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Home , Amblyopia, Diabetic retinopathy, Keratoconus

SEPTEMBER 2019 # 37

In My View In Practice Profession Sitting Down With Musings of a prospective The app making Why the fight for female Stefanie Schmickler: business- accessible to all leadership is far from over minded, patient-focused

12 – 13 32 – 35 46 – 49 50 – 51

Bringing into Focus

Sharpening up our response to this underdiagnosed condition 14– 26

NORTH AMERICA www.theophthalmologist.com FOR ROTATIONAL STABILITY, THERE’S NO COMPARISON1,2

1. Lee BS, Chang DF. Comparison of the rotational stability of two toric intraocular lenses in 1273 consecutive . . 2018;0:1-7. 2. Potvin R, et al. Toric intraoclar orientation and residual refractive : an analysis. Clin Ophthalmol. 2016;10:1829-1836.

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AcrySof®IQ Toric ASTIGMATISM-CORRECTING IOL

© 2018 Novartis 7/18 US-TOR-18-E-1605

105064 US-TOR-18-E-1605 TO.indd 1 1/30/19 4:04 PM ACRYSOF® IQ TORIC IOL IMPORTANT PRODUCT INFORMATION CAUTION: Federal (USA) law restricts this device to the sale by or on the order of a physician. INDICATIONS: The AcrySof® IQ Toric posterior chamber intraocular lenses are Image intended for primary implantation in the capsular bag of the for visual correction of and pre-existing corneal astigmatism secondary to removal of a cataractous lens in of the adult with or without , who desire improved uncorrected distance vision, reduction of residual refractive cylinder and Month increased spectacle independence for distance vision. WARNING/PRECAUTION: Careful preoperative evaluation and sound clinical judgment should be used by the surgeon to decide the risk/benefit ratio before implanting a lens in a patient with any of the conditions described in the Directions for Use labeling. Toric IOLs should not be implanted if the posterior capsule is ruptured, if the zonules are damaged, or if a primary posterior capsulotomy is planned. Rotation can reduce astigmatic correction; if necessary lens repositioning should occur as early as possible prior to lens encapsulation. All viscoelastics should be removed from both the anterior and posterior sides of the lens; residual viscoelastics may allow the lens to rotate. Optical theory suggests that high astigmatic patients (i.e. > 2.5 D) may experience spatial distortions. Possible toric IOL related factors may include residual cylindrical error or axis misalignments. Prior to , physicians should provide prospective patients with a copy of the Patient Information Brochure available from Alcon for this product informing them of possible risks and benefits associated with the AcrySof® IQ Toric Cylinder Power IOLs. Studies have shown that color vision discrimination is not adversely affected in individuals with the AcrySof® Natural IOL and normal color vision. The effect on vision of the AcrySof® Natural IOL in subjects with hereditary color vision defects and acquired color vision defects secondary to ocular disease (e.g., glaucoma, diabetic , chronic , and other retinal or optic diseases) has not been studied. Do not resterilize; do not store over 45° C; use only sterile irrigating solutions such as BSS® or BSS Fool’s Gold PLUS® Sterile Intraocular Irrigating Solutions. ATTENTION: Reference the Directions for Use This month’s image shows a specimen under the microscope. labeling for a complete listing of indications, Credit: Channdarith Kith, Resident of Ophthalmology, University of Health Sciences, Cambodia. warnings and precautions. Do you have an image you’d like to see featured in The Ophthalmologist? Contact [email protected]

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105064 US-TOR-18-E-1605_PI TO.indd 1 2/6/19 12:11 PM Contents

40

In My View

12 Musings of a Prospective Angle Closure Patient Chelvin Sng charts the rise and fall of LPI – the “gold standard” treatment for angle closure disease – and explains why she is looking forward to the 10 bespoke glaucoma management approaches of the future

03 Image of The Month Upfront Feature

08 Corneal Construction 14 Bringing Keratoconus 07 Editorial into Focus CXL Unbound, 09 A New Purpose With prevalence between three by Farhad Hafezi and 100-times higher than once 10 Bitesize Breakthroughs believed, early identification of keratoconus has never been more important. We bring On The Cover together the leading lights

SEPTEMBER 2019 # 37 of the field to explain why

In My View In Practice Profession Sitting Down With Musings of a prospective The amblyopia app making Why the fight for female Stefanie Schmickler: business- glaucoma patient screening accessible to all leadership is far from over minded, patient-focused

12 – 14 34 – 37 46 – 49 50 – 51 Seeing the world through timely treatment is key to the Bringing Keratoconus into Focus

Expert views on how to tackle the corneal disorder that is a lot more common than previously thought 16– 27 keratoconic eyes prevention of vision loss

NORTH AMERICA www.theophthalmologist.com ISSUE 37 - SEPTEMBER 2019 Editor - Aleksandra Jones [email protected] Deputy Editor - Phoebe Harkin [email protected] Content Director - Rich Whitworth [email protected] Publishing Director - Neil Hanley [email protected] Business Development Executive, Americas- Ross Terrone [email protected] Associate Publisher - Sam Blacklock [email protected] Business Development Executive- Paul Longley [email protected] Head of Design - Marc Bird [email protected] Designer - Hannah Ennis [email protected] Designer - Charlotte Brittain [email protected] 32 Digital Team Lead - David Roberts [email protected] Digital Producer Web/Email - Peter Bartley [email protected] Digital Producer Web/App - Abygail Bradley [email protected] In Practice Audience Insight Manager & Data Protection Officer- 50 Tracey Nicholls [email protected] 30 Just Asking Traff ic & Audience Database Coordinator - Hayley Atiz [email protected] The Advanced Glaucoma Project Manager - Webinars - Lindsey Vickers Technologies Forum audience [email protected] put questions to our expert panel, Traffic Manager - Jody Fryett [email protected] tackling everything from drug Traffic Assistant - Dan Marr delivery to artificial intelligence [email protected] Events Manager - Alice Daniels-Wright [email protected] 32 Tackling the Event Coordinator - Jessica Lines Global Vision Crisis [email protected] Of the nine million people Marketing Manager - Katy Pearson [email protected] living in Mumbai’s slums, Social Media Manager - Joey Relton only 48 percent have access [email protected] to healthcare facilities. Darcy Marketing Executive - Sarah Botha [email protected] Wendel presents the app Profession Financial Controller - Phil Dale making vision screening [email protected] accessible to all 46 F emale Leadership – is it in Accounts Assistant - Kerri Benson [email protected] Good Health? Senior Vice President (North America) - Fedra Pavlou Louisa Wickham explains why [email protected] we need diversity in ophthalmic Chief Executive Officer - Andy Davies [email protected] NextGen leadership – be it gender, Chief Operating Officer - Tracey Peers ethnicity or disability – in [email protected] 40 Pouring Oil on order to deliver the level of care Change of address/General enquiries [email protected] Troubled patients deserve The Ophthalmologist, Texere Publishing, 175 Varick St, New York, NY 10014. Silicone oil tamponades can +44 (0) 1565 745 200 inhibit scar tissue formation [email protected] Distribution in patients with a high risk of The Ophthalmologist North America (ISSN 2398-9270) is published monthly by Texere retinal scarring after retinal Sitting Down With... Publishing, 175 Varick St, New York, NY 10014. Single copy sales $15 (plus postage, cost available on detachment. But how much request [email protected]) more effective would these 50 S tefanie Schmickler, CEO of Non-qualified annual subscription cost is available on request Reprints & Permissions – [email protected] products be if they also Augen Zentrum Nordwest in The opinions presented within this publication are those of the authors and do not reflect the opinions of The Ophthalmologist or its publishers, Texere Publishing. delivered antifibrotics? Germany and Deputy Editor of Authors are required to disclose any relevant financial arrangements, which are presented at the end of each article, where relevant. Victoria Kearns investigates GMS Ophthalmology Cases © 2019 Texere Publishing Limited. All rights reserved. Reproduction in whole or in parts is prohibited.

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Find Your Wow Moment at www.YourWowMoment.com CXL Unbound Editorial What drives progress in medicine? Identifying and meeting unmet needs

ometimes, the sheer scale of an unmet need can surprise you. For many years, keratoconus was thought of as a rare disease: in 1986, a paper reported that 1 in 2,000 people Sin Olmstead County, Minnesota, had keratoconus. And that figure stuck for at least 30 years. But modern diagnostics revealed a different story. Keratoconus rates are higher – and vary by continent and climate. And that’s why efforts like the K-MAP global keratoconus prevalence study are so important; accurate data reveals the true unmet need. Can we improve how we treat keratoconus? It’s worth recognizing the work of Brillouin biomechanics researchers, such as J. Bradley Randleman and Giuliano Scarcelli, who are leading the way with accurate in vivo clinical assessments of corneal biomechanics. Their work dovetails perfectly with the efforts of others, such as Cosimo Mazzotta, who are trying to develop new “epi-on” CXL approaches that we hope someday will be as effective at stiffening the as the current gold-standard: “epi-off ” CXL. Education is vital too; I’d like to show appreciation for the dedication and leadership in training surgeons to perform best-practice CXL: José Álvaro Gomez, Nikica Gabrić, Adrian Lukenda, Qinmei Wang, Shihao Chen, Khaled Ayesh, Bojan Pajic, Gerd Geerling, Reza Dana, Oliver Findl, Heinrich Gerding, Mohammed Shafik Shaheen, Mouhcine El Bakkali, Anssi Poussu, Kamoun Heykel, Mahfoudi El Hadi, and Rohit Shetty. But this all for nothing, if people aren’t screened, identified, and able to access treatment. The biggest barrier? CXL is performed in an operating room. Certainly, operating rooms have the advantage of being sterile, but they are also costly and typically found only in primary care centers. What happens if you live in a rural area of a developing country and suffer progressive keratoconus but either cannot reach the hospital or cannot afford treatment? We know that CXL renders the cornea sterile – so why perform the procedure in the OR? Why not treat at the humble – found in every ophthalmologist’s office? Now that a slit lamp cross-linking device is available, CXL can be performed almost anywhere, reducing the cost of treatment for patients. I view this as democratization of CXL. CXL might yet be surpassed. A better basic understanding of the cornea – from the level of the gene upwards – could reveal new therapeutic avenues and better fulfil our patients’ unmet needs. But, in the meantime, knowing we’re able to do more – for less – means a lot.

Farhad Hafezi, Guest Editor Professor, University of Geneva and Medical Director at the ELZA Institute, Zurich, Switzerland

www.theophthalmologist.com 8 Upfront

unique? “Some researchers have developed Corneal artificial using and alginate Upfront hydrogel, but the layers of these corneas are Construction easily peeled apart, so the structure cannot be Reporting on the sustained,” he says. “Others have developed Researchers fine-tune 3D corneas with good cellular performance, yet innovations in medicine printing technology to fabricate the actual cornea remains opaque.” and surgery, the research better biomimetic corneas – To address these concerns, the team policies and personalities and predict a “breakthrough” started fine-tuning the printing process, in transplantation practice that shape the practice using different sized printing nozzles to around the world manipulate the arrangement of collagen of ophthalmology. fibers – a process not without its own Corneal diseases are responsible for around challenges. “One of our concerns was We welcome suggestions five percent of blindness worldwide, that different levels of sheer stress would on anything that’s but a shortage of corneas suitable for cause cellular , cell-cycle arrest, transplantation, particularly in the or cytoskeletal network alteration,” says impactful on developing world, leaves patients waiting Cho. Fortunately, the team were well ophthalmology; an average of five years for surgery (1). As prepared; they’d previously developed a please email edit@ a consequence, research teams around the qualified corneal bio ink and 3D printing theophthalmologist.com world are in competition to develop artificial system, so only minor modifications corneas that are suitable for mass production. were required. Could 3D printing win the race? Dongwoo Cho, Professor of Mechanical References Engineering at Pohang University of Science 1. World Health Organisation, “Priority Eye Diseases: and Technology in South Korea certainly Corneal Oppacities” (2019) Accessed June 12, 2019. believes so. “Many artificial corneas and 2. H Hong et al., “Compressed collagen intermixed associated studies are based on synthetic with cornea-derived decellularized extracellular biocompatible materials, yet studies have matrix providing mechanical and biochemical niches reported severe side effects,” says Cho. for corneal stroma analogue”, Mat Sci Eng, 103, “To overcome such limitations, we have 109837 doi: 10.1016/j.msec.2019.109837(2019) developed tissue-engineered corneas with 3. H Kim et al., “Shear-induced alignment of collagen 3D cell printing technology (2, 3).” fibrils using 3D cell printing for corneal stroma Cho’s team is not the first to trial such tissue engineering”, Biofabrication, 11, 035017 approaches, so what makes their work (2019). PMID: 30995622. Is there any prior research on montelukast First, by preventing leakage of vessels, A New Purpose being applied to ? which makes them more susceptible to No. But the is nervous system tissue degeneration through cysteinyl leukotriene Could an FDA-approved and montelukast has been shown to help receptor 1. Second, by blocking the medication offer protect in models of other diseases, generation of leukotriene B4. a therapeutic pathway for such as neurodegenerative diseases by diabetic retinopathy? multiple sclerosis. How soon do you think you’ll be able to translate the study to human subjects? Montelukast – a leukotriene inhibitor How significantly did the drug affect We have a manuscript in preparation that – is well known to asthma sufferers, degeneration in the study? looks at the leukotriene cascade in white who benefit from its proven ability Montelukast dramatically helped reduce blood cells from human subjects, which to prevent wheezing and shortness damage to retinal blood vessels. In , is the first step to translate the findings. of breath. But researchers believe it the small blood vessels or capillaries first We have more clinical studies planned may have a new indication: diabetic degenerate – this sets up areas of poor blood in the coming year. retinopathy. A team at the University flow in the retina and, in time, this leads to Hospitals Rainbow Babies and advanced diabetic where vessels What are the benefits of Children’s Hospital and Case Western try to grow back. As a result, they end up repurposing medication? Reserve University School of Medicine growing aberrantly – it is called proliferative Repurposing significantly speeds up the studied the effect of montelukast on diabetic retinopathy – so much so that vessels timeline to treatment of a new disease. All diabetic retinopathy – a condition can be easily damaged, which might result of the safety studies required of medications characterized by neuronal and in retinal hemorrhages that cause vision have been completed, so we can go straight vascular degeneration – using a mouse impairment. Montelukast worked to almost to advanced clinical trials. A benefit of the model of . The results completely prevent the diabetes-related drug is that you can orally administer it were impressive: after nine months, degeneration of capillaries and reduce the as a tablet once a day – no injections or the retinal microvasculature from generation of VEGF, which causes the procedures are necessary. We envision untreated diabetic mice demonstrated vessels to try and grow back erratically. using this someday as preventative a nearly threefold increase in capillary Where are concerned, Montelukast medication, starting in adolescence. With degeneration compared to mice treated did help with survival of neurons long a safe profile and daily dosing, there are with montelukast. We spoke to senior term, but short-term studies did not show few drawbacks to trying montelukast! author Rose Gubitosi-Klug, Chief significant improvement in function. More of Pediatric Endocrinology at UH research is needed to understand this finding. Reference Rainbow and the William T. Dahms 1. R Bapputty et al., “Montelukast Prevents Early Professor of Pediatrics at CWRU School What is the mechanism of action? Diabetic Retinopathy in Mice”, Diabetes, 98, 8 of Medicine, to find out more. We believe it works in a couple of ways. (2019). PMID: 31350303.

www.theophthalmologist.com 10 Upfront

Bitesize Breakthroughs

The latest ophthalmology research – in brief not for long. Researchers at the disease, on the ocular surface. By University of Washington have comparing the results of three models 1. Statins are commonly prescribed found a way to accommodate (a healthy eye, an eye with dry eye, for lowering cholesterol – but new aberrations. Using a combination of and an eye with dry eye plus lubricin) research may signal an alternative filters, lens distances and multiple the team were able to further our use. A recent study by Brigham and color illumination, the team has understanding of how lubricin works Women’s Hospital has found that developed a new customizable – and show the drug’s promise as a long-term statin use could strengthen imaging system that cancels out a treatment. The eye-on-a-chip method the neuroprotective mechanisms that person’s unique chromatic optical also offered insight on an unexpected prevent degeneration of the optic aberrations, allowing for a more subject: the eye itself. During the nerve, effectively lowering glaucoma accurate assessment of vision and eye study, the researchers found that risk. Researchers monitored 136,782 health. The team incorporated a new corneal cells become specialized at patients – 886 of which had primary optical assembly with conventional their particular jobs faster when the open-angle glaucoma – over a 15- adaptive optics instruments to artificial is blinking on top of year period. They discovered that produce individually tailored high- them, suggesting that mechanical participants who used statins for resolution, multiple-wavelength forces contribute significantly to how five years or more experienced a 21 pictures of the smallest cone cells function. Dan Huh, Associate percent lower chance of glaucoma photoreceptors in the eye, measuring Professor in the Department of than those who had never used just 2 microns across. The method Bioengineering, helped design statins. Interestingly, every 20 mg/ successfully overcame inconsistencies the eye-on-a-chip platform, and is dL increase in cholesterol level was in previous estimates of the human pleased that it has proved its worth: associated with a 7 percent increase eye’s native LCA related to depth “We are particularly proud of the in glaucoma risk. “As high cholesterol of focus, monochromatic aberration fact that our work offers a great and and statin use have been associated and wavelength-dependent light rare example of interdisciplinary with other neurodegenerative interactions with retinal tissue. The efforts encompassing a broad diseases, the interrelationship between team hope the breakthrough will lead spectrum of research activities, from cholesterol, glaucoma and these to new insights on visual halos, glare the design and fabrication of novel outcomes is also fertile ground for and color perception, as well as the bioengineering systems to in vitro further scientific inquiry,” commented effect of aging on the eye. modeling of complex human disease the paper’s lead author, Jae Hee Kang, to drug testing.” an Associate Professor of Medicine at 3. A team of University of Pennsylvania Brigham and Women’s Hospital (1). engineers has designed the world’s References first artificial -on-a-chip 1. J Kang et al., “Association of Statin Use and High 2. Like any optical element, the human – complete with blinking lid. The Serum Cholesterol Levels with Risk of Primary lens contains aberrations, which can chip acts as an animal-free drug Open-Angle Glaucoma”, JAMA Ophthalmol, 137, degrade the images received by the testing platform, made of a porous, 756 (2019). PMID: 31046067. retina and affect the images seen by 3D printed scaffold covered in 2. X Jiang et al., “Measuring and compensating clinicians during eye examinations. specialized corneal and conjunctival ocular longitudinal chromatic aberration,” Optica, Attempts to compensate for tissue. The lid – a mechanized gelatin 6, 8, 981 (2019). longitudinal chromatic aberrations slab – spreads artificial tear secretions 3. Penn Today, “Blinking eye-on-a-chip used for (LCA) have so far been based on with each blink. The design was disease modeling and drug testing” (2019). calculations for the “average” eye, used to study the impact of lubricin, Available at: https://bit.ly/2KDxlOC. Accessed but the results are variable. But a promising treatment for dry eye August 8, 2019. Sponsored Feature 11 

link between patients and exudates. We hope A Meeting healthcare providers. that the support provided by the of Minds Torres-Netto Does the Fellowship will allow technology work in remote us to perfect it soon. The winners of the ICO-Allergan areas? I’ve been to the Amazon Advanced Research Fellowship… a few times to perform surgery and Torres-Netto That is exactly what the in conversation I know it can be difficult to send data. Fellowship is there for: allowing researchers to take their work to the next level. Matias Iglicki, the latest recipient of Iglicki The process itself is quite simple – the ICO-Allergan Advanced Research patients only require an ID to take part. It Iglicki And tackle unmet needs. It’s an Fellowship, meets last year’s winner, Emilio is also simple from a clinical point of view, altruistic program. Where are you Torres-Netto, to discuss the award, their there is no need for a specific device – an with yours? work and the future of ophthalmology in iPhone could take the retina photo – so the developing world. it could be done anywhere. Torres-Netto Last year, we ran a study in Saudi Arabia, which we are now amplifying Matias Iglicki Emilio, how has the award Torres-Netto A direct approach! What worldwide. We have established that helped you? would happen to the patients if they were keratoconus is not a rare disease, merely not identified and did not have laser? underdiagnosed. Our study found a Emilio Torres-Netto It has certainly supported 100-times higher prevalence in some areas. me financially. Zurich [where Torres-Netto Iglicki In Buenos Aires, is a completed his masters] is an expensive city first-line treatment for the majority of DR Iglicki Do you treat the patients as well? and the award was invaluable in helping patients. The government even pays for me stay and continue my project. It also patients in the North to fly to the capital Torres-Netto Because it’s a global project, we funded the eye rubbing machine we for the procedure. The whole trip costs cannot afford to cross-link every patient. We used to study the effect of pressure on around $10,000 – excluding the cost of handle screenings – any patient between the keratoconus. Without the grant, it would social security benefits – and the prognosis ages of 6 and 21 – but the individual site is have been very difficult to fund. Why did is not even good! Our approach would be responsible for the treatment. you apply for the Fellowship? significantly more affordable, costing just $50 for laser and avoiding 85 percent of Iglicki Because at 30, progression more Iglicki The project actually started in 2004 — vitrectomies. DR is a huge unmet need, not or less stops, doesn’t it? 15 years ago – when we began working on just in developing countries like Argentina. an algorithm to detect diabetic retinopathy The US is currently experiencing a DR Torres-Netto Correct. Sometimes it is (DR). Like your project, costs are high as we epidemic. Many patients don’t even realize obvious that a person has keratoconus, need engineers and IT technicians to work they are diabetic, despite having had the but at other times it requires a more on the database. The support will help us condition for 30 years or more. But if they in-depth analysis. It can take a while to do. advance enormously by funding technicians had just seen a physician, that wouldn’t to improve the algorithm we already have. be the case. Timing is key with DR. The Iglicki You need an algorithm like ours… sooner the condition is identified, the Torres-Netto Where do you find sooner we can perform laser surgery and Torres-Netto We do – you are a worthy your patients? halt disease progression. That’s what we successor! set out to accomplish and we are very Iglicki Mainly in general practitioner clinics confident we will do it. Iglicki And we haven’t even started yet! and city halls. Our project works by Thank you so much for your feedback. identifying diabetic patients when they go Torres-Netto What are you working on now? Do you mind if we stay in touch? I would to renew their ID or driving license. Our love to have you input. algorithm scans their picture for signs of Iglicki The algorithm still requires a little DR – if any is found, they are sent to the work. While it works perfectly with some Torres-Netto Not at all. I would be happy ophthalmologist. It is our way of closing the patients, it struggles with lesions, such as to help.

www.allergan.com 12  In My View

glaucoma or raised IOP (1). Surveys show Musings of that 84.9 percent of ophthalmologists In My in Singapore (2) and 75 percent in the a Prospective would advise LPI for PACS (3). View Angle Closure Though I had resigned myself to Patient undergoing LPI at some point in my life, In this opinion section, truthfully, I have never been a fan of the laser procedure. The efficacy and safety experts from across the The “gold standard” of prophylactic LPI has not been well world share a single treatment for angle closure established, and LPI has been associated strongly-held view or disease is evolving – and it is with corneal decompensation, linear a welcome change key idea. photopsia and raised IOP (1). In addition, LPI only eliminates block, leaving other mechanisms unaddressed. It is for Submissions are welcome. this reason I welcome the findings of the Articles should be short, Zhongshan Angle Closure Prevention focused, personal and (ZAP) Trial, which showed that, even with observation, the incidence of angle passionate, and may closure disease was very low among deal with any aspect individuals classified as PACS (<1 of ophthalmology. percent per year). As the prophylactic They can be up to effect of LPI was modest (albeit 600 words in length and written in the first person. “The efficacy Contact the team at edit@ theophthalmologist.com and safety of By Chelvin Sng, Consultant prophylactic LPI Ophthalmologist, National University Hospital, Singapore; Assistant Professor has not been well at the National University of Singapore. established, and My interest in angle closure disease is both professional and personal. As LPI has been an Asian woman with a strong family history of glaucoma – my mother had associated bilateral acute primary angle closure (APAC) and my father is a primary angle with corneal closure suspect (PACS) – irido-trabecular contact seems written into my genetic decompensation, code. When I first embarked on my residency 15 years ago, laser peripheral linear photopsia iridotomy (LPI) was regarded as the “gold standard” treatment for angle and raised IOP (1).” closure disease, even in the absence of In My View  13

surgeons who had completed training patient. Using pre-treatment anterior in both general ophthalmology and segment OCT scans, we have developed “A limitation of glaucoma (5). an algorithm that predicts the efficacy Comparing phacoemulsification alone of LPI in PACS eyes, with predictive most studies, with combined phacotrabeculectomy in accuracy that is superior to fellowship- the treatment of medically controlled trained ophthalmologists (8). For including the ZAP primary angle closure glaucoma (PACG) personalized treatment to become a with coexisting , the combined reality, further research into mechanism- and EAGLE procedure has been shown to reduce specific treatment is required. And when the requirement for topical glaucoma I finally develop angle closure in the not- trials, is the medications, but was associated with too-distant future, I certainly hope for more complications and additional surgery management bespoke to my anterior exclusion of in the postoperative period (6). MIGS segment anatomy. procedures may have a role in reducing anterior segment the glaucoma medication burden in References PACG eyes, with reduced complications 1. P Chew et al., “Surgical treatment of angle- imaging in the compared with trabeculectomy. In an closure glaucoma”, Dev Ophthalmol, 50, 137 exploratory study, we have shown that (2012). PMID: 22517180. protocol, making it combined iStent implantation with 2. MH Ang et al., “National survey of cataract surgery was effective in lowering ophthalmologists in Singapore for the assessment impossible to the IOP and the number of glaucoma and management of asymptomatic angle closure”, medications in eyes with primary angle J Glaucoma, 17, 1 (2008). PMID: 18303375. determine the closure disease for at least 12 months, 3. HG Sheth et al., “UK national survey of with a favorable safety profile (7). prophylactic YAG iridotomy”, Eye, 19, 981 mechanisms of Further randomized trials are required (2005). PMID: 15375356. to determine the additional benefit 4. M He et al., “Laser peripheral iridotomy for the angle closure.” of MIGS in PACG eyes undergoing prevention of angle closure: a single-centre, cataract surgery. randomised controlled trial”, Lancet, 393, 1609 A limitation of most studies, including (2019). PMID: 30878226. significant), widespread prophylactic the ZAP and EAGLE trials, is the 5. A Azuara-Blanco et al., “Effectiveness of early LPI for asymptomatic PACS was not exclusion of anterior segment imaging lens extraction for the treatment of primary recommended on a population basis (4). in the protocol, making it impossible angle-closure glaucoma (EAGLE): a randomised Even in the presence of raised IOP and/ to determine the mechanisms of angle controlled trial” Lancet, 388, 1389 (2016). or glaucomatous , LPI closure. It is well established that PMID: 27707497. is no longer considered the treatment of PACG is a heterogenous disease with 6. CC Tham et al., “Phacoemulsification versus choice. In the EAGLE trial, clear-lens various mechanisms, including pupil combined phacotrabeculectomy in medically extraction showed greater efficacy and block, bulky lens, plateau and thick controlled chronic angle closure glaucoma with was significantly more cost-effective than peripheral iris roll. If a large proportion cataract”, Ophthalmology, 115, 21677 (2008). LPI. Significantly fewer participants in of study participants had bulky lenses, PMID: 19243831. the clear-lens extraction group required the results would likely favor lens 7. D Hernstardt et al., “Case series of combined any treatment to control IOP and the extraction over LPI. These findings are iStent implantation and phacoemulsification in mean number of glaucoma medications unlikely to be applicable to eyes with a eyes with primary angle closure disease: one-year required at 36 months was significantly significantly convex iris configuration outcomes”, Adv Ther, 36, 976 (2019). PMID: lower compared with the LPI group and minimal lens vault, which indicate 30820873. (0.4±0.8 vs 1.3±1.0, p<0.0001). The a predominantly pupil block mechanism. 8. V Koh et al., “Predicting the outcome of laser frequency of complications associated In the age of personalized medicine, peripheral iridotomy for primary angle closure with clear-lens extraction was low, I hope that angle closure treatment will suspect eyes using anterior segment optical though this may be because the evolve to address the specific anatomical coherence tomography”, Acta Ophthalmol, 97, 1, were performed by experienced characteristics and mechanism of each 57 (2019). PMID: 30284403.

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Feature 15

BRINGING KERATOCONUS INTO FOCUS

THE SOONER, THE BET T E R but only in cases when there is vision loss or irregularity of the cornea. And maybe we should. My colleague’s 19-year-old son Why early screening is essential in the fight recently developed increased astigmatism in one of his eyes. against keratoconus His eye doctor was wise enough to know that, when patients experience a significant change in astigmatism, you should perform By William Trattler a topography screening. And it was fortunate he did; the doctor diagnosed very early stage keratoconus. As with all eye conditions, Identifying keratoconus early is our biggest challenge, as changes knowing when – and who – to test is critical. in corneal shape typically occur before there is a loss of best- Early intervention is crucial; the sooner we catch the condition, corrected vision. As well, the slit lamp exam is typically normal the sooner we can perform cross-linking to stabilize the cornea in mild keratoconus as well as in many cases with even moderate and prevent progression. Though we can cross-link patients with keratoconus. Since loss of best-corrected vision is often a later moderate to advanced keratoconus who have already experienced consequence, patients with keratoconus can often have the vision loss, they may be forced to wear special contact lenses condition for a significant period of time or experience significant or . And that’s why clinicians are trying to catch people changes in corneal shape before they are diagnosed. There are a before their best-corrected vision drops to 20/40 or 20/60 – we few reasons for this: first, it takes a while for patients to recognize want to diagnose them when they are still 20/20. If we want our their sight has changed, and even longer for them to decide to patients to lead a normal life, we need to be responsive to any see an ophthalmologist or optometrist. Since keratoconus can be subtle suggestion that keratoconus may be present. If patients asymmetric, some patients can see and function normally with experience a significant shift in astigmatism power or axis, screen their less affected eye despite the contralateral eye experiencing them with topography. significant loss of vision. Second, when patients with early Unfortunately, a lack of affordable equipment is holding us keratoconus who still have good vision see an , back. Not every eye care location has topography available – and they often only undergo a standard eye exam, where early signs even those with the right technology may not offer it to every of keratoconus are easily missed. As a result, many patients with patient. My hope is that industry helps create affordable devices, so keratoconus are actually only diagnosed at eligibility screenings that patients and eye care providers everywhere can have access to for refractive or cataract surgery when a screening topography screening tests. I’m currently working with a company to develop is performed. Unexpectedly, these exams have become a useful an inexpensive topography unit that will hopefully cost around means of catching keratoconus in a mild or earlier stage, before a thousand dollars with a small monthly cost for cloud-based the condition becomes too advanced. integrated AI – affordable for even the smallest practice. The issue of keratoconus diagnosis is shared by optometrists and ophthalmologists alike. The fact is that we do not offer routine William Trattler is a cataract, corneal and refractive specialist at topography screenings to every patient who enters our clinics, the Center for Excellence in Eye Care in Miami, Florida, USA.

www.theophthalmologist.com “Risk amelioration strategies include treatment of the post-

THE MODIFIED EPI-OFF PROTO C O L operative ocular surface with prophylactic steroid How to avoid the complications of -off cross-linking – but this can interfere By Neel Desai with post-operative I see many keratoconus cases in my referral-based practice here re-epithelialization.” in Tampa, Florida – but, locally, the lion’s share of this condition is found within the practices of primary care ophthalmologists and optometrists. We’ve made significant efforts to educate these colleagues with regard to keratoconus identification; the diagnostic criteria we recommend to them include rapidly shifting for wound coverage and comfort, but some patients unavoidably will that are not refractable to 20/20, better vision with hard rather develop side-effects. Risk amelioration strategies include treatment than soft contacts, atopic or , , of the post-operative ocular surface with prophylactic steroid – but and eye-rubbing habits. Our broad aim is to help primary care this can interfere with post-operative re-epithelialization. In this physicians screen their patients and identify keratoconus as early as way, the net effect of the epi-off cross-linking approach is to set up possible. And it’s working – we see far more cases today than a few some patients for chronic non-healing epithelial defects, infectious years ago. In fact, I’d say we get about 25 to 50 newly-diagnosed keratitis, scarring and potential long-term visual decline. keratoconus patients in any given month. But once we have identified keratoconus, how should we Put on Prok e r a manage it? The epithelium-on (“epi-on”) method is used in Europe but is not yet approved in the US market; here, therefore, the Therefore, while epi-off is generally very safe and beneficial, standard approach remains “epi-off” cross-linking. The epi-off my view is that it is associated with risk factors that we should technique has been approved by the FDA on the basis of efficacy modulate if we can. Consequently, I have modified the way I data showing good riboflavin penetration into both anterior and perform cross-linking for keratoconus as follows: posterior stroma. Unfortunately, this method has some attendant issues that we must manage carefully. • during the cross-linking step, I mask the corneal limbus with a custom-cut, doughnut-shaped sponge that blocks UV Put off by epi-o f f ? light, thereby protecting limbal stem cells while still allowing riboflavin to cross the cornea and penetrate the stroma; Briefly, the epi-off technique comprises creation of a limbus-to- • after surgery, I monitor limbal stem cell progression and limbus epithelial defect followed by 30 minutes of UV irradiation. re-epithelialization: Inevitably – since there’s no standardized protocol for masking • if there is no progress at 24 hours, I apply a the corneal limbus from the UV light – the limbal stem cells are Prokera immediately also UV-irradiated throughout this time. Furthermore, given that • if progress is normal at 24 hours, I continue the protocol involves thirty minutes of induction with riboflavin to monitor them, and apply a Prokera if re- followed by thirty minutes of UV light, the eye is exposed to air epithelialization is not complete by 3-5 days. – without blinking – for a total of an hour or more. Thus, the epi- off procedure increases the risk of ocular surface inflammation, About 10-15 percent of my patients end up getting a Prokera particularly in predisposed patients; we can provide a with this protocol. Why Proke r a ? MORE AWARENESS, MORE DIAGNOSIS For me, Prokera is more than just an amniotic membrane – the cryopreservation-based manufacturing process preserves Desai has done a lot to raise awareness of bioactive molecules, notably high molecular weight compreses keratoconus in Tampa, Florida – but what about (HCHA) and PTX-3, such that these are delivered to the the rest of the US? Is it fair to say that too many ocular surface along with Prokera. These molecules have potent patients are being diagnosed too late? anti-inflammatory and pro-healing properties; for example, they are known to stimulate limbal stem cell expansion and Our community is probably unique in the US in terms of nerve regeneration. In consequence, they promote tissue repair, the effort we have made to provide keratoconus education prevent scarring and corneal haze, reduce the activation of to local optometrists, ophthalmologists, primary care inflammatory cells, assist in the management of post-surgical physicians and pediatricians. We really encourage them conditions (such as neurotrophic cornea or neurotrophic ulcer), to screen for keratoconus in younger increase goblet cell density and relieve dry eye symptoms. people – we want to catch patients as teenagers if we can – In other words, Prokera is a delivery device for bioactive and I think we’ve had a significant impact. But our situation molecules that mitigate the side-effects of the standard epi- is not representative of the US at all – it’s actually rather off collagen cross-linking protocol, offering broad benefit to atypical. To make changes at a national level will require the post-surgical ocular surface. No longer must we depend far more publicity and media attention, which seems to on steroid-mediated reduction of inflammation at the cost be the most effective way to encourage doctors to look of inhibited re-epithelialization. Furthermore, the well- for keratoconus cases and refer them to specialists. Even preserved cellular architecture of Prokera allows it to act as that wouldn’t entirely resolve the case-finding problem – an antibiotic depot – it takes up antibiotic and releases it in a mainly because current keratoconus diagnostics leave much sustained manner, thereby preventing post-surgical . to be desired. In particular, early keratoconus remains a Importantly, antibiotic release from Prokera avoids the peaks judgement call: is it frank keratoconus, is it just forme fruste and troughs typical of standard administration methods, such keratoconus, or are there co-morbidities that confound the that high antibiotic levels are maintained on the ocular surface. diagnosis? And deciding whether or not it is progressive This pharmacokinetic pattern is expected to be more effective keratoconus that requires cross-linking represents yet than that achieved by intermittent administration. another judgement call. Genetic testing for keratoconus is interesting, and might Onward and upw a r d bring more rigor to keratoconus diagnostics, but I think its utility will be relatively limited. Remember, we even have In summary, Prokera enables us to avoid many of the complications trouble identifying those patients with sufficient risk factors associated with delivery of vision-saving epi-off therapy. It to merit an eye exam, and still more trouble getting them promotes healing, prevents scarring, inhibits inflammation, to take an eye exam. It would require even more effort to improves goblet cell numbers and stimulates corneal nerve implement an effective genetic screening program, and I regeneration; furthermore, it may enhance antibiotic efficacy certainly can’t see us getting to the point where everyone via sustained release drug delivery. For us, this is a win- is genetically screened for keratoconus at birth. Far better, win outcome – we can continue using the approved epi-off I believe, to apply our resources to the education of our therapy to save vision, and at the same time avoid much of primary care colleagues with regard to the diagnostic signs the associated risk of scarring, infection and delayed healing. and referral criteria for keratoconus. Specifically, our rates of any delayed healing and corneal have gone down to zero, and we’re getting less scarring and haze. At the same time, our patients are healing more quickly, and require less chair time and fewer follow- ups. Everybody’s happy!

Neel Desai is a board-certified ophthalmologist specializing in LASIK, cataract and corneal diseases at The Eye Institute of West Florida, USA. 18 Feature

THE SCIENCE BEHIND EPI - O N pulsed protocol with no supplemental oxygen (see Figure 1) (9). When researchers compared two epi-on protocols, again in an Clinical trials evaluate the safety and efficacy animal model, a greater degree of corneal collagen stiffening of epithelium-off corneal collagen cross-linking occurred in eyes receiving riboflavin with benzalkonium treatment protocols with supplemental oxygen chloride (BAC), supplemental oxygen, and pulsed UV at 30 mW/cm2, with 1 sec:1 sec pulsing, and 10 J/cm2, compared By Michael B. Raizman with eyes that received riboflavin with sodium iodide, room air, and 4 mW/cm2, 15 sec:15 sec pulsing, and 4.1 J/cm2 UV Epithelium-off (epi-off) corneal collagen cross-linking (CXL) has (5). In my opinion, supplemental oxygen has the potential to been effective in stabilizing keratoconus, offering hope to many improve both epi-on and epi-off CXL. patients with this progressive condition (1). Epithelium-on (epi- on) CXL, in which the epithelium is minimally disturbed, has Clinical tri a l s historically not been as successful, but clinicians and researchers continue to explore this option, believing it may reduce the risk The scientific support for oxygen in cross-linking is currently being of infection and corneal haze (2). Although the risk of these evaluated in Phase III clinical trials of epi-on CXL. I am a clinical complications in epi-off procedures is low (1, 3), striving to further investigator in this prospective, randomized, controlled study of improve safety is always a worthwhile goal. In addition, patients a drug-device combination product from Avedro. In this study, undergoing an epi-on procedure may experience less postoperative several variables have been modified from traditional epi-off discomfort and faster visual recovery. protocols. We are applying riboflavin that has been modified Various attempts have been made to modify established cross- to enhance penetration through the epithelium into the stroma, linking protocols to make an epi-on version more effective. The delivering pulsed UV light at increased intensity, and providing complex biochemistry of CXL, in which riboflavin, ultraviolet supplemental oxygen using Boost goggles (see Figure 2). The (UV) light, and oxygen all play a role, forces us to confront several goggles are worn throughout the UV light application, increasing challenges. The intact epithelium blocks the transfer of riboflavin the oxygen concentration on the corneal surface to >90 percent. into the stroma and can absorb some of the UV light that must Enrollment in the study is now complete, with 275 patients with reach the stroma. Furthermore, the epithelium blocks atmospheric progressive keratoconus treated across 14 sites. Two-thirds of the oxygen from reaching the stroma and biomechanically reduces patients receive the investigational epi-on CXL treatment, and the amount of available oxygen. The chemical reactions in CXL the other one-third receive a sham treatment. When introducing procedures — both epi-on and epi-off — also deplete atmospheric this procedure to patients, I have explained that it is experimental. oxygen instantly, reducing stromal oxygen to very low levels. Pulsing, or cycling the UV light on and off to allow oxygen to replenish during the “off” cycles, is helpful, but has not been sufficient to restore oxygen to the desired levels (4). To perform epi-on CXL successfully, we ideally want to optimize all of the factors that we can control, including the riboflavin formulation (riboflavin, vehicle and other components), the intensity and delivery mode of the UV irradiation, and the delivery of supplemental oxygen. Exploring new strateg i e s

Currently, several new riboflavin formulations designed to facilitate epi-on CXL are under investigation (5, 6, 7). Early work on sustained release riboflavin and nanotechnology formulations has also been reported (8). One promising new strategy is to increase the ambient oxygen concentration on the cornea by delivering supplemental oxygen at the ocular surface throughout the CXL procedure. Recent laboratory research has demonstrated that this approach Figure 1. Stromal oxygen concentrations before, during, and after UV light significantly increased the oxygen availability in the stroma of ex vivo application in two different CXL protocols demonstrate that the supply of porcine eyes treated with high-irradiance epi-on CXL compared to a and demand for oxygen are balanced when supplemental oxygen is provided. Figure 2. Goggles deliver supplemental oxygen to the corneal surface during CXL.

However, the risk for the patient is very low. After six months School of Medicine, and co-director of the Cornea and Cataract Service of follow-up, the sham control group is eligible to receive and director of the Corneal Fellowship at Tufts Medical Center. treatment; rescue treatment is also available during the initial 6 months, if needed. He is a paid consultant to and a shareholder in Avedro. Although some clinicians in the US already perform epi-on CXL procedures off-label or with unapproved devices, I believe References it is important to wait for the clinical trial results. We know 1. PS Hersh et al., “United States Multicenter Clinical Trial of Corneal that the currently approved epi-off CXL treatment is effective Collagen Crosslinking for Keratoconus Treatment”, Ophthalmology, 124, and is considered the standard of care. Before starting to offer 1259 (2017). PMID: 28655538. epi-on to patients, we need to evaluate the safety and efficacy 2. N Soeters et al., “Transepithelial versus epithelium-off corneal cross-linking of new techniques in well-controlled clinical trials in humans. for the treatment of progressive keratoconus: a randomized controlled trial”, The results may help us determine which cases will benefit Am J Ophthalmol, 159, 821 (2015). PMID: 25703475. from epi-off or epi-on procedures and help us develop better 3. D O’Brart, “Corneal collagen crosslinking for corneal ectasias: A review”, Eur J treatment algorithms. Ophthalmol, 27, 253 (2017). PMID: 28009397. Cross-linking has been a wonderful advancement for our 4. L Sun et al., “Transepithelial accelerated corneal collagen cross-linking with patients with keratoconus. There is still room for improvement, higher oxygen availability for keratoconus: 1-year results”, Int Ophthalmol, and I am enthusiastic about the potential for new protocols 38, 2509 (2018). PMID: 29116549. that modify more of the variables we can control to achieve the 5. J Hill et al., “Biomechanical impact of drug formulation, supplemental greatest efficacy possible with an intact epithelium. In addition oxygen, and UV delivery on epi-on CXL”. Presentation at ARVO, April to the oxygen innovations described here, I hope that future 27-May 2, 2019, Vancouver, Canada. protocols may allow us to customize the application of UV light. 6. C Ostacolo et al., “Enhancement of corneal permeation of riboflavin-5’-phosphate Until now, in the US we have delivered a broad beam uniformly through vitamin E TPGS: A promising approach in corneal trans-epithelial across the cornea. Based on studies performed throughout cross-linking treatment”, Int J Pharm, 440, 148 (2013). PMID: 23046664. the world, it seems likely that we will achieve more effective 7. R Stulting et al., “Corneal crosslinking without epithelial removal”, J Cataract treatments by treating different parts of the cornea with different Refract Surg, 44, 1363 (2018). PMID: 30228014. levels of irradiance. Perhaps we will even be able to improve 8. R Rubinfeld et al., “Corneal cross-linking: The science beyond the myths and vision in patients with keratoconus, not just halt its progression. misconceptions”, Cornea, 38, 780 (2019). PMID: 30882538. 9. J Hill et al., “Stromal oxygen dynamics during high-irradiance epi-on Michael B. Raizman practices with Ophthalmic Consultants of corneal crosslinking”. Presentation at ARVO, April 27-May 2, 2019, Boston, is an associate professor of ophthalmology at Tufts University Vancouver, Canada.

www.theophthalmologist.com 20 Feature

THE (UN)USUAL SUSPE C T S

Don’t be afraid to tackle unusual cases. Given the right precautions, they can be just as successful as routine procedures

By Audrey R. Talley Rostov

In the past seven or eight years, I have treated more than 1,000 eyes with CXL, first as part of the CXL-USA study and later with the Avedro KXL system. The majority of these cases have been typical patients with progressive keratoconus – older teens and adults in their 20s and 30s — but it is worth discussing how to address less common CXL cases that surgeons may encounter. Younger or very anxious patie n t s

Young patients — and very anxious or claustrophobic adults — benefit from what I like to call “verbal anesthesia,” or a steady stream of reassurance that they are doing great, the procedure is going well, and so on. It can be very helpful for an anxious patient to be allowed to have a parent or other loved one in the room as a comforting, reassuring presence – perhaps even holding their hand throughout the procedure. We have a sound system in the treatment room so that patients can choose their own Pandora music station to help them relax. Patients with intellect u a l disabilit i e s

Patients with autism and other intellectual disabilities have Figure 1. A 47-year-old patient at initial consult (a); one year later, with been among my most difficult cross-linking cases — not progression (b), and nine months after CXL (c). because of any clinical aspects of the case, but due to the communication challenges and difficulty gaining the patient’s to consider general anesthesia. The UV light source unit is cooperation. Creativity may be required. One author recently portable and could be transported to a hospital if needed. The reported on a case of a teenager with whose anesthetist must ensure that sedation is deep enough to ensure father held a tablet computer just behind the UV light to help proper alignment of the light source without the eye rolling back. the child maintain fixation during the procedure (1). Patients Clinicians should be aware that patients with Down syndrome are with Down syndrome have a much higher than average at higher risk of anesthesia-related complications. They may also incidence of keratoconus, but also may be diagnosed at a later not be good candidates for corneal transplant, due to difficulty stage than those without intellectual disabilities (1, 2). following postoperative instructions. Soeters and colleagues recently With any patient with learning difficulties we schedule an extra provided a tool to help clinicians decide whether such patients can session with the patient and a parent or caregiver. This additional be successful under local anesthesia (1). time gives us the chance to introduce the concept and the procedure There is still an enormous issue with access to care in the room and practice some of the potential challenges: lying still; population with intellectual disabilities. In many cases, state fixating on a light; bringing the microscope or light source over Medicaid insurance programs still do not cover CXL, much as their head. The key to success with such patients is to ensure that they once covered penetrating keratoplasty but not the less invasive they feel secure and cared for throughout the procedure. DSEK and DMEK procedures. I believe that CXL will also With some patients with learning disabilities, it may be necessary eventually be Medicaid covered, with time and advocacy by corneal “Keratoconus is a life-long disease. Although it is less well recognized, some surgeons. For anxious and patients with learning disabilities patients can still have alike, it may eventually be very beneficial to have an FDA- approved epi-on procedure. A less invasive procedure could help significant progression anxious patients be less fearful. Older patie n t s after age 40.”

Keratoconus is a life-long disease. Although it is less well recognized, some patients can still have significant progression after age 40 (see Figure 1). It is not uncommon for a patient Additionally, I always try to address any underlying issues to notice their vision changing (beyond just presbyopia). Upon that may have led to eye rubbing, such as eczema, dry eyes exam, I may find unusual topographic features, but also some or . early cataract that makes it difficult to determine the source of With cross-linking, we have a wonderful opportunity the vision change. But when I see them again in 6-12 months, to potentially halt a sight-threatening disease and protect there is clear evidence of progression. The good news is that older patients’ vision. With proper verbal anesthesia and appropriate patients are probably progressing much more slowly than younger precautions for unusual cases, a wide range of patients keratoconus patients (3), so we do have the luxury of time to diagnosed with progressive keratoconus or post-refractive confirm the diagnosis and schedule treatment. ectasia can be treated very successfully. In addition to the slowing down or halting progression, CXL often results in some corneal flattening. I find this to be particularly Audrey Talley Rostov is a partner at Northwest Eye Surgeons in helpful with older patients (and essentially all patients), because it Seattle, USA, and serves as a Board Director for SightLife. may mean they can get back into an easier form of vision correction (4), with significant cost and lifestyle benefits. She is a consultant for Avedro.

Post-refractive ecta s i a References 1. N Soeters et al., “Performing corneal crosslinking under local anesthesia in I think it is still an open question whether true post-refractive ectasia patients with Down syndrome”, Int Ophthalmol, 38, 3, 917 (2018). actually exists. The cases we label as post-refractive ectasia may PMID: 28424993. have had undiagnosed ectatic disease before the refractive 2. M Shapiro and T France, “The ocular features of Down’s syndrome”, Am J surgery or there may be an inflammatory component (from Ophthalmol, 99, 659 (1985). PMID: 3160242. excessive eye rubbing), even though ectasia is traditionally 3. T McMahon et al., “Longitudinal changes in corneal curvature in defined as a non-inflammatory condition. In any case, in keratoconus”, Cornea, 25, 3, 296 (2016). PMID: 16633030. patients with previous , clinicians should be 4. K Singh et al., “Alterations in contact lens fitting parameters following very careful with epithelium removal along the flap edge so cross-linking in keratoconus patients of Indian ethnicity”, Int Ophthalmol, as not to accidentally disrupt the flap or open old incisions. 38, 4, 1521 (2018). PMID: 28646439.

www.theophthalmologist.com 22 Feature

INCORPORATING CROSS-LINK I N G INTO YOUR PRACT I C E

Strategic planning and education are key to establishing a cross-linking center of excellence and attracting patient referrals

By Neda Shamie

I have been performing CXL for three years and it has resulted in a paradigm shift in the way we treat keratoconus in our practice, mirroring changes in the standard of care throughout the world. The procedure can have tremendous benefits for patients. According to data from the Dutch National Organ Transplant Registry, the percentage of corneal transplants for keratoconus decreased by approximately 25 percent during the three-year period after CXL was introduced (1). I now have more than two-year follow-up on patients I have personally treated. What I have consistently observed in these patients is stabilization of their ectatic disease and often corneal flattening, as well. A few treated patients with mild to moderate keratoconus have even been able to achieve 20/25 or better uncorrected at the two-year mark, while others are able to successfully correct their vision with glasses or soft contact lenses. Beyond what this procedure does for patients, I also feel strongly that CXL is a necessary addition to the treatment options offered in any cornea practice treating patients with keratoconus. Offering CXL (see Figure 1) expands my scope of Figure 1. Shamie performing a cross-linking procedure. practice and completes the expertise I offer as a corneal specialist to referring doctors and their keratoconic patients. need to educate our optometric networks about treatments approved by the FDA, pointers for diagnosis and referral, Expanding awaren e s s and what to expect from CXL. My approach has been to communicate with colleagues through clinical e-blasts, social First, we need to educate our staff about keratoconus, the media, one-on-one meetings, presentations at practices that CXL procedure, and how patients can benefit from it. In provide specialty contact lenses, educational courses and local my experience, sharing stories about the dramatic impact optometric meetings (see Figure 2). Additionally, part of being of this treatment on individual patients has been the a good partner is reassuring referring doctors that patients will most effective way to ensure staff commitment to the new be sent back to them after CXL as, otherwise, those clinicians paradigm of treating progressive keratoconus. Despite the will stop referring patients. After all, CXL only stabilizes clear-cut advantages of CXL, the patients who would benefit keratoconus and those patients will still need long-term eye most do not necessarily present on the doorstep of cornea care – and will likely need to be fitted with specialized contact practices. More commonly, they are presenting to primary lenses for optimized vision. care optometrists with deteriorating vision and hoping for From a referral standpoint, the most valuable thing I have new glasses or contact lenses. Therefore, it is important to done in talking to optometrists is to emphasize the fact that adopt a number of educational strategies to share knowledge only the FDA-approved procedure is covered by insurance with those who are seeing these patients at the first point of companies, and to reassure them that I will work with their contact or offering continuing care to known keratoconics for patients to make sure they can have this medically necessary their specialized contact lenses. procedure without an excessive out-of-pocket expenditure. We As partners in caring for patients with keratoconus, we also market outside of the eye-care ecosystem. Just because a Feature 23

practice offers cross-linking doesn’t mean that patients will for a formal evaluation. This would be especially true in younger know that or be able to find the practice when they search patients, and ones with risk factors, such as a family history of online for information about cross-linking or keratoconus. keratoconus, eye rubbing, or prior LASIK. Insurance carriers have CXL is featured prominently on our website, and we have varying definitions for progression, so it is the responsibility of invested in search engine optimization to increase traffic to practitioners to learn the requirements of their major carrier(s) for our site when people type in relevant search terms. documenting progression. In addition, it is important for a practice incorporating CXL to designate one staff person to keep track of Understanding and diagnos i n g CXL billing and insurance pre-authorizations and appeals. progress i o n Set patient expectati o n s The goal of CXL is to slow or stop progression of keratoconus, so the earlier we can intervene — before there is significant thinning Patients need to know that, though CXL may slow or stop and vision loss — the better. Progressive keratoconus or ectasia keratoconus progression, it cannot reverse it. They will need glasses is the indication for CXL, but the definition of progression or contact lenses after treatment, but I give them hope that surgical is not clear cut and is left to the surgeon to determine. It is options may be available to correct their after especially challenging to determine if a patient has progressive the cornea has been completely stabilized, such as intracorneal disease if they have not had historical objective data on vision or ring segments, implantable contact lenses now available in topographic changes. I try to determine keratoconic progression toric form, topography-guided PRK or a refractive lens on the initial consult by establishing if there has been an exchange. Patients also need to understand that their vision otherwise unexplained decrease in best spectacle-corrected visual will worsen before it improves. Research has shown that at acuity or an increase in manifest cylinder. the one-month point, K values tend to worsen and steepen, (evaluating for inferior steepening) is useful in young patients, causing visual fluctuations (2). At three months, we start particularly if you are unsure whether refractive changes are due to see a more consistent flattening and are able to prescribe to keratoconus or simple progression of refractive error. And, of updated vision correction. course, advanced topography or tomography can help confirm We know that keratoconus often presents asymmetrically, whether there are early and pathologic changes to the anterior so patients will need guidance on the timing of CXL for or posterior cornea. both eyes. When one eye is diagnosed early, we may be able I have asked our optometric network to be on high alert to perform CXL in just that eye and monitor the fellow eye for patients with cylinder changes in the manifest , closely. In more advanced cases, we perform CXL in both eyes, especially if the eye is not easily correctable to 20/20 without the usually two to three months apart, taking care to optimize use of RGP or scleral lenses. Even without corneal topography, vision in the first treated eye as much as possible with rigid this may be enough of a signal that the patient should be referred gas-permeable or scleral lenses before CXL is done on the to a cornea specialist or an ophthalmologist who performs CXL second eye so patients can function while the eye recovers. Although there are a few marketing, logistical and billing challenges when incorporating CXL into a practice, the opportunity to change the course of a patient’s disease makes it so very worthwhile.

Neda Shamie is a partner in the Maloney-Shamie and a clinical professor of ophthalmology at the Keck School of Medicine, University of Southern California, USA. Shamie is a paid consultant for Avedro.

References 1. D Godefrooij et al., “Nationwide reduction in the number of corneal transplantations for keratoconus following the implementation of cross-linking”, Acta Ophthalmol, 94, 675 (2016). PMID: 27213687. Figure 2. Shamie presenting on cross-linking at the annual Maloney 2. C Chang and P Hersh, “Corneal collagen cross-linking: A review of 1-year Shamie Vision Institute Symposium for a large audience of optometrists. outcomes”, Eye Contact Lens, 40, 345 (2014). PMID: 25343263.

www.theophthalmologist.com 24 Feature

OPTIMIZING REIMBURSEMENT I N specialist defines progression. In our case, the dominant PRIVATE PRACTICE carrier in our region wanted to see an increase in Kmax ≥ 1.0 D over any time period, along with a change in Despite insurance hurdles, cross-linking can spherical equivalent of 1.0 D or a change in cylinder of be a practice-building procedure – once you 0.5 D. These requirements don’t make a lot of sense to know the ropes me, but I have learned to accept that, regardless of how I choose to clinically define progression in examining and By Jack Parker counseling my patients, I need to meet this coverage area for the procedure to be covered and paid. We reached a similar As a second-generation ophthalmologist in a small cornea practice, conclusion with the carrier’s requirements that the patient I have seen CXL evolve from an experimental procedure to an must have “failed conservative treatment.” Given that there out-of-pocket service – and, finally, to a treatment covered by is no other therapeutic treatment for keratoconus, how insurance. Today, the majority of commercial health plans in the should one demonstrate failure? My approach has been US – representing >95 percent of commercially covered lives – now to document that the patient “failed glasses and contact recognize FDA-approved CXL solutions and devices as a covered lenses.” Vision correction is a conservative approach and service. My father and I have been offering CXL (see Figure 1) it is reasonable to say that it has failed to stop the disease for several years and have performed more than 750 procedures from progressing. to date. Today, most of my insured patients are covered and our 3. Understand the carrier’s cadence for claims. practice is getting paid fairly – but it wasn’t always that way. We learned the hard way that insurance companies wanted When the payment model for CXL first changed, there was things to happen in a certain sequence that didn’t always a tremendous amount of confusion on the part of practices and make sense to us. For example, when we submit a claim for insurance carriers about how to bill for it. We had problems CXL for keratoconus, it routinely gets denied. The reason with the insurance carrier classifying FDA-approved CXL as for the denial is “must demonstrate progression.” Submitting an experimental procedure (it wasn’t); paying for the Photrexa evidence of progression with the initial claim did no good. drugs but not the procedure (or vice versa); and establishing non- The evidence for progression was only allowable (i.e. could intuitive and often nonsensical criteria for progression. In many only be submitted) after the initial rejection. So, we just cases, the procedure was “covered” but not paid at a sustainable adapted to the successful cadence: Submit claim; receive level. However, the insurance companies successfully climbed denial; provide evidence of progression; receive approval. the learning curve, and so did we. We now rarely have a problem 4. Build an efficient process. getting paid for the procedure (See box: “Billing Essentials”). Given that many of our patients travel long distances, we have tried to set up systems that allow them to be treated Learning on the j o b them quickly – preferably on a same-day basis. We perform CXL in an exam lane with our regular technicians assisting, Here are four lessons we learned along the way: so that the procedure can be worked in on any regular clinic 1. Fight for your patients. day, although we do cluster CXL procedures on Fridays There is definitely a learning curve in filing insurance when possible. We have also educated doctors who refer claims for CXL. We made the commitment to do the work to us to send us evidence of progression in advance so that ourselves, rather than ask patients to file appeals. We knew we can evaluate the patient and perform CXL the same that if the system was hard for us to navigate, it was going day. Those referring providers are then able to provide to be doubly hard for patients. It is important to assign postoperative care in a location that is geographically more someone knowledgeable and persistent with the task of convenient for the patient. Not only does this benefit the seeking pre-authorization, filing claims and following up on patient, it also limits unnecessary visits for our practice. appeals and payments. It will take much longer to get claims paid if the individual with this responsibility can’t answer CXL: uncove r e d questions herself or himself, and needs to ask the doctor about insurance company requests. Unfortunately, we still have two challenging categories for which 2. Understand what the insurance carrier needs to check the boxes. insurance will not reimburse. The first is patients with post- Insurance company requirements for documenting refractive surgery ectasia. Although it is an approved indication progression may differ significantly from how a cornea for CXL, carriers typically consider this a of an BILLING ESSENTI A L S

J code for riboflavin solutions J2787 (Photrexa and Photrexa Viscous)

0402T Office procedure code for CXL

Avedro Reimbursement Customer Hub program – online portal provides assistance with coding, billing, claims submission and appeals; and financial ARCH assistance for needy, uninsured patients. Expanded recently to support patients directly with benefit verification and status updates

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Figure 1. Corneal collagen cross-linking is now largely a covered and appropriately reimbursed procedure in our practice for quality care. Whether we perform CXL or not, we have proved to our patients – and their optometrists – that we can meet all elective procedure and therefore not a covered service. To me, their eye-care requirements, from corneal transplants to cataract that is regrettable, because many patients with ectasia probably surgery and glaucoma treatment. This success has come from us had subclinical or undiagnosed keratoconus before their LASIK offering CXL; it has boosted our patient and surgical volume, surgery. The second category is patients who have a combination solidified our reputation as providers and expanded our referral of Medicare and Medicaid coverage. Unfortunately, their network, not just in Alabama, but in several surrounding states insurance doesn’t cover or pay for CXL, so I don’t have a great as well. If you are considering adding CXL to your practice, solution for them. Avedro offers a patient financial assistance take our advice, learn from these lessons, and be prepared to program which helps often – but not in all cases. Fortunately, reap the rewards. this is a rare circumstance, as the need for CXL is uncommon in the Medicare-age population. Jack Parker is in private practice at Parker Cornea in We are now the busiest CXL site in Alabama, with a reputation Birmingham, Alabama, USA.

TESTING, TESTING increasingly more commonplace – which is something I see reflected in my own patient population, which is more skewed Where are we with keratoconus management from the point of view of a corneal specialist. One out of every today and why genetic testing will revolutionize three corneal consultations in my clinic involves a keratoconus keratoconus diagnosis — and improve refractive suspect. It seems obvious to say that advanced keratoconus is outcomes in the process not difficult to diagnose. You can almost diagnose the condition in a more advanced keratoconus case by reviewing the level of By Elizabeth Yeu astigmatism in the manifest refraction, coupled with the best- corrected vision that it yields, especially if there is a limitation to It was not long ago that keratoconus was seen as a rare disease, the spectacle-corrected visionBut the real problem with diagnosis with a commonly cited paper from 1986 indicating an incidence lies in mild cases. The issue is particularly critical for younger of 0.054 percent in the US population (1). We now recognize that patients who are coming in for refractive surgery consultations, is not nearly as rare, with keratoconus incidence being different because ophthalmologists run the risk of inducing clinically worldwide, more commonly seen in hotter climates and in eye relevant keratoconus by performing surgery. Also, keratoconus that rubbers. As a community, we have accepted the condition is starts in a younger age is often more aggressive in its progression,

www.theophthalmologist.com and this lends these patients to be more susceptible to requiring vision may continue to change. To accommodate any potential early . prescription shifts, I recommend for patients to maintain their Prior to the approval of collagen cross-linking in 2017, doctors current spectacles or contact lenses for the first six months. In the in the US were only able to warn patients against eye rubbing and first few months after surgery, it is not uncommon to see epithelial aim for best corrected vision, either with glasses or therapeutic hypertrophy and a bump of corneal steepening centrally as a result, contact lenses. There was no medical option to truly halt or stop especially after epi-off therapy. After six months or so, the corneal keratoconus progression. Various surgical therapies have been epithelium slowly smooths and flattens out. There is the possibility available, but reserved to surgically treat those who are contact lens that some patients will continue to flatten over time – with some intolerant or uncorrectable due to scarring or corneal steepness. studies showing evidence of progressive flattening upwards of six Surgical options include corneal ring segments (INTACS) and years post-surgery – though it is hard to identify exactly which corneal transplantation, either with a deep anterior lamellar patients will experience this phenomenon. keratoplasty (DALK) or a full penetrating keratoplasty (PKP). Keratoconus screening has advanced significantly over the Collagen cross-linking (CXL) acts as a bridge between these last decade, including various screening protocols, tomography extremes and offers patients new hope. Though its approval has advancements, corneal hysteresis and epithelial mapping. While been delayed in the US, there is over a decade’s worth of global these all provide insight and guardrails, there is yet to be a true data that does appear to demonstrate the ability of cross-linking definitive tool to rule patients in or out for sub-clinical disease. to halt the disease progression in some patients. These “unknowns” are what makes genetic testing so exciting. Regarding the CXL procedure itself, in the US, the standard It allows us to base our assessments on genuine insight rather cross-linking treatment follows the Dresden protocol, which is than best-educated guesses – something that will hugely benefit epithelium-off (“epi-off”), a 3-milliwatt epicurean at a 30-minute non-obvious keratoconus suspects. Though we know family history exposure. Other off-label CXL treatments include a higher fluence is a huge marker for keratoconus, it does not indicate speed or risk UV therapy for a shorter time duration (same total UV exposure) of progression. It is also useful in terms of deciding which patients and an epithelium-on (“epi-on”) protocol. Since the penetration are suitable for corneal refractive surgery. Studies have proven that of riboflavin is inhibited by the intact epithelium in an “epi-on” there is a higher prevalence of stromal dystrophies that manifest technique in the US, surgeons use different creative approaches after LASIK or PRK, particularly in East Asian populations. to help embed the riboflavin into the corneal stroma (topical Knowing this, we should be able to correctly identify patients tetracaine, longer soak period, micropuncture). genetically predisposed to go from sub-clinical to clinical – before I perform CXL both epi-off and epi-on, but lean towards their vision begins to seriously deteriorate. And that is the true “epi-off” for those who have more advanced disease. For the power of genetic testing. advantages mentioned above, my preferred treatment for patients When the tests become available, I will personally recommend with a less advanced form of keratoconus is “epi-on”, but for anyone them to every corneal refractive patient in my practice, and strictly with high risk of failure – be it K values over 53-54 diopters, require it to be performed on any refractive evaluation that has those with poor spectacle-corrected visual acuity, or extremely a suspicious risk factor (such as irregular astigmatism, steep Ks, young patients – I prefer the “epi-off” Dresden protocol because thin corneas). Additionally, young patients with rapidly shifting it offers the greatest chance at halting progression and flattening astigmatism or myopic errors are a target audience to genetically a steep corneal apex. , corneal haze, and delayed corneal test. Cross-linking patients early could ultimately prevent the re-epithelialization are the more common side effects of “epi-off” potential need for corneal transplantation, which, in turn, could CXL. With an “epi-on” CXL, pain is minimal and corneal halt the repeated transplants over the lifetime of a young patient. haze is infrequent, thus requiring less overall medication in the In my mind, it is worth the small investment to determine the post-operative healing period. Topical steroids are key to mitigate likelihood of a successful surgical outcome and reduce further corneal scarring and haze, and may require a very slow taper over complications in the future. four to six months, in order to prevent or treat corneal haze. In my own experience, delayed healing of the corneal epithelium Elizabeth Yeu is an Assistant Professor at the Department status-post collagen cross-linking is more commonly seen than of Ophthalmology and an Eastern Virginia Medical School in my PRK cases, leading me to believe there is a possibility that Shareholder at Virginia Eye Consultants, Norfolk, USA. exposure to UV light temporarily stuns the limbal stem cells. Though I don’t have data to prove this theory, I have certainly Reference seen it in my own practice. 1. RH Kennedy et al., “A 48-year clinical and epidemiological study of It is important to take a moment to counsel patients that their keratoconus”, Am J Ophthalmol, 101, 267 (1986). PMID: 3513592.

Sponsored Feature 27 

the capsule, and “This device positively Complex suspending it with changed my approach a device during to complex cataract , surgery is of vital cases. It is very gentle importance. on the pupil margin, Simplified Williamson it holds the pupil describes tools well, and its capability X1 Iris Speculum from Diamatrix traditionally used of also supporting gently enlarges the pupil and for such cases: iris the capsule is very stabilizes the capsule to improve hooks, or capsular reassuring. I often deal outcomes in complicated hooks: “These little with complex cases, and cataract cases devices can expand the having a device that can serve iris and capsule, by attaching to multiple purposes is an undeniable According to Charles Williamson, different points around the iris, but they advantage.” Solomon appreciates the ophthalmic surgery specialist and director are cumbersome for the surgeon and can smooth removal of the device: “It can of the Williamson Eye Center in Baton easily become dislodged during surgery.” be removed using a bi-manual technique, Rouge, Louisiana, exposure to the Other devices, which can expand the iris, which is very straightforward, and surgical field is the most important thing are only designed to be used on the pupil, minimally traumatic.” In his experience, in any surgery, and for cataract surgery and not the capsule itself. with the X1, the pupil after the surgery this relates specifically to the iris and Is there a better way to solve this looks intact, which is not always true of the capsular opening. It means that any issue? X1 Iris Speculum from Diamatrix, a the other devices. complications in surgery can be inversely speculum-like nitinol device is pre-loaded “The device is completely safe to use,” proportional to the size of the pupil. “In in a small barrel injected 2.4 mm into the comments Williamson. “It can be used cases of a small capsular opening during anterior chamber, which can capture four on of any size. It is very easy to phacoemulsification,” explains Williamson, separate points of the iris on its own, or manipulate any of the speculum blades “you could inadvertently injure the capsule the iris and the capsule together, which using a push-pull hook intraocularly.” itself, and that would prohibit the use of is important in areas of weak or missing Solomon agrees: “In my experience, certain IOLs, such as toric or multifocal zonules. Used before capsulorrhexis, it is any normal risk associated with surgical lenses, in which centration and ideal very easy to manipulate, and is completely procedures is minimized when using the placement in an intact bag are necessary.” removed after the surgery. It can be X1, owing to how gently the device is Jonathan Solomon, Surgical/Refractive used without the capsular tension ring. injected into the position. I have found that Director of Solomon Eye Physicians and Williamson, who has used X1 for many it is much less likely to create complications Surgeons in Maryland, lists the potential years, talks about the device’s advantages: than other methods of expanding the iris.” reasons for pupils not dilating properly: “The fact that the speculum captures What about the learning curve? Solomon “Certain medications can impact on it, and the iris and the capsule together unites believes that any surgeon will be able to there might be history of inflammation. the anterior and posterior chambers, use the ring, thanks to the memory metal’s There could be a potential source of which results in stable hydraulics during forgiving properties, and he recommends scarring between the iris and the lens, phacoemulsification, preventing fluid watching the insertion procedure on video preventing the pupil from dilating; and or particle loss.” He explains further: tutorials supplied by Diamatrix – he even finally, some patients’ pupils simply don’t “Normally, during phacoemulsification, uploaded some videos online himself, to dilate enough, irrespective of other factors.” fluid and lens particles migrate underneath demonstrate the proper delivery and Therefore, in the cases where the the iris, over the capsule and through the placement of the device. pupil isn’t dilated enough, or there is a zonules, but if the anterior and posterior Solomon’s final words, which will small capsular opening, it is important to chambers are sealed off together, the resonate with many surgeons: “The X1 expand the opening and stabilize it, to nucleus microchips are not migrating into is very competitively priced, compared avoid potential complications. In case of the posterior chamber.” to other devices I have encountered, phacodonesis or iridodonesis – vibration of Solomon, who has recently which is an added advantage for the lens or iris with eye movement, weak or started using the surgeons who have to consider missing zonules can be suspected, stabilizing X1, comments: the bottom line.”

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CLARUS700_FFA_DibeticRetinopathy_v02_CAM11533_TOPNA.indd 1 8/18/19 10:47 AM 30 In Practice

patients of excellent outcomes.” cell count. “Subsequent decisions are Just Asking Ahmed adds that there is limited made on a case-by-case basis,” says evidence for significant CyPass-associated Craven. “But over-prominent devices The Advanced Glaucoma damage: “The five-year COMPASS should be addressed.” Ahmed notes, Technologies (AGT) Forum study did not find any patients with however, that CyPass removal can be audience had the opportunity progressive permanent corneal edema or challenging: “It is strongly secured to to put a broad range of clinically evident corneal swelling.” He the angle – therefore we recommend a questions to our expert panel; suggests that more detailed investigations trimming technique.” topics included drug delivery, are required, noting that cell loss tends Finally, Weinreb reminds us that it’s in artificial intelligence and to be associated with deeply positioned, the nature of exciting new technologies to device-specific issues rather than anteriorly located, devices. have risks; we should expect to be learning “Assessment based on the number things about them after their introduction With Ike Ahmed, Earl Randy Craven, of rings is probably less useful than into clinical practice, he says, and Ahmed Marlene Moster, Constance Okeke, I. measuring how far the extends notes that updated data and guidance Paul Singh, and Robert N. Weinreb into the cornea.” are available online (1, 2). In summary, “Nobody in the COMPASS study was Weinreb concludes, “The CyPass affair For Ike Ahmed, the Advanced Glaucoma shown to lose any corneal vision,” says suggests the need for more research and Technologies (AGT) Forum has a clear Paul Singh. “The important point is the more data – it does not mean we should goal: “To discuss perspectives and practice risk-to-benefit ratio – in patients who need throw the baby out with bathwater with in the rapidly changing field of glaucoma lower IOP, I’m willing to risk endothelial regard to other MIGS procedures.” management – to talk about what’s real cell loss to preserve function.” and what isn’t, and what’s relevant for And that risk-benefit ratio is also likely Will the Innfocus make today’s practice.” And Forum participants to apply, in some form, to non-CyPass trabeculectomy redundant? were keen to drive that discussion with devices; as Constance Okeke says, “If we Marlene Moster answers carefully, noting pointed questions: dug deeper we’d probably find endothelial the advantages of the MicroShunt device: cell loss in other procedures – but we’d “It gives a good, diffuse bleb that is more How should we respond to the still do them routinely, just as we do tube predictable than the trabeculectomy bleb, CyPass situation? shunts despite their known risks.” and patients’ vision returns sooner than Robert N. Weinreb cautions against Randy Craven’s approach is to contact with standard trabeculectomy.” For those over-reaction: “If we applied similar each CyPass recipient using attorney- reasons, she believes Innfocus will become standards to the Baerveldt and the Ahmed approved wording, check the device a standard component of the toolkit for glaucoma products, they too would have position and take a baseline endothelial lowering IOP. been recalled, thereby depriving many

At a Glance • The Advanced Glaucoma Technologies Forum took place in New York, USA, in October 2018 • Audience members viewing the event live had a chance to ask the expert panel questions relating to the forum’s subject matter • Topics discussed in the live Q&A session included CyPass, Innfocus, drug delivery devices, the use of artificial intelligence in glaucoma, and potential future technology advances. Can drug delivery devices assist need for surgeons.” His own view is that more interactive and interventional, without glaucoma management? clinical risk modeling – for example, to forgetting that clinical decisions must be Recent developments in the field of determine those at greatest risk of glaucoma informed by quality of life considerations.” sustained drug delivery include intracameral progression or blindness, and hence to guide In brief, these are exciting times – but, as biodegradable and non biodegradable management – will rely on deep-learning always, the patient perspective remains of products, and intracanalicular biodegradable algorithms. He concludes that AI will fundamental importance. inserts for ocular surface drug delivery. bring great change, not only in healthcare Singh has been involved in trials of but throughout society. Indeed, AI is The Advanced Glaucoma Technologies sustained release prostaglandins and of already upon us – the first approval of an Forum was hosted by The Ophthalmologist the Glaukos sustained drug delivery device. AI test (for diabetic retinopathy) occurred and supported by Ellex, Santen, Heidelberg His view? “These products have excellent very recently. Weinreb adds, “Several Engineering, Reichert Ametek and Aerie efficacy and will no doubt help to answer other AI products are being developed Pharmaceuticals Inc. the compliance issue.” for diagnosing and monitoring glaucoma.” Ike Ahmed is Assistant Professor at the Craven too has experience of sustained Craven, however, identifies issues University of Toronto, Canada. release prostaglandin studies. “Surprisingly, that must be addressed before AI can Earl Randy Craven is Associate Professor of a single injection can keep IOP in the have its full impact: “Glaucoma is a Ophthalmology at Johns Hopkins University, middle or low teens for two years in 25 long-term disease – we’ll need a way of Maryland, USA. percent of patients,” says Craven. “And accessing and integrating all the various Marlene Moster is Professor of that’s why these products are likely to have imaging and field data people accrue as Ophthalmology, Wills Eye Hospital, some role in glaucoma management.” they relocate over time.” Nevertheless, Philadelphia, USA. There will be a logistical learning curve, Craven also points out that there is Constance Okeke is a glaucoma and says Singh, to fit these drug delivery devices already commercial interest in this field, cataract surgery specialist at Virginia Eye into our workflow and reimbursement and asserts his belief that solutions to Consultants, and also an Assistant Professor structures: “How often will they need to the data access and integration issue will of Ophthalmology at Eastern Virginia be administered, and who will pay?” Craven be found. Medical School, Virginia, USA. does not anticipate frequently repeated I. Paul Singh is an ophthalmic surgeon administrations: “We’ll probably initially Should we anticipate any other at Eye Centers of Racine and Kenosha, use this approach in selected patients who significant technology advances? Wisconsin, USA. might particularly benefit.” Singh concludes Technology continually moves ahead, in all Robert N. Weinreb is Distinguished Professor that drug delivery devices may be used as fields, but Singh is particularly excited and Chair, Ophthalmology, and Director, part of a hybrid approach, or as a pre-MIGS by methods of labeling apoptotic cells Hamilton Glaucoma Center, University of strategy to address compliance issues, but as in vivo. “If we can detect compromised California, San Diego, USA. time goes on, may see these delivery devices cells before significant cell loss, we being used even earlier in the disease. can treat patients much earlier – and References maybe also identify those who we are 1. Alcon, “CyPass Micro-Stent Market Withdrawal” How will artificial intelligence change unnecessarily treating,” says. (2018). Available at: https://bit.ly/2YDA5QX. our approach to glaucoma? Accessed August 2, 2019. Weinreb is unambiguous: “It will change Conclusions? 2. ASCRS, “Prelimiary ASCRS CyPass withdrawal everything – in fact, some predict that Ahmed wraps up: “This is a golden age for consensus statement” (2018). Available at: https:// in 50 years it will have eliminated the glaucoma; technology is enabling us to be bit.ly/2KcP2p7. Accessed August 2, 2019.

www.theophthalmologist.com 32 In Practice

Tackling the Global Vision Crisis

How an amblyopia app is tackling the global vision crisis – starting with kids

By Darcy Wendel

Once upon a time, vision screening for children was simple – all it took was a visual acuity chart. However, although inexpensive, positive predictive value was low because young children are often unable to truly comprehend the test, which is clearly problematic. For kids to have a good chance of visual recovery, they need to be tested before the age of five – after that age, the efficacy of treatment starts to decline. This isn’t an issue just in developing countries. In 2016, the American Academy of

At a Glance Pediatrics recommended that children detect disease and prevent vision loss. • GoCheck Kids is a smartphone- have their vision assessed annually, The second was that existing devices based application that allows beginning between the ages of one were extremely costly and most doctors pediatricians to screen for serious and three, with an instrument-based didn’t know that the test could be eye disorders – without the need for technique. Which meant using a reimbursed. Huang saw that there was specialist equipment purpose-built device costing around a gap in the market for affordable and • The app is designed to identify $10,000 – beyond the reach of some accessible pediatric vision screening – amblyopia risk factors such as pediatricians. GoCheck Kids was created particularly for serious eye disorders , hyperopia, , as the antidote to this unmet need. like retinoblastoma and amblyopia. and astigmatism, and may also Huang decided to leverage the inbuilt identify retinoblastoma and Camera, flash, action features of a smartphone – camera cataract, amongst other correctable Our founder, David Huang, co-creator and flash – to mimic a purpose-built visual disorders of OCT, came up with the idea after device. The final result was low-cost • As it is both low cost and easy to attending a conference with leading and easy to deploy, and crucially, deploy, it is well suited to healthcare retinoblastoma specialist, Linn ideal at screening for disease. Like workers in the developing world Murphree. It was there he noticed how that, GoCheck Kids was born: a CE- • GoCheck Kids has run screening few pediatricians offered vision screening marked, FDA-registered pediatric pilots in India, Nigeria, Ecuador, for serious eye disorders. And it turned photo screening application that can and Myanmar with partners such as out there were two reasons why. The detect amblyopia risk factors in kids. We Santen Pharmaceuticals – with more first was that most pediatricians were quickly went into development mode, sites on the horizon. unaware that early screening could help finally launching our product in 2014. In Practice 33

“Like that, GoCheck Kids was born: a CE-marked, The app was – and is – very – to see if the child in question is at straightforward. The user takes a risk. These are then quantified, and if FDA-registered photo of the child’s eyes, guided by they exceed a certain risk threshold, the the app. Once the picture is taken, app informs the pediatrician who then pediatric photo the software identifies the particular refers the child to an ophthalmologist. landmarks of the image. Proprietary GoCheck Kids is also capable of screening algorithms evaluate the image and then identifying risks for retina blastoma calculate the results which are displayed and cataract, amongst other sight- application that can immediately. In addition to calculating threatening conditions if they are in disorder for each eye separately, the the visual path. detect amblyopia software compares the difference in prescription between the two eyes, Saving the twinkle in children’s eyes risk factors in kids.” anisometropia – the number one risk Today, more than 4,500 pediatricians use factor in the development of amblyopia the app in the United States and even

www.theophthalmologist.com 34 In Practice

more worldwide. Because in truth, that is what GoCheck Kids is really about: making vision screening accessible to all. And that is truly where our story starts. Two years ago, we started the India project, in partnership with Santen Pharmaceuticals. The project’s mission was simple – to increase the number of children getting screened for serious diseases in India. We set our sights on the Aditya Jyot Foundation for Twinkling Little Eyes – a multi- speciality practice in Mumbai. It was the perfect location. Of the nine million people living in Mumbai’s slums, only 48 percent had access to healthcare facilities – leaving more than 4.6 million people without. The Foundation did what they could to screen children who lived in the slums by offering mobile eye exams in a specially equipped van. Children would fill out a questionnaire before being checked by healthcare workers and optometrists. The process cost 500 rupees per child and took around 15 to 20 minutes. The Foundation was able to screen 200 kids a month – 3,000 a year – using his method, but it had its drawbacks. Not only was there the cost and logistical burden of running the van and assembling a full team twice a week, it was also often difficult to convince parents to let their children be screened at all. Even when the parents did agree, there was no guarantee the kids would have the level of comprehension required to understand the screening procedure and get an accurate result.

Word of mouth Enter GoCheck Kids. Our app gave were able to use the app; consider that what seemed like our biggest obstacle healthcare workers a means of screening some outreach workers didn’t even own a was one of the easiest to overcome. It children in their own homes, leaving the cell phone, let alone an app, so we made took us a while to find a willing family, van free for treatment. It would be easy sure to provide the appropriate phones but it turned out one was all we needed. to use, accurate and – most importantly and training. We also had to be sure the There was 10 people in the family – five – fast, allowing the team to test a greater app would work without Wi-Fi – the of them children. We screened the kids number of children in a shorter space of answer was an offline function. The first and were about to leave when the time. But there were obstacles. First, we final challenge was convincing people rest of the family asked to be checked had to make sure the healthcare workers to let us into their homes. Strangely, too. By the time the healthcare workers In Practice 35

to screen more frequently and for a significantly reduced cost. With the previous method, it cost 500 rupees to screen a child; with the app, it cost 80: success. The Foundation performed a sensitivity and specificity study to verify the results after the project, and fully committed to the program this year. We’re happy to say that with every risk factor identified, the cost of screening and treatment reduces – and more children get the care they need.

Filling the gap Luckily, our work is being recognized. Last year, we won the Impact Pediatric Pitch Competition at SXSW, as judged by representatives from eight top US children’s hospitals, including Boston Children’s Hospital and The Children’s Hospital of Philadelphia. And that really raised our profile in the USA. We’ve already started European distribution – our app is being used in 350 locations throughout Belgium – and we have plans to expand into Israel, Lebanon, France, and Brazil in the coming months. Our mission screening programs are also set to expand. We have completed projects in Myanmar and Ecuador, and have recently begun testing in remote areas of Nigeria. The hope is that GoCheck Kids will continue to expand, because, truthfully, the problem of vision screening isn’t going away. One in four children has a , yet only 20 percent of children are screened. Since 80 percent of a child’s learning is visual, this needs to change and, hopefully, with the help of apps like GoCheck Kids, it will.

Darcy Wendel is Vice President of were done, there was a line of 50 people to be tested too. Clinical Affairs at GoCheck, Nashville, waiting outside the door to be screened. By using the app, the Foundation was Tennessee, USA. The children had run outside and told able to screen 2,000 children a month their extended family, who told their instead of 250. As the app didn’t require GoCheck Kids photoscreening procedure is neighbors, who then told their friends an optometrist – just a trained healthcare commonly reimbursed using CPT Codes that we were there, and they all wanted worker – the Foundation was able 99174 or 99177.

www.theophthalmologist.com 36  Sponsored Feature

procedure helps provide a platform for regenerative healing. Restoring By reconstructing the inferior fornix “The RR method this way, RR re-establishes the normal the Reservoir anatomical tear reservoir – fixing the eye’s offers unparalleled inability to hold fluid – and thus delivers Introducing an “unparalleled” superior results for patients. benefits: improved treatment for one root cause Arla Genstler – an ophthalmologist of stubborn dry eye and owner of Genstler Eye Center, tear drainage, who regularly uses the procedure It is estimated that 100 million people in her practice – can attest to such restored normal are affected by dry eye globally. These results. “The RR method offers individuals make up a large portion of the unparalleled benefits: improved tear anatomy and ophthalmic patient population, presenting drainage, restored normal anatomy with irritation, discomfort, light sensitivity, and blinking, and reservoir capacity. blinking, and and fluctuating vision. But despite This restored mechanical function is our best efforts, there are some who what provides the symptomatic relief reservoir capacity. experience little to no improvement in that the patient experiences.” their symptoms – even after maximum “From a surgical point of view, the This restored medical intervention. Dry eye patients procedure is relatively straightforward. who do not respond to treatment may One has to be cognizant of anatomy – you mechanical be suffering from a second condition: are resecting orbital fat around the ocular (CCh). CCh is caused muscles, after all – but, it is a procedure function is what by the degeneration of the Tenon’s capsule with good visualization,” says Genstler. – a result of high matrix metalloproteinase “When a patient has tried multiple provides the activity. The unhealthy Tenon’s causes modalities with limited success, they are the to loosen, creating grateful to have a procedure that offers symptomatic relief folds that interfere with the tear immediate and lasting relief. It’s great that meniscus, prevent tear clearance, and we can provide a definitive solution.” that the patient diminish the volume of the fornix. But, as with all procedures, postoperative Over time, the loose conjunctiva outcomes rely on preoperative planning experiences.” continues to contract – shortening – and that includes effective patient the fornix and further diminishing its communication. “It is important to stress ability to replenish the tear meniscus that the procedure only addresses one The procedure is gaining in popularity. sufficiently. Orbital fat prolapse can component of a multifactorial disease,” And Genstler is keen to spread the word further compound the problem. says Genstler. “It is not a cure-for-all, it further; her practice has put on several Previous surgical interventions have simply addresses the mechanical issue. roundtable discussions with optometric focused on eliminating folds by removing And so, if a patient has Meibomian gland colleagues to increase their awareness of part of the conjunctiva – but this is only a dysfunction or aqueous deficiency, they the RR procedure as a potential treatment temporary solution. Though conjunctiva will still have those same conditions for CCh. “It offers another means of removal alone offers some relief, it after the procedure. By educating the addressing the pathology of the ocular runs the risk of further diminishing patient ahead of time, you can set surface disease, with benefits beyond the tear reservoir – and it does little realistic expectations.” symptomatic relief. We can offer increased to prevent fat prolapse. So what’s the quality of life – allowing patients to enjoy solution? Enter the Reservoir Restoration activities like without (RR) procedure using AmnioGraft the constant feeling of cryopreserved amniotic membrane something in their eye,” from Bio-Tissue. Using AmnioGraft to says Genstler. “And that recreate a smooth ocular surface, the is priceless.” I use The RR Method Reservoir (see below) to reconstruct the reservoir. In short, I Restoration remove the degenerated Tenon’s, resect some of the 101, with anterior orbital fat, and then place a layer of amniotic membrane deep into the Arla Genstler surgical site. The process works beautifully – the tear meniscus returns, the staining Figure 1a CCh is becoming increasingly common, of the lid margin resolves, and the patient particularly among young people; I suspect enjoys an uninterrupted blink. this has something to do with the increase in The RR procedure is a wonderful inflammatory mediators from our diet and addition to the armamentarium of the marked increase in computer device ocular surface disease treatments. usage. In any case, the only procedure I would encourage anybody with a that I have used to treat CCh is RR. Why? comprehensive ophthalmology practice For one, I do not like any procedure to add RR to their skillset – particularly that shortens the inferior cul-de-sac. those with a surgical emphasis, where Figure 1b Instead, I believe we need to perform the ocular surface is crucial to pre- a full reconstruction and restore normal operative measurements and post- anatomy to offer benefits to the patient. operative outcomes.

all abnormal Tenon’s fascia from the The Reservoir episcleral surface Figure 2 8. Cauterize prolapsed orbital fat to Restoration further deepen the fornix 9. Cauterize the leading edge of Procedure - Tenon’s and prolapsed fat 10. Cut and glue down a small piece of Surgical Steps AmnioGraft® to cover the area of the rectus muscle insertion (This will 1. Apply 2 percent lidocaine gel replace Tenon’s and prevent muscle 2. Place a 7/0 Vicryl corneal restriction) (Figure 2) Figure 3 traction suture 11. Cut and glue down a larger piece 3. Inject (2 percent) lidocaine with of AmnioGraft® to cover the entire (1/10,000) Epinephrine sub- surgical site. (Figure 3). In the fornix conjunctiva in the area to push tissue up against the edge of be dissected the Tenon’s and over the edge of 4. Start your incision with a the conjunctiva (Figure 4) relaxing incision at the outside 12. Make sure edges other than in fornix edge of the dissection are covered by 1mm of conjunctiva 5. Begin a peritomy 1-2mm from 13. Glue down the small flap of Figure 4 limbus taking care to preserve the conjunctiva at limbus limbal stem cells 14. Check edges of conjunctiva to be Figures 1a and 1b. The Reservoir Restoration 6. Trim about 1-2mm of sure they are glued down Procedure can restore the tear reservoir and ocular conjunctiva (enough to recess its 15. Remove all excess glue surface to its normal state utilizing AmnioGraft, edge into the fornix) 16. Remove traction suture which facilitates the healing process and recovery. 7. Aggressively dissect and remove 17. Place bandage lens on cornea Figure 1a shows the eye pre-operation, and figure 1b post-operation.

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Research advances Experimental treatments Drug/device pipelines

40–43 Pouring Oil on Troubled Retinas Silicone oil tamponades can inhibit scar tissue formation in patients with a high risk of retinal scarring after . But how much more effective would these products be, if they also delivered antifibrotics? Victoria Kearns investigates

www.theophthalmologist.com 40 NextGen

Pouring Oil on Troubled Retinas

Silicone oil tamponades can inhibit scar tissue formation in patients with a high risk of retinal scarring after retinal detachment. But how much more effective would these products be, if they also delivered antifibrotics? We are about to find out

By Victoria Kearns

Conditions such as proliferative vitreoretinopathy and proliferative diabetic retinopathy can lead to retinal detachment (RD), followed by sight-threatening scarring. Silicone oil tamponades – replacement of the vitreous with silicone oil – reduce the

At a Glance • Replacing the vitreous with silicone probability of scar tissue formation, but Multiple disciplines oil can reduce scar tissue formation the success rate of this approach has Addressing this situation requires a in vitreoretinopathy and diabetic remained static for years. There are two multidisciplinary approach; fortunately, retinopathy, but attempts to combine reasons why efforts to combine silicone multidisciplinary interactions are the the oil with pharmaceuticals have oil tamponades with pharmacological norm in the Department of Eye and not yet been successful anti-scarring approaches have had Vision Science at the University of • A multidisciplinary team at little success. First, many drugs Liverpool, UK. In particular, our non- the University of Liverpool, are designed to be hydrophilic, and clinical, academic researchers collaborate UK, is working on achieving therefore are substantially oil-insoluble. closely with clinical teams at St Paul’s controlled drug release from Paradoxically, this forces us to use Eye Unit; the advantages of this system silicone tamponades to prevent lower than optimal drug doses, because are reflected in our history of translating retinal scarring the drug collects around the surface laboratory research, via industrial • Milestones of the research so of the oil, resulting in an excessively collaborations, to the bedside. This far include choosing the right high local accumulation. Second, environment has allowed me to apply my model drug and determining even lipophilic drugs are associated biomaterials expertise to the development its solubility in oil, as well as with imperfect pharmacokinetics of new ways to reduce retinal scarring. modulating the release kinetics of in these tamponade systems: the My team, including Steve Rannard and oil-drug combinations oil releases the compound into the Tom McDonald, and researchers Maude • The team has proven that modified eye too quickly, resulting in rapid Le Hellaye and Helen Cauldbeck is made silicone oils are non-toxic to relevant drug clearance and poor efficacy. In up of chemists, biologists, bioengineers cells, they enhance drug solubility consequence, there are at present no and surgeons, working with an industrial and extend drug release. accepted oil-antifibrotic combinations. partner. We are focused on achieving NextGen 41

Why focus oil (leading to ineffective drug loading, precipitation, on drug requirements for separate delivery from devices or additional drug injections, and drug silicone oil accumulation at oil-eye interface) tamponades? • release of the drug from the oil too quickly such that it • We know that drug is rapidly cleared from the delivery from eye, resulting in silicone oils is, in poor efficacy principle, possible • By improving and safe, both the drug delivery in animals characteristics of oil- and people: drug combinations, for example, we can avoid the aspirin (1) and aforementioned (2, 3) problems and • Problems with current improve the efficacy and approaches include: predictability of tamponade- • poor drug solubility in mediated scarring inhibition.

sustained, controlled drug release from following reasons: it is lipophilic; it has silicone oil tamponades, with the aim a role in eye physiology; it has diverse “Our key task was of developing a tamponade that will actions suggestive of an anti-scarring truly prevent retinal scarring (see: “Why effect (anti-proliferative; anti-oxidative; to modify the drug focus on drug delivery from silicone oil reduces matrix production; maintains tamponades?”). And now, after seven epithelial phenotype; antagonizes substance or oil – or years’ hard work – and the wonderful RPE65) and, importantly, it is the subject support from Fight for Sight and EPSRC of published work (4) against which we both – so as to – we are approaching the point where can benchmark our own investigations. our system can benefit patients. The next task was to determine the achieve a drug- solubility of atRA in silicone oil, which Multiple deeds turned out to be a surprisingly complex release profile that Our key task was to modify the drug exercise. Our initial data, using high- substance or oil – or both – so as to performance liquid chromatography endures over the achieve a drug-release profile that (HPLC) with UV detection, suggested endures over the several weeks that RD solubility levels 25 percent higher than several weeks that patients are at risk of scarring. And that published estimates (4). There are, required the successful execution of however, problems when applying UV- RD patients are at multiple smaller tasks. visible spectroscopy to the analysis of First, we had to pick a relevant model biological fluids, such as vitreous humor risk of scarring.” drug to use in our studies. We chose and cell culture media – not least, the all-trans retinoic acid (atRA) for the overlap in absorption peaks of media

www.theophthalmologist.com 42 NextGen

Figure 1. Development of a novel radiometric analysis method reveals (5) that the solubility of all trans retinoic acid is 20-fold higher than previously thought (4).

Days taken to reach percentage of release components and drugs. The challenges Cumulative percentage SiO1000 5% Blend 10% Blend forced us to develop a radiochemistry (49.2 µg/mL) (48.4 µg/mL) (46.2 µg/mL) method for measuring drug solubility 10 <1 <1 <1 in oil, which led us to one of our biggest surprises (5) – at RA solubility in silicone 20 <1 <1 <1 oil is actually over twenty times higher 30 1.7 1.8 1.6 than reported! (Figure 1). Once we were confident that we could 40 2.2 2.3 2.4 accurately measure the oil solubility 50 3.1 3.8 4.6 of drugs, we turned our attention to 60 5.1 6.2 7.9 modulating the release kinetics of oil-drug combinations. To this end, we developed 70 8.7 8.9 15.3 two novel technologies, comprising novel 80 16.2 17.1 50.8 polymers and polymer-drug conjugates.

90 59.0 65.5 - i. Novel polymers 100 - - - We synthesized (6) a range of novel copolymers containing Table 1. Drug release profile from tamponade oil blended with polydimethylsiloxane retinoate dimethylsiloxane and ethylene (PDMS-atRA). Note that 80 percent of drug has been released by day 16 with silicone oil as glycol repeat units within the compared to day 50 with the silicone oil-polymer blend. copolymer side-chains. Importantly, NextGen 43

the dimethylsiloxane units permit Multiple possibilities References solubilization in oil, whereas We have shown that our modified 1. MT Kralinger et al., “Safety and feasibility of the ethylene glycol units provide silicone oils are non-toxic to relevant a novel intravitreal tamponade using a silicone hydrogen bond acceptor sites to cell lines, and both enhance drug oil/acetyl-salicylic acid suspension for promote interaction with acidic drug solubility in oil and extend drug proliferative vitreoretinopathy: first results molecules. We demonstrated that the release. Furthermore, they are stable of the Austrian Clinical Multicenter Study”, copolymers were non-toxic to retinal at room temperature over extended Graefes Arch Clin Exp Ophthalmol, 248, pigment epithelial cells; subsequently, periods, and can be sterilized using 1193 (2010). PMID: 20424852. radiochemistry experiments with commercial protocols – both of which 2. G Fernandes-Cunha et al., “Determination atRA showed extended drug release increase their potential for commercial of in silicone oil and from silicone oil (6). Specifically, development. Finally, our technology of vitrectomised rabbits’ adding graft copolymer to oil (10 is compatible with different drugs, eyes: application for a pharmacokinetic study percent v/v) extended drug release and can accommodate a wide range with intravitreal triamcinolone acetonide (for example, ibuprofen release of initial drug loads – all suggestive of injections”, J Pharm Biomed Anal, 89, 24 was extended from >3 days to >9 applicability to a broad range of drugs (2014). PMID: 24252721. days). However, drug release is still and diseases. 3. M Da et al., “Distribution of triamcinolone relatively rapid with this formulation This project hasn’t always been easy, acetonide after into (for example 80 percent of atRA has and we’ve encountered a few surprises silicone oil-filled eye”, Biomed Res Int, been released after 25 days). and challenges along the way. From a 2016, 5485467 doi: 10.1155/2016/5485467 ii. Polymer-drug conjugates practical point of view, oils can make (2016). PMID: 27493959. The second technology (5) containers pretty slippery – you have 4. J Araiz et al., “Antiproliferative effect of involved chain-end modification of to be very careful when handling retinoic acid in intravitreous silicone oil in polydimethylsiloxane with atRA them! But now that we’ve developed an animal model of proliferative to produce polydimethylsiloxane the basic framework of a new ocular vitreoretinopathy”, Invest Ophthalmol Vis retinoate (PDMS-atRA). Adding drug delivery system, we’re looking Sci, 34, 522 (1993). PMID: 8449673. this to silicone oil was shown to both forward to applying it in the real 5. H Cauldbeck et al., “Modulated release increase atRA solubility and, more world. We are already working with from implantable ocular silicone oil significantly, extend the duration an industrial partner to combine our tamponade drug reservoirs”, J Polym Sci A of drug release. Interestingly, the drug release technology with marketed Polym Chem, 56, 938 (2018). PMID: drug release period was dependent oil tamponades; a key task is to ensure 29610546. on PDMS-atRA concentration, that we maintain the desirable physical 6. H Cauldbeck et al., “Controlling drug and independent of initial atRA properties of these products, such as easy release from non-aqueous environments: concentration. With this technology, injection and resistance to emulsification, moderating delivery from ocular silicone oil cumulative drug release does not and to ascertain that the new products drug reservoirs to combat proliferative reach 80 percent until ~day 50 (10 are at least as effective as the existing vitreoretinopathy”, J Control Rel, 244, 41 percent blend of polymer in oil) tamponades. In brief, we believe we (2016). PMID: 27845192. – as compared with day 16 for oil have developed a new paradigm in the alone (Table 1). [author – could you prevention of scarring subsequent to Victoria Kearns is Lecturer in Ocular confirm, please?] Again, the duration retinal detachment, and aim to have a Biomaterials, University of Liverpool, UK. of release is independent of initial product ready for first-in-human studies atRA concentration in the oil. within five years. She reports support from Fluoron GmbH.

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by becoming a leadership fellow with is that clinical leadership remains a less Female the Health Foundation, and a European recognized route in medicine when Leadership Fellow with INSEAD compared with academia or medical Leadership – is it Business School. These fellowships education, both in terms of career coincided with my appointment as a pathways and peer recognition. Clinical in Good Health? consultant at Moorfields Eye Hospital. leadership roles are still unpopular I have gone on to be a Clinical Director, among doctors, often being viewed Women are holding more and now Chief Surgeon at the hospital. with suspicion. The relatively low status positions of leadership in of clinical leaders amongst their peers, healthcare than ever before – Women of action with the exception of medical director but there’s plenty more to do Although my personal experience of roles, may partly explain why female leadership as a woman has predominantly representation in leadership forums has By Louisa Wickham been a positive one, women are grown quicker than in academic arenas. undoubtedly underrepresented in Although leadership and management My route to clinical leadership leadership roles across the NHS. The skills are now included in medical Towards the end of my registrar 2018 workforce census published by training, a guest speaker attended our the Royal College of Ophthalmologists departmental teaching session – and reports that 31 percent of consultants suddenly my eyes opened to the impact in the UK are female (1). This is an of clinician leadership on the provision improvement on the 2016 figures of 24 “One may ask, of high-quality healthcare. In my mind, percent, but it still shows how women are until that point, clinical excellence meant under-represented, given that 58 percent why is it important individual interactions with patients, of trainees in ophthalmology are female. rather than the environment in which I In ophthalmology, the opportunities for to see more worked, and its impact on good clinical women are similar to the statistics seen decision making. After attending that elsewhere in medicine. NHS Digital diversity, whether teaching session, I quickly enrolled in a reported that 26 percent of consultants Healthcare Management MSc distance in medicine are female, however it is it be gender learning course with London University. noteworthy that in surgical specialties Subsequently, I built on this foundation only 12 percent of consultants are female or ethnicity, (2). In the corporate environment female CEOs are still unusual. Of the CEOs in leadership At a Glance that make up the 2018 Fortune 500 list • Female representation in just 24 (or 4.8 percent) are women positions?” ophthalmology is similar to other (3). The statistics for female medical specialties leadership in healthcare are more • Clinical leadership roles still encouraging, with the appear to be unpopular among proportion of women doctors, which may explain on Trust boards being why female representation in 42.6 percent, and leadership forums has grown 39.5 percent on clinical quicker than in academia commissioning groups’ (CCG) • Gender and ethnic diversity in boards. However, only 24.6 leadership has a direct positive percent of medical directors effect on productivity are female. In the context of • Networking and support 77 percent of NHS workforce agencies – and a clear route to being women, we still have success – can help women pursue a long way to go (3). leadership positions. My personal observation Profession 47

school and junior doctor curriculae, it Different is better reflects the diversity of its client base, is difficult to predict whether this will One may ask, why is it important to see the services it offers are more responsive change the status of clinical leaders more diversity, whether it be gender or and representative of its client demands. in healthcare settings in the future, ethnicity, in leadership positions? Many Most would agree that in the current particularly in the context of clinical examples in the corporate sector prove NHS environment, these qualities are excellence awards becoming devalued, that increasing diversity has a direct paramount to its survival. and the work required to achieve them positive effect on productivity. In 2018, If it is well recognized that female being out of step with the rewards of the Boston Consulting Group looked at leadership increases the performance other endeavors, whether they be private 1,700 companies across eight countries, of organizations, why is it that we practice, work-life balance, or academic of varying sizes and from different have seen such a slow change in the achievements. It is also noteworthy industries. They showed that diversity representation of women in leadership that leadership roles in the NHS lend was related to increased revenue due to roles? Interestingly, the barriers to female themselves to women with families, innovation, and that it helped build a leadership can come from both male and if they are adequately recompensed in culture where “out-of-the-box ideas” were female workers. Although the qualities job planning, as it is easier to organize encouraged and nurtured (4). Moreover, of leadership may be the same for all time flexibly, compared with direct in the context of the public sector, there sexes (for example, being organized, clinical care sessions such as clinics is growing evidence suggesting that, ambitious, and intelligent), the way or surgical lists. when the leadership of an organization those qualities are applied does result

www.theophthalmologist.com 48 Profession

A Route Map to Leadership in specific management strategies and at solving problems, even though research each other, sometimes sabotaging careers leadership styles. Certainly, traits that would suggest that this is not the case. It of female peers (6). are often quoted as being more prevalent is also notable that in describing female At Moorfields, there has been significant in female leaders includes empathy, leadership, less attractive descriptions are encouragement and mentorship of female listening and collaboration (see Box: frequently used for the same traits; for leaders within the organization. Forty- Female leadership styles). example, bossy versus decisive. Women one percent of the consultant body is are often left with the dilemma of either female, above the national average for All is not what it seems adopting masculine leadership styles or ophthalmology. Leadership courses and Barriers to female leadership also originate being considered a poor leader by both male fellowships have actively been encouraged. in the perception others have of female and female colleagues. Indeed, research has Moorfields is perhaps also different from leadership styles. For example, when shown that 75 percent of female managers national statistics in terms of clinician asked to imagine a leader, a male leader is feel more comfortable with male leaders, management. There are many female often described by both male and female either due to social norms of patriarchy or leaders both in clinical services, education respondents. Further, men are often experience of the “queen bee” phenomenon, and academia; indeed, the Chairperson of described as being more decisive or better a process by which females compete with the Board is female. And that may explain Profession 49

Female qualities to work. Their qualities “It is not true to are described as being able to leadership listen, care, understand and say that female styles communicate well. 3. The Integrated Women: Women empowerment with strong leadership qualities Ana Marinovic and Steve Tappin found and influence through their only stems from that there were, broadly speaking, four ambition and drive to succeed main female leadership styles (5) personally, and to support equality female mentors.” 1. Female Pioneers: Often in the workplace. There is less with leadership styles that of a separation between work resonate with more masculine and home; these women have an why my experience overall has been a environments, such as forthright influential nature, and are very positive one. I think it is also important and “no-nonsense.” Although good at collaborating, empowering, to highlight that my leadership mentors they are often pioneers in male- connecting and co-creating with have been predominantly male, and I dominated environments, they both men and women. have been very fortunate to work with may sometimes be described as 4. Women of Inspiration: These medical directors and chief executives “the token woman.” women come from all generations who have been extremely supportive 2. Feminine Leaders: Women and generally embody all of the and encouraging in their both time and who have been exposed to more other leadership types. They are financial support. It is not true to say equality in their upbringing, both driven by a higher purpose, are that female empowerment only stems professionally and at home. Often often globally recognized, and from female mentors. I do, however, of generation X, they have the have broken free from male- see it as an important aspect of my role confidence to bring “feminine” dominated leadership constraints. to encourage female trainees to make career decisions based on their talents, and not on stereotypical bias. There are a number of female networking and support agencies in existence (such as Women in counterparts. Increasingly, women https://bit.ly/326tMIJ. Accessed July 3, Vision UK, Women in Ophthalmology make the major financial contribution 2019. and Ophthalmic World Leaders) to to household incomes. We do however 2. NHS Digital, “NHS Workforce encourage women to take a leadership need to recognize that diversity in the Statistics – March 2019” (2019). roles and also academic roles, and I hope workplace at leadership levels whether Available at: https://bit.ly/2XppiOs. that one day we will no longer feel that it be gender, ethnicity or disability, Accessed July 3, 2019. they are required to encourage women enhances our ability to deliver the 3. Fortune, “Fortune 500 List” (2018). to take up leadership roles. patient centered care we aspire to. Available at: https://bit.ly/2J8fEXN. In this modern debate Accessed July 3, 2019. about male/female Louisa Wickham is a 4. Boston Consulting Group, “How diverse equality in the workplace, Consultant Ophthalmic leadership teams boost innovation” (2018). we must not simplify Surgeon and Chief Surgeon Available at: https://on.bcg.com/30hp1uj. the argument. Not all at Moorfields Eye Accessed July 3, 2019. women have the same Hospital, London, UK. 5. HR Magazine, “The four types of female work ethic, wish for leadership” (2017). Available at: https:// family or work-life References bit.ly/326vRV3. Accessed July 3, 2019. balance. Some men 1. The Royal College of 6. K Reddy, Wisestep, “Male vs Female will have more in Ophthalmologists, Leadership: Differences and Similarities” common with “Workforce Census 2018” (2018). Available at: https://bit. their female (2018). Available at: ly/2F2THrv. Accessed July 20, 2019.

www.theophthalmologist.com Taking Care of Business

Sitting Down With… Stefanie Schmickler, CEO of Augen Zentrum Nordwest in Germany and Deputy Editor of GMS Ophthalmology Cases Photo by Alicia Kassebohm, Berlin. Sitting Down With  51

Why did you choose to specialize in before she left the hospital, she brought me ophthalmology? a bouquet of flowers. It’s a moment I will I originally wanted to go into dermatology, never forget. Another moment of great “I dream of as I had been suffering from severe acne – pride was when I opened my clinic in 2009 the reason I chose to study medicine in the and all surgeries went well without any having OCT first place – but there were already too many complications. A year later I was named doctors in Germany by the time I finished “top surgeon in cataract and refractive controls close to our my thesis. I had no chance of getting a surgery” by FOCUS magazine in Germany residency in dermatology. Ophthalmology – an award I have gone on to win another 10 patients’ homes, so had always been an alternative for me as times. Last October, I won a national prize I had been wearing contact lenses for for businesswomen – an acknowledgment of they don’t have to several years and liked the complexity my achievements of the last 10 years. Most of the human eye. Nevertheless, I still people believe that a doctor shouldn’t also wait around for like dermatopathology and I can imagine be a business person, but, in my opinion, assisting part-time in a laboratory when working efficiently – like a business person – a diagnosis.” I retire. has advantages for both patients and clinics.

How has ophthalmology changed over What are you focusing on right now? the course of your career? I’m fully focused on the business, which What advice would you give to It has changed a lot – and not just in I share with my partner, Olaf Cartsburg. ophthalmologists at the start of a scientific sense. There are now more Outside of surgery, organizing and their career? women in leading positions, which is optimizing our clinic is my primary First, ophthalmology is far more than why we founded the female eye surgeon focus. I am currently working to improve cataract surgery! There are so many network in Germany last year (www. patient workflow, especially for wet AMD interesting fields to discover – don’t augenchirurginnen.de). We wanted to patients, so we can offer our staff (all 220 only focus on cataract. We need doctors support our younger colleagues in their of them!) a great place to work and our with experience in glaucoma, uveitis, careers. From a medical point of view, patients the best possible therapy. , and more. Second, don’t there have been many changes, both in the only focus on ophthalmology! Soft anterior and posterior segment. When I What’s the next big thing in skills like team building and patient started in 1989, the rule in cataract surgery ophthalmology? communication are equally important. was to suture, with hardly any astigmatism. Artificial intelligence and telemedicine Third, you have to work hard for what Implantation size was around 5.5 mm. will become more important. Retinal you want in life. Sometimes that means Foldable lenses then came on the market examinations will take place outside having to leave other things behind but, and the 3.2 mm sutureless incision tunnel the clinic so patients will only need to by doing so, you will ultimately progress. was introduced. Avoiding posterior capsular see an ophthalmologist if something My last piece of advice is for women: opacification was a big issue and I took pathological is found in the examination. you do not have to dress like a man to part in many studies trialing different lens be successful. Wear whatever you feel designs to prevent that from happening. What is on your ultimate wishlist for comfortable in. “Business wear” doesn’t Another big change was FLACS, which eye care? have to mean suits. came on the market around 2010. I was I would like medicine to overcome vision- sceptical at first, but I now consider it to threatening diseases like AMD, glaucoma And advice at any stage? be the future of cataract surgery. and pigmentosa, and see a change Not everything in life can be solved by in how we treat wet AMD. We currently machines and money. Patients need What are the proudest moments of have to inject patients every one to three quality personal time with their doctor your career? months, which is problematic. I dream to feel reassured, while doctors need Every young surgeon remembers the of having OCT controls close to our good teams behind them to offer the first time a patient says: “Thank you!” I patients’ homes, so they don’t have to best level of care. It is only through performed strabismus surgery on a six-year- wait around for a diagnosis. We could just this combination that our profession old girl during my time at Dortmund and, phone them later to tell them the result. can be successful.

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Seamless clarity Because his passion is on the line. from near to far.1 T:10.5” B:11” S:10”

TECNIS® Personalized Vision refers to combining a TECNIS Symfony® IOL in one eye and a TECNIS® Multifocal IOL in the fellow eye. To learn more, see us at AAO 2019 booth 1439

Indications and Important Safety Information or visit TecnisIOL.com Rx Only TECNIS SYMFONY® EXTENDED RANGE OF VISION IOL INDICATIONS: The TECNIS Symfony® Extended Range of Vision IOL, Model ZXR00, is indicated for primary implantation for the visual correction of aphakia, in adult patients with less than 1 diopter of pre-existing corneal astigmatism, in whom a cataractous lens has been removed. The lens mitigates the e† ects of presbyopia by providing an extended depth of focus. Compared to an aspheric monofocal IOL, the lens provides improved intermediate and near visual acuity, while maintaining comparable distance visual acuity. The Model ZXR00 IOL is intended for capsular bag placement only. WARNINGS: Patients with any of the conditions described in the Directions for Use may not be suitable candidates for an because the lens may exacerbate an existing condition, may interfere with diagnosis or treatment of a condition, or may pose an unreasonable risk to the patient’s eyesight. Lenses should not be placed in the ciliary sulcus. May cause a reduction in sensitivity under certain conditions, compared to an aspheric monofocal IOL; fully inform the patient of this risk before implanting the lens. Special consideration should be made in patients with macular disease, amblyopia, corneal irregularities, or other ocular disease. Inform patients to exercise special caution when driving at night or in poor visibility conditions. Some visual e† ects may be expected due to the lens design, including: a perception of halos, glare, or starbursts around lights under nighttime conditions. These will be bothersome or very bothersome in some people, particularly in low- illumination conditions, and on rare occasions, may be signifi cant enough that the patient may request removal of the IOL. SERIOUS ADVERSE EVENTS: The most frequently reported serious adverse events that occurred during the clinical trial of the TECNIS Symfony® lens were cystoid (2 eyes, 0.7%) and surgical reintervention (treatment injections for cystoid macular edema and , 2 eyes, 0.7%). No lens-related adverse events occurred during the trial.

TECNIS® MULTIFOCAL FAMILY OF 1-PIECE IOLs INDICATIONS: The TECNIS® Multifocal 1-Piece intraocular lenses are indicated for primary implantation for the visual correction of aphakia in adult patients with and without presbyopia in whom a cataractous lens has been removed by phacoemulsifi cation and who desire near, intermediate, and distance vision with increased spectacle independence. The intraocular lenses are intended to be placed in the capsular bag. WARNINGS: Physicians considering lens implantation should weigh the potential risk/benefi t ratio for any conditions described in the Directions for Use that could increase complications or impact patient outcomes. Multifocal IOL implants may be inadvisable in patients where central visual fi eld reduction may not be tolerated, such as , retinal pigment epithelium changes, and glaucoma. The lens should not be placed in the ciliary sulcus. Inform patients about the possibility that a decrease in contrast sensitivity and an increase in visual disturbances may a† ect their ability to drive a car under certain environmental conditions, such as driving at night or in poor visibility conditions.PRECAUTIONS: Prior to surgery, inform prospective patients of the possible risks and benefi ts associated with the use of this device and provide a copy of the patient information brochure to the patient. Secondary glaucoma has been reported occasionally in patients with controlled glaucoma who received lens implants.ADVERSE EVENTS: The rates of surgical re-interventions, most of which were non-lens related, were statistically higher than the FDA grid rate for the ZLB00 (+3.25 D) lens model. The re-intervention rate was 3.3% for both the fi rst and second eyes in the ZLB00 group.

ATTENTION: Reference the Directions for Use for a complete listing of Indications and Important Safety Information. See the Passion in Each Patient REFERENCE: 1. DOF2018CT4021. Johnson & Johnson Surgical Vision, Inc; 2018. TECNIS and TECNIS Symfony are trademarks of Johnson & Johnson Surgical Vision, Inc. ©Johnson & Johnson Surgical Vision, Inc. 2019 | TecnisIOL.com | PP2019CT4953

PR06664_JJV_PV_8_3x10_5_TheOpthamologistUS_4C.indd M19JJSV_PV_AAO_TO8_25_ Personalized Vision Ad 8.3” x 10.5” 1 6.05” x 8.5” CMYK 7.8” x 10” 100% 8.875” x 11” -- Gotham, Minion Pro JJV The Opthamologist US PR06664 8-19-2019 8:36 PM -- 8-19-2019 8:36 PM -- Ferreira, Jamy (TOR-MWG) Cyan, Magenta, Yellow, Black -- Steve.Ferreira --