September 2013 # 01

Upfront In Practice NextGen Profession Are Britain’s Corneal Cross-Linking Harminder Dua Describes How to Build a Practices “Failing”? Combats the Discovery of ‘His’ Layer Practice

10 25 – 36 39 – 45 47 – 55

In the Eye of the Storm

The new role for ophthalmologists in tackling chronic diseases 16 – 23 and

● Vitreomacular traction (VMT), including macular hole, can be progressive and may put patients at risk of central vision loss1–4 ● To date, there have been only two options (1) Watch and wait; (2) Vitrectomy INTRODUCING JETREA® (ocriplasmin) Intravitreal (IVT) Injection The fi rst pharmacologic treatment for vitreomacular traction (VMT) in adults, including when associated with macular hole of diameter ≤400 µm1

● In clinical trials, a single injection of JETREA® (ocriplasmin) Intravitreal (IVT) Injection was shown to resolve VMT and to help close macular hole as compared to placebo2 ● 26.5% of patients treated with JETREA® achieved resolution of VMT at Day 28 (vs 10.1% with placebo)2 ● 40.6% of patients treated with JETREA® with full-thickness macular hole achieved closure of macular hole of diameter ≤400 μm at Day 28 (vs 10.6% with placebo)2

(ocriplasmin) Concentrate for solution ©2013 Novartis for injection, 0.5mg/0.2ml Date of preparation: Aug JET/OCR: HCP 059:03/13:AL (A) JETREA is a registered trademark of ThromboGenics N.V., licensed to Alcon.

REFERENCES: 1. JETREA Summary of Product Characteristics. ThromboGenics NV. Belgium; January 2013. 2. Stalmans P, Benz MS, Gandorfer A, Kampik A, et al. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular hole. N Engl J Med. 2012;367(7):606-615. 3. Carrero JL. Incomplete posterior vitreous detachment: prevalence and clinical relevance. Am J Ophthalmol. 2012;153(3):497-503. 4. Schneider EW, Johnson MW. Emerging nonsurgical methods for the treatment of vitreomacular adhesion: a review. Clin Ophthalmol. 2011;5:1151-1165. Brief Summary –Please see the JETREA® package insert for full prescribing information JETREA® 0.5 mg/0.2 ml concentrate for solution for injection (ocriplasmin) Prescribing tration to both eyes or repeated administration in the same eye is not recommended. machinery. Undesirable e ects: Very common: Vitreous  oaters, eye pain, conjunctival Inform ation (Refer to full Summary of Product Characteristics (SmPC) before prescribing). Clinical data is not available on concomitant use with VEGF-inhibitors. Treatment is haemorrhage. Common: Visual acuity reduced, , vision blurred, Presentation: Type I glass vial containing 0.2ml concentrate for solution for injection not recommended in patients with large diameter macular holes (> 400 microns), retinal haemorrhage, vitreous haemorrhage, retinal tear, , intra- (excipients: mannitol, citric acid, sodium hydroxide (pH adjustment), water for injections). After high , , history of rhegmatogenous retinal detachment, lens zonule ocular pressure increased, macular hole, , retinal degeneration, dilution with 0.2ml of sodium chloride 0.9% solution for injection, 0.1ml of the diluted solution instability, recent ocular surgery or intraocular injection (including laser therapy), macular oedema, retinal oedema, retinal pigment epitheliopathy, metamorphopsia, contains 0.125mg ocriplasmin. Indication(s): Treatment of vitreomacular traction (VMT) in proliferative , ischaemic retinopathies, retinal vein occlusions, vitreous adhesions, conjunctival oedema, eyelid oedema, vitritis, anterior chamber adults, including when associated with macular hole of diameter less than or equal to 400 exudative age-related macular degeneration (AMD) and vitreous haemorrhage. cell, anterior chamber  are, iritis, photopsia, conjunctival hyperaemia, ocular hyper- microns. Posology and method of administration: Adults, including the elderly: Intravitreal There is potential for lens subluxation or phacodonesis. Exercise caution if treating patients aemia, vitreous detachment, retinogram abnormal, eye irritation, dry eye, foreign injection of 0.125 mg (0.1 ml of the diluted solution) to the a ected eye once only as a single with non-proliferative diabetic retinopathy, history of or signi cant eye trauma. body sensation in eyes, eye pruritus, ocular discomfort, , chromatopsia. dose. Children and adolescents: Not recommended. Hepatic and renal impairment: No Ocriplasmin e cacy is reduced in patients with an or a diameter of VMA > Uncommon: transient blindness, lens subluxation, , visual  eld defect, dosage adjustment necessary. Contra-indications: Hypersensitivity to ocriplasmin or any of 1500microns. Due to potential increase in tractional forces, there is a risk of occurrence of new or , hyphaema, , pupils unequal, corneal abrasion, anterior chamber the excipients. Active or suspected ocular or periocular infections. Warnings and precautions: enlarged macular holes. There is a risk of signi cant but transient loss of visual acuity during the in ammation, eye in ammation, conjunctival irritation. Prescribers should consult Proper aseptic injection techniques must always be used and patients should be monitored  rst week after the injection. Interactions: Formal studies have not been performed. Systemic the SmPC in relation to the side e ects. Overdose: Clinical data are limited. If an overdose for any side e ects such as, but not limited to, intraocular in ammation/infection interactions are not anticipated. Administration in close temporal association in the same occurs, close monitoring is recommended. Incompatibilities: Must not be mixed with other and elevation in IOP. Transient increases in IOP including transient blindness and eye with other medicinal products is not recommended as this may a ect the activity of both medicinal products except for the speci ed diluent. non-perfusion of the optic nerve have been seen within 60 minutes of injection of JE- products. Pregnancy and lactation: Do not use unless the clinical bene t outweighs Special Precautions for Storage: Store frozen at -20°C ± 5°C. TREA. Patients should be instructed to report symptoms of intraocular in ammation/ the potential risks. Fertility: No fertility data are available. E ects on ability to drive and MA Number(s): EU/1/13/819/001. Further information available from the MA holder: infection or any other visual/ ocular symptoms without delay. Concurrent adminis- use machines: If visual disturbances occur, wait until vision clears before driving or operating ThromboGenics NV, Gaston Geenslaan 1, B-3001 Leuven, Belgium.

83344 JET/OCR_HCP 059-03/13-AL (A).indd 1 8/30/13 2:52 PM Online this Month

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Harminder Dua Find more from The Ophthalmologist. Connect and interact offers candid online through Facebook, LinkedIn, Google Plus, our thoughts on YouTube channel and via Twitter (@OphthoMag) his discovery, sceptical colleagues, media interest, the nature of evidence and The Dotted Line ...... (not) achieving a work-life balance. To guarantee your next copy of The Ophthalmologist, sign up online and confirm your print subscription. And please Go to the video or read the interview article at: feel free to pass this invitation onto colleagues. Subscription theophthalmologist.com/issues/0113/402-1 is qualified but free: theophthalmologist.com/login Contents

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52 58

03 Online This Month Upfront Feature

10 UK Ophthalmology Service is 16 In the Eye of the Storm 07 Editorial “Failing”, Says Report Mark Zacharria investigates how A Fresh Perspective, adaptive optics can be used to by Richard Gallagher 11 , From the fight chronic systemic disease. Patient’s Perspective

08 Contributors 12 Big Pharma Loves Ophtho In Practice

12 Retinal Images Predict Future 26 Constructive Cross-Links On The Cover Stroke Risk Arthur Cummings on transformational outcomes for September 2013 # 01 Photo taken from the 2008 15 Eyeball-Licking: What If… keratoconus patients.

Upfront In Practice NextGen Profession Are Britain’s Ophthalmology Corneal Cross-Linking Harminder Dua Describes How to Build a Practices “Crumbling”? Combats Keratoconus the Discovery of ‘His’ Layer Presbyopia Practice

10 25 – 36 39 – 45 47 – 54x performance of Tosca at Bregenz In the Eye of the Storm

The new role for ophthalmologists in tackling chronic diseases 18 – 23 Festival. Reproduced with the 30 An Intrepid Assault on AMD permission of Bregenz Stereotactic radiation helps Festspiele GmbH. patients with wet AMD, says E. Mark Shusterman. ISSUE 01 - SepTEMBER 2013

Editor - Mark Hillen [email protected]

Editorial Director - Richard Gallagher [email protected]

Graphic Designer - Marc Bird [email protected]

Managing Director - Andy Davies [email protected] 26 Director of Operations - Tracey Peers [email protected] 33 BAK Off The preservative-free future of Profession Publishing Director eyedrops, by Mark Hillen. - Neil Hanley 48 Building a Presbyopia Practice [email protected] 34 Pediatric Glaucoma, East and West The key to success is understanding Differences in presentation and the presbyopia patient say Jeff Audience Development Manager best therapeutic options are Machat and Sondra Black, who - Tracey Nicholls compared by Nadar Bayoumi. run a successful presbyopia practice [email protected] in Toronto.

NextGen 51 Glaucoma Tug-of-War David Andrews explains why Published by Texere Publishing Limited, 40 To Galen, Mundinus and Tulp, Australian ophthalmologists Booths Hall, Booths Park, Add Dua and optometrists, once firm Chelford Road, Knutsford, Cheshire, Harminder Dua desribes the friends, are now battling to treat WA16 8GS, UK discovery of Dua’s layer, and patients with glaucoma. General enquiries: discusses the medical www.texerepublishing.com implications of the finding. 52 Under Pressure [email protected] Mark Hillen talks to the +44 (0) 1565 752883 42 Seeing the Unseeable Sensimed team about [email protected] Retinal implants can now restore successfully translating a good sight in patients who have been idea into a great product. Distribution: blind for many years, says The Ophthalmologist distributes Eberhart Zrenner. 17,934 printed copies and 7,295 electronic copies to a targeted Sitting Down With European list of industry 45 TheVitreous Proteome professionals. More than 1,000 proteins 58 Rolf Schwind, CEO, ISSN 2051-4093 are present in the vitreous humor. SCHWIND eye-tech-solutions Our infographic provides a GmbH & Co. KG functional classification. QUICK & EASY IOP MEASURING

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*CLINICAL USE OF A NEW POSITION-INDEPENDENT REBOUND TONOMETER ‘Measurements obtained with the RTPRO, either in the upright or in the supine position, show good correlation and agreement with those provided by applanation and dynamic contour tonometry.’ J Glaucoma 2012 Visit us at ESCRS Amsterdam – stand B03 A Fresh Perspective Editorial Focusing on ophthalmologists rather than just on ophthalmology will generate an engaging, accessible and, above all, useful new publication.

elcome to a new and different publication: an ophthalmologist’s magazine, rather than an ophthalmology magazine. The difference is that instead of an impersonal overview of a particular branch of medicine, our focus is on the people who Wbring it alive – you and your 200,000 ophthalmology colleagues around the world. How you apply your knowledge and skill to treat disease, and how you feel about doing it, is our passion. We have four guiding principles for developing content. The first is to tell stories. We want to go below the surface, to delve into the hopes, fears, motivations and aspirations of key figures in the field. We believe that exploring the narrative of ophthalmology from multiple perspectives will help you to gain a deeper appreciation of your subject, a fuller understanding of where it is headed, and a clearer sense of where you want to go. The second is to generate practical, pragmatic articles that are meaningful to your daily working life. This will include opinion and discussion on best practice, comparisons of surgical technique, evaluations of new technology, assessments of novel therapies and more. Our expert authors share their professional experiences that will translate directly to your practice. The third is to deliver comprehensive coverage of professional issues. Look out for articles on such topics as personal and career development, advice on managing a practice – and on managing staff, and analysis of the interface between ophthalmology and other specialties, amongst many other topics. The fourth is engagement. The content that we publish is just the start of a conversation. We want your feedback, your suggestions and your submissions. The resulting network of ideas, debate and personal connections will enhance the field and those in it. Our content is available in the formats that you use; print, PDF, iPad app, and on the web at www.theophthalmologist.com. Going digital gives you a rich array of additional, interactive content. We will judge our success on how well we meet your needs, so please let us know what you like, what you don’t, and what you want to see us cover. It’s your publication.

Richard Gallagher Editorial Director Contributors

Eberhart Zrenner A graduate in electronic engineering as well as in medicine, Eberhart Zrenner’s career has merged his clinical and research interests. He founded the Institute for Ophthalmic Research at the University of Tübingen Center for Ophthalmology, where he runs a special clinic for patients with hereditary retinal degenerations. His research pursuits include retinal physiology and pathophysiology, ophthalmogenetics and retinal implants. In this issue, he writes about the development of a subretinal active microphotodiode array (MPDAs) to replace degenerated photoreceptors in blind people. Read Zrenner’s description of retinal implants on page 42.

Mark Zacharria An American in Paris, Mark Zacharria is a writer and marketing specialist in the area of applied optics-photonics technologies. After several years building a marketing agency that he co-founded, Zacharria joined the executive team at a company bringing an innovative adaptive optics device to market. “In the not-so-far-off future, such retinal vascular imaging will be used routinely in diagnosing and monitoring systemic diseases,” he says. Thanks to a cochlear implant, Mark was able to overcome his sudden hearing loss; he now volunteers his time to help other professionals do the same. Read his feature on the unfolding role of ophthalmology on page 16.

Arthur Cummings “I started my career in South Africa as a retinal surgeon, and developed a special interest in the anterior segment,” says Arthur Cummings. Today based in Dublin, Cummings is an internationally renowned expert on customized laser treatments having performed upwards of 15,000 LASIK procedures and 4,000 and other intraocular lens procedures. His research interests include refractive surgery, cataract surgery and corneal surgery for keratoconus. On page 26, he writes about stabilizing corneal structure using UV-A-activated riboflavin.

Jeff Machat and Sondra Black Within months of graduating in 1990, Jeff Machat dedicated his practice completely to laser vision correction technology and techniques; a year later he was among the first to perform laser vision correction in North America. Sondra Black practiced optometry for 20 years in a private practice until March 2000, when she became clinical director for a custom LASIK center working on clinical trials, among other activities. Today, they work together at Crystal Clear Vision, which Machat founded and for which he serves as Chief Medical Director; Black is VP and Director of Clinical Operations. They have helped evaluate multiple approaches to presbyopia for the correction of reading vision, including multifocal ablations, scleral implants and corneal inlays. Read their recipe for a successful presbyopia practice on page 48. Transforming Lives Through Better Vision

As the global leader in eye care, Alcon is committed to enhancing the quality of life by helping people see better. We o er the widest spectrum of surgical, pharmaceutical and vision care products in the industry. Our 24,000 associates partner with eye care professionals to take on the world’s most pressing eye care needs and deliver innovations that reinvent lives. The future of eye care starts with Alcon.

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© 2013 Novartis

83344 Corporate TO.indd 1 8/30/13 2:52 PM 10 Upfront

for avoiding such problems in Ophthalmology the future. Upfront The issue most frequently raised in Service in UK complaints was “a chronic mismatch between capacity and demand within Reporting on the “Failing”, the service.” There have not been innovations in medicine enough ophthalmologists around to Says Report meet patient demand for a long time and surgery, the – a fact acknowledged by hospitals and research policies and A stark picture of an primary care administrators. But the personalities that shape overstretched, fragile College criticizes previous reactions service, often at odds with to the shortages, noting that they ophthalmology practice. hospital management, is are “…often reactive and sporadic painted in a recent RCO rather than forward-looking and We welcome suggestions report. What can be done? concerted.” It also bemoans “simplistic on anything that’s solutions [that are] frequently offered,” By Mark Hillen among them, the suggestion that impactful on practicing ophthalmologists “just ophthalmology; When the UK’s Royal College of need to discharge more patients to please e-mail Ophthalmologists (RCO) the community.” Furthermore, the receives a complaint about report implies a growing disquiet: [email protected] an ophthalmology practice, “under these circumstances, clinicians, they investigate. Now the managers and commissioners may College has distilled what it start to blame each other for being has learned from a decade’s inefficient or inflexible or failing to worth of investigations understand the true situation.” into a particularly The report’s authors acknowledge candid document (1) that “some ophthalmology services that also provides are at an inherent disadvantage when recommendations compared with others, for reasons of difficult geography, crumbling estate or a legacy of poor organizational planning,” but are realistic about the extent of what needs to be done to improve matters: “There may not be quick or easy solutions to all of these problems.” The College offers recommendations of its own for remedying the problems. They note that, since both geographic and demographic factors influence needs for ophthalmology clinics, a full understanding of both factors is necessary for planning service provision. Also, the sooner a struggling practice realizes that it is struggling the better; to this end, the College has produced a self-assessment questionnaire as an early-warning system. Upfront 11

The biggest headache is understaffing: of ophthalmologists’ time. However, the If you work in the NHS, do you feel “sustainability of an ophthalmology greatest emphasis is on training, which that the RCO report presents a fair and service depends on having both the right is often the first thing to be neglected accurate picture? How is your day-to- numbers of health care professionals and by a practice in crisis. “The training and day workload? How could your working the right mix of skills to meet the needs supervision of ophthalmologists,” the conditions be improved? of the population”. Currently, according report concludes, “requires dedicated to the authors, the departure of a single time which must be factored into Have your say at: www. staff member can throw a practice “into workforce planning.” theophthalmologist.com/issues/0113/201 crisis”; succession planning also needs to be improved. The report also champions Reference the delegation of roles and tasks previously 1. Our ophthalmology service is “failing”, please undertaken by ophthalmologists to help! http://www.rcophth.ac.uk/core/core_ support staff, making more efficient use picker/download.asp?id=1798 a b

“Patients and carers are able to use Glaucoma, the app to understand how glaucoma can damage their vision by showing From the the impact of progressive field loss on the camera view of the device,” explains Patient’s Moorfields’ Nick Strouthidis. “Much of the initial feedback, however, has Perspective been from clinicians who have been finding the tool useful as an intuitive, Free glaucoma simulation app interactive prop during consultations to reinforces the importance of help explain the condition and the need taking medication for treatment.” The app doesn’t stop at glaucoma By Sophia Ktori simulation. An educational section Figure 1. The Glaucoma SIM app. (a) offers medical images of basic anatomy Patients can increase the severity of glaucoma A recently-launched free app for and physiology of the eye, and experienced, by moving the Glaucoma iPhones and iPads will help newly further sections explain how elevated Progression slider from left to right. (b) An diagnosed glaucoma patients better intraocular pressure – and therefore educational section details the anatomical and understand how the condition will glaucoma – develops. A supporting physiological changes to the eye that underlie affect their vision as it worsens, website (www.glaucomasim.co.uk) the development of glaucoma. reinforcing the importance of taking provides additional information, such prescribed eye drops and attending as what a patient might expect when simulation app is an opportunity to tap eye clinic. The Glaucoma SIM app visiting an ophthalmologist for the first into this new platform.” (see Figure. 1) uses the device’s time following a referral. Strouthidis The developers hope that, as well camera and video to simulate the sees the app as part of a wider trend as providing an educational tool effects of glaucoma on visual field for using mobile app technology for patients, carers, and the general over time. It was developed by MSD as a medium for education and population in the UK, Glaucoma SIM Pharmaceuticals in collaboration communication. “Despite the fact that may have utility much further afield. with the International Glaucoma glaucoma is a disease of ageing, many “There has been quite a bit of interest in Association and ophthalmologists at of our patients own mobile phones or launching the app in other countries,” Moorfields Eye Hospital in London. tablets,” he points out. “The glaucoma notes Strouthidis. 12 Upfront

Big Pharma billion acquisition of Bausch & Lomb, one of the world’s largest Loves Ophtho suppliers of eye health products, earlier this year. ophthalmology is frequently cited as Why the pharmaceutical • Bayer HealthCare and Regeneron’s a lucrative and growing market. And industry is making entry into the ophthalmology market many pharmaceutical companies, acquisitions in ophthalmology last year with aflibercept. Approved suffering from dwindling pipelines and – and why it won’t stop in the EU to treat wet AMD, blockbuster drugs going off-patent, are aflibercept is also under anxious to buy into a winning trend. By Mark Hillen consideration for treatment of According to Jean-Marc Wismer, visual impairment due to macular CEO of Sensimed (see page 52) and The world’s pharmaceutical companies edema secondary to central-retinal- veteran of the Swiss ophthalmology have fallen heavily for the charms of vein occlusion; in the US, the FDA biotech scene, “Ophthalmology is an ophthalmology in recent times, with has approved both indications. attractive space for both Big Pharma. a string of acquisitions and product • Shire’s procurement of SARcode It is a growing market, margins are launches, including: Bioscience in May for $160 million, good, and new drugs and technologies driven in part by the appeal of the – both devices and instruments – are • Abbott’s recent US$400 million dry therapy, the T-cell going to transform the way the disease purchase of OptiMedica, four years antagonist Lifetegrast. is diagnosed and managed. Companies after the purchase of Advanced that make the right strategic acquisitions (now Abbott) Medical Optics. Why? Pipelines and profits. In press that connect all of the dots are likely to • Valeant Pharmaceuticals’ US$8.7 releases announcing acquisitions, be very successful.”

is an independent risk factor for stroke with mild, or moderate-to-severe Retinal Images in patients with – even , respectively. in those whose blood pressure is well Even patients with well-controlled Predict Future controlled with antihypertensive drugs. blood pressure had 96 percent increased The researchers studied 2,907 patients risk of cerebral infarction – which rose to Stroke Risk with hypertension without a history of a 198 percent increase in patients with stroke for a mean follow-up period of 13 severe hypertensive retinopathy. The level of hypertensive years. Patients had retinal photographs “These findings suggest that a retinal retinopathy is an independent taken at the beginning of the study, and examination may be valuable for the long-term risk factor the level of hypertensive retinopathy assessment of stroke risk in patients was assessed as either none, mild or with hypertension,” the team concludes. By Sophia Ktori moderate/severe. Individuals with a It’s also “a non invasive and cheap history of either coronary heart disease or way of examining the blood vessels of A recent study has demonstrated that were excluded from the study, as the ,” Ikram adds although, he retinal photographs can reveal the future hypertensive and diabetic retinopathies cautions, additional studies are needed stroke risk of hypertensive patients – can be difficult to distinguish. to validate the utility of the approach up to a decade in advance of the event. During the follow-up period, for assessing stroke risk in a routine Reporting in the American Heart ischaemic stroke occurred in 146 clinical setting. Association’s journal Hypertension, patients and haemorrhagic stroke in a team led by Mohammad Kamran fifteen. After adjusting for known stroke Reference Ikram at the National University of risk factors, and compared with patients 1. YT Ong et al., “Hypertensive Retinopathy Singapore’s Eye Research Institute, has without retinopathy, stroke risk was 35 and Risk of Stroke,” Hypertension, doi: 10.1161/ shown that hypertensive retinopathy and 137 percent higher among patients HYPERTENSIONAHA.113.01414 The Power of Colour ToPograPhy

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Upfront 15

corneal epithelial cells. This is not, in regulation of tear viscosity, binding Eyeball Licking: as is often proposed, attributable to and release of lipids, endonuclease amylase action; rather, it is due to the inactivation of viral DNA, binding of What If… hypotonicity of the saliva (isotonic saliva microbial siderophores. It also has anti- is not toxic). But the data comes from inflammatory activity. Introducing In the event of an oculolinctus prolonged exposure of cultured corneal other mucosal fluids, that contain no or craze, we are ready (thanks to epithelial cells. In intact eyes, blinking little TLC, may alter its concentration The Daily Mail and others) renders the interaction with undiluted sufficient to impede its role. saliva brief, and unlikely to be damaging. Further concerns? Debris in the By Grace Willatt Saliva microflora differ between saliva or extensive licking could scratch individuals, reflecting diet and hygiene. the cornea. Indeed, David Granet of the This summer, Western media leapt It could be speculated that oculolinctus Shiley Eye Center in San Diego, CA, upon a post on Japanese curation site presents a high load of bacteria or viruses told The Huffington Post that “There Naver Matome which detailed a sudden to the eye and, especially if it is introduced are ridges on the tongue that can cause a increase in the practice of oculolinctus. from a diseased mouth or other body part, corneal abrasion. And if a person hasn’t Oculolinctus, or “worming”, is the niche could lead to or . washed out their mouth, they might put activity of eyeball-licking. The story has The antimicrobial defence of the tear acid from citrus products or spices into since been exposed as a hoax, deliciously film is adept at dealing with the usual the eye.” playing on the love of certain sections of introduction of microorganisms: a little Forewarned is forearmed. If ever the media for bizarre news. saliva seems not to pose a threat, as there is an “EYEBALL LICKING However, the exposure given to the evidenced by the number of people that craze that’s sweeping Japan and causing topic makes an outbreak of oculolinctus, habitually lick their contact lenses to a surge in eye infections” (1), we now considered by some to be a sexual fetish, no ill effect. But extended exposure via know what to expect. more likely. How damaging could the oculolinctus does, theoretically, raise one practice be to the eye? issue. Tear lipocalin (TLC) is a major Reference Undiluted, sterile saliva is toxic to component of the tear film and is involved 1. The Daily Mail, June 13, 2013. The global obesity pandemic is causing a chronic cardiovascular and diabetic disease crisis. Advances in retinal microvascular imaging offer hope in tackling these problems… but are ophthalmologists ready for a prominent role in the fight against systemic disease?

By Mark Zacharria 17 At a Glance Feature • Chronic systemic disease is increasing alarmingly, driven by skyrocketing obesity rates • What is visible in the eye can predict vascular damage elsewhere • Adaptive optics technology will soon be applicable to clinical practice, advancing retinal microvasculature imaging • Thiswill expand ophthalmologists’ front-line involvement in diabetes or cardiovascular disease

hronic systemic diseases directly related to obesity, like heart disease, stroke and diabetes, already account for six out of every 10 deaths – and soak up a substantial proportion of all healthcare spending. Despite one major risk factor for cardiovascular disease – tobacco use – being curbed, the number diagnoses of diabetes and hypertension continues to rise

inexorably. Skyrocketing rates of obesity, which the American Rate of obesity Medical Association recently classified as a disease, mean that one ill has simply been replaced by another. It is possible that ophthalmologists will play a leading role Year in the battle against chronic disease. Indeed, it could be argued that they already do. Eye specialists diagnose half of all type II Figure 1. Obesity Rates. Analysis of past and projected future trends diabetes cases, and cardiologists commonly refer many of their in selected member countries of the Organisation for Economic Co- high-risk patients for fundus imaging. Yet, despite being widely operation and Development (2009 data). commended for their role in saving vision, ophthalmologists’ contribution to the diagnosis and management of life- Systemic disease and the eye threatening systemic diseases is often underplayed. That may be Type II diabetes can go unnoticed for many years before clinical about to change. The literature is full of descriptions (1) of how signs like lethargy, polydipsia and polyuria manifest themselves. valuable current clinical imaging techniques are for generating Ocular symptoms of type II diabetes can often present first, information on the retinal vasculature. Fundus photography, meaning that patients are frequently initially diagnosed by an scanning laser (SLO) and optical coherence ophthalmologist. Presentation typically manifests as a loss in tomography (OCT) are all commonly used in the diagnostic visual function due to proliferative diabetic retinopathy (PDR) chain, as well as in the monitoring of retinal and systemic but even when the disease is diagnosed in its earliest stages, manifestations of these chronic diseases. almost all patients show signs of non-proliferative DR (NPDR). The utility of these techniques could be significantly increased if Although most cases of arterial hypertension are diagnosed they were able to resolve the retina’s smallest vessels that are first during routine physical examinations, it is far from unheard of for affected by disease. Although fundus photography and SLO can it to be diagnosed by an ophthalmologist. Like diabetes, this occurs reveal signs of microaneurysms in diabetes, SLO’s resolution is when the patient has already suffered acute loss in visual function. often insufficient to clearly distinguish them from other anatomical Hypertensive retinopathy (HR) is the second most common features present in healthy eyes. In arterial hypertension, these same retinal vascular disease after diabetic retinopathy, and co-diagnoses techniques can reveal arteriolar narrowing and arterio-venous of chronic hypertension with type II diabetes is common. nicking – potential precursors to retinal vascular occlusion – but There is no shortage of public awareness campaigns that target the same resolution limitations restrict what can be imaged to obesity, the leading underlying cause of the aforementioned structures that might be considered macroscopic in relation to the diseases. Despite this, the rise in the numbers of patients retina’s overall size. With chronic cardiovascular disease, observing becoming overweight and obese remains unchecked (see damage to the retina’s microvasculature will almost always mean Figure 1). Strict adherence to dietary, exercise and pharmaceutical that there is vascular damage elsewhere. In the case of hypertension, regimens is absolutely necessary to mitigate the effects of obesity retinal microvascular damage can predict similar vascular damage on its associated chronic diseases, yet many patients are unwilling in the brain, and in diabetes it may be a precursor to vascular damage to do this, with dire consequences. Hypertension is the leading in peripheral limbs. Because of this association, leading clinical cause of death in the developed world, and diabetes is in the top researchers are actively pursuing ophthalmic imaging to diagnose five. Furthermore, diabetes is the leading cause of new blindness and manage these diseases, as they discuss later in this article. in people aged under 50 years. The impact of blindness on quality 18 Feature

recently spoken to have voiced their skepticism about the value $250 $245 billion of visualizing individual cone photoreceptors. This is because

$200 foveal cones cannot be consistently imaged nor quantitatively analyzed in a reliable manner, and as the fovea is the primary $150 region of interest for many ophthalmologists, their hesitation $109 billion is understandable. Nevertheless, AO-enabled research devices $100 have developed a solid track record within ophthalmology in

$50 $35 billion terms of tracking the progression of multiple diseases that are Cost of disease (US$ billions) associated with cone loss. Compared with current clinical 2004 PRA data 2011 CDC data 2012 ADA data $0 imaging techniques, AO can track a lesion Eye Cardiovascular Diabetes Disease over weeks, rather than over months, and AO can quantify cone depletion in pigmentosa and . Figure 2. Approximate costs of chronic diseases in the US. However, while being able to quantify cone numbers in cone- loss diseases using AO is an achievement, there is no effective of life and productivity – for patients and their friends and treatment for these diseases. Consequently, the market for AO families – is severe. The economic impact is equally substantial; instruments – for this application – has been limited. for example, the total cost of obesity each year to US companies Over the past several months, a number of publications and has been estimated at $13 billion. presentations (3–6) have focused on AO’s potential in non- Patients with diabetes or arterial hypertension are encouraged invasive, high-resolution microvascular en face retinal imaging. to undergo comprehensive dilated ophthalmic examinations, Two experts, Marco Lombardo and Richard Rosen, offer their the frequency of which depends on the severity of the disease. opinions on the following pages, describing their experiences to Putting new tools in the hands of ophthalmologists that will date and their views on how AO will impact the diagnosis and enable them to visualize retinal microstructural details will go a monitoring of systemic diseases. long way in helping doctors to save vision… and lives. The groups of Lombardo and Rosen are just two of a number of groups worldwide investigating AO applications in The adaptive optics era ophthalmology. Michel Paques, of the Quinze-Vingts National First used in astronomical telescopes to great effect, adaptive Ophthalmic Center in Paris also has extensive experience in optics (AO) technology awed the ophthalmic world in 1997 when vascular imaging with AO. His group recently demonstrated Junzhong Liang, Donald Miller, and colleagues published the first that AO retinal artery imaging is not only feasible, it can produce in vivo images of human cone photoreceptor cells. AO works by consistent and reproducible results – in particular, to measure measuring the effects of wavefront distortions – and compensating the thickness of the walls of arteries, an important parameter for them with a deformable mirror. In (astronomical) telescopes, for patients with arterial hypertension. Already, Paques’ group this acts to remove the distorting effects of the atmosphere, has shown that parietal thickness increases linearly with blood increasing image resolution. With eyes, the wavefront distortions pressure, and is currently evaluating longitudinal thickness changes are caused by ocular aberrations in the many structures of the in patients treated for hypertension. This will be of significant eye between the retina and the lipid layer of the tear film. Once utility to ophthalmologists, cardiologists and neurologists in corrected by AO, resolution is greatly improved (2). terms of tracking and mapping vascular disease progression, and In 1997, AO technology had a very long way to go before it will permit timely interventions that might prevent some of the could become accessible for widespread clinical research and worst consequences of cardiovascular disease – stroke, systemic mainstream clinical applications. Prohibitive cost, instrument embolism or myocardial infarction – from occurring. size and the complexity of operation were key factors that The knowledge that AO imaging in systemic vascular diseases needed to be overcome. Recent developments have significantly is a viable and reproducible technique means that automated reduced these barriers, but still, some ophthalmologists I have diagnostic software for longitudinal observation can be developed, Feature 19

which will be of utility to ophthalmologists and cardiologists alike Already, ophthalmologists can, when needed, use anti- for the tracking and mapping of vascular disease progression. VEGF and photodynamic therapies to treat certain retinal Another prominent researcher, Stephen A. Burns at the manifestations of systemic diseases. In contrast, what cardiologists, University of Indiana, has published extensively on experiences endocrinologists, and general practitioners can provide for patients with AOSLO. Establishing the biomarkers that will enable with chronic disease is surprisingly limited, mostly to prophylaxis. ophthalmologists to differentiate between healthy and Ischemic strokes – particularly in patients with atrial fibrillation pathologically-affected eyes is essential for the technology to – can be prevented with oral anticoagulant therapy, which find its way into everyday clinical practice. Burns’ group has (despite the introduction of newer drugs that inhibit thrombin or generated data on the measurement and analysis of retinal Factor Xa) for most patients means taking a rat poison, warfarin. blood flow velocity for this purpose. Much like Rosen’s Cholesterol- and clot-filled cardiac arteries can have their filling AOSLO FA method, the combination of anatomical and – and eventual occlusion – slowed with statins and antiplatelet functional (that is, physiological) imaging will greatly enhance drugs, typically aspirin and clopidogrel. But these interventions the ability of eye specialists to diagnose diseases and to assess only occur when patients are quite a way down the slippery slope the efficacy of therapeutic interventions. of cardiovascular disease and diabetes is at an advanced stage. Diabetes drugs are moderately effective at controlling blood Where is it leading? glucose levels, but many cause weight gain, and all have non-trivial The fact that AO imaging technology has been adopted by many event rates of particularly non-trivial side effects. Prevention is far, prominent research groups for vascular imaging in systemic far better than the alternative; there are no cures. disease may provide the proverbial “killer app” that Rosen The implications are clear. Given that the first presentation of mentioned. It comes down to basic economics. many systemic, vascular diseases is in the eye, ophthalmologists, The total cost of the top four major vision disorders (age- using emerging imaging techniques like AO, offer a real chance related macular degeneration (AMD), diabetic retinopathy, of early intervention. They truly are at the front line of the battle, cataract and glaucoma) in 2004 in the United States has been and have the ability – given a receptive patient – to not only save estimated by Prevent Blindness America to be $35.4 billion. That vision, but to save lives. same report states that the numbers of patients with cataract and glaucoma far outweigh the numbers in the other two groups. References Meanwhile, according to a paper published by the US Centers 1. R. Hazin, F. Lum, Y. J. Daoud, “Ophthalmic features of systemic diseases”, Ann. for Disease Control (CDC) in 2011, cardiovascular disease costs Med., 44 (3), 242-252 (2012). the US economy an estimated $108.9 billion annually. And the 2. A. Dubra and Y. Sulai,“Reflective afocal broadband adaptive optics scanning economic consequences of diabetes are more frightening still. ophthalmoscope”, Biomed. Opt. Express., 2 (6), 1757-1768 (2011). In 2012, the American Diabetes Association estimated that 3. D. Rosenbaum et al., “Imagerie des artérioles rétiniennes par optique adaptative, diabetes cost the US economy $245 billion (see Figure 2). faisabilité et reproductibilité”,. Ann. Cardiol. Angeiol. (Paris), 62 (3), 184-188 (2013). If an ophthalmologist can spot type II diabetes in the early 4. S. A. Burns, “Adaptive Optics Imaging for Studying Retinal Vasculature in stages – where it can be reversed through treatment and lifestyle Health and Disease”, Conference Paper, CLEO: Applications and Technology interventions – the benefits to the patient and to society are San Jose, California USA (2013). potentially massive. Undetected, and left to develop, diabetes 5. J Tam et al., “Subclinical Capillary Changes in Non-Proliferative Diabetic management requires expensive long-term therapy. Advancing Retinopathy”, Optometry Vision Sci., 89, E692-E703 (2012). visual and vascular problems result, ultimately, in patients who 6. J. K. Sun et al., “Photoreceptor Mosaic Changes in Diabetic Eye Disease are highly visually impaired and immobile (some of whom will Assessed by Adaptive Optics Scanning Laser Ophthalmoscopy (AOSLO)”, undergo limb amputation) that require an immense amount of Invest. Ophthalmol. Vis. Sci., 53, ARVO E-Abstract 4647 (2012). medical care and familial support. It’s a similar situation for patients 7. M. Lombardo et al., “Analysis of retinal capillaries following myocardial infarction or stroke; both groups suffer from in patients with type 1 diabetes and nonproliferative diabetic retinopathy using substantial morbidity and their care requirements are considerable. adaptive optics imaging”, Retina, 33 (8), 1630-1639 (2013). 20 Feature

a b c d

Figure 3. (a) Imagine Eyes’ rtx1 Adaptive Optics Retinal Camera. Panel (b) shows a wide field fundus image from the right eye of a patient with a diagnosis of type 1 diabetes 11 years before and no clinical signs of DR. The white box indicates the area of the retina shown in panels (c) and (d). (c) Adaptive optics retinal imaging allows for a more detailed – and non-invasive – visualization of the capillary network. High-resolution images of the photoreceptor layer (d) can be acquired at exactly the same location of the overlying structures of the inner retina with AO ophthalmoscopy. (c) and (d) Scale bars represent 100 µm.

Adaptive optics imaging in Did AO reveal information that the other techniques non-prolific diabetic retinopathy did not? Retinal capillaries were not resolved by SLO or CFR in A conversation with Marco Lombardo any eye. In AO images, the retinal capillaries appeared as faint vessel segments intersecting each other and forming a Can use describe your study? network of arterioles and venules both in NPDR and control We recruited eight patients with a diagnosis of type 1 eyes (see Figure 3b-d). The average lumen of retinal capillaries diabetes and NPDR with no . Eight age- was statistically significantly narrower in NPDR eyes (6.27 matched healthy subjects were recruited as controls. Patients ± 1.63 µm) than controls (7.31 ± 1.59 µm; (7)). On average, and controls were submitted both to AO retinal imaging the retinal capillary lumen was 15 percent narrower in NPDR and conventional imaging using SLO and color fundus than in control eyes. Microaneurysms could equally be retinography (CFR). Using AO, the focal plane was adjusted noninvasively observed in NPDR cases. to acquire images of the retinal capillaries of the inner nuclear layer in order to maximize the sharpness of vascular images. How might this information be used in diabetes care? The capillary network of the inner nuclear layer was imaged The detection of pre-clinical abnormalities of retinal 210-230 µm anteriorly to the photoreceptor layer. We used microcirculation may represent the real advantage of AO a semi-automated procedure to measure the retinal capillary retinal imaging in the management of patients with diabetes. lumen caliber in two regions of interest located close to the The capability to resolve retinal capillaries has been shown for border of the foveal avascular zone (FAZ). all existing AO ophthalmic imaging modalities, namely AO- flood, AO-SLO and AO-OCT. What device did you use? (FA) has been implemented in an AO-SLO, providing We used was an rtx1 AO fundus camera commercialized from further in-depth investigation of the capillary network. Imagine Eyes (see Figure 3a). The device uses IR reflectance to The combined longitudinal assessment of the capillary provide 4° x 4° images at a resolution of 250 lppmm, which literature density, capillary lumen caliber and the FAZ area by AO retinal reports as ±2 µm in transverse resolution that can be acquired at imaging might provide valuable information on DR onset and different depths depending on the structures of interest. progression. AO-SLO and AO-OCT can also characterize the Feature 21

blood flow in retinal capillaries, and a significant reduction in histological section. the capillary blood velocity in patients with diabetes has been While there are certainly challenges to the clinical shown as one of the earliest changes in DR. application of AO retinal imaging, the rapid growth in AO retinal imaging promises early detection of DR the past few years suggests these will soon be overcome. A and monitoring of the progression of the disease with number of multi-disciplinary collaborations between clinical micrometric resolution. Moreover, AO can be used to and non-clinical researchers have been initiated to resolve the evaluate the efficacy of new treatment options at a level that specific needs of clinical AO imaging. was heretofore unavailable. Marco Lombardo is Senior Researcher at the Clinical Trial What needs to be accomplished for AO to become a part of Research Center of the IRCCS Fondazione G.B. Bietti in everyday clinical practice? Rome, Italy. He is responsible for the study protocol on AO Several factors must be resolved, including the development imaging in patients and other projects related to the application of easy-to-use software interfaces, fast image processing of innovative biotechnologies to ophthalmology, including approaches and reliable analysis software. Improvements in nanotechnology and regenerative medicine. These projects are AO-SLO have already enabled it to obtain images of retinal a collaboration with CNR-IPCF, under the supervision of capillaries with incredible resolution – comparable to a Giuseppe Lombardo.

High-resolution AO-SLO fluorescence alone, we are able to simultaneously image fluorescein angiography both the intraluminal space with AO-SLO FA (visible on the 488nm channel; see Figure 4b) and the vessel wall with A conversation with Richard Rosen AO-SLO reflectance (visible on the 790 nm channel). This allows us to delve into the delicate relationship between wall What are the key differences between conventional FA and changes and luminal infiltrates. Differentiating between AO FA? perfused and non-perfused vessels is also possible by AO-SLO FA permits enhanced resolution, allowing comparison of AO-SLO FA images (functional perfusion finely detailed imaging of multiple layers of capillaries, map) and AOSLO reflectance images (structural). microaneurysms, microvascular anomalies, capillary dropout and microleakage. How did you work around any potential glitches? The ability to gain early-phase information and monitor What device do you use? transit time of conventional FA is sacrificed in AO-SLO FA The AO-SLO used in our lab is a replica of the one due to the more time-consuming technique of successive developed by Dubra and Sulai at the Medical College of acquisition of individual small fields of 1.75°, which are then Wisconsin (see Figure 4a), with the visible channel modified tiled together into larger montages offline. To accommodate for fluorescein angiography (FA) imaging (1). During the extended imaging sessions, oral fluorescein was chosen AO-SLO imaging, simultaneous reflectance (790 nm) to provide a more consistent signal for a longer time than and fluorescence (488 nm) image sequences are acquired with an intravenous bolus. This is easier to administer and and registered. improves the safety and comfort of the procedure, when compared with intravenous administration. Does the system have any particular strengths? While conventional FA can identify vessels based on their 22 Feature

a

How will your research improve diagnosis and management Figure 4 (a) AOSLO of vascular disease? system built by the Improved resolution of fine capillary structures along Advanced Ocular Imaging with the ability to look at the photoreceptor mosaic and Program at the Medical nerve fiber layer will lead to a better understanding of the College of Wisconsin and anatomic basis of retinal disease. We hope that, with this installed at the New York advance in resolution to image the microvasculature, we will Eye and Ear Infirmary. (b) discover more accurate explanations for the pathogenesis of AOSLO FA image from vasculopathy and visual malfunction. We hope this will lead NY Eye & Ear acquired at to more targeted approaches to treatment and prevention of ~8° superior on retina from progressive deterioration. b a 48 year old female with The ability to study microvascular disease in vivo will allow NPDR. Scale bar = 50 µm. us to study microscopic changes dynamically over extended periods of time, giving an advantage over conventional FA undergoing various treatment regimens will help us to better and traditional histology. Following these changes in patients understand some of the underlying processes taking place Chairman’s Research Fund theNYEEI of andNIH. Lowenstein Family Foundation, Family Wise Foundation, Family Marrus Foundation,receives fundingfrom Bendheim- Shah, Toco Chui, Gan, Alexander andMoataz Razeen. group The Dubow, thatincludesMichael Pinhas,Alexander Infirmary Nishit Richard ateam Rosenleads attheNew York Eye andEar managingmacular for edema. meter andiscritical app”so-called “killer isasurrogate –theway OCT VEGF monitoring, depends on ofimagingfor which thislevel the implementationalsodemandanapplication, will Clinical conventional FA image as much can as180°inasingletake. 15° radiusaround (1.75°atatime)whereas fovea wide-field limitations ofAO-SLO FA, we are abletovisualize only are sustainable.not commercially to current technical Due expensive, that tolevels ofthesystems theprice drives which minutes. Currently, theAO mirrors are hand-made andvery deliver ananswer thatcan inafew automatic instrument of hardware ofacompact, allowtheconstruction semi- encounters, with clinical congruous and the cost and design improves, thetesttoalength thespeedofstudyshortens AO beready will real-time for once image processing what needstobeaccomplished thattohappen? for practice, AO will clinical ofeveryday When become part and to management. diabetic retinopathy may lead to more rational approaches disease. pathstoprogression Understandingthevarious of may helpusunderstandsimilarprocesses inrenal andcardiac revascularization dropout andpartial accompany capillary whereasthemicrovascular which events studying recovery may helpusto betterunderstandstrokevein occlusions diseases. toxic maculopathies and episodicinflammatory asglaucoma,manifest progressive vascularretinopathies, clinically,dynamics we plantoinvestigate thechangesthat of theretinal tissue. tostudy capillary thisability With laser photocoagulation of and the fine structure response resolution andare intheprocessimpact of ofstudying reperfusion andmicroaneurysm therapy on capillary response tospecifictherapies. clinical within the macroscopic picture of disease progression and Studying vascular remodeling after branch artery and artery branch vascularremodeling after Studying We have already witnessedtheimpact ofanti-VEGF RZ_Anz_CutterMach2_266x100_The Ophthalmologist_E.indd1

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Surgical Procedures Diagnosis New Drugs

26-29 Constructive Cross-Links Treatment of keratoconus and post- LASIK ectasia is being transformed by corneal cross-linking

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And the fourth had a thermal procedure rate of keratoconus progression slowed Constructive – either microwave thermoplasty or even stopped, but some of the corneal (Keraflex) or conductive keratoplasty steepening is actually reversed (see Figures Cross-Links (CK) – followed by CXL, to improve 3 and 4). Patient expectations must be vision and stabilize the keratoconus. The managed to reflect the fact that only Corneal cross-linking (CXL) is only common component of treatment around 70 percent of those who undergo having a transformative impact was CXL. the technique experience improved vision. on the treatment of keratoconus There genuinely is this much disparity The primary use of CXL is in cases and post-LASIK ectasia. in “best practice” across the continent. It’s a where the keratoconus and its associated function of the regulatory climate in which corneal steepening and By Arthur Cummings a device can be used to treat patients once continue to progress despite treatment it has been awarded a CE mark, which with a rigid gas-permeable contact lens Picture this scenario: 25-year old denotes compliance with EU product (RGP-CL). Until January 2011, the quadruplets, each one living in a different legislation. This contrasts with the US, two main recommendations for CXL European country, develop keratoconus where ophthalmologic technology must were in cases where there is evidence of at the same time. Keratoconus is a undergo clinical trials and demonstrate keratoconus progression and where an degenerative condition characterized benefit before receiving approval for a RGP-CL-wearing patient finds that he by conical protrusion of the cornea specific indication (and where CXL is not or she can no longer wear the lens and and irregular astigmatism. The four yet in routine practice since sponsorship faces keratoplasty (either lamellar or siblings each present to their local expert issues led to trials being halted, so FDA full-thickness). These recommendations ophthalmologist who specializes in approval is still awaited). Are the various were modified following the 7th CXL surgical management; all four want their approaches used in Europe equally good Meeting held in Milan, Italy in January vision improved rather than just stabilized. – a version of “the lottery where everyone 2011, where it was recognized that Six months after treatment is wins” seen on The Simpsons television the chances of keratoconus disease completed, all four quadruplets are show – or is there truly a best option? It’s progression is high; it was agreed satisfied that their vision has improved, not an easy question to answer. Ideally, that patients with keratoconus aged and the keratoconus has been stabilized in my view, new devices would undergo 27 years or younger should undergo CXL in all cases. Yet the four identical cases randomized, controlled clinical trials in following diagnosis, rather than waiting were managed quite differently. The first Europe to generate a safety and efficacy for evidence of disease progression. quadruplet was offered topography- evidence base before widespread adoption. CXL is not without its share of guided photorefractive keratectomy with complications. The first step is to remove corneal cross-linking (CXL) to improve Exploring CXL the epithelium; this will cause pain or and stabilize vision. The second received Despite the issues mentioned above, the discomfort, and can take three to five days intracorneal rings followed by CXL utility of CXL, a technique which uses to heal. Complications can occur, including some months later. The third was treated UV-A light and a photosensitizer to infection, delayed healing, scarring with CXL and a phakic intraocular lens strengthen chemical bonds in the cornea, and loss of best corrected visual acuity implant (IOL) to correct the residual is not in doubt (see figures 1 and 2, page (BCVA). These have led to the practice refraction following the CXL procedure. 27). My practice introduced the approach of performing CXL without corneal in January 2007, following EU-approval epithelium removal, using a procedure of the first illumination lamp. Before then, known as “epi-ON” CXL. Epi-ON CXL At a Glance only a small number of European centers is less painful, safer, and results in a more • CXL stabilizes keratoconus, and can performed CXL as part of clinical trial rapid return to vision and work in general. improve it programs for keratoconus and post-laser- However, questions remain regarding the • Optimal combinations of CXL with assisted in situ keratomileusis (LASIK) effectiveness of epi-ON CXL. Studies other treatments are not fully defined ectasia. Today, while CXL might still be have shown it to be less effective than epi- • Development of the technique is ongoing considered a new procedure, there is ample OFF, and it usually provides little or no • Implementation in the US lags published support for its effectiveness. In overall benefit to the patient (1). Newer behind Europe many CXL-treated eyes, not only is the approaches to epi-ON CXL are currently CXL Theory and Practice CXL involves a single application of a photosensitizer – riboflavin (vitamin

B2) – to the eye, followed by 30 minutes of UV-A light (see Figures 1 and 2) to activate the riboflavin. Activated riboflavin causes new bonds to form across adjacent collagen strands in the stromal layer of the cornea; this cross-linking helps to recover and improve the mechanical strength of the cornea, stabilizing and potentially improving keratoconus. Figure 1. Patient undergoing the corneal cross-linking procedure with the IROC UV-X 2000. being studied, including iontophoresis (also known as electromotive drug administration) and other technologies to UV-A Light increase the amount of riboflavin (the key Activated Oxidative Collagen substrate in CXL reaction) in the corneal Ribo avin ribo avin Cross-linking tissue. Initial data looks promising, but longer term follow-up is required. An expert group, under the chairmanship of Jerome Vryghem, will meet in October 2013 prior to the ESCRS conference in Amsterdam to discuss the Figure 2. Main principles of photo-oxidative corneal cross-linking. Ultraviolet-A (UV-A) light best means of determining the success and activates riboflavin applied to the cornea; activated riboflavin causes oxidative cross-linking of corneal failure of different CXL procedures. These collagen, stabilizing the corneal structure. are fundamental issues that still need to be addressed. Most ophthalmologists use US-based study sites for the treatment of thickness in the periphery. A ten minute the decreases in average and maximum keratoconus. More than 100 studies have treatment exposes the central cornea to keratometric values (K-max, see Figure already been published addressing the the same total energy that the Dresden 3) as parameters to follow pre- and post- safety and efficacy of CXL for keratoconus protocol provides in 30 minutes. This operatively as a measure of the success and post-LASIK ectasia. Most employ the study has concluded enrolment. Follow- or failure of CXL. Alas, in reality these initial Dresden protocol, that is, epithelial up data at one-year is not yet available but parameters may not be specific or robust removal, riboflavin loading for 25–30 at the moment it appears that the AXL enough to accurately reflect the efficacy of minutes, followed by 3 mW ultraviolet-A protocol causes more corneal flattening the procedure. It has been suggested by A. (UV-A) light for 30 minutes (2, 3). than the 3 mW lamp, albeit potentially John Kanellopoulos that surface variation Some studies have employed higher- with increased corneal inflammation. and height decentration indices (ISV and intensity illumination for shorter periods Studies performed at University IHD) are parameters that correlate more (4) including one, dubbed AXL – the College Dublin’s Applied Optics closely with the patient’s subjective reports accelerated CXL study – at my own Department demonstrated that a beam on their vision. institute. This uses the IROC UV-X 2000, intensity of >30 mW had limited CXL Currently, the American-European which has an optimized beam profile that effect on porcine corneas imaged with College of Ophthalmic Surgery (ACOS) compensates for the peripheral part of the second-harmonic imaging; 3 mW and and Avedro are performing a CXL safety cornea where efficacy is typically lost due 10 mW treatments appeared to have and efficacy study involving up to 100 to corneal curvature and increased corneal similar effects (5). Speaking to fellow  28 In Practice

Keratometric Readings (D) Keratometric Readings (D)

62 62 62 62 62 62 60 60 58 58 58 58 58 58 55.45 56 56 54 53.63 53.87 54 54 52.92 53.21 54 54 54 53.25 52.93 54 52.28 52 52 50.12 49.64 50 50 48.54 50 50 50 50 48.24 47.86 47.98 47.5 47.46 47.51 48 47.14 48 45.61 46 46 46 46 46 44.58 46 44.68 44.4 44.27 43.94 44.13 43.89 43.43 43.6 44 44 41.79 42 42 42 42 42 42 40 40 38 38 38 38 38 38 a Preop 1 3 6 12 24 b Preop 1 3 6 12 24 K-Steep K-Max K-Flat K-Steep K-Max Visits (Months) Visits (Months)

Figure 3. Corneal curvatures after corneal cross-linking (A) and accelerated corneal cross-linking (B). The orange line represents K-Max while the green and blue lines represent the central 3 mm steep and flat Ks respectively. ophthalmologists who have access to does occur. A quarter of my patients shape changes, but in the absence of different CXL systems, there appears receive SimLC. They have the qualifying any CXL the corneal shape regresses to be some agreement that the ideal factors: enough corneal tissue (>470 µm), to pre-operative levels within about illumination time is probably around the reduced BCVA (normally worse than three months. CXL applied shortly 10 to 15 minutes when using a lamp that 6/10) and a specific desire to want to after the patient undergoes the thermal can deliver the same total energy as the improve their quality of vision. procedure greatly enhances the longevity Dresden protocol. Intracorneal rings are also well of the thermal procedure’s effect (7). A represented in the literature, and presentation at the AAO in October Combination treatments their use will often improve corneal 2012 showed that the timing of CXL Returning to our quadruplets, one of the astigmatism as well as improve myopic relative to the thermal procedure was procedures used, topography-guided refraction. To be suitable for intracorneal important (8). Simultaneous CXL PRK, has over nine years of follow-up data rings, the corneas need to be sufficiently failed to add stability to the outcomes, (6). I have six years of follow-up using a thick at the zone where the channel is to but CXL carried out at six hours or later variant of this treatment, called “SimLC” – be created – either mechanically or using did. The most successful cases already simultaneous laser CXL – that specifically the femtosecond laser. have two-year follow-up and are still only treats the topography component Implantable collamer lenses (ICLs) – demonstrating beneficial effects of the on the laser ablation (PRK) with no whether toric or non-toric – have also been thermal procedure. refractive component. Other procedures, widely used to correct the refractive errors If you encounter four surgeons, such as the Athens protocol, treat some of that exist after CXL has stabilized the who each provide just one of the the refraction depending on the ablation cornea. The IOL can be placed as soon as procedures above, they will typically depth and the existing corneal thickness. the corneal shape changes have stabilized, be passionate about their protocol and With SimLC we never ablate to a depth often around six to 12 months post- defend it strongly. Those surgeons who greater than 50 µm and therefore do not treatment. It is also possible to carry out provide two, three or even all four of the address any refractive errors. CXL of the cornea when the eye already procedures will use a decision tree to Topography-guided PRK always has a phakic IOL in situ. determine which is the most suitable for flattens the cone and steepens the The thermal procedures have the the patient. Nevertheless, a consensus will superior flat cornea through the use advantage that, unlike the PRK only be reached once formal clinical trials of hemi-hyperopic treatment at the procedure, they do not remove tissue nor, have been conducted, and the outcomes superior far periphery of the cornea. unlike the intrastromal ring procedures, analyzed. Until then, surgeons will On average, SimLC flattens K-Max by do they implant material into the perform the procedures that they believe 5.9 D, whereas, in our experience, regular cornea. However, they are unstable when in and will continue to think that they CXL flattens K-Max by 2.1 D in the 70 used alone – the thermal procedures have provided their patients with the best percent of cases where some flattening certainly bring about positive corneal possible outcomes. In Practice 29

A B Arthur Cummings is a Consultant Ophthalmologist at the Wellington Eye Clinic and UPMC Beacon Hospital, Dublin, Ireland.

Videos

To see videos that describe the indications for CXL and Keraflex, please visit The Ophthalmologist website: top.txr.to/0113-4011

References 1. G. Wollensak, E. Iomdina, “Biomechanical and histological changes after corneal cross-linking Figure 4. Pre-operative Pentacam image (A) and 1 year post-corneal cross-linking image with and without epithelial debridement”, J. (B). The central Ks have flattened from 54.1 to 52.2 D and the steepest Ks from 57.8 to 55.8 D. Cataract. Refract. Surg., 35, 540-546 (2009). 2. G. Wollensak, E. Spoerl and T. Seiler, “Riboflavin/ LASIK Xtra If CXL is applied in an abbreviated flash ultraviolet-A-induced collagen crosslinking for A CXL technique that is starting to make form at the end of the LASIK procedure, the treatment of keratoconus”, Am. J. Ophthalmol., inroads into clinical practice is LASIK the patient can leave the operating room 135, 620-627 (2003) Xtra. This technique involves a short burst with improved vision and a cornea that 3. E. Spoerl et al., “Safety Of UVA riboflavin cross- of CXL – termed “flash CXL” – that is is potentially no weaker than it was prior linking of the cornea”, Cornea. 26, 385-389 (2007). applied to the LASIK bed after the laser to surgery. Further studies are required to 4. S. Schumacher, L. Oeftiger and M. Mrochen, ablation has been completed and the determine efficacy, safety, techniques and “Equivalence of Biomechanical changes Induced anterior stroma has been soaked with dosages to ensure optimal treatment, but by rapid and standard corneal cross-linking, riboflavin for a shorter than usual period: this does appear to be fulfilling much of its using riboflavin and ultraviolet radiation”, Invest. the normal soak time is around 20 minutes, initial promise. Ophthalmol Vis. Sci., 52, 9048–9052 (2011). but with LASIK Xtra this is only one 5. A.B. Cummings and R. McQuaid , “Accelerated to two minutes. The illumination phase Conclusion CXL versus Standard CXL: 2nd Harmonic duration is also greatly reduced – normally CXL is a vital and innovative tool. By Imaging of Porcine Corneas”, CXL to half of what the standard would be with stabilizing progressive keratoconus, it will Congress 2012. that particular lamp. reduce the number of corneal transplants 6. A. J. Kanellopoulos and P. S. Binder, “Collagen LASIK Xtra is used to treat high myopia required. It has been combined with Cross- Linking (CCL) With Sequential when the residual corneal thickness is less other procedures to improve the vision in Topography-Guided PRK: A Temporizing than 300 µm – especially in young women patients with keratoconus, and has made Alternative for Keratoconus to Penetrating who may become pregnant in the future it easier to wear rigid gas-permeable Keratoplasty”, Cornea, 26, 891-895 (2007). (9). Some ophthalmic surgeons have and soft toric contact lenses. Most 7. M. K. Nguyen and R. S. Chuck, “Corneal collagen also adopted LASIK Xtra procedures significantly, it halts progressive corneal cross-linking in the stabilization of PRK, for hyperopia, as it has been shown that steepening for LASIK ectasia cases. LASIK, thermal keratoplasty, and orthokeratology”, it stabilizes the refractive and corneal Further studies of CXL are needed, Curr. Opin. Ophthalmol., 24, 291–295 (2013). topography changes induced by hyperopic particularly to inform guidelines to 8. A. B. Cummings, “Factors Influencing the Stability LASIK. The procedure is particularly help physicians decide where, when, of Keraflex Treatments for Keratoconus”, Optom. appealing from the patient’s perspective, and what procedures are best suited Vis. Sci., 89, E-abstract 125080 (2012). because LASIK is known to weaken the to individual patients. We may soon 9. F. Hafezi et al., “Pregnancy may trigger late onset cornea by 10 to 30 percent (depending view today’s techniques as crude, but of keratectasia after LASIK”, Letter to Editor, J. on the flap thickness and the ablation CXL is a positive (for the most part) Refract. Surg., 28 (4), 242–243 (2012). depth) and applying CXL strengthens contribution to improving the lives of the corneal fibers and increases rigidity. patients with keratoconus.  30 In Practice

received the disturbing diagnosis of welcome development. An Intrepid neovascular (wet) age-related macular Yet for all their value, anti-VEGF degeneration, or AMD. It was a mixed drugs have significant limitations. Assault on blessing. There is no known cure for Research shows that they are wet AMD, but Gathorne-Hardy was most effective when administered AMD fortunate in the sense that he was frequently (1). This translates into diagnosed early enough to prevent regular eye injections, as this is how Stereotactic radiation therapy severe and irreversible vision loss. Left anti-VEGF therapies are delivered; is a new treatment aimed undetected and untreated, wet AMD understandably, many patients do at wet age-related macular can lead to blindness within months, not relish the thought of this. In degeneration. The results of a and more and more elderly people addition, receiving these therapies randomized, sham-controlled are at risk of missing the window for results in considerable inconvenience trial are encouraging. diagnosis and early treatment. to patients and their families, like Wet AMD is the leading cause traveling to distant locations for both By E. Mark Shusterman of blindness in people over 65 in injections and post-treatment follow- the Western world. In the UK, for up. Consequently, many patients In his 17th century stone house in example, it affects approximately drop out of therapy after a year or Norfolk, England, Jonny Gathorne- 260,000 people, and approximately two, and incur the substantial risk of Hardy surrounds himself with tomes 40,000 new cases are diagnosed progressive visual loss. Despite this, of all kinds, especially reference books, each year. Often, early wet AMD it’s not uncommon for medical staff biographies and histories. Some he is asymptomatic. Patients who do to work long hours to accommodate penned himself, and others hold display symptoms may notice sudden the volume of anti-VEGF injections valuable insights that will enrich his loss of central vision, deterioration of that need to be administered; this next work. It is here, often in front of a visual acuity, optical distortions, or will only continue to increase as the gas fire or wood stove, that Gathorne- blind spots. baby boomers age. Additionally, this Hardy will write hundreds of words a represents an enormous cost burden day, polishing his prose well into the Evolving Therapeutic Strategies to healthcare systems that must night. He is a renowned and versatile What must the medical community support an indefinite commitment to author, and many of his children’s do to reach the elderly population with expensive and frequent therapy. books, novels, short stories and plays the urgency and frequency demanded Anti-VEGF injections are the have been published. of wet AMD? Early diagnosis can not current gold standard for treating Several years ago, Jonny noticed only save vision, it can also expand the neovascular AMD, but adjunctive his vision was deteriorating. He treatment options available to those therapies with other drugs or treatment had worn reading glasses, but they whose sight is threatened. modalities are garnering increasing were no longer able to compensate The excitement around anti- interest. Stereotactic radiation therapy for his failing sight. Ultimately he vascular endothelial growth factor is already commercially available (anti-VEGF) drugs is well justified. in Europe, and the pipeline of Medications such as investigational treatments worldwide At a Glance (Lucentis), pegaptanib (Macugen), is burgeoning: pills, eye drops, • Anti-VEGF therapy is the current and (Avastin) have sustained-release delivery systems gold-standard for treatment of completely changed the treatment and stem cell therapies are among the wet AMD paradigm for wet AMD, saving innovations under development. • A plethora of approaches offer promise vision in what previously would As these new approaches emerge, of effective adjunctive therapies have been nearly hopeless situations. they raise important questions for • Stereotactic radiation prevents Aflibercept’s (Eyelea) benefits of less clinical management. Who is best growth of abnormal blood vessels frequent dosing and potential efficacy suited for monotherapy? Which • Single treatment reduces the need for for those who are resistant to other patients can benefit most from on-going anti-VEGF injections anti-VEGF treatments are also a adjunctive therapy? At what point will In Practice 31

it be necessary to identify candidates for additional therapies? How will the best responders for these new therapies be identified? Many patients do well with anti- VEGF injections but the treatment burden and costs are significant. Alternative therapies offer one means to address this critical need. While such treatments may or may not eliminate the need for anti-VEGF injections entirely, they may at least reduce their frequency, lessening the inconvenience to patients and the cost burdens on the health care system. Figure 1. (Top) An Oraya Therapy treatment room featuring the IRay® Radiotherapy System. Stereotactic radiation (Bottom) Mr. Gathorne-Hardy positioned in the IRay System. Radiation has a long history in the treatment of cancer. It is very effective more radiosensitive than senescent of low-voltage X-rays for the in the destruction of rapidly dividing or slowly-dividing cells, so ionizing treatment of AMD-related choroidal tumor and vascular cells. Unlike radiation is used medically for its anti- neovascularization. The Oraya ablative therapies, such as laser angiogenic, anti-inflammatory, and device uses a proprietary narrow, photocoagulation that burn tissue anti-fibrotic effects, which likely play low-energy (100 kVp) X-ray beam and often cause permanent scarring, a role in its impact on wet AMD (2). to treat a small volume of the retina ionizing radiation disrupts cell division Oraya Therapy (see Figure 1), at the macula. The X-ray beam is by affecting DNA repair mechanisms. developed by Oraya Therapeutics, incident onto an integrated beam- Cells undergoing rapid growth are Inc., is the stereotactic delivery stop, so scattered radiation levels are  Just VISMED® !

Preservative-free hyaluronic acid very low, meaning that additional of injections and had substantially shielding is unnecessary. The highly drier compared with controls lubricant eye drops collimated beams, 4 mm in diameter, who did not receive radiation (2). allow precise targeting of the macula Additionally, 25 percent of the Oraya while minimizing dose exposure to Therapy patients needed no further other tissues. The patient total-body injections during the first year of effective dose is comparable to a head follow-up, and the mean visual acuity radiography series, or one-tenth of a of this group was maintained compared head CT scan. The entire procedure with controls, even though significantly takes about 20 minutes and the patient fewer injections were administered. can go home after appropriate post- A well-defined subgroup of patients treatment evaluations are made. that has lesions that fitted within the Gathorne-Hardy was first diagnosed X-ray beam spot, and also exhibited with neovascular AMD in his left significant macular fluid, achieved eye in 2008 and received ongoing a 55 percent reduction in injections ranibizumab injections. Unfortunately, with over a line of vision superiority he gradually lost vision. Then his right compared with the subgroup controls. eye developed the disease in June 2010. This group of patients is estimated to Moderate Severe In part, because the condition in his represent over 60 percent of the wet Dry Eye Dry Eye right eye was identified early, he was AMD patient population. considered to be a prime candidate for This is an exciting time for the treatment with stereotactic radiation, treatment of wet AMD. As more and was enrolled in the INTREPID therapies come onto the market, their Preservative-free clinical trial, a study that evaluated integration into practice patterns and for excellent tolerability Oraya Therapy as an adjunct to anti- interpretation of new research findings VEGF injections that was performed will present challenges. It’s a nice Sterile up to 3 months at King’s College Hospital, London, in problem to have, and patients will reap  after opening August 2010. the benefits. After treatment, Gathorne- for patient safety Hardy’s visual acuity in the right E. Mark Shusterman is the Medical eye significantly improved, with a Director for Oraya Therapeutics. New softer squeezable nine-letter gain, even without any container subsequent injections into the eye or Videos any other treatment. More than two for easier handling years later, he continues to enjoy a 1. orayainc.com/oraya-therapeutics/ seven-letter improvement. With the 2. orayainc.com/about-oraya-therapy/video/ subsequent commercial availability in 3. orayainc.com/patients/resources/ the United Kingdom, Gathorne-Hardy is now keen to see if the Oraya Therapy References can be used on his other eye, which has 1. D. F. Martin et al., “Ranibizumab and been badly affected by wet AMD and bevacizumab for treatment of neovascular requires continued injections. age-related macular degeneration: two-year In the INTREPID study, which results”, Ophthalmology, 119, 1388-1398 (2012). enrolled a wet AMD patient 2. T. L. Jackson et al., “Stereotactic Radiotherapy population previously treated with for Neovascular Age-Related Macular Swiss Quality in Healthcare anti-VEGF for up to three years, the Degeneration: 52-Week Safety and Efficacy Oraya Therapy group experienced a Results of the INTREPID Study,” 32 percent reduction in the number Ophthalmology, 120, 1893-900 (2013).

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TRB.indd 1 05/09/2013 15:40 Often patients use more BAK Off than one BAK-containing eyedrop and, as Russell Is the future of eyedrops Young of the International preservative-free? Glaucoma Association explains: “The allergic response By Mark Hillen to BAK is dose-related. Anyone on two or three medications has Itching. Irritation. Dry eye. In extreme an increased exposure to BAK, cases, keratosis and scarring. Adverse increasing the likelihood of strong events occur in one in 10 patients who irritation or an allergic response” (1). are on long-term therapy with eyedrops This has been mitigated in recent for conditions like glaucoma or uveitis. years by the introduction of combined For many, these side-effects are caused drops. “It has been very useful,” notes by preservatives. Young, “for example, with Cosopt increases the cost. With healthcare you've got timolol and dorzolomide systems around the world under Why do eyedrops have preservatives? in the same bottle, reducing the pressure to cut costs, and with 90 In essence, to stop bacteria growing. patient’s exposure to BAK.” percent of patients tolerating BAK, Patients with chronic eye diseases “giving preservative-free eyedrops tend to be elderly and have poor Can BAK be eliminated altogether? for all patients is difficult to justify,” sight and reduced dexterity; they can Yes, preservative-free preparations states Young. On the other hand, those have difficulties using (and reusing) of some of the most commonly-used patients who have poor outcomes eyedrops in a way that minimizes glaucoma medications (including increase the cost to the healthcare the chance of bacterial transfer. And timolol, pilocarpine, travoprost, provider. “Every patient must be bacterial infection is something to tafluprost, bimatoprost, latanoprost considered as an individual and treated be avoided: conjunctivitis is never and even Cosopt) are either now appropriately,” is Young’s conclusion. pleasant, and in cases where the eye available, or will be shortly. To isn’t intact, like in corneal abrasion, minimize bacterial contamination Is BAK always to blame? infections that penetrate into the eye risk, they come in single-use, No, patients may be sensitive to other can be serious. Hence the preservatives. disposable packaging. This raises some eyedrop components. “If you’ve got a issues – they are small and awkward to patient on multiple drops and they’re What is used and how does it work? use. Despite the packaging containing starting to develop allergic reactions, Benzalkonium chloride (BAK) is the more than double the volume required it’s difficult to decide if it is the BAK preservative of choice; mercurials, for a single use, there is the possibility exposure, or one of the compounds from chlorhexidine and chlorobutanol have that none of it will be successfully the three drops they’re taking,” says also been used. BAK is a surfactant; at applied. “A small number of patients Young. “The ophthalmologist might try the concentrations used in eyedrops, have difficulty using the unit dose replacing BAK-containing eyedrops it acts as a bactericide, dissolving preservative-free drops – and with preservative-free eyedrops – if bacterial cell membranes. BAK also compliance aids are not yet available these are available, and if appropriate has cleaning properties, and is used at to assist them,” Young says. – or go down the laser surgery or higher concentrations as a detergent trabeculectomy route to reduce exposure in many soaps, cosmetics, disinfectants So why is BAK still used? to the irritant. It’s a judgment call for the and spermicides. It comes down, partly, to cost. BAK- ophthalmologist.”  containing eyedrops cost less than What are the potential side-effects preservative-free eyedrops. Some of Reference of BAK? the BAK-associated adverse events, 1. J. Hong and L. Bielory “Allergy to Ophthalmic BAK not only irritates the eye, it can like dry eye, can be controlled with Preservatives”, Curr. Opin. Allergy Clin. also damage ocular structures (1). different eyedrops, although this also Immunol., 9 (5), 447–453 (2009). 34 In Practice

segment of the eye – optic nerve morbidity from childhood onwards. This Pediatric cupping – and it is referred to as “juvenile impacts immediate family, care providers glaucoma”. A couple of nuances exist and the community as a whole. Improperly Glaucoma, East in the terminology: if no other ocular managed, the disease has significant or systemic diseases are present, this morbidity. Worldwide, childhood and West is referred to as “primary” glaucoma, glaucoma accounts for approximately whereas the prefix “secondary” is used if 18 percent of all children in institutes for Management approaches for a congenital ocular, or acquired ocular or the blind, and is responsible for about five best outcome vary by location. systemic disease has caused the glaucoma. percent of all (3). Ultimately, this ends up with significant By Nader Bayoumi East versus West losses in productivity and community Pediatric glaucoma is rare in the Western resources, to an extent that rivals other eye Glaucoma is exceeded only by world, where the incidence is estimated diseases acquired in adulthood. To top it as a cause of blindness. In 2002, the at 1 in 10,000 live births. It is far more all, caring for a disabled child takes a heavy World Health Organization estimated common in the pediatric age group toll on the productivity of family members that 12.3 million people worldwide had elsewhere, particularly in communities and/or care providers. On the other hand, been blinded by glaucoma. The disease with high rates of consanguineous proper and timely management results in occurs when intraocular pressure (IOP) marriages. For example, the incidence in significant improvement and reduction rises above a level that damages the optic Saudi Arabia is estimated at 1 in 2,500 in morbidity (see “Who Makes a Full nerve, leading to visual field defects and live births (1) and in Slovakian gypsies it Recovery, and Who Doesn’t” ). eventually, if left uncorrected, blindness. is 1 in 1,250 live births (2). In my home Progressive cupping of the optic nerve In children, undetected – and therefore country of Egypt, the incidence is likely (see Figure 1b), which is the hallmark untreated – glaucoma raises the tragic to parallel that of Saudi Arabia, as we of pediatric glaucoma, is associated with prospect of lifelong blindness. Early have similar, close community structures. elevated intraocular pressure (IOP). glaucoma detection is important for Although no formal data are available, This is difficult to quantify accurately in people of all ages, but is absolutely critical my local hospital statistics reveal that children, who do not want to have their – and particularly challenging to perform – almost two new cases present every eyes interfered with. Optic nerve cupping in pediatric cases. month. This is in stark contrast to the is ascertained by fundoscopy (mostly Childhood glaucoma comes in a Western community; in the UK, a general indirect) in cases of clear media, or number of forms. Present at birth, it is ophthalmologist can expect to see one sonographically in cases of opaque media. “congenital glaucoma”; if it develops new case every 5 years! IOP can be measured by a multitude of before a child’s third birthday, it is Glaucoma presents in Western methods, such as with slit-lamp-mounted “infantile glaucoma”. In both cases, communities typically as a mild form, with Goldman applanation tonometers for there are morphologic changes in the predominantly large, usually clear, cornea; (cooperative) older children. For less anterior and posterior segments of the mild to moderate IOP elevation, and cooperative children, anesthesia may be eye. Typically, when glaucoma develops minimal optic nerve cupping. In contrast, required – with its well-established risks – after the age of three, the morphologic the most common presentations in Egypt, but can potentially be avoided by using a changes occur only in the posterior Saudi Arabia, and South-East Asia are the hand-held applanation tonometer called more severe forms, with large, usually hazy, the Tonopen (Figure. 1c) or a Schiotz At a Glance corneas (see Figure 1a) and severe IOP (indentation) tonometer. Portable • Childhood glaucoma requires early elevation with an optic nerve that is unable rebound tonometers are also useful for diagnosis and treatment to be visualized on examination. measuring IOP in children and do not • “Western” glaucoma is typically less require eye-drops to be used. severe than “Eastern” Diagnosis Even with these advances in tonometry, • Diagnosis is challenging, often Despite occurring relatively rarely, examination under anesthesia (EUA) requiring the patient to be sedated ophthalmologists and physicians need to be plays an important role in the diagnosis • Surgery is almost always the answer; particularly vigilant for pediatric glaucoma. of congenital and juvenile glaucoma. drugs need to be used sparingly Untreated, it results in significant, lifelong EUA lowers IOP, making it particularly In Practice 35

a b Who makes a full recovery, and who doesn’t?

In the West: A population-based study in Olmsted County, Minnesota, USA (4) surveyed childhood glaucoma cases over a 40-year period. Twenty percent of untreated cases eventually resulted in enucleation of a blind painful eye. However, timely management resulted in over 85 percent of children having vision better then 20/200 after five years, with 77 percent retaining this c d level of acuity after 10 years.

In the East: A study in Saudi Arabia supports the view that glaucoma presentations are more severe in Eastern communities. Timely management combined with surgery resulted in complete success in close to 75 percent of cases; less aggressive interventions had lower success rates (5).

In my series, successful surgery has managed to cure 95.5 percent of children with PCG and 83 percent with glaucoma after surgery. Of these, corneal edema and scarring with Figure 1. Childhood glaucoma. a) A typical child with primary congenital glaucoma demonstrating left subsequent partial morbidity accounted large hazy cornea. b) The optic disc showing increased cupping. c) Measurement of the IOP using Perkin’s for 15 percent of PCG cases and seven tonometer. d) A scan axial length measurement. percent of glaucoma after congenital cataract surgery cases. Permanent difficult to quantify IOP accurately. Treatment morbidity was present in the failed cases The key to the diagnosis is therefore Most children have surgery to treat their (4.5 percent and 17 percent respectively). “change”; progression of the examined glaucoma; medication is only used as ocular parameters, especially optic a temporary measure when preparing nerve cupping, which happens early and for surgery, or if surgery fails to reduce (CNS) penetration leading to CNS quickly in children, is crucial to prove IOP to acceptable levels. Many drugs depression, which can result in reductions the diagnosis, particularly in cases where are available to control adult glaucoma, in heart and breathing rates, and there is a reasonable level of doubt. but two key issues come into play when potentially loss of consciousness, coma Secondary changes in ocular biometric they are used in children. In practice, and even death. β-blockers like timolol parameters include possible increases in α-agonists such as brimonidine or are no safer and need be used at the lowest the corneal diameter with broadening apraclonidine are best avoided, but if they possible dose to avoid potential systemic of the limbus and axial length (see are used at all, it must be with caution. toxicity from nasal mucosal absorption. Figure 1d). Pediatric use risks central nervous system Children have a much lower body  36 In Practice

a b transcleral cyclophotocoagulation being the procedure of choice. Endoscopic cyclophotocoagulation is an additional option that allows controlled selected destruction of ciliary processes and is considered to be safer. Pediatric glaucoma has high morbidity, a lifelong impact, and causes significant economic burden. Timely diagnosis and intervention are crucial. Medical therapy is a temporizing measure, but only c d surgery provides a definitive treatment – and many surgical options are available. If diagnosed early enough, and properly managed, a child can have a near-normal lifestyle and be saved from a grim future of poor vision progressing to blindness. 

Nader Bayoumi is Assistant Professor of Ophthalmology at Alexandria University Figure 2. Treatment. a) Ab-externo trabeculotomy. b) Sclera flap dissection for a trabeculectomy. Faculty of Medicine, Egypt. c) Intraoperative antimetabolite application. d) Kelly punch trabeculectomy. References surface area than adults; for any given trabeculotomy (Fig. 2a) – is an effective 1. B. A. Bejjani et al., “CYP1B1mutations and drug dosage, drug exposure is therefore far and valid choice, and normally highly incomplete penetrance in an inbred population greater in children than in adults, hence successful. For cases with hazy cornea segregating primary congenital glaucoma suggest the increased risks. This is particularly and an accompanying severe elevation of frequent de novo events and a dominant modifier marked with drugs that have narrow IOP (that is, case presentations typical of locus,” Hum. Mol. Genet., 9, 367-74 (2000). therapeutic indices, such as α-agonists Egypt and other Eastern locations), the 2. A .Gencik, “Epidemiology and genetics of primary and β-blockers. “Safer” therapeutic only possible angle surgery is ab externo congenital glaucoma in Slovakia. Description of choices in children include carbonic trabeculotomy. Other options include a form of primary congenital glaucoma in gypsies anhydrase inhibitors, such as dorzolamide trabeculectomy with special emphasis on with autosomal-recessive inheritance and complete or brinzolamide, or prostaglandin analogs the use of antimetabolites, and primary penetrance,” Dev. Ophthalmol., 16, 76-115 (1989). (PGAs) like latanoprost or travoprost, glaucoma drainage devices, such as the 3. C. E. Gilbert et al., “Causes of blindness and severe with PGAs being especially effective Bærveldt implant or the Ahmed valve. In visual impairment in children in Chile,” Dev. Med. for juvenile glaucoma, particularly the severe cases, a combination of procedures Child Neurol., 36, 326-33 (1994). secondary forms. is especially useful, such as combined 4. P. B. Mullaney et al., “Combined trabeculotomy Surgical choices in juvenile glaucoma trabeculotomy-trabeculectomy and topical and trabeculectomy as an initial procedure in are limited, with filtering surgery, also application of cytodestructive mitomycin uncomplicated congenital glaucoma,” Arch. known as trabeculectomy (see Figure C, for which reported success rates are in Ophthalmol., 117,457-60 (1999). 2b, 2d), along with antimetabolites (see the range of 75 to 94 percent (4, 5). 5. A. K. Mandal, T. J. Naduvilath, A. Jayagandan, Figure 2c) being the clear procedure In Egypt, multiple surgical procedures “Surgical results of combined trabeculotomy of choice. Choices for congenital and are commonly required to control IOP, and trabeculectomy for developmental glaucoma,” infantile glaucoma are more diverse. In particularly for the severe, “Eastern” case Ophthalmology, 105, 974-82 (1998). cases with clear corneas and relatively mild presentations. My personal reoperation 6. N. Bayoumi, “Primary congenital glaucoma in the IOP elevation (that is, a typical Western rate is close to 20 percent (6). For most populous Arab country, a single surgeon presentation), angle surgery – whether apparently hopeless cases, cyclodestructive experience. Poster P304 at the 5th World Glaucoma ab interno goniotomy or ab externo procedures remain a valid option, with Congress, Vancouver, Canada, July 17–20, 2013. For Glaucoma Tough on IOP. Easy on Eyes.

The first preservative-free prostaglandin Effective IOP-lowering (1 Low risk of hyperaemia (2

Abbreviated Prescribing Information TAFLOTAN® (tafluprost 0.0015% eye drops, solution, single-dose container).Presentation: Low-density polyethylene single-dose containers packed in foil pouch. Each single-dose container has a fill volume of 0.3 ml and there are 10 containers in each foil pouch. The following pack sizes are available: 30 x 0.3 ml and 90 x 0.3 ml. One ml of eye drops contains 15 micrograms of tafluprost. Indication: Reduction of elevated intraocular pressure in open angle glaucoma and in patients who would benefit from preservative-free eye drops or who are insufficiently responsive or intolerant or contra-indicated to first line therapy, as monotherapy or as adjunctive therapy to beta-blockers. Dosage and Administration: The recommended dose is one drop of TAFLOTAN® in the conjunctival sac of the affected eye(s) once daily in the evening. Not recommended in children or adolescents (under the age of 18). In renal or hepatic impairment use with caution. Contraindications: Hypersensitivity to tafluprost or to any of the excipients. Precautions: Before treatment is initiated, patients August 2013 should be informed of the possibility of eyelash growth, darkening of the eyelid skin and increased iris pigmentation. Some of these changes may be permanent, and may lead to differences in appearance between the eyes when only one eye is treated. Caution is recommended when using tafluprost in aphakic patients, pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema or iritis/uveitis. There is no experience in patients with severe asthma. Such patients should therefore be treated with caution. Interactions: Specific interaction studies with other medicinal products have not been performed with tafluprost. Pregnancy: Do not use in women of childbearing age/potential unless adequate contraceptive measures are in place. Driving: Tafluprost has no influence on the ability to drive. Undesirable Effects: The most frequently reported treatment-related adverse event was ocular hyperaemia. It occurred in approximately 13% of the patients treated with preserved tafluprost and 4.1% of the patients treated with preservative-free tafluprost. Other side effects include: Common (1% to 10%): eye pruritus, eye irritation, eye pain, changes in eyelashes, dry eye, eyelash discolouration, foreign body sensation in eyes, erythema of eye lid, blurred vision, increased lacrimation, blepharal pigmentation, eye discharge, reduced visual acuity, photophobia, eyelid oedema and increased iris pigmentation and headache. Uncommon (0.1% to <1%): superficial punctate keratitis (SPK), asthenopia, conjunctival oedema, , ocular discomfort, anterior chamber flare, conjunctival follicles, , anterior chamber cell, conjunctival pigmentation and abnormal sensation in eye, hypertrichosis of eyelid. Overdose: If overdose occurs, treatment should be symptomatic. Special Precautions for Storage: Store in a refrigerator (2°C - 8°C). After opening the foil pouch keep the single-dose containers in the original foil pouch, do not store above 25°C, discard an opened single-dose container with any remaining solution immediately after use. MA Holder: Santen Oy, Niittyhaankatu 20, 33720 Tampere, Finland. Date of Preparation: 11/2012. 1) Taflotan lowered IOP by 6.9 - 9.7 mmHg in masked, randomized studies 1-4. 1. Uusitalo H et al. Acta Ophthalmol 2010; 88: 12-19 2. Traverso C et al. J Ocul Pharmacol Ther 2010; 26: 97-104 3. Konstas AG et al. Comparison of 24-hour efficacy with Tafluprost compared with Latanoprost in patients with primary open-single glaucoma or ocular hypertension. Abstract 5104/A2458 4. Chabi A et al. Am J Ophthalmol 2012; 153: 1187-1196 2) Low risk of hyperaemia among prostaglandins: SPC texts of preservative-free Taflotan. Please visit us at EsCRs Booth # C05

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TheOphthalmologist_sep2013_FEMTO_LDV_Corneal_Inscisions_Ad_210x266.indd 1 06.09.13 09:38 NextGen

Research advances Experimental treatments Drug/device pipelines

40-42 Anatomy’s 21st Century Update Remarkably, a new layer of the cornea has recently been described. What are the implications?

45 The Vitreous Proteome Over 1,000 proteins, who would have thought it? Here is a functional classification.

42-44 Seeing the Unseeable How sight is being restored in patients who have been blind for many years using retinal implants. 40 NextGen

Did you have an inkling that this additional layer was present? Yes. Let me give you a bit of background. Corneal transplantation had been around for over a hundred years. Initially, no matter what the problem, the whole disc was cut out and replaced. The biggest risk of this procedure was rejection, which involves the endothelium. The logical response was that when the endothelium was not involved in the disease, it should be retained, not replaced. A gentleman called Mohammed Anwar introduced the use of air to separate the inner lining of the cornea, the Descemet’s and the endothelium, from the rest. The idea was that by replacing only the rest of the cornea, you would never get graft failure due to endothelial rejection. Bingo! It was a great idea and even though results were unpredictable as the bubble that separates the layers did not always form, when it did separate the Descemet’s membrane the outcome was good. This procedure was referred to as a ’Descemet’s baring technique’. Every textbook says that the technique separates Descemet’s membrane. On occasions, big bubbles in different planes were observed and the explanation offered was that this was due to a split between the banded and non-banded What exactly is Dua’s layer? zones of the Descemet’s membrane. To Galen, It’s a thick, tough, acellular layer of However there were certain observations collagen found just before (anterior to) that did not add up and provided clues Mundinus and Descemet’s membrane in the cornea. that the big bubble separation was When you blow air through the cornea, occurring in a different plane. When the Tulp, add Dua it travels throughout the whole stroma air bubble doesn’t extend to the trephine as tiny bubbles until it reaches Dua’s mark one has to separate the stroma from It’s a rare discovery that layer, which is lifted up as a dome: it is the underlying Descemet’s membrane necessitates changes to impervious to air. The collagen fibers manually in that sector. During this anatomy textbooks. Here, here are smaller in diameter than in separation one often sees strands of Harminder Dua describes the adjacent corneal stroma, meaning tissue extending between the stroma and how he discovered the that there is more space between them the membrane. Yet, when you transplant eponymous new layer of the for gel-like proteoaminoglycans. This the donor in this operation, you take cornea, and discusses its probably explains why it does not let off the donor’s Descemet’s membrane, significance. air through. which peels off very smoothly and there NextGen 41

are never any strands. That distinction science”. Donald Tan, president of the get the bubble between this layer and the was an important clue. Cornea Society and of the Asia Cornea Descemet’s membrane. The Descemet’s Another was that when you stitch Society, who was in the chair that day membrane bubble is very delicate and the tissue of a full-thickness cornea commented “anatomy text books will less able to withstand pressure and into the recipient, you see the edge of have to be rewritten”. At another talk, I simple handling maneuvers. Previously, the Descemet’s standing very proudly was told, “You know, I’m not surprised we didn’t recognize the issue and during as the needle passes just anterior to the you discovered it, I’m disappointed the operation the Descemet’s bubbles Descemet’s through deep stroma and I didn’t, because I see this under my have burst, forcing conversion to a full- we avoid puncturing the Descemet’s. eyes every week but I didn’t catch on thickness graft. It should now be possible But in deep lamellar transplantation, to what it was”. People who perform to tell intra-operatively which type of the donor’s Descemet’s is removed and the operation relate to it immediately: bubble we’ve got and take necessary we still see the edge when placing the people who don’t, take a little while to precautions to prevent a Descemetic sutures: there must be something else grasp it. bubble bursting. It will actually improve producing this sharp edge. In addition, The media interest has been outcomes, it will make the operation a many surgeons have commented that phenomenal. I’ve had a lot of emails of little safer. after a deep lamellar graft the eye is congratulations from all over the world. Clinically, there are certain diseases much stronger than following a full- For example, a group from Namsos, of the cornea where this layer may thickness graft. Descemet’s is not strong Norway (Anita Blixt Wojciechowski have a role to play. One is keratoconus, enough to impart this strength, so that and Astrid Meistad) sent me a picture of where the cornea becomes more and was another clue. Enough for us to a six-layer cake that they baked to honor more conical in shape and in some decide to investigate that. the discovery. To the cornea’s known five instances the Descemet’s membrane layers they added a sixth, in green, to tears and suddenly the cornea gets Was there a race to characterize represent Dua’s layer. hydrated, a condition called acute this layer? hydrops. We hypothesize that the tear Not quite. It didn’t click with others Extraordinary that we are still making is not just in the Descemet’s, but also in that there was another layer. The stromal discoveries about the morphology of this layer. Two cornea colleagues from tissue attached to the Descemet’s the eye! India, Rajesh Fogla and Mohammed membrane after failed operations was Yes, it is. Some people argued, and rightly Shahbaaz, have sent me images and commented upon, but no-one latched so, that since we only showed it in adults videos of cases of macular dystrophy of on to the idea that it was very different (the mean age group of our patients is the cornea, where they have performed to the rest of the stroma and might be 77 years) it may not be a true layer: is it a successful big bubble separation and a different layer relevant to the surgical present in children? they asked. When demonstrated that the stromal opacities anatomy of the cornea. I was in Thiruvananthapuram in India also involve this layer. In such situations, a young corneal surgeon, Vinay Pillai, one may consider peeling this layer off What was the reaction when you showed me OCT and histology images as well, which has been accomplished announced your findings? from the cornea of a nine-year-old girl though it is tricky. I’m getting videos We submitted the paper for publication who had a failed deep lamellar graft, and sent from colleagues all over the world in August 2012, and in September 2012 you can clearly see this layer, beautifully where they are encountering things. This I presented it for the first time at the illustrated. Personally I’m convinced. It is will condense the time it will take for EuCornea meeting in Milan. It was the different from the rest of the cornea and this layer to affect our understanding of EuCornea medal lecture, in front of an is very, very relevant to surgical anatomy. diseases and their treatment. audience of 800 corneal specialists from across the world, including some leading Will it change clinical practice? How does it feel to join Achilles, names. Prominent specialists told me, I think it changes clinical understanding Fallopio and Langerhans in having an “I have learned so much about my tremendously. Where it could change eponymous body part? operations which I didn’t understand” clinical practice is in the cases where I think it is mixed feelings, because and that it was “So clear, the clinical we get mixed bubbles and Descemetic in a way it’s embarrassing. When I implications, the anatomy, and the bubbles. In two out of ten occasions we presented the early data in 2007 and  42 NextGen

when we wrote the paper, I called it press, but will interest the scientific morning doing BJO (British Journal of “A Novel pre-Descemet’s Stromal community. There’s always something Ophthalmology) work, then I get on Layer”. My colleagues suggested “Dua’s new. Simple things are still there to be the treadmill for some exercise, go into layer” and we included it in the title in discovered. Our understanding – what the office and in the evening, I have my brackets. Everybody just picked up on we take for granted now – is, I think, social bit. To quote, “If you enjoy what that. Normally it is for your peers to not complete. you’re doing, you don’t have to work a ascribe the eponym. single day in your life”.  How do you balance research, Do you think we now know the clinical work, administrative work and Harminder Dua is the President of the complete anatomy of the eye, or are family life? Royal College of Ophthalmologists, Chair there other surprises in store? I’ve found myself sleeping less, four or and Professor of Ophthalmology at the Well, we are preparing a follow-up five hours a night. The thing is, if you University of Nottingham and head paper, an extension of the anatomy... enjoy what you’re doing, then you want of the Division of Ophthalmology and It won’t be as exciting for the lay to do more. On Saturdays, I spend the Visual Sciences.

At a Glance • Biomedical implants have the potential to restore vision to patients with • Clinical trials with epiretinal and subretinal implants have generated positive results • Two devices has received regulatory certification in Europe • Themost advanced biotechnological approach uses subretinal microchips

Retinitis pigmentosa (RP) describes a restore vision to patients with late-stage Seeing the heterogeneous group of genetic disorders RP. The final frontier is using artificial that cause progressive peripheral vision to treat completely blind patients. Unseeable vision loss and night vision difficulties, Retinal implants represent the most eventually leading to central vision loss. promising advance in vision restoration Retinal implants offer hope It affects one in every 3–4,000 people via two main approaches – subretinal for the treatment of inherited in the Western world and is among the and epiretinal microchips. blindness. Clinical trials of leading causes of progressive sight loss. The main difference between these battery-powered subretinal Symptoms usually appear in childhood two approaches is the location of the and epiretinal devices have and increase in severity over time. chip. Epiretinal implants sit on the demonstrated that patients The pharmaceutical industry retina addressing the neuronal output. with retinitis pigmentosa, is currently investigating various Subretinal implants (see Figure 1a) blind for many years, can once approaches to slow the progression are placed beneath the retina replacing again recognize objects. of the disease, but all still require photoreceptor function at the input side many years of clinical study, and these – specifically in the macular region – and By Eberhart Zrenner potential therapies are not expected to work along with the natural processing NextGen 43

a d

b c Figure 1. The Alpha IMS sub-retinal implant. (a) How the implant works. (b) The thin foil, with gold wires and the chip on its tip, leaves the eye at the connection point to the round power cable. (c) The chip with 1,500 pixels to be implanted into the retina is connected to gold wires that provide power and control signals. (d) The chip seen through the pupil after placement under the transparent retina; normal retinal vessels are crossing the chip. of images in the human brain (1). neurons is unlikely to loosen over time. a 3 x 3 mm2 array containing 1,500 tiny Suprachoroidal implants are available, At present, subretinal microchips (3) can light-sensitive photodiodes, each with an which are also implanted underneath the contain considerably more pixels than are amplifier that augments the light-evoked retina, but from the scleral side, meaning available in epiretinal (4) devices (1,500 current and forwards it to an adjacent that the choroid and pigment epithelium versus 60), thereby providing higher electrode (see Figure 1c). This chip is are located between the chip electrodes spatial resolution and greater contrast. placed on the tip of a very thin foil that and retinal neurons. The risks associated carries gold wires to supply power and with this surgical technique are lower, but Development and testing provide signal control of the amplifiers. only a few suprachoroidal implantations The consortium that developed the At the other end of the 25 mm-long foil, have been made, since spatial resolution is subretinal implant (see Figure 1b) there is a connection pad with a thin cable inferior with these devices. started in 1995 at the Institute of that leads to a receiver coil that is around In recent years, many researchers have Ophthalmic Research, part of the Centre the size of a large coin. Apart from a thin come to agree that positioning implants of Ophthalmology at the University of cable that leads from the battery pack subretinally, where the light-sensitive Tübingen in Germany, in cooperation kept in the patient’s pocket (that leads to a photoreceptor cells were located before with the Institute for Microelectronics transmitter coil behind the ear) nothing is they degenerated, may be the most Stuttgart (IMS) and the Natural and visible externally. favorable approach (2). With the image Medical Sciences Institute (NMI) During implantation, the surgeon receiver positioned within the eye, vision in Reutlingen. After eight years of makes a tiny window into the globe is restored as the eye scans from left to preclinical work a company, Retina of the eye within the orbit and gently right and up and down, allowing for Implant AG, was founded in 2003 in advances the light-sensitive array under the immediate focus and recognition of nearby Reutlingen to produce the retinal the retina towards the fovea, the area items in the patient’s field of vision. The implant chips and to sponsor clinical trials. of optimal vision (see Figure 1d). The location in between retinal layers also The Alpha IMS subretinal implant microchip’s thin power connection foil provides excellent mechanical stability, was designed to imitate the eye’s natural (also under the retina) leaves the globe meaning that the chip’s connection with processing of light. The team designed through the window, which is closed  44 NextGen

after this. It is then linked to the cable could distinguish between a fork, knife Looking ahead that is routed (under the skin) to a place and spoon. Placement of the implant Research to advance the subretinal behind the ear where the coil is placed beneath the fovea clearly provided microchip technology continues, in subcutaneously (see diagram at start optimum visual results, allowing this order to build on the success of the two of article). The chip is activated when and other patients to recognize objects clinical trials. Plans are underway to the patient puts another coil externally and facial expressions as well as read commence a clinical trial in the United above the subdermal coil. The external words and see dots on a pair of dice. States, the results of which will form coil remains in place via a small magnet, A second clinical trial began in 2010 the basis for a regulatory application to and the pairing of both coils powers the in Germany. For the first time, patients the FDA. device and enables the transmission of in this trial were allowed to keep the These results of epiretinal (4) and signals through the skin. The implant is chip implanted permanently, enabling subretinal (3, 5) trials prove that the powered by a mobile phone-sized battery researchers to assess the benefits in technology can offer patients who are pack that can be easily carried around by everyday life outside of the laboratory. blinded by photoreceptor degeneration the patient. The pack features two control Initial results indicated that over the the freedom of having visual buttons – for contrast and for brightness three-to-nine month observation perception outside of the laboratory – enabling the sensitivity of the subretinal period, functional vision was restored setting. New comprehensive clinical micro-photodiode array to be adjusted in the majority of the patients trial programs will allow us to learn depending on the available light. implanted (5). Additionally, the visual more, and by listening to feedback A key advantage of this approach acuity of two patients surpassed the from patients participating in the trial, is that there is no camera outside the highest visual resolution of any patient we can customize the device to suit body. The light-sensitive chip sits in the in the first trial, and three patients their needs.  ideal position – on the retina – where were able to read letters spontaneously. photoreceptors had previously been Patients also reported the ability to Eberhart Zrenner is the Distinguished before they deteriorated. The chip and distinguish objects such as telephones Professor of Ophthalmology at the its array of 1,500 electrodes move with and read signs on doors. Institute of Ophthalmic Research at the the gaze of the eye, meaning that the With the momentum of positive Centre of Ophthalmology, University patient can view objects in the whole results from the clinical trials to date, of Tübingen, Germany. He is also an volume in front of them, at a ±50° and the generation of US$18 million initiator of the SUBRET consortium angle both horizontally and vertically. in venture capital funding, trial sites and one of the founders of Retina Furthermore, natural microsaccades outside of Germany were added, Implant AG. help to constantly refresh the image including sites in Oxford, London and to avoid image fading. and Hong Kong. In June 2013, the References To date, 36 patients have received Alpha IMS device received a CE 1. E. Zrenner, “Artificial vision: solar cells for the this subretinal microchip in clinical mark, enabling it to be marketed across blind,” Nat. Photonics, 6, 344-345 (2012). trials across Europe and Asia. The the EU. This represented the first 2. K. Mathieson et al., “Photovoltaic retinal company’s first clinical trial began in European regulatory certification prosthesis with high pixel density,” Nat. 2005 at the University Eye Clinic of for the company, and the decision Photonics, 6, 391–397 (2012). Tübingen, Germany, where eleven marks an important milestone in the 3. E. Zrenner et al., “Subretinal electronic chips patients received the implant – which journey to make subretinal microchip allow blind patients to read letters and combine at that time, was still cable-bound technology accessible to the wider them to words,” Proc. Biol. Sci., 278, 1489–97 – for three months. The results were patient community. It provides (2011). encouraging (3); the most successful clinicians across Europe with a chance 4. M. S. Humayun et al., “Interim Results from recipient went from being able to to offer their patients a new pathway to the International Trial of Second Sight’s Visual identify vertical and horizontal lines regain vision. This epiretinal approach Prosthesis,” Ophthalmology, 119, 779-88 (2012). on a computer screen to form letters now has both CE mark and FDA 5. K. Stingl et al., “Artificial vision with wirelessly into words; in one extraordinary approval and is therefore available for powered subretinal electronic implant alpha- moment, he corrected the spelling of use in the European Union and the IMS,” Proc. Biol. Sci., 280 (1757):20130077 his name! He recognized a banana and United States. (2013). The Vitreous Proteome sustains the morphology and function of adjacent tissues through a complex but Well over 1,000 different defined collection of proteins. proteins have been cataloged in A detailed list of the proteins in the the vitreous humor. vitreous is a first step to understanding Here’s how they break down. the structure’s biological processes. Recently, a team led by Jürgen Kopitz The vitreous humor, comprising four- of the Institute of Pathology, University fifths of the volume of the eyeball, is a of Heidelberg applied in-depth transparent, colorless, gelatinous mass proteomic screening technologies to that holds the eye tautly in place. It also the human vitreous.

Purication and analysis Human vitreous samples

1111 Unique proteins 261 Known enzymes Plasma and vitreous proteomes (to scale)

Plasma proteome

Found in Vireous plasma Protein function proteome proteome

Not found in plasma proteome 498 Binding

265 Coagulation cascade/ 35 complement Signalling Visual perception 30 Enzymes 261 191 Cytoskeleton Protease inhibitors 35 S. Aretz et al., 47 Receptors Apoptis “In-depth mass 91 Transport 186 spectrometric mapping of the human Cytokines 11 51 Proteases vitreous proteome,” Peptide hormones 15 5 Growth factors Proteome Sci, 11, 22 (2013).

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48-50 Building a Presbyopia Practice The key to success is understanding the presbyopia patient.

51-52 Glaucoma Tug-of-War In Australia, optometrists and ophthalmologists are having a very 52-55 public disagreement about glaucoma Under Pressure care. Here, the ophthalmologists Want to start a company? Here’s one speak out. example of translating a good idea into a physical, purchasable product. 48 Profession

At a Glance • Thenumber of presbyopes is increasing dramatically • New approaches improve vision and quality of life • To build your practice, good customer interaction, education and listening skills are crucial • Everyone should have a presbyope on their staff

Building a slightly perturbed. But when you have Europe. This population is physically to slide the card under the slit lamp to active and engaged in activities that Presbyopia see if they are reading it correctly, you’ll require a full range of vision. For instance, be truly dismayed. We both know this 66 percent send text messages, 90 Practice from personal experience. To us it feels percent use a computer and 72 percent that presbyopia is ubiquitous; indeed, the plan on continuing to work in some With an ever-growing market statistics tell us we’re not far off. Happily, capacity after retirement. These days, and new treatment options there are exciting new options for presbyopes generally feel younger than on hand, presbyopia offers an treating us and our presbyopic patients, their chronological age and are frustrated attractive business proposition. and we are now orienting our practices with reading glasses which, they find, Understanding the patient and towards them. intrude on their lifestyles. Plus, wearing building your practice around Historically, our practice has been reading glasses is a definite – and most her/him is key to success. focused on refractive surgery. While the unwelcome – sign of aging. Here’s how we have done it. LASIK market remains significant, the The nature of the condition can be numbers have leveled off. The global difficult to get across. Explaining the By Jeff Machat and Sondra Black presbyopic population, on the other concept to hyperopic presbyopes is hand, is large and continuing to grow. It especially challenging: in spite of long When you first have to put on reading is projected that by the year 2020 there conversations, some patients fail to truly glasses to decipher the reading card that will be over 336 million in the United understand that their eyes can no longer your patient is looking at, you will feel States and over 410 million in Western make the accommodation from distance Profession 49

MYOPES vs PRESBYOPES light to reach the retina. It is implanted Aspiring financial independence Financially independent monocularly into the non-dominant eye. With thousands of patients now treated, Image conscious Age conscious the data show a mean improvement in Want reassurance Want richer information uncorrected visual acuity (UCVA) from Like finance options Not interested in finance J6 to J1 at near, and 20/40 to 20/20 at intermediate. Distance UCVA decreases Majority say main concern is cost Priority is health, looking/feeling younger slightly in the implant eye from 20/16 Minority of friends are myopic Majority of friends are presbyopic to 20/20, but binocular distance UCVA remains stable at 20/16 (2). While optometrists can sometimes be to near focus. We try to explain to these uncomfortable with suggesting surgery presbyopes that if we correct their to patients, much of this concern is distance vision, everything up close alleviated with the corneal inlay, will be blurry, and they likely won’t as it can be removed if required. be able to read or see anything The procedure is reproducibly within arm’s reach without and precisely performed; help. Patients often respond the recommendation is to that they can currently read create a corneal pocket with without their glasses, and a femtosecond laser. The they don’t want that changed, technique can be combined failing to understand what with LASIK, allowing they have just been told. myopes, hyperopes and They ask us to just correct emmetropes to all benefit. their distance vision and leave their reading vision as is. Even Patient engagement patients who seem to understand To be a market leader at this come back after surgery dismayed intersection of aging baby boomers that they can’t do crossword puzzles or and new treatment options, the whole shave their armpits. practice needs to cater to the presbyope. The first step is to understand that A new intervention the presbyope is a significantly different Historically, surgical options for factor but when they are able to see and proposition than a LASIK patient. These presbyopes have predominantly involved function at both near and far – but neither are 45-60 year-olds at the height of some form of refractive surgery that is spectacular – the response ranges from their careers and peak of their spending resulted in monovision. For some ambivalence to annoyance. potential. They tend to be early adopters patients, this can be a great option. Another option is the small-aperture of technology, and are not afraid to try The average success rate for elective corneal inlay which is available in new things. Whereas LASIK patients monovision surgery is reported to be 73 many countries worldwide and like to interview any number of physicians percent (1), which more or less coincides under review by the Food and Drug before making a final treatment decision, with the experience in our practice: even Administration (FDA) in the USA. which is based largely on price, once a though we require a contact lens trial The KAMRA corneal inlay (AcuFocus) presbyope is convinced that you can help prior to surgery to ensure they can adapt, procedure improves near vision without them get rid of their reading glasses, they of the 15 percent of patients on which compromising intermediate or distance are ready to jump in with both feet. What monovision was performed, about a third vision. The inlay is an opaque ring 5 µm prevents them from reaching this point is ended up having the procedure reversed. thick and 3.8 mm in diameter with a not knowing that their condition can be The reality is that when you give a patient 1.6 mm central opening. The aperture treated or lack of a relationship with their really crisp distance vision, there is a wow design only allows central collinear eye-care professional.  50 Profession

Checklist for Once your practice and staff are ready, This requires a very satisfied patient, a Successful a it’s time to reach out to the presbyopes which comes from knowing your Presbyopic Practice: that are already in front of you. Spotlight patient, educating them well and setting your presbyopia treatment prowess using suitable post-operative expectations. brochures, banners and signs to subtly Sincerely ask all of your patients for ✔ Educate staff on unique needs inform your audience of the problem and feedback about their experience, and of the presbyope its solution. Incorporate a checklist in make any appropriate changes to your ✔ Understand and expect that the patient chart to remind staff to speak customer service or educational materials. presbyopes will require different with every patient aged over 40 about Capture a short patient testimonial on care than a LASIK patient presbyopia and your preferred treatment. your phone or tablet to use as a third- ✔ Promotions should connect Search your patient database for the correct party endorsement. Post these on your with patient needs demographic and then create an email and Facebook, and YouTube page as well as ✔ Ensure every patient over 40 years text campaign that has a message that will on your website. In addition, use social is informed about presbyopia resonate with presbyopes. media networks such as Facebook to and your preferred treatment Once you have their attention, it’s become friends with your patients. ✔ Hire presbyopes to interact with important to really listen to these A large percentage of a presbyopes’ these patients new patients. They are entering a friends, colleagues and associates are ✔ Treat a staff member with your stage of their lives where they will also presbyopes – don’t miss out on the preferred presbyopia treatment likely have multiple comorbidities, excellent referral service they can provide! – if possible and a thorough accounting of their The presbyopic population is ✔ Recommend a specific lifestyles and all ocular issues will currently an untapped and underserved treatment for your patients allow you to make the best treatment patient group. In our practice, the ✔ Capture and use patient recommendation. In addition, the reception for the KAMRA inlay has testimonials patient will need to be guided about been phenomenal, both from eye care their current situation, as well as the professionals and patients, which are changes their eyes will likely undergo sometimes one and the same. We have in the not-too-distant future. One of found that focusing on the presbyopic Staff and physicians can make the the benefits of the KAMRA corneal market can be rewarding personally, first step towards building a bridge to inlay is that the gain in near visual professionally and financially. To capture the presbyopic patient demographic acuity remains stable over time, even as the opportunity, you must pay attention by finding out what it means to have the presbyopia progresses. In addition, to your patient interactions and presbyopia. Do you know what it’s like to cataract surgery may be performed communications, and provide surgical stop off for coffee after a tennis game and with the inlay in place, or the inlay may solutions that meet the unique needs of not be able to read the menu, or to go to the be removed, both successfully. the presbyope.  market for foods that don’t contain high- Tease out the entire ocular history to fructose corn syrup only to realize that you understand their greatest vision-related Jeff Machat and Sondra Black are CEO can’t read the labels? We advise that if you concerns but be mindful not to give up and Clinical Director, respectively, of don’t currently have a presbyope on your control of the consultation. Patients the Toronto-based Crystal Clear Vision staff, hire one! A fellow presbyope is the are in your practice because they want Canada Inc. most likely to understand and relate to a something done to improve their presbyopic patient, making them the most eyesight. Engage in the conversation References natural and logical patient consultant. with the assumption that he or she 1. S. Jain, I. Arora and D. T. Azar, “Success of Performing the KAMRA inlay procedure is going to agree to have the inlay monovision in presbyopes; review of the literature on the presbyopic patient consultant who procedure: a confident, positive attitude and potential applications to refractive surgery”, will be charged with interacting with is contagious. Surv. Ophthalmol., 40, 491-9 (1996). these patients is an even better option, as You can get fast payback for exceptional 2. O. Seyeddain et al., “Small-aperture corneal inlay nothing has more weight with potential customer service by incorporating happy for the correction of presbyopia: 3-year follow-up”, patients than a live testimonial. patients into your marketing efforts. J. Cataract. Refract. Surg., 38, 35-45 (2012). Profession 51

At a Glance • Ophthalmologists and optometrists traditionally worked together on glaucoma diagnosis, treatment and monitoring • Now, the optometrists want to perform all of these functions independently • Australian regulators have approved this change • Ophthalmologists, believing it not to be in the best interest of patients, are mounting a challenge

is set out comprehensively in the National was (however inadvertently) putting Glaucoma Health and Medical Research Council patients at risk across all areas of specialist (NHMRC) Guidelines for the Screening, medicine in Australia. Tug-of-War Prognosis, Diagnosis, Management and In response, RANZCO lodged a Prevention of Glaucoma. comprehensive submission to AHPRA In Australia, the highly “With glaucoma and other eye diseases, focusing on the education and training of successful collaborative collaboration is key,” says RANZCO ophthalmologists and optometrists, and care approach for glaucoma President and glaucoma specialist on the risk to patient safety. As Stephen patients has been ripped apart Stephen Best. “Ophthalmologists and Best noted, “An optometrist has typically by the optometrists’ regulatory optometrists should be working together, studied for four or five years to earn an body. Can it be repaired? with ophthalmologists overseeing a undergraduate degree, after which time Ophthalmologists are making a patient’s treatment; this is in the best he or she can prescribe and fit glasses determined effort. interests of the Australian public.” or contact lenses. An ophthalmologist is a medical doctor who, in addition to By David Andrews The Challenge gaining a medical degree in six years, has On November 23 2012, with no prior undertaken five years of specialist training Patient safety in Australia is protected by warning, the status quo for glaucoma in the diagnosis and management of long-established procedures centered on care was turned on its head. The disorders of the eye and visual system. In the fundamental principle that medical optometry profession is regulated by the the course of their specialist training, an practitioners are allowed to independently Optometry Board of Australia (OBA); ophthalmologist will typically have seen treat serious medical conditions while “Regulation of Health Practitioners” more than 7,000 ophthalmic patients.” allied health professionals assist in the (see page 52) explains the structure of Despite RANZCO’s arguments, treatment, and in many cases are the the regulatory arrangements. the OBA submission was endorsed by primary providers of care. Glaucoma On that date, the OBA submitted AHPRA. The result is that optometrists treatment offers a good example of a proposal to The Australian Health with minimal hours of additional this approach: ophthalmologists have Practitioner Regulation Agency therapeutic training can now diagnose taken responsibility for diagnosis, initial (AHPRA) requesting that optometrists and treat glaucoma with no oversight treatment and oversight of patient be able to independently treat patients from an ophthalmologist. Many in the management, with optometrists seeing with chronic glaucoma or those at risk of Australian eye-care community have the patient regularly to ensure compliance developing the disease, something that was expressed shock at this turn of events. For and, when necessary, referring him or her previously only undertaken by medically- example, Steve Hambleton, President of back to the ophthalmologist for review trained ophthalmologists. The OBA, a the Australian Medical Association, said and adjustment of treatment. This model bureaucratic organization established to that, in making its decision, the OBA of care was developed over many years and administer the registration of optometrists, had failed to safeguard the interests of  52 Profession

Regulation of Health which have the responsibility scope of practice to independently Practitioners for regulating their respective diagnose and manage glaucoma. health professions, to protect ASO and RANZCO have begun the public and set standards and lobbying politicians and senior • The Health Practitioner policies that all registered health departmental executives to ensure that Regulation National Law and practitioners must meet. they are aware of the health risks involved its recognized health • The AHPRA legislation grants for the Australian population. The two professions are represented by equal status to both allied health organizations continue to work together National Boards that are and medical discipline Boards. preparing numerous submissions and regulated under the National (The optometry profession is engaging with key stakeholders through Registration and Accreditation governed by the Optometry correspondence and face-to-face meetings. Scheme. Board of Australia [OBA]). It As Stephen Best explains, “RANZCO • The Australian Health also enables groups to increase does not believe that it is in the patients’ Practitioner Regulation their scope of clinical practice interests for optometrists to seek to Agency (AHPRA) supports without expert oversight or increase their scope of practice through these National Boards, clinical review. legislation rather than clinical education.” Ophthalmologists greatly appreciate the valuable role of optometrists in screening for eye-care diseases and those suffering glaucoma, now and in interests of patient safety. RANZCO believe that an integrated eye-care the future. “This is not an example of is encouraging continued collaboration model gives the patient the best possible health reform. This is an example of the between the two professions to prevent outcome. The move by the OBA not only fragmentation of health care, which is the the creation of a two-tier health system puts this model at risk but also threatens enemy of quality care, the enemy of efficient in Australia. On Thursday, 20 June, 2013, the relationship between optometrists care, and the enemy of affordable care.” the OBA was served notice that ASO and ophthalmologists. It also highlights a and RANZCO are jointly launching disturbing loophole in the administration The Response a Supreme Court action with respect of Australia’s healthcare system.  At present, RANZCO, together to the OBA’s unilateral decision, which with the Australian Society of has been endorsed by the Australian David Andrews is the Chief Executive Ophthalmologists (ASO), is appealing Health Practitioner Regulation Agency Officer of the Royal Australian and New against the OBA’s decision, in the (AHPRA), to increase optometrists’ Zealand College of Ophthalmologists.

Here’s how to get long-term dimensional changes of the eye over the Under Pressure measurements on intraocular pressure last day and night. You are then in the (IOP). You place a sensor-containing position to form an objective, informed How do you translate a contact lens on the eyeball of your diagnosis and a treatment plan for good idea into a physical, patient and switch on the wireless your patient. purchasable product? recording device; the portable recorder Technical, medical, regulatory tells you that everything is working Idea to Product… and business skills are a must, well. The patient then leaves your clinic, Matteo Leonardi, founder and Chief as is an immense ability to goes about their everyday business as Technology Officer of Sensimed, resist pressure – especially normal, and returns with a treasure- decided to tackle long-term IOP when your device measures it. trove of IOP-related data 24 hours later. monitoring back in 1998 while studying You Bluetooth it over to your laptop, Biomedical Engineering at the Swiss By Mark Hillen and within seconds, you’re looking at Federal Institute of Technology the patient’s profile of spontaneous (EPFL) in Lausanne. When the subject Profession 53

How To Build Your Own Company

Do you have a great idea for a drug, device or service that will revolutionize ophthalmology? Here are tips from Matteo Leonardi and Jean-Marc Wismer on how to get it off the ground.

At a Glance “Perseverance. We had so many hard · Fifteen years ago, as a student, Matteo Leonardi times; so many reasons to quit. To discovered his passion succeed, it almost feels like you have · With partners, he has developed a company to to have perseverance and resilience in build and market his product your DNA.” · Thedevice offers 24-hour IOP monitoring · Development of a knowledge base is central to “Think carefully about your business the company’s goals model. The finance situation has · Other applications of the technology are in dramatically changed in the last the pipeline decade; there’s less money to go around. So think really carefully before embarking on an expensive was discussed by a multidisciplinary licensed exclusively to a new company, business model.” group of engineers and physicians, a big Sensimed. Leonardi co-founded idea emerged: a contact lens that could Sensimed with Sacha Cerboni, who “Educating your market costs continually monitor IOP over a 24- brought expertise in health economics, more than you think. It consumes hour period. Fifteen years later, the lens, quality assurance and regulatory money, so do not underestimate that Triggerfish, is on the market. knowledge – plus a fresh perspective when doing your calculations.” Leonardi’s gentle demeanor belies – to the party. Today, Cerboni is the grit, determination and sheer responsible for Sensimed’s quality “Murphy was an optimist. You need perseverance he – and the team who assurance and regulatory program. a plan B and C and D. More sweat, have worked alongside him – have had As momentum gathered, so did the more time and more money.” to show to get this far. “Financing for requirement for cash. The Sensimed innovation is very tight,” he explains, team managed to tap almost every “Passion is a major asset. If you like “and it has been a long journey.” possible source of Swiss start-up the domain you are into, have a vision Initially, financing wasn’t the biggest funding, and secured a coup by for a great contribution to society, it problem; it was time. Matteo was a achieving funding for Triggerfish from will feed you with the extra energy you research assistant at EPFL, pursuing the European Union (EU) Healthy need to carry you through hard times.” the IOP project in his spare time. Aims and EU Sixth Framework At that he point he was trying to Programmes. But a different league of “In a start-up environment the team determine if it could even be achieved financing was required if the product is crucial, as there are few to face the using existing technology. By 2004 was ever to be commercialized. This big challenges; you need everybody to he was working on it full-time – it is where Jean-Marc Wismer came in. think big and be willing to work in had become his PhD research topic A veteran of the Swiss biotech scene, cross-functional projects.” – and he made a prototype that was with extensive experience of both used in preliminary clinical trials. By management and obtaining start-up then, a patent had been granted to funding, Wismer made an immediate the EPFL for the device, which was impact. By the end of January 2008,  54 Profession

YEAR > 1998 1999 2000 2001 2002 2003 2004 2005

Company Founded with Sacha Cerboni + First presentation Company

Milestones Matteo of the Porcine Leonardi’s prototype eye trial idea The Patent wired lens published Funding Funding

Milestones Seed Loan + EU research de Vigier grant award Timeline: Key milestones in the journey from idea to market. Keyin the journey milestones Timeline: from Prizes

Sensimed had closed Series A funding potential customers. “Our first doctors to use it looked at these traces of CHF 8 million. surprisewas that while various advisors and thought: what do I do with this? This funding was crucial for and the opinion leaders we consulted Now all doctors know how to decipher Sensimed’s continued existence. with were telling us that the device QRST peaks and work out what’s Although the prototype had worked was great, ophthalmologists are more wrong.” Sensimed needed more time to well and had provided excellent proof- conservative than we thought, and it was develop and educate the market… and of-concept, it had no possibility of difficult to move them from their usual more funding. meeting regulatory requirements. “We practice and reference instruments,” The company obtained Series B had to totally redesign the electronics, Leonardi recalls. One barrier was funding of CHF 18.6 million in 2010, the telecommunications and the that Triggerfish doesn’t measure IOP and with it, some breathing space. The manufacturing procedures in order to in the conventional units, mmHg. money financed early commercial satisfy medical and radio frequency Rather, it senses a direct consequence activities and meant that Sensimed legislation,” Leonardi explains. The of changes in IOP – ocular volume – could transform into a full-blown costs were considerable: Wismer via an embedded circular strain gauge medical device corporation. They notes that Sensimed “burned through in the lens. It reports circumferential spent time identifying prominent most of the CHF 8 million getting changes at the corneoscleral area in ophthalmologists who were likely to to the production models – on the millivolts and this is converted into not only try Triggerfish, but to also industrialization, the clinical trials, and arbitrary units. “When they first got adopt the device, validate the earlier the marketing aspects.” this information, ophthalmologists clinical research and develop larger didn’t know what to do with the data,” clinical trials. “Some ophthalmologists …to Market Wismer says. “There is an analogy just get it straight away,” Leonardi says, The next challenge was educating with the electrocardiogram. The first “They realize that it gives you lots of Profession 55

2006 2007 2008 2009 2010 2011 2012 2013

SENSIMED Jean-Marc Triggerfish First First human Wismer joins receives commercial trial as CEO CE mark availability published $$$$$ $$$$$ $$$$$ $$$$ $$$$$ $$$$$ $$$$ $$$$$ $$$$$ $$$$ $$$$$ Series A Series B Series C Gebert Ruef 8 Million 18.6 Million 25 Million cash award CHF CHF CHF

CTI start-up label

info, that it gives you dynamic behavior market, he states that Sensimed have the knowledgebase, discriminate the information – such as how IOP drops “good visibility; we’ve put out papers, patient’s condition, and give guidance when the patient wakes up.” Others abstracts, white papers, and presented to offer the best treatment. The total need more time, and education, to at the big congresses.” solution.” Investors agree; Sensimed understand the utility of our device. has achieved Series C funding of CHF “Currently, ophthalmologists look at Future Plans 25 million this year, and the future the optic nerve, try a treatment, give it Sensimed doesn’t actually want won’t involve just IOP measurement six months, reassess, and repeat; it’s trial to be a device company; rather, it in glaucoma. “The sensor technology in and error,” he states. “With Triggerfish, sees itself as a knowledge company. Triggerfish can be used for a number of we show how the eye adapts to “There is huge potential in the disparate applications, from measuring physiological stress, and we’re seeing information,” says Wismer. “We have intracranial pressure in the intensive different profiles in different disease a centralized registry, where data care unit, to sensing humidity changes states – indeed, we can identify the can be automatically uploaded and in building walls,” explains Leonardi. disease from the profile.” Can glaucoma examined by our algorithms. We have So, while device development, really be reclassified according to the statistics – constantly being updated – integrating the best of engineering, profiles and is IOP valid for diagnosis? that determine what has worked best and clinical research will continue to be “I don’t think we’re quite there yet,” is previously, meaning that we can inform a focus, there is no doubt in Wismer’s Leonardi’s answer. “We are just about treatment choice.” mind what is most important. “It’s the to differentiate between stable and How will that impact on the knowledgebase that we’re building,” progressing patients, and to predict company’s development? “In five years’ he says. “That’s where our value will at-risk patients who will progress to time,” he states, “we want to supply the come from. Applications age like fish; glaucoma.” In terms of educating the device, generate the profile, maintain information ages like wine.”  Travel Award

Case Studies will be judged by How Do You Identify a panel of experts based on: and Manage DME? Initial Diagnosis of DME • How adequately the patient’s initial Share your knowledge and win a trip to DME was characterized • What characteristics changed to Chicago to attend AAO 2014 warrant an intervention

Long-term Management of DME • What management strategies were With Diabetic Macular Edema (DME) increasing in prevalence, a major employed before and after the patient question facing ophthalmologists today is how to manage insufficiently was diagnosed responsive, long-term cases. There are treatment options, but when should a • Characterization of the patient’s patient be considered unresponsive? What diagnostic criteria provide useful response and subsequent lack of categorization of the patient population? What readouts of responsiveness response to therapies to therapy are most reliable? Progression of DME To help stimulate discussion of best practice within the community, • Considerations made – and The Ophthalmologist is organizing a competition for Case Study reports treatment strategies employed – in that address DME management. the management of patients who failed to sufficiently respond to The five leading entries will be published as part of a feature in the print current therapies edition The Ophthalmologist, and the authors will be invited to attend the • Criteria generated that might enable 2014 Annual Meeting of the American Academy of Ophthalmology, to easier or better diagnoses of be held in Chicago, October 18–21, as our guests. Flights, accommodation subsequent patients as being and delegate fees will be covered. insufficiently responsive to current therapies The ten best submissions will be published online at: • Recommendations for a physician www.theophthalmologist.com. treating a patient presenting with an identical case Case reports should include relevant positive and negative findings from history, examination and investigation, and should include Management of Side Effects clinical photographs. • Cerebro- or cardiovascular side effects • Cataract extraction The closing date for submission is March 31, 2014. • Assessment of patient for steroid- Full information on how to submit your entry can be found at induced changes in intraocular www.theophthalmologist.com/travel-award pressure • Recommendations to ensure Submit your Case Study today and help the ophthalmology community to intravitreal steroids are used identify and manage patients with DME. appropriately, safely and effectively Five x first prizes of flights, accommodation and delegate fees for AAO 2014

Enter online at: theophthalmologist.com/ travel-award In collaboration with

Sponsorship for these travel awards, including funding for travel, accommodation, and registration, is kindly provided by Alimera Sciences Limited. The Eminence of Eye Tech

Rolf Schwind, CEO, SCHWIND eye-tech- solutions GmbH & Co. KG Sitting Down With 59

What is SCHWIND eye-tech-solutions versions, with 1050, 750 and 500 Hz innovation. The five key values that define known for? repetition rates. our daily work are motivation, integrity, We develop, produce and market a teamwork, openness and determination. comprehensive product portfolio for Can you tell us about the early days of Interdepartmental and interdisciplinary the treatment of ametropia and corneal the company? When did you join? collaboration is the norm and employees diseases. This includes diagnostic It was founded in 1958 by my father, are encouraged to apply for patents and systems, software modules for individual who was an ophthalmic practitioner. publish research articles. treatment planning, and nanosecond The company initially concentrated and excimer laser systems. on glasses as the solution for visual Where are your major markets? SCHWIND is known as an owner- deficiencies – he specialized mainly in To date, more than 1,300 SCHWIND operated family enterprise whose products diagnostics, equipping eye doctors and laser systems have been installed are synonymous with precision, safety and eye clinics with examination units – but worldwide. Customers include eye predictability of treatment results. it grew to become an all-round provider surgeons in ophthalmology practices, laser of diagnostic systems. clinics and university hospitals. Our major How do you stay at the forefront of Two innovations established the market bases are Europe, Latin and South the sector? company as a pioneer within the America, and the Far East. Asia has seen Ours is a niche strategy in a market industry in Germany. The first central strong growth in recent years. mainly dominated by multi-national, examination unit for ophthalmologists listed corporations. We concentrate on was introduced in 1966, and was Not the United States? corneal refractive surgery and we are followed in 1972 by the launch of the No. While the technical and committed exclusively to our customers. first soft contact lens, through former organizational requirements for approval Our energy is devoted to developing affiliate company Titmus Eurocon. of the SCHWIND AMARIS excimer innovative solutions, and we place I joined the company in 1984 as laser are nearly identical in Europe and the continuity and reliability ahead of short- soon as I had completed my university US, the Food and Drug Administration term profits. entrance diploma and studies in Business (FDA) requires additional hurdles to be The company has tremendous expertise Administration, and performed cleared. We estimate that a minimum and abundant in-house experience, and community service. From Day One I investment of $12 million and three years we perform our development work in focused all of my energy on the goal of of work would be needed to gain approval. close co-operation with internationally- improving vision. In 1985, I assumed This is not an attractive proposition for a renowned refractive surgeons. The the position of managing partner of the medium-sized company like mine; our resulting technological innovations SCHWIND company. priority is to invest in the continuous are backed up by intensive support development of our technology, to benefit through application and service, and At what point, and why, did the company the surgeon and, ultimately, the patient. by a very responsive approach to the commit to high-tech laser systems? needs of individual customers. It is this The first eye correction with a Finally, what do you enjoy most about your combination of factors that is so highly SCHWIND laser took place in 1992. job and what is exciting to you right now? appreciated by our users. Two years later we introduced the first I enjoy the great variety of challenges that passive eye-tracking system. Since 1999, we face, in R&D, in sales, in marketing, What is your most successful product the company has concentrated its entire in application and in service. I also like and why? knowledge and resources on laser surgery. working in so many different countries, it The “Total Tech” SCHWIND AMARIS presents constant challenges and learning excimer laser product family is most Can you give us a snapshot of your experiences. I also take satisfaction in successful. Since its introduction in 2007 company today? ours being a family company that uses it has been the pace-setter in the market, The company employs a highly motivated all the tools at our disposal to challenge establishing itself as the leading eye laser team of more than 100 experts and we are “big business”. What’s exciting me most in the premium segment. We are about represented in more than 120 countries. at the moment is our development of a to expand the product family with the We have an inspiring and creative work nanosecond laser, which is our answer to launch of three additional AMARIS environment that actively promotes the femtosecond laser. VISIT US AT EURETINA BOOTH H136A

RETINAL DISEASE IS OUR FOCUS

At Alimera Sciences, we are dedicated to developing innovative, vision-improving treatments for chronic retina diseases.

Our commitment to retina-treating ophthalmologists and their patients is manifest in a product portfolio designed to treat early- and late-stage diseases such as DMO, wet and dry AMD, and RVO.*

Moving the back of the eye to the forefront of research and development.

© 2013 Alimera Sciences Limited

Date of preparation: September 2013 ILV-00182-ERTA

* DMO-diabetic macular oedema; AMD-age-related macular degeneration; RVO-retinal vein occlusion.