therapies to save and restore sight.
Causes of blindness, such as cataract and age-related macular degeneration, are more common than corneal disease, however, they are also increasingly treatable. Corneal blindness is typically irreversible.
Quality of life in keratoconus can be lower than that for macular disease, with mental health, role difficulty, driving, dependency and ocular comfort affected
Keratoconus, which affects 86 in 100,000 people, and corneal infection (keratitis) which affects all ages, are common ocular conditions. Corneal (limbal) stem cell deficiency is less common, but has devastating effects and typically affects patients of working age.1 Research is finding new knowledge and helping to direct treatments and therapies to improve outcomes from these conditions.
Keratoconus progressively reduces vision. Onset in childhood or as a young adult brings with it the burden of life long visual disability and is paralleled by significant costs to the individual and health system.2 Quality of life in keratoconus can be lower than that for macular disease, with mental health, role difficulty, driving, dependency, and ocular comfort affected.
Do we Know Enough About the Natural History?
Corneal crosslinking aims to prevent progression and avoid corneal transplantation in keratoconus. However, uncertainty still exists on what defines progression in keratoconus. The Global Consensus on Ectasia3 identified difficulties in determining disease progression and few studies have investigated the natural history of keratoconus.4 To make informed decisions on when the benefits of interventions outweigh their risks, clinicians need to know how to predict progression. At Save Sight Institute, The University of Sydney, we have in press in the journal Ophthalmology, the first systematic review and metanalysis of keratoconus natural history data with lead author Dr Alex Ferdi.1 We analysed 11,529 eyes with keratoconus from prospective or retrospective studies. We found that patients who were younger and had a maximum keratometry (Kmax) steeper than 55D at presentation had a significantly greater risk of progression. Our conclusion was that patients less than 17 years of age and with a Kmax greater than 55D should be followed more closely or the clinician should have a lower threshold for crosslinking. This study also highlighted that we need to know more about the natural history of keratoconus. Landmark studies investigating keratoconus’ natural history were performed prior to the routine clinical use of modern corneal imaging devices, and subsequent studies have had variable follow up and inclusion and exclusion criteria.
How Can We Learn More About Progression?
Clinical registries have an increasing role in ophthalmology. Our recent publication in Ophthalmology, with lead author Dr Jeremy Tan, reported 97 clinical eye registries with most originating in the European region, North America, and Australia.1 Nine of the registries were multinational, this included the Save Sight Registries. Registries now have important roles, not only in quality improvement but also in research. The Save Sight Registries started by Professor Mark Gillies provide a scientific, web-based platform for eye specialists worldwide to capture high quality clinical data on patient treatments and outcomes from routine clinical practice. They have led the way in fighting ocular blindness and improving patient outcomes in Australia and internationally. In a first of its kind in the world, the Save Sight Registries hold 10 years of data on ophthalmic treatment outcomes for neovascular age-related macular degeneration (wet AMD). As of January 2019, over 184,562 treatments have been captured in the database for approximately 10,100 patients and 12,949 eyes treated for wet AMD.
The Save Sight Keratoconus Registry data has helped us understand the natural history of keratoconus, with a steeper baseline Kmax or K2, worse visual acuity (VA) and pinhole VA being risk factors for progression
To address the need for real world evidence for corneal disease, I expanded The Save Sight Registries with the launch of the Fight Corneal Blindness Project in October 2015. This project has collected outcomes data on 2,211 patients and 4,074 eyes with keratoconus from 63 centres across Australia, New Zealand and Europe, including 2,052 crosslinking treatments. The Save Sight Keratoconus Registry data has helped us understand the natural history of keratoconus, with a steeper baseline Kmax or K2, worse visual acuity (VA) and pinhole VA being risk factors for progression. We have learnt that in keratoconus the vision in a patient’s better eye correlates with reading and mobility scores, and in contrast the vision in the worse eye with emotional scores.2
Corneal Crosslinking to Stop Progression
Corneal crosslinking aims to prevent progression and avoid corneal transplantation5 but is being performed using various protocols with evidence lacking on their safety and efficacy.6 Guidelines for crosslinking are needed to inform the timing and protocols.
There is also little to guide patients on when they should proceed with crosslinking and the impact of the treatment. The National Institute of Clinical Excellence (NICE) in the United Kingdom, has recommended the collection of outcomes data for this procedure. The Save Sight Keratoconus Registry is a simple yet powerful tool that collects data from each patient visit in under 60 seconds and produces a real-time graphical output of the patient’s treatment journey.7 Data from the registry has shown that vision, Kmax, and corneal pachymetry can be stabilised with crosslinking over at least three years following treatment. Adverse events include clinically significant haze, being the most common, although this typically resolves. Scarring, stromal oedema, and a steroid responsive increase in intraocular pressure occur less frequently but may have long term issues for the patient. The Keratoconus Research Outcomes Questionnaire developed by Prof Konrad Pesudovs, has been incorporated into the registry to collect patient reported outcomes and can be used to evaluate quality of life parameters (in submission). Patient reported outcomes will allow the benefit to patients to be determined. Improvements in care are being driven via clinicians comparing their data to the systems’ benchmarked data.1
• Keratoconus progression is more likely in the young and a Kmax greater than 55D.
• Corneal crosslinking can stabilise corneal parameters and vision in keratoconus.
• Registries can collect outcomes data in keratoconus, including the benefit to patients of treatment.
• Protocols for crosslinking require outcomes collection to determine best practice.
Real world evidence on the order, timing, benefits and risks of delivering treatments for corneal disease will improve patient outcomes. Patient reported outcomes will ensure treatments have a meaningful benefit for the patient. Understanding the natural history of disease will provide data to guide and inform clinical practice.
LIMBAL STEM CELLS
Stem cells replace the rapidly dividing surface layer of the cornea – the epithelium.8 These stem cells are known as limbal epithelial stem cells, as they reside in the limbus – the region between the cornea and the conjunctiva. Every seven to 10 days, the entire epithelial surface of the eye is replaced by new epithelial cells produced by limbal epithelial stem cells.
The presence of estrogen in the conjunctiva, lacrimal gland and meibomian gland, suggest it has an effect on tear production
Patients with a deficiency of limbal epithelial stem cells (LESC) lose vision and suffer discomfort. Indeed, around the globe, corneal (limbal) stem cell deficiency has devastating effects on vision and typically burdens patients of working age.9
This is because an intact corneal epithelial surface is needed for clear vision and to protect the cornea from disease (including infection), and trauma. An intact corneal epithelial surface is also needed to prevent pain as the cornea is 300 to 600 times more sensitive than skin. Moreover, limbal epithelial stem cells are needed to heal a cornea following common corneal diseases, trauma, and common surgical procedures. Following trauma, sight is often lost from unhealed corneal wounds allowing infection.10 This is an increasing problem due to the emergence of antimicrobial resistance.11
Limbal stem cell therapies thus have the potential to promote and hasten healing, and could be used following corneal infection or similarly following conditions that result in corneal epithelial defects, eg. corneal grafts – the most common transplant procedure in humans – and some laser refractive procedures, e.g. photorefractive keratectomy, and phototherapeutic keratectomy.
Stem cell therapies, able to improve the corneal surface and vision, are commercially available in Europe. However, these therapies are not currently available to Australian patients and are not universally successful.12-14 At the Save Sight Institute, we developed a world first stem cell treatment technique able to treat patients with limbal stem cell deficiency and have recently reported its mediumterm success.15 To optimise this treatment, Professor Nick Di Girolamo has used a unique model of limbal stem cell failure. This model allows us to trace the cells from a single stem cell population. We have found that rather than the epithelial cells ‘sliding’ or ‘rolling’ into the wound bed after an injury, corneal wounds heal by migration of the basal cells. Increased population pressure in the limbus forces the basal cells into the wound bed due to expansion of these cells. For therapies looking to enhance corneal wound healing, this is an important finding as it highlights that cells are not just active at the wound edge but rather at the limbus. When we looked at what happens after transplantation for limbal stem cell deficiency, we found that not all transplanted stem cells were retained. This was likely due to insufficient stem cells being present in the transplants and loss after transplantation, including due to the limbal stems being corneal like.
Advising Patients Seeking Treatment
Today patients are already seeking stem cell treatments for the eye. The lack of available stem cell therapies in Australia is a source of great frustration to many patients and their families, resulting in some seeking non-evidence based treatment abroad.16,17 Our recent paper with lead author Dr Samantha Bobba – Ocular Stem Cell Therapies;16 the Royal Australian and New Zealand College of Ophthalmologists (RANZCO), and Stem Cells Australia’s position statement on ocular stem cells, as well as the Stem Cells for Sight patient information leaflet have provided much needed information on the current state of ocular stem cell therapies. The aim of these initiatives is to protect patients from seeking stem cell treatments that lack evidence on their safety and efficacy. The brochure can be accessed at: ranzco. edu/ArticleDocuments/176/Ocular%20 Stem%20Cell%20Therapy%20-%20 Leaflet.pdf.aspx?Embed=Y
• Limbal stem cell deficiency reduces vision and causes discomfort.
• A ‘whorl-like’ keratopathy is an early sign of stem cell deficiency and occurs due to cell migration patterns.
• Techniques for limbal stem cell transplantation are still evolving.
• Discuss the risks and benefits of stem cell treatments with patients and be wary of those that lack evidence on their safety and efficacy.
The eye is an ideal site to develop stem cell technologies due to its accessibility, reduced clinical trial risk, and established models with in vivo imaging techniques. New ocular stem cell therapies are likely to reach the clinic.
CORNEAL INFECTION AND TRAUMA
Corneal infection (microbial keratitis) and trauma are ophthalmic emergencies. They are a significant cause of corneal blindness and keratitis is one of the more common causes of visual impairment in working age adults.4 Keratitis sufferers face the risk of vision loss, reduced quality of life, and significant costs.15 For society, there is a heavy burden on the health system.15 In the elderly, one in 10 patients lose an eye to microbial keratitis, and 40% are left legally blind in the affected eye. Children with keratitis can face a life time of poor vision from amblyopia due to corneal scarring. Following minor ocular trauma, vision can be lost from infection.
Aromatase inhibitors are focused on reducing estrogen levels,19,20 and women taking these drugs have a higher rate of dry eye symptoms
To improve outcomes in keratitis and trauma we need to know more.
Australia is currently lagging behind in research on keratitis. For example, ocular surveillance studies conducted overseas have until recently not been done here, and the Australian Group on Antimicrobial Resistance (AGAR) and the National Antimicrobial Prescribing Survey do not collect ocular data. The World Health Organization has recognised antimicrobial resistance as an increasingly serious threat to global public health. Thus there is a need for rational, evidence based prescribing patterns and measurement of antimicrobial resistance to improve outcomes.
Keratitis Updates From New South Wales
Our Keratitis Antimicrobial Resistance Program (KARSP), with contributions from Maria Cabrera Aguas and Pauline Khoo, reported that Staphylococcus spp. and Pseudomonas spp. were the most common micro-organisms isolated and resistance was low to cefalotin and ciprofloxacin. Contact lens wear, including orthokeratology was a risk factor for keratitis and if tap water was used, acanthamoeba keratitis could occur. Fungal and acanthamoeba keratitis were less common than bacterial but still found to have poor outcomes and a protracted course, particularly if diagnosed late.
In Australia, the cause of open globe injuries varied with the patient’s age. In the elderly, globe rupture occurred after falls and a history of intraocular surgery whereas in the young, ruptures were mainly associated with assault and working with metal.18 Globe rupture and perforating injuries had poorer outcomes. Based on these findings from our recent study, and data we are collecting via The International Globe and Adnexal Trauma Epidemiology study (IGATES), we are formulating prevention strategies. The use of eye protection has been highlighted as an area that we need to focus on.
History has provided lessons on the role of eye protection in ocular trauma. Our recently published perspective, with lead author Annette Hoskin, highlighted that advances in eye protection material and design as well as appropriate education have led to changes in the epidemiology of eye injuries.3 Proportionally, occupation related injuries have decreased while injuries during sport and at home have increased. As a profession, we need to keep educating patients about eye protection at work but also on the sports field and when needed at home, for activities such as ‘DIY’.
• Educate patients on correct hygiene for contact lenses.
• Avoid tap water, especially for orthokeratology.
• Manage ocular trauma promptly to reduce the risk of infection.
• Eye protection can prevent ocular trauma,particularly in the workplace, for sport and during at risk activities at home.
Corneal infection and trauma are often preventable. Eye care practitioners can play an active role in educating patients on the risk factors and advising on eye protection.
Dry Eye and Breast Cancer
Dry eye, the most common eye disorder, is frequently accompanied by blepharitis (eyelid inflammation) which has an overall prevalence of nearly 40%. People with dry eye and blepharitis have their daily activities disrupted and work productivity lowered due to recurrent blurred vision and ocular discomfort. Patients report it negatively affects their appearance. Moderate to severe dry eye damages the ocular surface – some patients find it as painful as angina and it can lead to blindness following infection. The consequences of these common conditions occur despite maximal use of lubricating drops and ointments, which address only the symptoms and not the underlying cause.
Breast cancers need estrogen to grow. Aromatase inhibitors block production of estrogen and are an important class of drugs in the treatment of post-menopausal women with breast cancer. Estrogen has been detected in meibomian glands, the lacrimal gland, conjunctiva, cornea, lens, iris and ciliary body, and even in the retina! The presence of estrogen in the conjunctiva, lacrimal gland and meibomian gland suggest it has an effect on tear production. Aromatase inhibitors are focused on reducing estrogen levels,19,20 and women taking these drugs have a higher rate of dry eye symptoms which affect their quality of life and may contribute to them stopping treatment. Currently, in the oncology community, awareness of the scale and severity of this dry eye problem and the impact on patients is low. This means that a potentially debilitating symptom that can be managed effectively, is under-recognised and under-treated.
If You Don’t Ask You Will Not Find Out
An exposure group consisting of women on adjuvant aromatase inhibitors for breast cancer (n=93) was recruited in Sydney, NSW for a landmark study on the link between aromatase inhibitor therapy for breast cancer and dry eyes. A control group was recruited from women presenting for routine mammography screening (n=100). The presence of dry eye syndrome was assessed using the Ocular Surface Disease Index (OSDI) questionnaire, a validated and widely used tool to evaluate dry eye symptoms.21 The prevalence of dry eye syndrome (OSDI > 12)22 in the exposure group was 35% vs 18% in the control group (p=0.0036). On logistic regression analysis, the only significant association with dry eyes was exposure to aromatase inhibitors and the odds ratio of dry eye syndrome on an aromatase inhibitor was 2.51 (95% confidence interval 1.29–4.87). We concluded that patients on aromatase inhibitor therapy suffer with higher rates of dry eye.23 We are now examining patients on aromatase inhibitors prospectively to determine the type of dry eye they have so we can target treatments.
Meibomian Gland Disease And Dry Eye
Evaporative dry eye is the most common type of dry eye and a leading cause of meibomian gland dysfunction. We recently evaluated the effectiveness of pharmaceuticals for meibomian gland disease with Pauline Khoo as the lead author.4 Despite a range of interventions including omega 3, omega 6, oral and topical tetracyclines, combination dexamethasone and cyclosporine, we found limited comparative clinical trial evidence to guide management. Limited data however, did suggest that such treatments were safe.
HMG CoA reductase, the enzyme responsible for cholesterol production, is present in the meibomian glands.24 In a pilot study, dry eye signs and symptoms improved in patients on topical statin.25 Specifically the patients’ tear breakup time increased. Interestingly in Blue Mountains Eye Study patients, we found that oral statins were associated with moderate to severe dry eye disease.5 This is in contrast to the effects of topical statin and could reflect cholesterol having an underlying role in the pathogenesis of meibomian gland disease that is not affected by oral statins due to their low local concentration.
• Consider dry eye in patients on aromatase inhibitors for breast cancer.
• Look for evaporative dry eye in patients with dry eye symptoms; it is most common.
Dry eye remains a significant burden for patients, the health system, and society. Future therapies will be tailored to individual patients based on the findings from new diagnostic devices and paradigms.
CLINICAL TRIALS: THE PATHWAY FOR NEW THERAPIES TO REACH THE CLINIC
To bring new therapies to the clinic we need clinical trials. I am currently the principal investigator on two trials that will hopefully bring relief to patients with meibomian gland disease and dry eye. The RUBY trial is a phase 2, multicentre, randomised, double masked, placebo controlled study to evaluate the clinical safety and efficacy of OKG-0301 in treatment of acute adenoviral conjunctivitis. Patients with three days or less of symptoms from viral conjunctivitis can be screened for inclusion in the trial. National centres are recruiting patients and an online portal is available for patient referrals: rubytrial.com.au
The Azura trial is a multicenter vehicle controlled, randomised study to evaluate the safety, tolerability, systemic pharmacokinetics, and pharmacodynamics of AZR-MR-001 in patients with meibomian gland dysfunction and evaporative dry eye disease. This study is evaluating a potentially exciting new treatment for evaporative dry eye that aims to improve meibomian gland disease. To refer patients to the trial, please contact Winnie Zhang at winnie.zhang@ sydney.edu.au or phone (AUS) 02 9382 7386.
• Clinical trials enable new treatments to safely reach the clinic.
• Australian patients can now participate in world-first clinical trials.
Australia has an excellent clinical trials network. Future treatments may reach Australia first via these trials and support a vibrant culture of innovation.
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Professor Stephanie Watson Sc(Med) (Hons I), MBBS (Hons I), PhD, FRANZCO is a clinician researcher and innovator. She is head of Eye Innovation at the Save Sight Institute and a Sydney Medical School Foundation Fellow. She has published over 198 articles in high-ranked peer reviewed journals and book chapters, and holds international patents. Professor Watson has given over 187 presentations at national and international meetings. As Chair of the Ophthalmic Research Institute of Australia; Regenerative Medicine Representative for Stem Cells Australia; Editor for the Cochrane Eyes and Vision Group UK; and NSW representative of the Corneal Society, she contributes to policy. She is a member of the Association Research in Vision and Ophthalmology (ARVO) Outreach and Advocacy committee, Women in Ophthalmology, and on the NSW Branch Committee for RANZCO.
Many collaborators and students have contributed to the corneal research projects in this article including Professor Nick Di Girolamo, Dr Ken Ooi, Dr Maria Cabrera-Aguas, Dr Alex Ferdi, Pauline Khoo, Annette Hoskin, Dr Jack Tan, Dr Jeremy Tan, Dr Samantha Bobba, Dr Himal Kandel, and the Save Sight Registries’ team including Professor Mark Gillies.
- Tan J, Ferdi A, Gillies M, Watson S. Clinical registries in ophthalmology. Ophthalmology. 2018.
- Sykakis E, Karim R, Evans JR, Bunce C, Amissah-Arthur KN, Patwary S, et al. Corneal collagen cross-linking for treating keratoconus. Cochrane Database Syst Rev. 2015;3:CD010621.
- Gomes J, Tan D, Rapuano CJ, Belin MW. Global consensus on keratoconus and ectatic diseases. Cornea. 2015;34(4):359-69.
- Ramdas W, Mutlu U, Van Dooren B. The role of Scheimpflug imaging derived parameters in the progression of keratoconus: A systematic review and retrospective study. Invest Ophthalmol Vis Sci. 2015;56:1128.
- Godefrooij D, Gans R, Imhof S, Wisse R. Nationwide reduction in the number of corneal transplantations for keratoconus following the implementation of cross-linking. Acta Ophthalmologica. 2016;94:675-8.
- Pron G, Ieraci L, Kaulback K, Medical Advisory Secretariat HQO. Collagen cross-linking using riboflavin and ultraviolet-a for corneal thinning disorders: an evidence-based analysis. Ont Health Technol Assess Ser. 2011;11(5):1-89.
- 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. 2015;43 (Suppl 1):48.
- Di Girolamo N. Moving epithelia: Tracking the fate of mammalian limbal epithelial stem cells. Prog Retin Eye Res. 2015;48:23.
- Shortt A, Secker G, Notara M, Limb G, Khaw P, Tuft S, et al. Transplantation of ex vivo cultured limbal epithelial stem cells: A review of techniques and clinical results. Surv Ophthalmol. 2007;52(5):483-502.
- Robaei D, Watson S. Corneal blindness: a global problem. Clin Exp Ophthalmol. 2014;42(3):213-4.
- Ophthalmic Antibiotics and Antimicrobial Resistance, (2011).
- Shortt AJ, Tuft SJ, Daniels JT. Corneal stem cells in the eye clinic. British Medical Bulletin. 2011;100(1):209-25.
- Zhao Y, Ma L. Systemic review and meta-analysis on transplantation of ex vivo LESC on amniotic membrane in limbal stem cell deficiency. Cornea. 2015;34:9.
- Utheim T. Limbal epithelial cell therapy. Methods Mol Biol. 2013;1014:41.
- Bobba S, Chow S, Watson S, Di Girolamo N. Clinical outcomes of xeno-free expansion and transplantation of autologous ocular surface epithelial stem cells via contact lens delivery: a prospective case series. Stem Cell Res Ther. 2015;6(23):1-14.
- Bobba S, Di Girolamo N, Munsie M, Chen F, Pebay A, Harkin D, et al. The current state of stem cell therapy for ocular disease. Exp Eye Res. 2018;2018(177):65-75.
- Petersen A, Seear K, Munsie M. Therapeutic journeys: the hopeful travails of stem cell tourists. Sociol Health Ill. 2014;36(5):670-85.
- Beshay N, Keay L, Dunn H, Kamalden TA, Hoskin AK, Watson SL. The epidemiology of Open Globe Injuries presenting to a tertiary referral eye hospital in Australia. Injury. 2017;48(7):1348-54.
- Turaka K, Nottage JM, Hammersmith KM, Nagra PK, Rapuano CJ. Dry eye syndrome in aromatase inhibitor users. Clinical & experimental ophthalmology. 2013;41(3):239-43.
- Hutchinson CV, Walker JA, Davidson C. Oestrogen, ocular function and low-level vision: a review. 2014;223(2):R9.
- Ozcura F, Aydin S, Helvaci MR. Ocular surface disease index for the diagnosis of dry eye syndrome. Ocul Immunol Inflamm. 2007;15(5):389-93.
- Miller KL, Walt JG, Mink DR, Satram-Hoang S, Wilson SE, Perry HD, et al. Minimal clinically important difference for the ocular surface disease index. Archives of Ophthalmology. 2010;128(1):94-101.
- Inglis H, Boyle FM, Friedlander ML, Watson SL. Dry eyes and AIs: If you don’t ask you won’t find out. The Breast. 2015;24(6):694-8.
- Ooi K, Rao A, Goh J, Gracie G, Cherepanoff S, Madigan M, et al. HMG-CoA reductase expression in human eyelid tissue and in a human meibomian gland epithelial cell line. . Graefe Arch Clin Exp Ophthalmol. 2019:7.
- Ooi KGJ, Wakefield D, Billson FA, Watson SL. Efficacy and safety of topical atorvastatin for the treatment of dry eye associated with blepharitis: A pilot study. Ophthalmic Res. 2015;54(1):26-33.