Lisa Stewart

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	Eighty-three children with rapidly progressing myopia have been treated with nightly atropine drops in Tel Aviv since January 2015. Their 2-year results were reported by Professor Yair Morad of the Assaf Herofeh Medical Centre at the recent European Society of Ophthalmology meeting in Barcelona.

	Atropine drops can significantly slow the progression of myopia. Since this was demonstrated in the ‘atropine for the treatment of childhood myopia’ (ATOM) studies,

children have begun to receive treatment in clinics around the world.

	The ATOM1 study showed that 1% atropine administered nightly over a 2-year period slowed myopic progression by 77%.

ATOM2 went on to demonstrate that the effect was dose-dependent and that 0.01% was sufficient to significantly suppress myopia progression.

	A ‘rebound effect’ was evident in both studies: that is, myopia increased when the atropine treatment was stopped, to a greater extent in children who had received higher doses. The least rebound effect was seen with 0.1% atropine; patients receiving this dose had the least overall progression of myopia after 5 years (3 years after the end of treatment).

	Two years of 0.01% atropine treatment provided, after 5 years, a 50% reduction of myopia compared with the predicted value.

	The children treated in the Assaf Herofeh Medical Centre, all of whom were progressing by at least 0.75 D/year, were initially given 0.01% atropine drops in both eyes every night. After 6 months, their myopia had stopped progressing (≤0.25 D) in almost all cases.

	“We were really amazed to see that after 6 months of treatment almost all children really stopped progressing,” Professor Morad said. “This is actually different from the study in Singapore [ATOM1], where the treatment did not have a profound effect in the first year.”

	There were no side effects reported. The mean age of the children at the start of treatment was 9.2 years and their mean refraction was –4.7 D (range –3 to –12 D). Myopia was moderate in 88% and severe (>7 D) in the remaining 12%. Most of the children (72%) had myopic parents.

	Only one child, who had a baseline refraction of –6.5 D and two parents with high myopia, continued to progress (by 0.75 D). His dose of atropine was increased to 0.05%.

	After 12 months (n = 56), most of the patients were still progressing by 0.5 D or less; two children progressed by 0.75 D (relative to baseline) so were switched to 0.05% atropine.

	After 18 months (n = 36), almost all the children had still not progressed more than 0.5 D; only three children progressed more than 0.75 D. And after 2 years (n = 16), 11 children had really stopped progressing, with a decrease of 0.5 D or less.

	The remaining five children continued to progress by 1 or 1.25 D, but this is a great result, Professor Morad said, bearing in mind that all these children progressed by at least 0.75 D per year before treatment, and that some were progressing by 1.5 or even 2 D per year.

	Myopia progression was reduced to <0.5 D per year in two of the three patients whose atropine dose was increased to 0.05%. One patient continued to progress but only by 1 D per year, which was still much better than the progression he had been experiencing before.

	The mean progression across all the children was 0.32 D per year. There were no side effects or discomfort reported, even in those children who received 0.05% atropine.

	The best responders were those who had low myopia and no family history. Those with high myopia and two myopic parents did not see such good results.

	The most difficult question that remains unaddressed is when to stop the treatment, Professor Morad noted. In the ATOM studies, treatment was given for 2 years and then stopped. If the patient continued to progress by >0.5 D per year, treatment could be reinitiated.

	“This seems like a sensible approach but there are other possibilities,” Professor Morad said. “Perhaps treatment should be continued until around 13 years of age, when myopia usually stops progressing.”

	Another important consideration is cost. Atropine is not yet commercially available as 0.01% drops, so the treatment has to be prepared in a pharmacy-in Israel the cost varies from $20 to $80 per bottle, which could place a high burden on the parents.

	Lastly, the long-term side effects are unknown. The studies from the 1970s that looked at 1% atropine showed no significant side effects except for difficulties in accommodation after prolonged treatment.

	Professor Morad pointed out that the dose used in these children is much lower and no side effects were reported, which is “hopeful”.

	Myopia is common and its prevalence is increasing (for example, myopia prevalence, monitored in nearly 1 million people who were joining the Israeli army at the age of 18, increased from 20% in 1990 to 28% in 2002)

. The economic burden is huge, estimated at around 260 billion dollars annually worldwide.

	The main influence on myopia progression is genetics.

More than 20 genetic loci for myopia are known and a child whose parents are both myopic has six times the risk for myopia than a child with non-myopic parents.

	It has recently been explored how time spent outdoors is firmly associated with less myopic refraction. A study from China showed that the prevalence of myopia significantly decreased, from 39% (control group) to 30%, in schoolchildren who had 40 minutes of outdoor activities every day.

	There are many studies showing a definite relation between near work and myopia progression. A meta-analysis of 27 such studies (25,025 children) showed that myopia increased by 2% for every hour of near work per week.

	Atropine drops were first used to arrest myopia in the 1970s: they were initially believed to work by blocking accommodation. However, atropine prevents form myopia from developing in chicks when one eye is blocked, so this cannot be the mechanism.

	Instead, it blocks receptors on the sclera, the scleral muscle and retina, and inhibits the thinning and stretching of the sclera that is characteristic of form myopia.

	1.     Chua WH, et al. Atropine for the treatment of childhood myopia. 

 Atropine for the treatment of childhood myopia: safety and efficacy of 0.5%, 0.1%, and 0.01% doses (Atropine for the Treatment of Myopia 2). 

 Atropine for the treatment of childhood myopia: effect on myopia progression after cessation of atropine. 

 Five-Year Clinical Trial on Atropine for the Treatment of Myopia 2: Myopia Control with Atropine 0.01% Eyedrops. 

 The changing prevalence of myopia in young adults: a 13-year series of population-based prevalence surveys. 

 Potential lost productivity resulting from the global burden of uncorrected refractive error. 

 Advances in the genomics of common eye diseases. 

Effect of Time Spent Outdoors at School on the Development of Myopia Among Children in China: A Randomized Clinical Trial. 

	9.     Huang HM, Chang D-ST , Wu P-C. The Association between Near Work Activities and Myopia in Children-A Systematic Review and Meta-Analysis. 

	Professor Morad works at Assaf Harofeh Medical Center, Tel Aviv University.

Articles

Children in Tel Aviv have been treated with nightly atropine drops, significantly slowing the progression of myopia.

Low-dose atropine for myopia in children: two years of experience

I started my surgical career as an anterior segment surgeon using a head loupe with a magnifica­tion of ×4 and without the possibility of IOL implanta­tion. A 180° opening of the eye with a knife, suturing it after expression of the cataract, was the rule.

Impressive improvements have been made but there are still obstacles to overcome.

The discovery of a short-acting (15–30 minutes) mydriatic would enable the patient to function nearly normally immediately after the procedure, and cataract surgery being performed in the upright position would also be beneficial to some patients. Most importantly, immediate sequential bilateral cataract surgery has many potential advantages such as fewer hospital visits for the patient, faster visual recovery and lower health care costs.

IOL/capsular bag dislocation decades after cataract surgery is an increasing problem. An estimated 1% of all cases will need to be revisited.

In the meantime, there are numerous variants of sulcus fixation. However, these are time-consuming, technically challenging and not without a certain poten­tial for complications.

I am working intensively on a simple, safe and effec­tive solution to the problem. I cannot reveal more yet, but the first clinical applications will start soon. That is my personal biggest challenge for the coming year and I hope to be able to report on it by the end of 2023.

The biggest challenge for our refractive surgery department in 2023 will be the incorporation of SMILE—or, better, call it laser lenticular extraction.

With the market introduction of new technical­ly competitive laser systems, the time seems to be ripe for this. Whether femto-LASIK will lose its gold standard status remains to be seen. It is the results that count, not the specifications from marketing depart­ments. However, it is quite possible that patients will decide which procedure will prevail in the end. Either way, laser lenticular extraction is an incredible enrich­ment to laser vision correction.

Endothelial keratoplasty such as Descemet membrane endothelial keratoplasty (DMEK) is the standard treatment for Fuchs endothelial corneal dystrophy and chronic corneal oedema.

However, surgical treatment without endothelial ker­atoplasty may serve as an alternative and could reduce the need for corneal transplantations. Recently, promis­ing results were presented for the injection of endothelial cells into the anterior chamber or Descemet stripping only, with or without Rho-kinase inhibitors, as well as for the implantation of an artificial endothelial layer.

Upcoming randomised controlled trials are necessary to evaluate and compare the results with those for cur­rent treatments such as DMEK.

Wearing a face mask has become routine. We are currently experiencing an increased prevalence of patients suffering from dry eye syndrome. Some of the symptoms can be directly connected to wearing face masks, thereby affecting all age groups, with an increased emergence being reported among the paediatric population.

While wearing a face mask, the exhaled air flows upwards, especially when the mask sits loosely around the nose and cheeks. Until now we have had no scientific proof for the cause of those symptoms. This needs to be evaluated because we have to educate our patients on how to avoid such symptoms.

The field of inherited retinal diseases has, over the past decade, seen an explosion in different therapeutic strategies being investigated to slow disease progression or even potentially restore visual function in end-stage disease.

One approach aims to use gene therapy to restore light sensitivity to remaining inner retinal cells once rods and cones have degenerated, with the aim of restoring vision in advanced disease. This method, known as optogenetics, has shown great advances in recent years, with four clinical trials now underway evaluating different gene therapy approaches, some in combination with visual prosthetic devices that augment the light stimulus to optimise responses. The patients who would benefit from these therapies are those with advanced visual loss (acuity of hand move­ments only or perception of light) but with preservation of inner retinal structures on optical coherence tomog­raphy scans.

Preliminary data from three of the ongoing trials have been released, with no serious adverse effects reported; two out of three trials report some improve­ment in visual function. Further data from these trials are keenly awaited, to determine whether optogenetic strategies may be able to restore visual function in blind patients.

For around 15 years I have been supporting the non-governmental organisation Light for the World,

 which is a global development organisation empower­ing people with disabilities and enabling eye health ser­vices in low-income countries. The organisation builds eye hospitals in Africa and delivers, in a very efficient way, eye care in less-developed countries.

We know that glaucoma is the most frequent cause of incurable blindness and must be stopped at all costs. Therefore—specifically for these undeveloped countries, mostly in hot climates—better and longer acting glaucoma eye medication has to be developed.

Using drops twice a day for a lifetime or accessing glau­coma surgery is not straight­forward in these countries. More efficient single doses, long-acting medication and the propagation of cheaper and easier to use glaucoma drainage implants may pre­vent further optic nerve dam­age and keep these people far away from blindness.

The longer lifespan of mankind is accom­panied by age-related diseases such as cataract and age-related macular degeneration (AMD). Unfortunately, for around 20 years, treatment has been available only for the less-common form, wet AMD.

For the most common form of macular degeneration, dry AMD, which represents about 80% of diagnosed cases, there is no efficient treatment yet.

Estimations are that, in the USA alone, 11 million peo­ple have dry AMD, while 1.5 million (~15% of all AMD) are affected by the advanced stages of the disease.

It would be a major challenge to find a way to pre­vent or eventually cure this disease. Millions of people would benefit from such a realisation.

Wet and dry AMD (wAMD, dAMD) is still a major sight-threatening disease. Healing of the disease is still not possible.

Anti-VEGF drugs seem to be a breakthrough. Howev­er, a portion of our patients do not respond adequately and their retinal pigment epithelium is altered as a result of the continous treatment.

In the next year we are expecting the first medi­cal treatments for dAMD and several biosimilars for wAMD. We will have to use our complete armamen­tarium (artificial intelligence in combination with multimodal imaging) to critically evaluate these new approaches/drugs.

A welcome challenge for retinal spe­cialists in 2023 is the advent of new, and in some cases longer acting, anti-VEGF agents for the treatment of retinal disease.

We have seen through 2022 the licensing and ap­proval of faricimab (Roche), an intravitreal agent that inhibits both anti-VEGF and Ang-2, with clinical trial data reporting a maintenance dosing interval of 16 weeks in approximately 45% of patients with AMD at week 48 after starting treatment.

We now therefore have four licensed anti-VEGF medications (ranibizumab [Novartis], aflibercept [Regeneron], brolucizumab [Novartis] and faricimab), with ranibizumab biosimilars also available, for both neovascular AMD and diabetic macular oedema.

It is now in the hands of retinal specialists to weigh up the relative benefits and cost-effectiveness of these different medications for their patient populations and to implement optimal protocols.

Further real-world data emerging through 2023 will aid and clarify these decisions, and clinical trials are also ongoing for gene therapy approaches to treat neo­vascular AMD, which may lead to even longer acting therapies in the coming years.

We are entering a new era of thinking. Senescence is no longer something we are willing to accept as a part of our life. We have enough scientific proof to look at senescence as a disease entity which can be—at least partly—antagonised. Several biotech companies are investigating drugs to help us achieve this goal. Ophthalmology is ideally suited to participate in this new development because we are facing a dra­matically increasing number of patients suffering from age-related diseases such as AMD, diabetes, glaucoma and cataract. Thus, we have to carefully observe the de­velopments and ideally participate as early as we can.

Because cataract is age-related, the need for surgery will go up with the rising average life expectancy of people on this planet. Although the cat­aract surgical rate is increasing in some countries—for example, in India the number of operations per million people per year increased from just over 700 in 1981 to 6000 in 2012

—there are still significant waiting lists in many countries. The surgery has to be made more affordable and eventually paramedics will have to be included in performing cataract surgery.

Patient Management and Demand for Services

We will need to improve perioperative management. Our productivity is insufficient. It starts with the acceptance of patients when we do not have sufficiently efficient telephone and appointment acceptance.

Patient counselling needs to start more effectively before patients come into the clinic. For now, we are just sending information leaflets to the patients. Tele-con­sulting would outsource precious chair time and help us to better pre-select the patients regarding their IOL preferences.

We currently lose too much time during the exam­ination in the clinic. Two to three hours is too much; we want to get to a maximum of 90 minutes. We will review everything that hinders the processes and increasingly focus on multifunctional aperitive diagnostics.

Here, too, artificial intelligence will play an important role. Maybe not in the coming year, but it will not be long before we will be able to compensate for the bottle­necks on the personnel side by significantly increasing productivity.

A major challenge we face as retinal spe­cialists is rapidly increasing demand. In the UK, the Roy­al College of Ophthalmologists predicts a 59% increase in cases of neovascular AMD between 2015 and 2035,

 and facilitating already stretched services to meet this challenge will require innovation and novel approaches.

Potential solutions include home monitoring of pa­tients with AMD, with the aim of detecting neovascular changes at an early stage. Several devices have shown positive results in clinical trials and are approaching utilisation in clinical practice, which may help to reduce the frequency with which patients need to be monitored in a hospital or clinic setting, as well as being more con­venient for this elderly group of patients.

Diabetic macular oedema and AMD con­tinue to increase. One of the major challenges in 2023 will be coping with the large number of patients in diag­nosis and therapy. We very much hope that the support of diagnostics by means of artificial intelligence and the approval of long-acting drugs will support us in this.

A further and ongoing challenge remains in delivering high-quality care across different patient populations who may have a range of barriers prevent­ing engagement with health care.

A prime example is that of diabetic screening: the UK is fortunate to have a national, population-based screening programme to detect diabetic eye disease, and if patients are detected to have significant or po­tentially sight-threatening changes of pre-proliferative or proliferative retinopathy, or maculopathy, they are referred to hospital eye services for further evaluation and treatment.

 in 2018/19, 2.8 million people with diabetes in the UK were invited to diabetic eye screening, 82.6% of whom attended their appoint­ments, with 74% to 92% uptake across different regions of the UK.

Given that 48% of people with type 1 diabetes and 28% of people with type 2 diabetes may develop retinal changes, it is essential to keep engaging with our patients with diabetes to improve screening uptake to enable early detection of potentially sight-threatening changes.

It is known that multiple factors influence screening uptake including social deprivation, being of an ethnic minority background, poorer blood sugar control, smoking and a lack of awareness of the risk of visual loss. We must therefore endeavour to overcome these barriers in conjunction with our physician colleagues by continuing to provide better education regarding the importance of screening.

Other documented barriers have been reported as accessibility, time (such as competing demands), sched­uling and doctor–patient communication, and although it is challenging to address these factors, with limited resources in many areas, the benefits of doing so are clearly evident.

Robot-assisted surgery has made its entrance in ophthalmic surgeries but, compared with other disciplines in medicine, we ophthalmologists— with some exceptions—are lagging behind in its use.

With robotic instrumentation, a precision of 1 mm may be provided and tremor can be avoided. The inte­gration of robotics in complicated surgical procedures has a long way to go, and the limited availability and high cost are challenges to be overcome. Higher effi­ciency and faster surgery in complicated cases could be the outcome.

The use of existing robots (such as the da Vinci sys­tem telemanipulator used for anterior and posterior interventions) has to become more widespread once some existing limitations have been addressed.

Artificial intelligence (AI) is rapidly finding its way into the health care systems around the world. The greatest challenge is to make AI as practical as possible. Different systems need to be combined to achieve a performance that is clinically acceptable.

Thus, the most significant technical challenge arises from the need for adequate training data and external validation. A further challenge is what happens in the case of misclassification or practical mistakes in gen­eral in terms of liability, i.e. whether the AI provider or the clinician is responsible.

In addition, many of these challenges are associated with the usual differences in access to health care.

After 30 years of clinical practice, I will slowly but surely prepare for retirement. Ophthalmology will then increasingly be more research and development for me.

But I will also have more time to take care of my personal well-being and that of my family, and I will have more time for writing. I am especially looking forward to that.

Joachim N, Mitchell P, Burlutsky G, et al. The incidence and progression of age-related macular degeneration over 15 years: the Blue Mountains eye study. 

Chou R, Dana T, Bougatsos C, et al. Screening for impaired visual acuity in older adults: updated evidence report and systematic review for the US preventive services task force. 

Heier JS, Khanani AM, Ruiz CQ, et al. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. 

Murthy GVS, Jain B, Shamanna B, Subramanyam D. Improving cataract services in the Indian context.

The Royal College of Ophthalmologists. The Way Forward: Age-Related Macular Degeneration and Diabetic Retinopathy. 

Public Health England. Atlas of variation in risk factors and healthcare for vision in England. 

Pichler PP, Jaccard IS, Weisz U, Weisz H. International comparison of health care carbon footprints. 

Members of the Ophthalmology Times Europe® Editorial Advisory Board were asked to predict developments in their ophthalmic specialties and interests for 2023. A focus is our ageing population, while efficiency and productivity are also on their minds. The board members agree that one of the major challenges in the year to come will be the large number of patients awaiting diagnosis and treatment, which is only going to increase with the rising average life expectancy worldwide.

2023: What ophthalmologists in Europe anticipate for the year ahead

	Ocular allergy affects millions of people worldwide. It is generally intermittent but sufferers’ quality of life is affected by the resulting ocular discomfort and inflammation: in severe cases they may experience vision disturbance and find that daily activities are hindered.

	Common causes of ocular allergy include mites, animal allergens and moulds, which are found indoors; grass, tree and weed pollens, and mould spores, found outdoors; food allergens such as fruits, vegetables, nuts, milk, eggs, shellfish or fish; and injected allergens including insect venoms and therapeutic proteins.

	Changes to our environment from the combined effects of warming and more CO

 mean that the allergy season is becoming longer from year to year, with pollen seasons starting earlier, lengthier peak-pollen periods and even some pollen presence in the winter.

	Rising temperatures are changing the botanical landscape, increasing the geographic distribution of allergenic plants, and the amount of pollen in the air will continue to increase as climate change worsens.

	As an example of the direct link the environment can have with our health, the number and severity of ocular allergies was observed to increase dramatically in spring 2012 when air pressure, temperature, pollen count and PM10 levels were unusually high. These phenomena seem to increase every year: 2017 was the second-hottest year on record according to NASA data, and was the hottest year that did not have the short-term warming influence of an El Niño event.

	Air pollution constitutes one of the main threats to public health in Europe. Significant impacts on morbidity and mortality have been observed, even in cases of low exposure and when pollutant levels are within limits set by the European Union.

	Focusing on ocular surface diseases, patients commonly present with a type of conjunctivitis that is not strictly of allergic, infectious or dry-eye origin. Clinical studies and experience have shown a cause-and-effect relationship between these allergy-like symptoms and environmental factors, including outdoor air pollutants and poor indoor air quality.

	People with this ‘urban eye allergy syndrome’ experience ocular symptoms that are increased by chemical triggers and pollution in the atmosphere rather than by true allergens.

	Proposed mechanisms for the syndrome include free-radical generation and oxidative stress; increased expression of pro-inflammatory cytokines; modification of key intracellular proteins or the innate immune response; stimulation of autonomic nervous system receptors; adjuvant effects on the immune system; and suppression of normal defence mechanisms.

	It seems likely these all play roles at different stages of the developing syndrome. These individuals certainly appear not to be 

 to pollutants but rather to be experiencing an allergic-type response to pollutants stimulating the mucosal immune system.

	In a recent large survey performed at a national level, focused specifically on ocular allergy, only 40% of subjects diagnosed as affected by allergic conjunctivitis had an associated allergic condition such as rhinitis, asthma or eczema.

 Therefore, it is quite common for patients with eye symptoms to request an ophthalmological evaluation before the allergy consultancy.

	In this survey, pollens were indicated as the most frequent triggers; however, nonspecific environmental conditions, pollutants, cigarette smoke and particular weather conditions were also reported as common factors in inducing ocular symptoms.

	True ocular allergy involves both IgE- and non-IgE-mediated mechanisms. Seasonal and perennial allergic conjunctivitis are primarily IgE-mediated and can be treated using topical and oral antihistamines and topical mast cell stabilisers, whereas non-IgE-mediated disorders such as contact blepharoconjunctivitis require anti-allergic drugs and topical corticosteroids to treat.

	Atopic and vernal keratoconjunctivitis (VKC) have a mixture of IgE-mediated and non-IgE-mediated components and require intense and prolonged anti-allergic drugs, frequently in combination with corticosteroids or topical immunomodulators such as cyclosporine.

	The diagnosis of ocular allergy is relatively simple, being based mostly on clinical history, signs and symptoms, and being confirmed by the results of allergy tests. In general, asking the right questions to patients should reveal not only signs and symptoms but also their frequency, duration and severity.

	VKC is a severe ocular disease that occurs predominantly in children living in warm climates. It is frequently complicated by corneal involvement that manifests in a variety of forms including Tranta’s dots; superficial punctuate keratitis; shield ulcer; corneal plaque; corneal neovascularisation; lipid infiltration; bacterial or fungal keratitis; keratoconus; pseudogerontoxon; and corneal opacification.

	Even though it is relatively easily diagnosed because of its distinct clinical history and ocular manifestations, VKC requires particular attention and is not easy to manage.

	Warm climates and sun exposure probably explain the characteristic north-south gradient prevalence of this form of ocular allergy. VKC is associated with other allergic manifestations in approximately half of patients and often arises in response to exposure to specific allergenic triggers: these observations suggest it does indeed have an allergic component.

	Tear levels of IgE and mast cell mediators are high, which supports this conclusion. However, this does not explain the length of the disease, its typical regression after puberty or the fact that it most often manifests in response to non-allergenic triggers such as sunlight, heat and wind. Antigen-specific Th2 cells have not been demonstrated infiltrating the conjunctiva, and several non-IgE-mediated mechanisms are believed to also be involved.

	Some of the aforementioned mechanisms may involve the integrity of the epithelial barrier. Whereas the junctional complexes are intact in the normal conjunctival epithelium, denying allergens entry, epithelial barrier dysfunction may be induced by endogenous proteases (e.g., metalloproteases) and environmental assailants including some viruses; components of air pollution; cigarette smoke; house dust mites; and pollens, which have intrinsic protease activity.

	Initially, epithelial cells were considered to be a passive barrier impeding allergen penetrance, but we know now that they may recognise allergens and mount an innate immune response with multiple factors such as cytokines, alarmins and endogenous danger signals that activate the dendritic cell (DC) network and other innate immune cells.

 As a consequence, local immune responses may be initiated, beginning the transition from innate to adaptive immunity.

	In particular, allergens induce the production of reactive oxygen species, which activate DC and epithelial cells through NF-kB activation. The innate immunity of epithelial cells not only recognises microbial invasion but may also respond to pollen components from plants, triggering inflammation.

	In fact, in response to allergen recognition, epithelial cells promote Th2 immunity through activation of DCs, by activating innate immune cells such as ILC2s, which can help DCs to polarise Th2 responses in naive T cells.

	Increased expression of heat-shock proteins (HSPs) in VKC patients was recently described by Leonardi 

 The HSP-chaperones are highly conserved during evolution and play essential roles in cell survival; however, they are also implicated in the pathogenesis of various diseases such as some types of cancer and inflammatory and autoimmune disorders.

	Expression of HSPs is induced by environmental and oxidative stress and forms a link between adaptive and innate immunity. Increased HSP levels induced by agents known to initiate or aggravate VKC, such as histamine, cytokines and UV-B, indicate an active interaction between the chaperoning and the immune systems, with perhaps a mutual modulatory role between the two systems.

	HSP27, HSP40, HSP70 and HSP90 seem to be actively involved in VKC, where they may initiate and perpetuate inflammation.

	New mass spectrometric techniques to analyse peptide profiles in human tears may elucidate differences between healthy subjects and patients affected by different phenotypes of ocular allergy and possibly identify target proteins that might be of use in the diagnosis, prognosis and management of VKC and other inflammatory ocular surface conditions.

	For example, hemopexin, transferrin, mammaglobin-B and secretoglobin 1D were found to be significantly overexpressed in VKC samples and dramatically reduced after treatment with topical cyclosporine.

	Recently, collecting and optimally processing sufficient RNA from conjunctival surface cells allowed Dr Leonardi’s group to perform a successful transcriptome-wide expression analysis. Factors involved in both innate and adaptive arms of the immune system, including several Toll-like receptors and other pattern-recognition receptors, were found to be overexpressed in VKC samples.

	In addition, they highlighted the increased expression of multiple chemotactic factors for eosinophils and T cells and multiple co-stimulatory signals required for T-cell activation and survival, confirming that VKC is mostly a cell-mediated pathology.

	Larger studies including different types and severities of ocular allergy should reveal significant gene expression trends that can be targeted to improve the treatments available for ocular allergy.

	Understanding of the role of these different possible mechanisms involved in ocular allergy will open new therapeutic scenarios leading, for example, to the use of specific topical inducers or inhibitors of key proteins in order to prevent the induction of allergic inflammation on the ocular surface and prevent potential severe complications.

	1.     World Meteorological Organization. https://public.wmo.int/en.

	11.  Leonardi A, et al. Presented at ARVO Seattle, 4-9 May 2016; 

	This article was adapted from a presentation given by Dr Andrea Leonardi at the 2017 EuCornea Congress. Dr Leonardi is an associate professor at the Department of Neuroscience, Ophthalmology Unit, University of Padua, Italy, and a board-certified specialist in ophthalmology and in allergy and clinical immunology. Dr Leonardi consulted for Santen; Thea; Novartis; Dompè; Shire (no fee received); Baush & Lomb; and Faes Farma in 2016-17.

Ocular allergy affects the quality of life of millions of people every year. Understanding the different mechanisms involved will increase their future therapeutic options.

Immune mechanisms in allergic eye disease

	The purpose of corneal angiography is to locate the blood vessels within the cornea and evaluate their condition. The ‘gold standard’ technique used to do this is anterior segment colour imaging, but it is not straightforward and the images acquired are often of poor quality.

	Consequently, Dr Martin Hodson of the St Paul’s Eye Unit, Liverpool, started using dyes to improve the imaging of corneal neovascularisation. After seven years of experience he is well placed to share his expertise and gave a presentation entitled ‘Angiography Within Anterior Imaging’ during the joint Ophthalmic Imaging Association and Ophthalmic Photography Netherlands photographic and imaging session at the European Society of Ophthalmology meeting in Barcelona in June.

	When colour images are required, Mr Hodson uses a Topcon system: a diffuse beam is used, magnification is set at 10 x and the light is set at a 45° angle. The use of the Heidelberg Engineering system when dye has been injected is primarily because it has the capability to record video, which improves the likelihood of recording a useful image compared with a one-shot technique.

	When more in-depth images are required, indocyanine green (ICG) and fluorescein dyes are introduced. There are various considerations, one of which is which lens to use.

	The 30° lens gives the best view of the corneal shoulder and the limbus, but for work on the cornea itself the blue OCT lens is best due to its ability to flatten the image, bringing more of the vessels into focus.

	It is also important to get the focus right, which can of course be difficult because the cornea is completely transparent. Mr Hodson gets the best results by setting the focus to 34 D.

	Lastly, it is important to ensure the eyelids do not interfere with the picture. Many patients find it hard to keep their eyes open when confronted with a bright light and it is likely that it will be necessary for the technician to physically hold the eyelids out of the way.

	Once the dye has been injected and has been seen to appear within the eyelids, a 30-second video is started.

	Figure 1 compares images taken using the different techniques. There is much more detail apparent using ICG compared with the (good) gold standard colour image, because use of the dye in conjunction with infrared light allows one to see past the corneal scarring.

	The ‘early’ (30 seconds) and ‘late’ (about 2–3 minutes) fluoroscein images allow the age of the vessel to be estimated: older vessels, which have better-developed walls, will show leakage in the mid- to late-stage images, whereas younger vessels will leak between 30 seconds and 1 minute.

	The clarity of images taken using these new techniques are such that it is starting to become possible to identify the feeder vessel from a mass of vessels. If the feeder vessel can be identified, fine-needle therapy can be used to block it. Similarly, the Eye Unit is starting to look at vessel structure in papillomas and carcinoma in situ.

	In summary, Dr Hodson reiterated that it is important, every time you go to the camera, to remember that every patient is different so your technique might be slightly different. You should keep an open mind how the camera will be positioned, and remember that most patients cannot focus on the bright light. He is now seeing five to six patients every week and demand for the technique is rising.

	Dr Hodson is senior imaging technician and lead oncology imager at St Paul’s Eye Hospital Liverpool, and world lead in corneal neovascularisation angiography imaging. He is a committee member of the Ophthalmic Imaging Association. He has no conflicts of interest to report with this article.

It is important with corneal angiography to remember that every patient is different so your technique might very slightly from patient to patient.

Author | Lisa Stewart

Articles

2023: What ophthalmologists in Europe anticipate for the year ahead

Immune mechanisms in allergic eye disease

Angiography within anterior imaging

Low-dose atropine for myopia in children: two years of experience