A Life- Changing Gift

SEPTEMBER 2018 # 25

In My View NextGen Profession Sitting Down With Making the case for intracameral A non-invasive approach to How the Himalayan Cataract Elizabeth Yeu, aspiring antibiotics in the US refractive correction Project keeps on climbing for greatness

17 37 – 38 46 – 49 50 – 51

One patient and one physician on what it really means to restore 20/20 vision. 18 – 25

NORTH AMERICA www.theophthalmologist.com 1,386,254.5 Diopters of astigmatism went unmanaged in U.S. cataract ORs in 2016.*,1

Astigmatism Management is your bridge to cataract refractive outcomes. You manage sphere for every patient. Why leave cylinder on the table?

Visit www.CrushSomeCyl.com for resources, passion and partnership.

*Based on data from Dr. Warren Hill. Assumes mid-range distribution of pre-op astigmatism. Excludes irregular and other conditions that impact toric selection. 1. Alcon Data on File.

102883 US-CRD-16-E-4772 TO.indd 1 7/26/18 2:53 PM Image of the 1,386,254.5 Diopters Month of astigmatism went unmanaged in U.S. cataract ORs in 2016.*,1

Astigmatism Management is your bridge to cataract refractive outcomes. Fun After Hours These images were submitted by Trina Toyama, a Clinical Applications Specialist at Heidelberg Engineering. “As a technician, I have You manage sphere for every patient. Why leave cylinder on the table? had the privilege of using many precision eyecare instruments and cameras. Though the retina is an endless source of fascination, over my career I have used non-ocular images as a way to better understand the functions, strengths, and limitations of a device. Turning the camera to the plants and debris surrounding clinic buildings created these images, which were acquired with a SPECTRALIS diagnostic imaging platform.” Using only the tools and features available with the system – such as automated real-time tracking – Visit www.CrushSomeCyl.com for resources, passion and partnership. Toyama says that the device “easily transitions from the most demanding science to playfully act as a fascinating high magnification camera with a lot of latitude for after-hours fun.” But can you guess what they are? Credit: Trina Toyama, Clinical Applications Specialist, Heidelberg Engineering. Top left, flower; top right, leaf; bottom left, acorn caps; bottom right; flower.

*Based on data from Dr. Warren Hill. Assumes mid-range distribution of pre-op astigmatism. Excludes irregular and other conditions that impact toric selection. 1. Alcon Data on File. Do you have an image you’d like to see featured in The Ophthalmologist? Contact [email protected]

102883 US-CRD-16-E-4772 TO.indd 1 7/26/18 2:53 PM Contents

In My View

14 Think LASIK has reached its peak? Think again. Rod Solar says the refractive market could be multiplied in less than a decade, but only the most adaptable will enjoy the benefits.

15 In this digital age, are we doing enough to champion truly great minds? That’s the question Karl Stonecipher asks in his time-bending piece, “Pioneer or Buccaneer?”.

10 17 If intracameral antibiotics reduce the risk of cataract surgery complications, why aren't more US surgeons using them? John Berdahl shares his thoughts. 03 Image of the Month Upfront

08 Blinded by the Light 07 Editorial Feature The Gift of Sight..., 09 Inject or Reject by Ruth Steer. 18 A Life-Changing Gift 10 Not Immune to Damage Corneal transplants are all in a day’s work for an 11 An Abnormal Connection ophthalmologist – but for a On The Cover patient like Crystal Ellis, they

SEPTEMBER 2018 # 25 12 Changing the Program mean the world. With the help

14 36 – 39 46 – 49 50 – 51 Artwork inspired by the uplifting of her physician, Christine A Life- Changing Gift

One patient and one physician on what it really takes to restore 20/20 vision. 18 – 25 story of Crystal Ellis, a corneal 12 Bitesize Breakthroughs Sindt, she explains what it’s transplant recipient and Transplant really like to suffer sight loss – NORTH AMERICA www.theophthalmologist.com Games of America medal winner. and how it feels to get it back. ISSUE 25 - SEPTEMBER 2018

Editor - Ruth Steer [email protected] Assistant Editor - Phoebe Harkin [email protected] Content Director - Rich Whitworth [email protected] Publishing Director - Neil Hanley [email protected] Associate Publisher - Abigail Mackrill [email protected] Head of Design - Marc Bird [email protected] Designer - Hannah Ennis [email protected] Junior Designer - Charlotte Brittain [email protected] Digital Team Lead - David Roberts [email protected] Digital Producer Web/Email - Peter Bartley [email protected] Digital Producer Web/App - Abygail Bradley [email protected] Audience Insight Manager - Tracey Nicholls [email protected] Traff ic & Audience Database Coordinator - Hayley Atiz 46 [email protected] Credit: Ace Kvale, Mekelle, Ethiopia. Mekelle, Kvale, Ace Credit: Traffic & Audience Associate - Lindsey Vickers [email protected] Traffic Manager - Jody Fryett [email protected] Traffic Assistant - Dan Marr [email protected] In Practice Events Manager - Alice Daniels-Wright [email protected] Marketing Manager - Katy Pearson 28 DME, Steroids and Glaucoma [email protected] Intravitreal steroids for DME: 39 Navigating the Long Road Financial Controller - Phil Dale Charles Wykoff discusses [email protected] Uveal melanoma can be a long- Accounts Assistant - Kerri Benson which patients can benefit, and term systemic disease. Kathleen [email protected] Vice President (North America) - Fedra Pavlou addresses concerns associated Gordon and Jonathan Zager [email protected] with the therapy. discuss a team approach to Chief Executive Officer - Andy Davies care, and overview current and [email protected] Chief Operating Officer - Tracey Peers 31 The Matchmaker emerging treatments. [email protected] Paul Ursell introduces his Change of address cataract training program – [email protected] The Ophthalmologist, Texere Publishing, an easy-to-use system that 175 Varick St, New York, NY 10014. Periodical Postage Paid at New York NY and additional offers patients lower risks of Profession mailing offices. complications, regardless of General enquiries surgeon experience. 46 Climbing Mountains for a Cure www.texerepublishing.com [email protected] From Bhutan to West Bengal, +44 (0) 1565 745 200 Tibet to Tanzania, Geoff Tabin [email protected] explains the origins of The Distribution The Ophthalmologist North America NextGen Himalayan Cataract Project (ISSN 2398-9270) is published monthly by Texere Publishing, 175 Varick St, New York, and looks back on an almost NY 10014. Periodical Postage Paid at New York, 36 Engineering Non-Invasive 30-year journey. NY and additional mailing offices. POSTMASTER: Send address changes to Refractive Correction Texere Publishing ,175 Varick St, New York, NY 10014 Mechanical engineer, Single copy sales $15 (plus postage, cost available on request [email protected]) Sinisa Vukelic, shares the Non-qualified annual subscription cost is science behind femtosecond Sitting Down With... available on request Reprints & Permissions – [email protected] laser-induced corneal The opinions presented within this publication are those of the authors and do not reflect the opinions of The Ophthalmologist or its publishers, crosslinking, and explains why 50 Elizabeth Yeu, Cataract and Texere Publishing. Authors are required to disclose any relevant financial arrangements, which are presented at the end of each article, where relevant. the procedure could change Refractive Surgeon at Virginia © 2018 Texere Publishing Limited. All rights reserved. refractive surgery forever. Eye Consultants, VA, USA Reproduction in whole or in parts is prohibited. Ellex-iTrack-TOP-DEC2017-PRINT.pdf 1 29/11/2017 3:37 pm

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LEARN MORE AT WWW.GLAUCOMA-iTRACK.COM The Gift of Sight… Editorial … is one that truly keeps giving. How and where the gift is presented can vary widely, but the impact is always great.

f I were to ask you what you find most rewarding about your occupation (which I do on a regular basis), many of you will answer, “saving and improving sight” – Iunsurprising, as it is at the very core of what you do on a daily basis. But in a profession that encompasses many different specialties and disciplines – and varies across countries - how each individual ophthalmologist works to present this gift can be very different. And that’s why this issue features two inspiring – but quite different – approaches to saving sight. In our cover feature, a patient and physician tell their stories. Crystal Ellis was in middle school when, for an unknown reason, she lost vision in one eye. She had a corneal transplant – but her vision did not improve. A positive individual, Crystal shares her experiences and perspectives as a patient. She also tells the heart-warming tale of her relationship with the cornea donor’s family, which really brings home the humanity integral to tissue and organ donation and how ‘precious’ that gift can be. Around the same time, Crystal crossed paths with Christine Sindt – Professor of Ophthalmology at the University of Iowa hospital – whose innovative, custom-printed prosthetic lens technology went on to give Crystal 20/20 vision. Sindt explores her motivation to create a product to restore sight to those with corneal defects. And Crystal offers the perfect example of impact with her relentless motivation to ‘go for gold’ with her sight restored. Following on the theme of the gift of sight, in our Profession section Geoff Tabin reveals the backstory to the Himalayan Cataract Project. Many of you will be familiar with the Project and its aims to eradicate global blindness. A truly inspiring individual, Tabin reveals how his interest in humanitarian efforts arose from him witnessing, first-hand, the global inequity in access to care. Almost 30 years after setting up the project, Tabin hasn’t wavered in his goal – and has extended the project well beyond the Himalayas to tackle blindness in many other countries. The long and the short of it is: whether working for profit or for non-profit, the impact of the gift of sight is universal – and it is clear that everyone working in ophthalmology strives to make a real difference to people’s lives in their own way.

Ruth Steer Editor

www.theophthalmologist.com 8 Upfront

Upfront Reporting on the innovations in medicine and surgery, the research policies and personalities that shape the practice of ophthalmology.

We welcome suggestions on anything that’s impactful on ophthalmology; please email edit@ theophthalmologist.com

Blinded by trans-retinal (ATR), could irreversibly distort PIP2 (a plasma membrane-bound the Light phospholipid), disrupting downstream signaling and inducing oxidative How blue light can induce damage, ultimately leading to cell death retinal cell death (Figure 1; 1) “When retinal absorbs blue light, it As a child, you may have been told, becomes excited with photon energy. It “Don’t spend so long in front of the releases that energy to oxygen, which TV… your eyes will go square!” – but generates highly oxidative chemical what if the truth was more serious? A molecules, oxidizing important signaling team at the University of Toledo, OH, lipids and proteins in cells, leading to USA, has found that blue light emitted cytotoxicity,” explains Karunarathne. by digital devices – and the sun – could And the results were the same when permanently affect eyesight. the team introduced retinal molecules The research, led by Ajith to other non-receptor cell types. “Many Karunarathne, found that, when reports have indicated the likelihood exposed to photoexcitation by blue light, of blue light being cytotoxic,” says the photoreceptor chromophore 11-cis Karunarathne. “Our work clearly retinal (11CR) and its photoproduct, all- shows cell death occurs when retinal Upfront 9

molecules are present, even without photoreceptors.” Given that photodegradation of this kind is linked with diseases such as AMD, can anything be done to avoid blue-light induced vision loss? “Avoiding prolonged exposure can help,” says Karunarathne, who also recommends sunglasses that not only block out UV light but also blue light, as well as advising against looking at cell phones or tablets in the dark. Karunarathne has a worthy end goal in mind: “By learning more about the mechanisms of blindness, and searching for a method to intercept the toxic reactions caused by the combination of retinal and blue light, we hope to find a way to protect the vision of children growing up in a high-tech world (2).”

References 1. K Ratnayake et al., “Blue light excited retinal intercepts cellular signalling”, Sci Rep, 8, 10207 (2018). PMID: 29976989. 2. The University of Toledo, “UR chemists discover how blue light speeds blindness”,

(2018). Available at: https://tinyurl.com/ Credit: K Ratnayake et al., (1). y735e8cq. Accessed August 16, 2018. Figure 1. Proposed mechanism of how blue light-excited retinal incudes PIP2 distortion.

into how to boost success rates. points to one likely possibility: “VIP Inject or Reject Previous studies have revealed that increases the migration of corneal vasoactive intestinal peptide (VIP) endothelial cells, and decreases cell Are vasoactive intestinal could enhance corneal cell survival apoptosis by modulating resistance to peptides the secret to corneal during donor cornea storage, so a pro-inflammatory cytokines.” transplant survival? team from Massachusetts’ Eye and If the findings successfully translate Ear Institute, Boston, USA, theorized to the clinic, the implications are Globally, there are millions of people that it could also help after corneal significant, says Kheirkhan. “The use with corneal blindness. But as countries transplantation. “Our experiment of VIP could help a large number struggle generally with donor cornea revealed that our hypothesis was of patients with corneal endothelial shortages, there is another factor correct; the postoperative use of VIP abnormalities, and enhance the that can affect the availability – and improved the survival of corneal grafts outcome of corneal transplantation.” success – of corneal transplants: in mice,” says Ahmad Kheirkhan, co- corneal endothelial cell integrity. If author of the paper (1). Reference corneal endothelial cell density or The team is currently conducting 1. V Satitpitakul et al., “Vasoactive intestinal function becomes inadequate after further studies to unravel the exact peptide promotes corneal allograft survival”, the transplant, graft opacity and/or mechanisms by which VIP enhances Am J Pathol, [Epub ahead of print] (2018). rejection can occur, prompting research corneal graft survival, but Kheirkhan PMID: 30097165.

www.theophthalmologist.com 10 Upfront

glaucoma patients whose IOP was T cells compared with control subjects, Not Immune perfectly controlled would still undergo suggesting that a similar mechanism progressive vision loss. We began to underlies the disease process in humans. to Damage speculate that elevated eye pressure Though only a 2–3 week elevation of triggered a long-lasting event, such as IOP is sufficient to induce HSP-specific Could activated T cells immune reactions, that contribute to T cell responses in mice, we do not play a major role in driving vision loss. We thus looked for T and yet know what duration in humans is neurodegeneration in B cells in the glaucomatous retina and required to induce a response. However, glaucoma? found T cells, which should not be we speculate that at least some patients present because eye is thought to be an with normal tension glaucoma have had Glaucoma may be one of the leading immune privileged site. a transient elevation of IOP. causes of irreversible blindness worldwide but it is also one of The impact… the most mysterious. Elevated We believe that our findings may IOP might explain some of lead to a future paradigm shift the pathology, but fails in both the diagnosis and to explain glaucomatous management/treatment damage occurring in of glaucoma.First, patients with normal though glaucoma causes IOP – or in those whose permanent loss of vision, IOP is maintained with its early diagnosis has therapy. As research teams long been a challenge. the world over look to unravel Our finding may provide the complex mechanisms driving a potential biomarker for the disease, a research group early diagnosis of the disease. from Massachusetts’s Eye and Second, current therapies for Ear Hospital, Boston, MA, USA, glaucoma solely target reducing have evidence suggesting another IOP, which slows vision loss rather factor might be at play: autoimmunity. than curing the disease. Our findings In brief, the team found that suggest new therapeutic targets, which increased IOP could induce stress on may eventually lead to the cure of the retinal neurons, leading to an elevated Unexpected findings… disease. expression of heat shock proteins (HSPs), We were surprised that mere elevation of which, in turn, activates HSP-specific eye pressure for a short time can induce T Next steps... CD4+ T cells. Primed by commensal cell infiltration into the eye and cause T Our goals are to develop and evaluate microbial flora, these T cells appear to cell-mediated attack to neurons. Second, new interventions that target T cell or induce progressive neurodegeneration. we were surprised that mice never immune pathways for preventing vision Dong Feng Chen, senior author on the exposed to bacteria are completely free loss in glaucoma. In collaboration with paper (1), talks about their work. from getting the disease, which truly clinicians, we’d like to examine the indicates that elevation of eye pressure possibility and potential of predicting The inspiration… is not the direct cause of glaucoma, but disease development or progression by The work was started several years ago, rather the immune responses that lead detecting abnormal or heightened T cell when we first developed an inducible to neuron and vision loss. responses to HSPs. model of glaucoma in mice. We noted that a transient 2–3 week elevation of In humans… Reference IOP resulted in progressive neuron loss By examining human blood samples, 1. H Chen et al., “Commensal microflora- even after the eye pressure returned to we showed that patients with primary induced T cell responses mediate progressive a normal range. This finding agreed open angle glaucoma (POAG) exhibited neurodegeneration in glaucoma”, Nat with clinical observations that many five-fold higher levels of HSP-specific Commun, 9, 3209 (2018). PMID: 30097565. Upfront 11

lateral rectus, and the sole behavioral muscle – the brain and eye muscle, An Abnormal role is to generate outward eye respectively. “The involvement of movements, this allows us to evaluate protocadherins in strabismus has not Connection the effects of a genetic mutation at the been established yet in humans, but we molecular, cellular and behavioral level.” hope our work in zebrafish contributes Uncovering mechanisms Their target? Protocadherin – a protein to help estimate the risk of developing that may underpin the expressed in abducens motor neurons strabismus, and increase the chances development of strabismus that the team hypothesized might play of initiating early treatment to prevent a key role in axon growth. impaired eye movement.” Outside the Strabismus is just one of the conditions Using CRISPR-Cas9, the team realm of ophthalmology, Asakawa caused by abnormalities in the cranial induced mutations in pcdh17 – the and his team hope to explore how neuromuscular system. Despite affecting gene encoding for protocadherin. “The protocadherins contribute towards four percent of the US population changes that occurred were striking,” connecting other neurons and muscle (1), tissue inaccessibility has left it, says Asakawa. “When mutant Pcdh17 fibers. “Some connections in the brain and other brain-muscle conditions, was expressed, the abducens motor and eye are selectively resistant to relatively unexplored. It’s why a team neurons formed cellular aggregates, degeneration. We hope our work can at the National Institute of Genetics in and failed to position properly in the go some way in contributing towards Japan has turned to zebrafish to help brain and extend axons toward the the protection of motor neurons in fatal understand genetic mutations that might eye globe. This led us to believe that diseases such as ALS.” be driving the condition. abducens motor neurons actually “Strabismus is one of the conditions repel each other.” He adds: “This was References where brain and muscle connections can somewhat counterintuitive to us because 1. American Association for Pediatric be abnormal. The connection between neurons with similar functions usually Ophthalmology, “Strabismus” (2018). abducens motor neurons and their cluster together, making it difficult for Available at: https://www.aapos.org/terms/ target muscle – the lateral rectus – is us to imagine repulsive force operating conditions/100. Accessed August 17, 2018. an excellent model to study the basic in between.” 2. K Asakawa et al, “Protocadherin-Mediated principle of brain-muscle connections,” According to Asawaka, their findings Cell Repulsion Controls the Central explains Kazuhide Asawaka, who led have uncovered the importance of Topography and Efferent Projections of the the associated study (2). “As neurons in protocadherins in connecting the Abducens Nucleus”, Cell Reports 24, the abducens nucleus connect only with abducens nucleus to the lateral rectus 1562-1572 (2018). PMID: 30089266.

www.theophthalmologist.com 12 Upfront

Lead investigator, cells were reprogrammed Changing the Bo Chen, explained: in Gnat1rd17Gnatcpfl3 mice, “This study opens the team were able to Program a new pathway for show that the mice could potentially treating respond to light. Reprogramming murine blinding diseases by Although there is a Müller glia to drive manipulating our own long way to go between photoreceptor genesis and regenerative capability the laboratory bench and restoration of vision to self-repair” (2). the clinic, Chen said In their study, they that their work could Müller glia cells, abundant in the retina, reprogrammed Müller “lead to extraordinary are known to support retinal cell function. glia to generate rod opportunities in the But they also have another support photoreceptors through future where we function: retinal regeneration. In cold- a two-step process. First, can potentially use blooded vertebrates, such as zebrafish, it they induced Müller glia the same strategy to is well known that Müller glia can act as a proliferation in adult mice reactivate these stem source of stem cells to induce retinal repair through gene transfer of cells in the diseased and regeneration. But this regenerative β-catenin. Second, they human eye” (2). capacity is absent in mammals; although reprogrammed the proliferating cell proliferation might occur in response Müller glia cells into rod photoreceptors References to injury, these cells do not repair or through gene transfer of the transcription 1. K Yao et al., “Restoration of vision after de regenerate the retina. Now, a team from factors Otx2, Crx and Nrl. After novo genesis of rod photoreceptors in Icahn School of Medicine at Mount confirming that they could generate mammalian retinas”, Nature, [Epub ahead of Sinai, New York, USA, have shown rod photoreceptors, the team tested print] (2018). PMID: 30111842. that they were able to reprogram Müller whether reprogramming Müller glia in 2. Mount Sinai Newsroom. “Mount Sinai glia to generate rod photoreceptors, and a mouse model of congenital blindness researchers discover how to restore vision using restore light perception in a mouse model (Gnat1rd17Gnatcpfl3) could restore visual retinal stem cells”. Available at: http://bit.ly/ of congenital blindness (1). function. Four weeks after Müller glial MSinai. Accessed: August 20, 2018.

the team identified retinal thinning, Technology in Brisbane are now Bitesize and found that it correlated with working with Allergan, who co- disease severity and may be linked founded the research, to incorporate Breakthroughs with an increased loss of dopamine- a synthetic long-chain lipid chain producing brain cells. Looking to into future dry eye treatments (2). Analyzing the tear film layer, the future, the authors hope this screening for neural disease, study may help neurologists detect D for Diagnosis and a curious contact lens Parkinson’s in its earliest stages with case: a brief selection of the a simple eye scan. • Researchers at the University of latest ophthalmology news Washington, Seattle, USA, have Dry Eye Developments uncovered potentially promising Eye Spy screening criteria for Alzheimer’s • Using advanced mass spectrometry disease. By analyzing a population • A team at Seoul National techniques, a team of Australian of 3,855 patients, they identified University, South Korea, has researchers have characterized a significant association between linked thinning of the retina with ultra-long-chain fatty acids the disease and three common Parkinson’s disease (1). In patients from human meibum. The team eye conditions – AMD, diabetic with early stage Parkinson’s disease, from Queensland University of retinopathy and glaucoma (3). Upfront 13

Contact lenses recovered from treated sewage sludge which, according to new research findings, could harm the environment (6).

RP Revelations

• Birch et al. (4) have published findings showing that oral valproic acid was no better than placebo for the treatment of autosomal dominant retinitis pigmentosa (ADRP). In the randomized Phase II multicenter placebo-controlled trial, 37 patients with ADRP were treated for 12 months with 1,000 mg or 500 mg valproic acid; 42 patients were administered placebo. Valproic acid failed to meet its Credit: Charles Rolsky primary endpoint – change in visual field area between baseline and 12 the age of 14 when she was hit in the References months. The authors noted that one eye with a shuttlecock during a game 1. J Ahn et al., Neurology [Epub ahead of print] (2018). scientific premise for the study was ofbadminton. The authors report it PMID: 30111550. the “concern that patients with RP isn’t clear why the lens resided in the 2. SE Hancock et al., J Lipid Res., 59, 1510-1518 were taking off-label valproic acid eyelid asymptomatically for 28 years. (2018). PMID: 29907595. without adequate monitoring.” • According to findings presented 3. CS Lee et al., Alzheimers Dement., [Epub ahead of at the American Chemical Society print] (2018). PMID: 30098888. Contact Lens Concerns annual meeting, disposable 4. DG Birch et al., “Effect of oral valproic acid vs placebo contact lenses are an emerging for vision loss in patients with autosomal dominant • In a curious case, a 42-year-old patient environmental contaminant (6). retinitis pigmentosa”, JAMA Ophthalmol, 136, presenting with eyelid swelling As 15–20 percent of contact lens 849–856 (2018). PMID: 29879277. and ptosis has had a contact lens wearers reported flushing their 5. S Patel et al., BMJ Case Rep, (2018). PMID: removed from her eyelid – 28 years lenses down the toilet or sink, 30097548. after it became embedded there (5). it might be time to check how 6. American Chemical Society. “The environmental cost According to the authors, the patient patients are disposing of their of contact lenses”. Available at: http://bit.ly/ACSLens. believed that the lens had been lost at disposables... Accessed: August 20. 2018.

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IRIDEX_The_Ophthalmologist_Ad.indd 1 7/18/18 2:54 PM 14  In My View

surgeons have performed 40 million Awakening LASIK procedures since 1991 (2). That In My might sound like a significant number, Sleeping Giants but considering just how many people worldwide have refractive errors it’s an View How and why the laser exceedingly small penetration rate. refractive market is set to grow I think that a significant opportunity In this opinion section, is appearing on the refractive horizon: presbyopic LASIK. And I believe that experts from across the ‘Generation X-ers’ (born 1965–1979) world share a single and ‘baby boomers’ (born 1946–1964) strongly-held view or are the sleeping giants of the refractive key idea. surgery market. Here’s why: 1. The market size for presbyopic Submissions are welcome. LASIK is much larger than that Articles should be short, By Rod Solar, Director of Practice of regular LASIK. According focused, personal and Development, LiveseySolar, London, UK to Statista (3), the population of millennials in the USA is passionate, and may What if I said that the size of the laser estimated to be 72 million, with deal with any aspect refractive surgery market could be the population of Generation of ophthalmology. multiplied fourfold in less than a decade? X-ers estimated at 66 million, and They can be up to And that only those with foresight and baby boomers at 74 million. But 600 words in length adaptability will have a chance to grasp there are together 140 million this opportunity? Generation X and baby boomers and written in the Since the early 2000s, companies have – almost double the size. And first person. introduced improvements to traditional when you consider that only half LASIK, such as wavefront-guided of millennials are likely to even Contact the Editor at procedures, femtosecond flaps and small need refractive surgery (around incision lenticule extraction (SMILE). 36 million), and compare that [email protected] Results improved, complication rates with the numbers of people over declined, and today, LASIK is as safe 50 that have presbyopia (roughly and effective as ever. Consumers have, 120 million), it is clear that the however, responded tepidly. Since presbyopic opportunity is almost the financial crisis of the late 2000s, four times the size. Of course, as volumes have not grown significantly. some of these elder Boomers will The primary target for laser refractive present with early signs of cataract surgeons today is millennials (born they will be ideal candidates 1980–2000). But despite the hopes for refractive lens replacement. placed on them to fuel a laser vision With that said, a significant correction renaissance, procedure percentage of them will require volumes have remained relatively flat an enhancement to achieve since 2009 (1). Why is that? I think a key ‘20-perfect’ vision. problem is that equipment manufacturers 2. People aged over 40, especially are optimizing procedures for only one emmetropes, are highly motivated market segment: people with refractive to have vision correction treatment errors who dislike their glasses and for presbyopia. It’s not difficult to contact lenses enough to opt for laser understand why so many people eye surgery. So far, EyeWorld estimates who could benefit from laser eye In My View  15

tend to exhibit more motivation to surgeons should look to new technologies “I believe that address a problem they have trouble and adapt their marketing strategies for adapting to versus a problem they when the sleeping giants awaken. ‘Generation X-ers’ adapted to when they may have been cut ‘were’ more neurologically References and ‘baby boomers’ flexible and plastic (0 to 25 years 1. Statista. “Number of LASIK surgeries in of age). Europe from 2004 to 2020 (in thousands)”. are the sleeping 3. The presbyopic market has Available at: http://bit.ly/EuLASIK. Accessed: the spending power. Business July 31, 2018. giants of the Insider reports: “Millennials, are 2. Ellen Stodola. “LASIK worldwide”. Available spending less on consumer goods at: http://bit.ly/LASIkworld. Accessed: August refractive surgery because of expensive healthcare 15, 2018. and education costs. But baby 3. Statista. “Resident population in the United market.” boomers, are the ‘biggest States in 2017, by generation (in millions)”. spenders’ because they have extra Available at: http://bit.ly/StatsUSPop. cash from decades of saving Accessed: July 31, 2018. surgery haven’t elected to do it. and investing” (5). 4. M Matamales et al., “Aging-related dysfunction They’ve adapted to their glasses and of striatal cholinergic interneurons produces contact lenses. But evidence exists The take home message? Generation conflict in action selection”, Neuron, 90, in mice that age can limit neural X-ers and baby boomers have the size, 362–373 (2016). PMID: 27100198. adaptability (4), which may partly the motivation and the spending power to 5. Ashley Lutz. “Baby Boomers are the sexiest explain why some people over 40 potentially quadruple the laser eye surgery consumers in retail”. Available at: http://bit.ly/ experience difficulty adapting to market. In my view, presbyopic LASIK is mktBusIn. Accessed: July 31, 2018. reading glasses. Though I have yet likely to be the most significant opportunity to find specific evidence supporting on the refractive horizon for the next 30 Financial disclosure: Solar reports that he is a this claim, it follows that people plus years. Growth-minded refractive Consultant for Carl Zeiss Meditec.

Pioneer or Buccaneer? “People like Harold

Great minds across the ages Ridley and Charles have struggled to make their work understood. In the digital Kelman changed the age, are we doing enough to push truly pioneering efforts to surgical world as we the forefront? know it, but were that it was all about medicine in the By Karl Stonecipher, Medical Director of early 1800s – before people thought hammered by TLC Greensboro, NC, USA microbes caused disease. Believe it or not, the conversation around infection mainstream I was lost in a great read the other is still relevant today. Postoperative day: “The Butchering Art” by Lindsey infection prevention is, and always ophthalmologists of Fitzharris. I asked my staff if anyone had will be, a number one priority with any read it – they hadn’t and couldn’t believe type of surgery. Patients don’t want to the day.” a book like that even existed. I explained be hurt as a result of a procedure – not

www.theophthalmologist.com 16  In My View

least one you performed. like Harold Ridley and Charles Kelman Which brings me nicely to the changed the surgical world as we know point of this article. In 2018, what is it, but were hammered by mainstream “Where’s the middle the difference between a pioneer and ophthalmologists of the day. Now, let’s a buccaneer? Technically, a pioneer is think of the modern ophthalmologist. ground between defined by Webster as, “a person or She has a great idea, but how that group that originates or helps open idea develops is dependent on where protecting patients up a new line of thought or activity” she lives in the world. If it involves (3). A buccaneer is, “any freebooter embryologic tissue, religion may jump from adversity – the preying on Spanish and English in. If the cost-to-goods are high, private ships and settlements, especially in equity jumps in. If she needs to run an buccaneer – and the 17th and 18th century” (4). These investigative review-board sponsored guys and girls got out of prison and device exemption trial as a surgeon, providing patients moved to the Islands. When... they cost and liability come in to play. Those got bored of sipping piña coladas, they are just some of the inhibitors to really with sight they decided to take a bold move forward – great ideas today. The old guard hate commandeer a boat and rob the Spanish transition and the new guard embrace want – the and English oppressing them. That’s it. As the world becomes flatter, we see what the pirates of the 17th and 18th across the planet in a femtosecond (5). pioneer?” century are known for, and why the We can think of the ‘new’ world as a modern definition of a buccaneer is “an big web with thoughts being shared unscrupulous adventurer especially in instantly by Googling this or that, but Kelman, and the surgeon today want politics or business.” the exchange of ideas is occurring at a people to have a better existence. With that in mind, let’s go back to phenomenal rate. Doctors do what they do to make the 19th century. It was here that one of In 2018, we are looking at an people better – the money is just a the most famous doctors of the decade explosion of technology to treat necessary evil. Remember, in the early performed an amputation in under dysfunctional lens syndrome – or “I 19th century, many surgeons weren’t three minutes without anesthesia. can’t see what I want to without glasses even paid. So what are the hurdles That’s pretty amazing in itself – until or contact lenses” syndrome. Who is to enlightenment today? How do we you remember that the technician the buccaneer and the pioneer of today? create a better world? How do we define helping, the medical student watching, How would Webster define it if he the pioneer and the buccaneer? Only and the patient all died. With 300 were still alive? The definition could time can tell. percent mortality in one procedure, fast be legal, technical or geographical. We isn’t always better. It may be more cost have companies that finally get Food References efficient, but does it help the patient? and Drug Administration approval but 1. L Fitzharris, “The Butchering Art”, Scientific Fast forward to the early 20th century have ended up bankrupt, while other American: October 17, 2017. ISBN: when a guy called Eddington wanted to companies fall out of the running 9780374117290 prove that another guy called Einstein because of a lack of venture capital. 2. A Isaacson et al, “3D bioprinting of a corneal was a genius. The problem? Everyone Where’s the middle ground between stroma equivalent. Experimental Eye was at war. Instead of working on the protecting patients from adversity – Research”, Exp Eye Res, 173, 188-193 theory of relativity, scientists were the buccaneer – and providing patients (2018). PMID: 29772228 figuring out how to kill soldiers with with sight they want – the pioneer? And 3. https://www.merriam-webster.com/ mustard gas. Eddington decided to how can we make it affordable? That dictionary/pioneer go to Africa and prove that Einstein is the million or 100-million-dollar 4. https://www.merriam-webster.com/ was right, which he did. Immediately, question – because that’s roughly what dictionary/buccaneer Einstein was hailed a hero back home. it costs for a company to participate in 5. T Friedman, “The World is Flat: A Brief In doing so, Eddington proved that the an investigator device exemption for an History of the Twenty-First Century”, buccaneer was really a pioneer. indication for surgery in the US today. Farrar, Straus and Giroux: April 5, 2005. In terms of ophthalmology, people For the most part, Einstein, Ridley, ISBN: 1593 In My View  17

have to be creative. Some take Vigamox Fancy Your straight from the bottle and inject it into the eye, others dilute it themselves – “In my mind, $25 is Chances? while others have their local hospital or pharmacy compound it for them. As you a small price to pay Intracameral antibiotics can imagine, this homemade approach reduce the risk of cataract has its flaws. There have been some to guarantee a good complications – so why aren’t isolated but well-publicized incidents we using them? where improperly mixed intracameral outcome for my antibiotics have led to concentration errors. In some cases, toxic vehicles within patients.” the antibiotics have caused significant vision loss due to inflammation inside the eye. Vancomycin, one of the drugs same way. Part of the problem is that associated with the procedure, has also intraocular injections are considered been implicated in a condition called part of the bundle of cataract surgeries, HORV – hemorrhagic occlusive retinal which means we can’t bill patients or vasculitis. Although patients appear well insurance companies for individual after their first eye surgery, a very small treatments. Understandably, there are subset begin to exhibit hypersensitivity few people willing to invest dollars in after their second, experiencing bilateral the development of a technology that retinal vasculitis and some even cannot return those dollars later down bilateral blindness. the line. These stories have made US Europe has already proved the value ophthalmologists wary of intracameral of intraocular antibiotics in the clinical By John Berdahl, Partner at Vance antibiotics, even though the majority sphere – but in the US we need to put Thompson Vision, Sioux Falls, SD, USA of us know that they are ideal for the an economic engine behind it. The prevention of endophthalmitis. first step? Establishing a satisfactory Cataract surgery is the most common Right now, I use a non-FDA approved reimbursement program. Fortunately, ophthalmological procedure in the world. combination of FDA approved drugs, there are a number of groups encouraging And like all procedures, it has some including dymethazine, moxifloxacin the FDA and Medicare to collaborate risks – the worst being endophthalmitis. and ketorolac. They are all prepared on a solution. If they succeed and we Endophthalmitis affects between 0.13 under 503B manufacturing conditions, find a way of returning investment, we percent and 0.7 percent of patients (1) which means that the manufacturer, can start the large-scale clinical studies and can have devastating consequences, Imprimis, is FDA-inspected to the needed to demonstrate the safety and with some losing light perception all same high standards a traditional efficacy of intraocular antibiotics. together. So what can we do about it? drug manufacturer, resulting in I am hopeful that we will get an FDA The answer is intracameral antibiotics. an exceptionally high quality approved antibiotic in the next few years. In my mind, they’re one of the most product. To my knowledge, there As with all new products, they will go important innovations in modern have been no reports of improperly through the natural innovation process ophthalmology. Several studies have formulated medication. before prices eventually settle. It is only shown that intracameral antibiotics The second reason US ophthalmologists then we’ll be able to provide real value unequivocally decrease the incidence are wary of intraocular antibiotics is cost. to investors – and, crucially, to our of endophthalmitis. But we’re not using Compounded intraocular injections cost patients too. them in the US. around $25 – and come directly from Why? Firstly, there are no the surgery center or doctor’s pocket. Reference commercially available antibiotics for In my mind, $25 is a small price to pay 1. N Mamalis et al., “Postoperative intracameral use in the US, so surgeons to guarantee a good outcome for my endophthalmitis”, Curr Opin Ophthalmol, who want to use intracameral antibiotics patients, but not every surgeon feels the 13:14–8 (2002). PMID: 11807383.2

www.theophthalmologist.com

Feature 19 A LIFE- CHANGING GIFT

We share the story of one patient, one donor family and one physician to show what it really takes to restore 20/20 vision.

Phoebe Harkin with Crystal Ellis and Christine Sindt

Ophthalmic surgeons perform around 40,000 corneal transplants in the US every year. Here is the story of just one of them. Crystal Ellis was in middle school when she lost sight in her right eye. It took 19 years and the ingenuity of Christine Sindt for her to see properly again.

www.theophthalmologist.com 20 Feature

to cut it. It felt like I could never say enough, so I said nothing. “Just a regular kid” I had already taken an entire semester off college and was just about finding my feet when I discovered I had thyroid cancer. – the Patient’s Perspective It took another four years before I had a full bill of health. I was 24 when I finally finished college. I was moving into With Crystal Ellis my first house a year later when I rediscovered and re-read It all started in 1999. I was just a regular kid – going through the letter. Why had I never replied? After I stopped crying middle school, trying to pass driver’s ed. I woke up one morning over what a terrible person I was, I wrote to tell them about with blurry vision in my right eye. I went to the doctor thinking it everything I had been going through – while admitting it was was pink eye and they treated it like that for two weeks. When it no excuse for not getting in touch. I told her how I thought didn’t go away, they referred me to an ophthalmologist; but they about her and her family every day. We wrote each other back were stumped too. Scarring, which looked like pockets of crystals, and forth and I really got to know her; Misty was a kind, suggested a viral infection, but there was no evidence to prove it – generous woman and mother to a beautiful family. and there is still none to this day. Without a diagnosis, there was nothing they could do. And that’s how I lived for the next few years. Fulfilling a dream, reliving a nightmare A gift that’s impossible to repay I had wanted to go skydiving for a long time, but scarring from the transplant had left me with a thin cornea, and the Fast forward to 2005, and my eye was in really bad shape. doctors didn’t know if it could take the pressure of the jump. Everything seemed dark and murky; it was like trying to see I got the all-clear just in time for my birthday. I invited Misty through layers of wax paper – there were blobs of color but and her family to come down as a way of saying thank you no definition. Not only that, but the scarring had thinned the for the gift they gave me. They said they couldn’t make it but corneal tissue. A doctor took one look during a check-up and appreciated the offer. said, “If you bump your head, your eye could rupture. You The big day came and I did the jump. As I landed, I need surgery – now.” walked past a bunch of people – including my donor family. It takes a lot to psych yourself up for surgery. I didn’t realize Apparently, my stepmom had been coordinating with Misty just how much until I woke up and was told that the transplant the whole time. It took me a minute but as soon as I realized hadn’t happened. The donated cornea had been cut incorrectly who they were, I burst into tears. It took seeing Misty in person and would have been rejected by my eye. I was crushed. Luckily for me to truly realize that I’d been given a gift I could never for me, it only took two weeks before another became available. repay. Even now, it gives me goosebumps just thinking about it. So, on June 5, 2005, I got my new cornea. That day was a turning point for me. Misty and her children Part of me thought I would wake up from the transplant became my extended family, and now we volunteer together and my eye would be like it was before. But it wasn’t at all. as donor and recipient speakers at the Iowa Lions Eye Bank. My vision had barely improved. Instead of looking through It is so rewarding to hear people say, “I was going to write to multiple sheets of wax paper, it now felt I was looking through the people who received my loved one’s organ or tissue, but one. I could make out a letter or a number if the writing was I didn’t know what to say. Now that I’ve seen how much it big enough, but that was it. I told myself this is how it’s going means to you, I’m going to reach out to them.” And I know to be forever. I better get used to it. people say the same thing to Misty too. Misty and her family About six weeks after the operation, the Iowa Lions Eye live two hours away, but we get together when we can to share Bank asked if I wanted to receive a letter from the donor family. our stories. What they sent was beautiful. It was from a mother who had Despite accomplishing my dream to skydive and gaining a just lost her five-year-old son – my donor. She told me how new extended family, I was still having trouble with my eye. he had been an outdoorsy, adventurous little boy who loved The stitches had started to pop through the surface of the animals and fire trucks. That’s when it hit me that someone had transplant. To remove them, the doctor had to break the knot to die for me to see. This little boy had saved my sight – my life. under the surface, which was uncomfortable. Not only that, my I didn’t write back straight away. I just didn’t know what to eye didn’t heal correctly: instead of being round, it protruded say… “Thanks, and I’m so sorry your son died,” wasn’t going at the top, and I still couldn’t see much. Feature 21

“That’s when it hit me that someone had to die for me to see. This little boy had saved my sight – my life.”

A twist of fate

Around the same time, Steven Jacobs – my ophthalmologist since 1999 – was retiring; I didn’t know what I was going to do. Steven, and everyone who worked in his department, were like family to me (I still send them Christmas cards now!). As luck would have it, his replacement was Elizabeth Geiger, who had just done an internship at the University of Iowa, where she’d met a doctor called Christine Sindt. Christine was apparently doing “amazing things” – inventing an entirely custom-made lens that had the potential to correct my vision. Elizabeth got me an appointment right away – and Christine told me I was a great candidate for the lens. The catch? It costs $4,000 and my insurance wouldn’t cover it. So here it was, the thing I’d been waiting for – a way to see again – and I couldn’t afford it. I almost didn’t want to tell my friends and family about the appointment, because I couldn’t bear to see the

www.theophthalmologist.com 22 Feature

“It feels strange reflecting on my journey because, for a long time, I didn’t think I’d see properly again and I’d come to terms with that.”

disappointment on their faces. But telling them was the best decision I have ever made; they suggested I set up a “YouCaring” page to Crystal w ears ask for donations. It was actually easier a ri bbo n b than I thought. I had been sharing ea rin my transplant story on Facebook g th e for years, and people had got to fa ce o know me and my ‘bionic eye.’ f h e r I posted a link to the page d o n and within two weeks, I o r , had $5,000. fi i v e I called the clinic that

y e a day and told them I had r

l d the money. I’m not sure

J a who was more surprised r

n – them or me! From

o there, the money was

s e

r split three ways – $1,000 for the imprint, $2,500 for the contact, and $1,500 between office visits, co-pay for a specialty doctor, and tools, solutions and saline sticks to get the contact in and out of my eye. Christine was wonderful through it all – but particularly when it came to the impressions. They were done with an epoxy mold like the kind you Feature 23

EyePrintPRO: How it works

The The impression The impression is process captures impression is 3D scanned and The lens is sent the precise then shipped to machined to create a back to the patient, curvature of the EyePrint prosthetic scleral ready for fitting ocular surface Prosthetics for cover shell digitizing design

get at the dentist. I remember sitting in the chair watching on a switch, but it doesn’t work that way. Christine flick blue goo into a funnel. “What are you going I recently had the honor of representing Team Iowa in the to do with that?” Transplant Games of America. The Games is a multi-sport “We’re going to take a mold of your eye,” she said. event for people who have undergone life-changing transplant “You’re going to do what?” surgeries. It celebrates the lives of donors and recipients, and She must have seen my face because I was told that it would raises awareness of the need for organ, eye, bone, and tissue be totally painless: “I’m going to do it so quick you won’t even transplants in every state. When the Iowa Donor Network know it happened.” And she was right, it didn’t hurt at all. asked me to take part, I was uncertain at first because I don’t have a competitive bone in my body! But it was Deb Schuett, my contact at the Iowa Lions Bank, who encouraged me to say yes. Deb was the person who put me in touch with my A second gift donor family, and we were still very close. With her support, I joined Team Iowa, and we even ended up rooming together I vividly remember the day I received my lens. It was winter and at the games! Despite not playing a day in my life, I decided I was wearing a purple jacket. Up until that day, colors were dull on cornhole and darts. When I told Christine, she couldn’t – even with my good eye. Being able to see properly with my believe my choice: “Don’t you know darts is a leading cause new lens made everything so bright. I remember walking out of of eye injuries?!” Christine’s office and seeing a picture of a sunset on the wall. I The games turned out to be a huge success – not only started bawling. “Look at that picture!” I said. “It’s so orange! because I didn’t get hit in the eye, but also because I won Was it always that way?” I couldn’t get over how pretty it was. gold in darts and two golds in cornhole – one for playing as Even my jacket looked beautiful – how could it be… so purple? part of a team, and another as an individual. It must have It feels strange reflecting on my journey because for a long been beginner’s luck! But the medals were just a small part time, I didn’t think I’d see properly again and I’d come to terms of what made the games so amazing. I met some phenomenal with that. My eye had healed – no more ‘virus’, no more scar. people, and made new friends that will be part of my life Getting told there’s a chance I could see was almost worse, forever. I also got the chance to hear the most beautiful and because I couldn’t stand the disappointment if it didn’t work. heartbreaking stories. It was incredibly humbling to consider But it did work and now, for the first time in years, I have that many of these people would not be around without organ 20/20 vision. Of course, there have been some teething issues. and tissue donation. But here they were – cheering each Trying to tell my brain to use that eye again is hard. After all, other on, celebrating each other’s victories. It was the best I couldn’t see properly for 19 years! You want to simply turn experience ever. Life is good.

www.theophthalmologist.com 24 Feature

take an impression of the eye, and then use high-resolution Seeing Eye to Eye instrumentation to develop a 3D model that can be used to create a custom lens – in as little as two days. – the Physician’s Like all good ideas, it took significant time and effort to get where we are today. And I am very fortunate that Perspective I have always had patients with patience! One patient in particular had keratoconus and wasn’t eligible for a With Christine Sindt transplant, so we kept trying new things. He was with About 20 years ago, I was treating a little girl who fell on a glass. me through more eye impressions than I like to remember It shattered and a shard went in her eye. She lost the lens and had until I finally got “the one.” When we discovered he’d got a large corneal scar that caused a millimeter height difference in 20/20 vision using his eye print, he cried – and I sat next to her ocular surface. I administered corneal gas permeable lenses him and cried too. for as long as I could, but she became intolerant. I thought there had to be a better way. In eyes that have suffered trauma, like hers, the ocular surface stops being round. If I could just get a lens to lock in to the eye like a Lego piece, I could get this child to 20/20. Making a good impression And that’s really where my journey into “eye printing” all began. I thought about my patients and decided that I had to develop The impression process was particularly important to me. something that met the unique complexity of their eyes. I Previously, molds were made using alginate, which was wanted the design to work, not just in terms of the eye-to-lens uncomfortable and painful for the patient. By using polyvinyl relationship, but also on a human level. Whatever it was, it had siloxanes, we found we could still capture the eye’s precise to be fast. As physicians, we can make our patients crazy when curvature, without any discomfort. Patients actually call it we don’t have answers. I wanted to be able to say: “This is what’s “cool blue goo.” It doesn’t hurt, it doesn’t need anesthetic, and going to happen next.” it doesn’t disrupt anything on the surface of the eye. Not only that, the impressions can be done anywhere. I’ve gone to the bedside of quadriplegic patients, I’ve gone into operating rooms, I’ve gone into the field – and I’ve even done impressions at A human(e) approach parties. We can go where people don’t have high-tech devices and high-tech scanners, and offer world-class healthcare in a This drive to do better for my patients formed the foundation very affordable way. for the EyePrintPRO, an optically clear prosthetic scleral device Once the impression is taken, it is sent for digitizing. We use designed to match the exact contours of each individual eye. We the latest 3D scanning technology and numerically controlled

Crystal having her impression taken in Sindt’s office Feature 25

“Because each lens is custom, it allows us to use really unique optics on the device – and not just in the center as with other lenses.”

do – their goals in life – will determine what choices we make together. Oftentimes, there are several different routes we could take, but I can’t advise somebody unless I know what’s really important them. And that makes it a very personal journey. Take Crystal. Her story is unique. By getting to know it, and her, we were able to find a solution. And I’m happy to say her vision is now as fabulous as she is! She has such a positive attitude, despite everything that has happened to her. When machining systems to get an exact match I see her, I also see the five-year-old boy who gave his cornea of the individual cornea and sclera. so that Crystal could see. I choke up when I think about it. Because each lens is custom, it allows us to What I do, I do for people like him and his mom. I do it for use really unique optics on the device – and not all eye donors. just in the center as with other lenses. I can put higher order When it comes to my patients, I know I’ve done a good job aberrations on the lens, I can put prism in any direction, I can when they stop talking to me about their eyes and start showing put a multifocal on the lens, I can do torics – I can even do me pictures: “Do you want to see my kids?” – “Do you want to them all at the same time. And the best part? It all happens so see where I went on vacation?” It means their eyes aren’t their quickly. We use a virtual eyeball to do a theoretical fit to get the number one concern anymore. I’ve worked myself out of a job best alignment, the best optics, the best comfort – 95 percent – and that, to me, is a huge success. of lenses are completed within two attempts. Compare that process with current pre-manufactured designs that use trial and error to find the best fit. Crystal Ellis is a volunteer for the Iowa Lions Eye Bank and the Iowa Donor Network.

Christine Sindt is a Director at Contact Lens Service, and a Changing lives Clinical Professor of Ophthalmology and Visual Sciences at the University of Iowa. Sindt reports that she is Founder of My patients aren’t eyeballs in a chair, they are people – and it’s EyePrintProsthetics and co-creator of the EyePrintPRO. always important to remember that. Because what they want to Dr Sindt is the inventor and owner of EyePrint Prosthetics.

www.theophthalmologist.com OPHTHALMOLOGY INNOVATOR AWARDS DINNER GALA

wednesday, october 24th, 2018 Marriott Marquis Chicago | Chicago, Illinois

Over the past decade, OIS has been bringing together key leaders to collaborate and foster the development of ophthalmic innovation. To celebrate the history of OIS and to commemorate the 10th anniversary of the inaugural summit, the ophthalmology community is invited to come together and help us recognize those who have made a significant impact on innovation.

Visit www.ois.net/awards to cast your ballot for the Ophthalmology Innovator Awards. Ballots are due by Wednesday, September 19th, 2018 at 5:00 pm PDT. To attend the OISX Dinner Gala – complimentary with your OIS@AAO registration – visit www.ois.net. vote | PARTICIPATE | Celebrate www.ois.net/AWARDs In Practice

Surgical Procedures Diagnosis New Drugs

28–30 DME, Steroids and Glaucoma Charles Wykoff addresses concerns of IOP increases when using steroids for management of DME, and highlights the benefits that this treatment approach can have for some patients.

31–33 The Matchmaker When it comes to cataract surgery training, there is always a learning curve. Paul Ursell presents a system of matching trainees to case complexity – and overviews the benefits it has brought to their clinic. 28 In Practice

There are legitimate reasons to atrophy of the optic nerve and loss of DME, Steroids pause before initiating corticosteroid retinal ganglion cells and their axons.” therapy for DME. First, they are and Glaucoma well recognized to increase the risk of Elevating the discussion of steroid- cataract acceleration. In my view, even induced IOP Addressing concerns about a single intravitreal steroid injection While elevated IOP is not synonymous steroid-induced intraocular permanently changes the trajectory of with glaucoma, that does not negate pressure increases and the risk cataract progression in that eye. Second, the real clinical concern that steroid of glaucoma when managing they have the potential to increase treatments can and often do increase diabetic macular edema intraocular pressure (IOP); but there can IOP in treated patients. Specifically, be misconceptions about the correlation approximately 30-40 percent of patients By Charles C. Wykoff between IOP and glaucoma. treated with intravitreal steroids will Elevated IOP alone does not constitute experience a clinically relevant elevation In my practice, I consider using glaucoma. This simple distinction is of IOP. In consideration of how to intravitreal corticosteroids for managing often confused on the podium and in manage such an elevated IOP clinically, diabetic macular edema (DME) in two the published literature. While more it may help to consider what we know categories of patients. First, among data is needed related to the scenario of about its cause and its course in reported patients who respond adequately to elevated IOP following pharmaceutical prospective clinical trials. anti-VEGF therapy, but the durability interventional, multiple studies have The pathophysiology of IOP of current generation anti-VEGF considered the complex relationship elevation following intravitreal steroid monotherapies is insufficient for their of absolute IOP and glaucoma. For treatment is incompletely understood. lifestyle or preference. In this context, example, the Baltimore Eye Survey It is hypothesized that such elevation utilization of a steroid implant can involving 5,308 individuals (ages 40 may be related to increased outflow often achieve a decreased treatment years and older who underwent detailed resistance (4). Specifically, increased burden. Second, among patients who ocular exams including perimetry), IOP may be facilitated by modulation demonstrate an incomplete response to reported that even with an IOP of of glucocorticoid receptors within adequate anti-VEGF dosing. 30 mmHg, the majority of patients trabecular meshwork cells, theoretically (95 percent) did not have glaucoma (1). altering the rate of protein synthesis Additionally, the Ocular Hypertension and inhibiting degradation of the At a Glance Treatment Study (OHTS) reported extracellular matrix (ECM) (5). • Intravitreal corticosteroids are that with an untreated IOP of 24 to However, other studies have reported associated with risks, including 32 mmHg, 9.5 percent of participants the opposite (6). IOP elevation which occurs in developed primary open-angle glaucoma Some of the clinical factors to approximately 30–40 percent of (POAG) after 5 years of follow-up; this consider when determining if steroid treated patients rate was reduced in OHTS to 4.4 percent treatment may be appropriate include • Elevated IOP alone does among participants randomized to use of historical points such as a personal or not constitute glaucoma, a topical ocular hypotensive medication immediate family history of POAG, and when secondary to an regimen (2) (Figure 1). or a history of steroid-induced IOP intravitreal steroid injection, Recognition that elevated IOP is not elevation. Examination findings to is usually readily manageable a surrogate for a diagnosis of glaucoma consider include higher baseline IOP, with observation or topical was highlighted by the removal of IOP high myopia, evidence of glaucomatous ophthalmic drops in the large as part of the definition of POAG in the nerve damage even in the absence of a majority of cases American Academy of Ophthalmology definitive diagnosis of glaucoma, and • For appropriate DME patients, (AAO) 2015 Preferred Practice Pattern® evidence of angle recession. In any of intravitreal corticosteroids can Guidelines for POAG (3). The current these situations, I am typically more represent a valuable alternative definition reads in part: hesitant to consider administering treatment option, with the “POAG is defined as a chronic, intravitreal steroids. possibility of a decreased progressive optic neuropathy in adults in When treating patients with treatment burden. which there is a characteristic acquired intravitreal steroids, data from the In Practice 29

prospective MEAD and FAME trials the collective results of the 36-month are good sources of information to FAME trials, which consisted of two gauge risk and guide management of randomized, sham-controlled, phase “There are IOP elevation. In the MEAD trial, the III studies reported that 38.4 percent of pooled results from two randomized, 0.2 µg/day fluocinolone acetonide legitimate reasons sham-controlled, 3-year studies of treated patients were prescribed IOP- 347 0.7 mg dexamethasone- and 350 lowering drops compared to 14.1 to pause before sham-treated patients found that 27.7 percent of control patients. The study percent of patients given dexamethasone also found that while 4.8 percent of initiating had an IOP increase >10 mmHg from 0.2 µg/day fluocinolone acetonide baseline; 41.5 percent were prescribed treated patients underwent incisional corticosteroid surgery for elevated IOP, prior ocular steroid treatment correlated strongly therapy for DME.” with this risk; specifically, no 0.2 µg/ day fluocinolone acetonide-treated patients who received prior obtain a retinal nerve fiber layer (RNFL) ocular steroids required IOP- OCT scan if not already obtained; lowering surgery (9). This this allows me to follow their RNFL finding contributed to the longitudinally for evidence of thinning. FDA-approved package In the setting of mild IOP elevation, insert for fluocinolone I will often simply observe the patient for DME which without intervention and in many cases requires that patients the IOP will return to baseline as the be “previously effect of the steroid diminishes. If IOP treated with a course rises to above 30 mmHg, regardless of of corticosteroids” baseline risk status, I often treat with a and not have “a topical IOP-lowering medication. If IOP clinically significant has risen more than 10 mmHg but is not rise in IOP” (10). above 30 mmHg, I will follow these eyes closely often without treatment. When Focusing on initiating topical therapy, I typically management will use an aqueous suppressant. If In my own practice, intravitreal steroid therapy is continued, patients treated with I will continue the topical IOP-lowering intravitreal corticosteroids medication; if intravitreal steroid therapy are typically monitored every is discontinued, I will often discontinue one to two months initially and the topical IOP-lowering medication then at longer intervals, generally once the IOP has normalized. In most not exceeding 3 months, after achieving cases, steroid-induced elevated IOP can disease stability. When a patient presents be treated with topical IOP-lowering with elevated IOP following intravitreal medications. In cases where alternative IOP-lowering drops compared to 9.1 steroid delivery, how I manage them or additional treatment is required, percent of control patients. The study depends on the degree of IOP elevation laser trabeculoplasty and surgery that also found that two patients (0.6 and their individual baseline risk profile could involve either a trabeculectomy percent) in the 0.7 mg group underwent (11). When possible, since an individual’s or tube shunt are options to consider; surgical intervention for elevated IOP, IOP can vary, correctly assessing levels I often co-manage these patients with one attributed to steroid-induced IOP and potential treatments are ideally based either referring ophthalmologists or elevation and one to neovascularization of on several IOP measurements rather than referring optometrists comfortable with the anterior segment (7, 8). Additionally, a single assessment. In most cases, I will managing IOP.

www.theophthalmologist.com 30 In Practice

Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma”, Arch Ophthalmol, 120, 701–713 (2002). PMID: 12049574. 3. AAO PPP Glaucoma Panel. “Primary open-angle glaucoma PPP - 2015”. Available at: http://bit.ly/2nDB9Eg. Accessed: August 14, 2018. 4. TF Freddo and H Gong, “Etiology of IOP elevation in primary open angle glaucoma”, Optometric Glaucoma Society E J, 4 (2009). PMID: 22957318. 5. X Zhang, et al., “Regulation of glucocorticoid responsiveness in glaucomatous trabecular meshwork cells by glucocorticoid receptor-beta”, Figure 1. OHTS was a randomized trial conducted at 22 clinical centers. A total of 1,636 participants Invest Ophthalmol Vis Sci, 46, 4607–4616 40 to 80 years of age, with no evidence of glaucomatous damage and an lOP between 24–32 mm Hg in (2005). PMID: 16303956. one eye and 21–32 mm Hg in the other eye were randomized to either observation (n=819) or 6. Z Jing-ying Z, et al., “Reversible changes in treatment with commercially available topical ocular hypotensive medication (n=817). The goal in the aqueous outflow facility, hydrodynamics, and medication group was to reduce the lOP by 20 percent or more and to reach an lOP of 24 mm Hg or morphology following acute intraocular less. The primary outcome was the development of primary open-angle glaucoma (POAG) in one or pressure variation in bovine eyes”, Chinese both eyes (2). Log rank P value < .0001, hazard ratio 0.40, 95% confidence interval (0.27, 0.59). Med J, 126, 1451–1457 (2013). Cumulative proportion POAG at 60 months, 9.5 percent in observation group and 4.4 percent in PMID:23595376. medication group. Adapted from (1, 2, 11). 7. RK Maturi, et al., “OZURDEX® MEAD Study Group: Intraocular pressure in patients Summary Eye Institute; and Associate Professor of with diabetic macular edema treated with With an appreciation of the multiple Ophthalmology at Weill Cornell Medical dexamethasone intravitreal implant in the pathophysiologic pathways involved in College, Houston Methodist Hospital, 3-year MEAD study”, Retina,23 1143–1152 DME, corticosteroids can play a role Houston, Texas, USA. (2016). PMID: 26871523. in its management in certain patient 8. DS Boyer,et al., “OZURDEX® MEAD populations. Based on current evidence Wykoff reports the following disclosures: Study Group: Three-year, randomized, and my experience with patient responses Consultant for Alimera Sciences, Allergan, sham-controlled trial of dexamethasone to intravitreal corticosteroids, while IOP Bayer, Clearside Biomedical, D.O.R.C. intravitreal implant in patients with diabetic elevation is a common clinical reality International, Genentech, Novartis, macular edema”, Ophthalmology, 121, in treated patients, these elevations are Regeneron, Roche; Speaker for Allergan, 1904–1914 (2014). PMID: 24907062. typically readily managed with either Regeneron; and Research Support from 9. RK Parrish, et al., “FAME Study Group: observation or topical IOP-lowering Aerpio, Alcon, Allergan, Apellis, Clearside Characterization of intraocular pressure medications. Isolated IOP elevation is Biomedical, Genentech, Heidelberg, NEI, increases and management strategies following not equivalent to a diagnosis of glaucoma. Novartis, Ophthotech, Regeneron, Roche. treatment with fluocinolone acetonide The potential benefits of corticosteroids intravitreal implants in the FAME trials”, need to be weighed against the risks of References Ophthalmic Surg LasersImaging Retina, 47, cataract acceleration and IOP elevation 1. A Sommer et al, “Relationship between 426–435 (2016). PMID: 27183546. for each individual patient. intraocular pressure and primary open angle 10. ILUVIEN prescribing information. glaucoma among white and black Americans”, 11. BE Prum, et al., “Primary open-angle Charles C. Wykoff is Director of Research Arch Ophthalmol, 109, 1090–1095 (1991). glaucoma suspect: Preferred Practice Pattern® at Retina Consultants of Houston; Deputy PMID: 1867550. Guidelines”, Ophthalmology, 123, P112–P151 Chair for Ophthalmology at Blanton 2. MA Kass et al., “The Ocular Hypertension (2016). PMID: 26581560. In Practice 31

The Matchmaker

Introducing the easy-to-use system that offers patients lower risks of complications – regardless of surgeon experience

By Paul Ursell

Cataract surgery is very safe – but it could be even safer. A third of all cataract procedures in the UK are performed by trainees; junior trainees have posterior capsule rupture (PCR) rates of 3.2–5.1 percent (1–3), which compares poorly with the overall PCR rate of 1.9 percent. Intuitively, we all know we could improve this situation by protecting less experienced trainees from more difficult cases. But how can we do this in practice? In my clinic, we

At a Glance • In the UK, cataract surgery is often performed by trainees – with complication rates two- to three- fold higher than consultants • We have devised a cataract surgery scoring system to stratify patients according to risk, categorize surgeons by experience, and match have been matching surgeons to cases patients to surgeons accordingly on a rational basis for nine years – and • Data from over 8,000 cases our retrospective data analysis (4) shows “We haven’t shows that our system removed the a significant reduction in complications. association between case complexity eliminated the and posterior capsule rupture, Mix and match and almost completely eliminated Like much good research, our work has learning curve in outcome differences between been low tech – but high concept and high trainees and consultants impact. In brief, our study builds on a 2009 cataract surgery, • Our system reduces cataract report (5), which used data from around surgery complications, assists 56,000 cataract operations to calculate the but we have practice management and ensures odds ratio of a surgical complication arising compliance with recent NICE in a given case. Though useful work, it wasn’t controlled its impact guidelines. We believe the concept very user-friendly – it required a complicated is also applicable to other surgical program to calculate the complication on patients.” procedures. probability. I wanted to make it easier for

www.theophthalmologist.com 32 In Practice

(CND); we also incorporated important in practice? As you can imagine, it took Examples of patient-specific factors (absent in the CND a bit of time to introduce it into a multi- cataract surgery dataset) that suggested an experienced disciplinary National Health Service surgeon would be more appropriate than (NHS) department and get everybody and complexity a trainee – for example, patients with on board. But to everyone’s credit it scores (4) corneal edema or only one eye. It took some was adopted successfully. One reason thought, but eventually we identified 16 risk for that success is the simplicity of the factors, and assigned them values that fairly system; the doctor marks a few things Factors associated with PCR represented our own surgical experience. on the patient’s score card, the nurse adds Next, we needed a sensible way additional information, such as biometry, • Male, assigned score: 1 of grouping surgeons according to and double-checks the information. The • Age 80–90 years, experience. Bearing in mind that, in result is a total patient score. assigned score: 2 the UK, surgeons who have performed We found that our system generated • Dilated pupil ≤4.0 mm, 350 or more cataract procedures are many unforeseen – but welcome – knock- assigned score: 5 deemed competent, we created five on effects. First, the trainees were much • White cataract/ no fundal view, skill categories based on procedures more comfortable knowing their cases assigned score: 8 performed: 0–50, 50–100, 100–250, were more appropriate to their level. • Patient specific score 250–350, and 350 or more. Second, it helped with scheduling: the • Significant hearing impairment, Then, we had to develop a rational assigned score: 2 way of matching patient scores to • Pachymetry ≥600 μm2, surgeon skill and experience. Obviously, assigned score: 5 a Category 1 surgeon needs to be given • Permanent VA (other eye) 6/36 the easiest cases, while the most complex or worse, assigned score: 8 cases should be passed to Category 5 individuals – surgeons who’ve done 350 Complexity score and trainee or more cataract procedures. But where recommendations should the risk cut-off points be for each intermediate category? My feeling was • Group 1 complexity: total that surgeons should reach the stage of assigned score of 0–1, for ‘unconscious competence’ – where they trainees with a minimum of can perform effectively without having to 0–50 cases think about it – before they move on to the • Group 5 complexity: total next level. Therefore, we arranged cut-offs assigned score of ≥10, for trainees with the intent that surgeons don’t move with a minimum of 351 cases up to the trickier levels until they are really competent at the previous level. Finally, as a test, we checked the scoring system against historical cases where a trainee-operated patient had developed clinics to assess the risk of a given case: complications. It was so exciting to see what we needed, I thought, was a system of that in about 20 percent of cases that classifying both patients and surgeons, and had a PCR or other complication during matching them accordingly (see Sidebar). surgery, the trainee had been attempting The first step was to sit down with a cases that, according to our scoring system, group of surgeons, discuss the various were beyond their competence. It looked case presentations and risk factors, and certain that we were onto a winner. assign each factor a risk value. We based our approach on the 11 PCR risk factors Real-world advantages identified by the cataract national database The theory was sound – but what about In Practice 33

trainees and the secretary would organize because the scoring system and outcomes I believe we’ve produced something the list so that there were always cases of data were stored in different databases. incredibly powerful. Our aim was to an appropriate level for the trainee, and I was very fortunate to be joined by a minimize complications, optimize the consultants picked up the rest. Third, trainee called Paul Nderitu, who worked outcomes, and maximize patient safety, the system helps us avoid situations on merging the two databases; from six and I think we have done all of those where a case list is over-burdened with years of operation (January 1, 2011, to things. Our system rationally matches difficult cases and leads to surgeries over- December 31, 2016) and 11,468 cases, patients with surgeons in a way that is running (and when that is unavoidable, he extracted complexity data on 8,200 good for both. It is ideal for cataract the complexity scores justify the time cases. The results of the analysis were surgery, because the procedure doesn’t taken, defusing discussions with clinic better than I’d hoped for: our system vary much – but I’m sure the concept could managers). Fourth, when patients are had practically eliminated the variation be applied in other types of ophthalmic reluctant for a junior doctor to operate between trainees and consultants in terms surgery – or other medical fields, such on them, we can reassure them that under of complications and patient outcomes! By as orthopedics. To that end, I’d like to our scoring system, trainees only operate rationally allocating cases to appropriate explore ways of publicising our work in within their level of competence. And surgeons, we ensured that our patients other surgical disciplines. I’m very proud fifth, it alerts clinicians to complex cases were subjected to similar chances of of what we’ve done; we haven’t eliminated where the patient should, as part of the complications, and equivalent outcomes, the learning curve in cataract surgery, but informed consent obligation, be informed regardless of the surgeon’s experience. In we have controlled its impact on patients. of particular procedure risks. other words, the risk of complications is And that is a wonderful thing! almost the same regardless of whether a trainee or a consultant is operating – Paul Ursell is a consultant ophthalmologist simply because we match case difficulty at Epsom & St Helier University NHS to surgeon competence. It puts me in the Trust, Surrey, UK. happy position of being able to assure patients that they will be allocated References a surgeon of a level suitable for their 1. JM Sparrow et al., “The cataract national data specific needs, and that the outcome set electronic multi-centre audit of 55 567 won’t change – regardless of the operations: case-mix adjusted surgeon’s outcomes individual surgeon. for posterior capsule rupture”, Eye (Lond), 25, 1010–1015 (2011). PMID: 21546922. Good matching 2. P Jaycock et al., “The Cataract National Dataset I don’t know if others are using our electronic multicentre audit of 55 567 operations: system, but plenty of people have asked me Updating benchmark standards of care in the about it over the years. I’d expect increased United Kingdom and internationally”, 23, interest – the NICE guideline on cataract 38–49 (2009). PMID: 18034196. surgery in the UK, which came out earlier 3. AC Day et al., “The Royal College The impact has been very positive this year, recommends that all cataract ofOphthalmologists’ National Ophthalmology in our department. And now surgery units use some form of scoring Database study of cataract surgery: report 1, that people have understood its system, and ours is by far the largest and visual outcomes and complications”, Eye (Lond), advantages, it is part of the process. most validated of the available cataract 29, 552–560 (2015). PMID: 25679413. In fact, we’ve come to rely on it very scoring systems. Remember, it was not 4. P Nderitu and P Ursell, “Updated cataract heavily; it’s considered bad practice when only derived from validated national surgery complexity stratification score for trainee a patient score is missing. cataract data, but also validated with 8,000 ophthalmic surgeons”, J Cataract Refract Surg, of our own cases, which provided strong 44, 709-717 (2018). PMID: 30041740. More compatibility, less complication evidence that our system is effective. If you 5. N Narendran, et al., “The Cataract National We’ve been running this scoring and want to improve outcomes (and comply Dataset electronic multicentre audit of 55,567 allocation system in our department for with NICE guidelines if you are in the operations: Risk stratification for posterior capsule almost a decade now. But analyzing and UK), you could do far worse than to adopt rupture and vitreous loss”, Eye, 23, 31-37 quantifying its effect was challenging our system! (2009). PMID: 18327164.

www.theophthalmologist.com .

Advanced Glaucoma Technologies

Technology Sponsors

Ike Ahmed Robert Weinreb Constance Okeke

Diagnostic Sponsors

Inder Paul Singh Marlene Moster Randy Craven

AGT forum teaser ad.indd 1 21/08/2018 13:40 .

NextGen

Research advances Experimental treatments Advanced Glaucoma Drug/device pipelines Technologies

Join Ike Ahmed and a panel of world-leading experts in the field of glaucoma surgery for a live discussion. The live and online program will provide ophthalmologists with an impartial and authentic body of content that addresses many of the questions, concerns or barriers to adoption of MIGS and other technologies. Registrants will also have the opportunity to interact with the discussion and direct questions to each of our experts. Broadcast live from The Harold Pratt House, New York, NY, USA; October 6, 2018. 36–38 Engineering Non-Invasive Refractive Correction Could the future of refractive surgery be non-invasive? Sinisa Vukelic shares his team‘s groundbreaking Technology Sponsors work on corneal cross-linking with low density plasma.

39–43 Ike Ahmed Robert Weinreb Constance Okeke Navigating the Long Road Kathleen Gordon and Jonathan Zager discuss how a uveal melanoma cluster has brought to light the need Diagnostic Sponsors for a team approach to managing the disease, and overview current and future potential treatments.

Inder Paul Singh Marlene Moster Randy Craven

AGT forum teaser ad.indd 1 21/08/2018 13:40 36 NextGen

Engineering Non-Invasive Refractive Correction

Could femtosecond laser- induced corneal crosslinking transform standard refractive surgery – and provide a vision correction procedure that is suitable for all?

By Sinisa Vukelic

My laboratory in the Department of Mechanical Engineering at Columbia University (New York, USA) approaches ophthalmology in a very different way from most: in particular, our expertise in biomechanics and laser materials processing provides a fresh perspective on the eye. was happening. It took years! The end result Of course, we’ve had to learn a lot about is a procedure that is rather different from collagen and tissue biomechanics – very the standard ophthalmological application At a Glance different from the single crystal and of lasers – we are using femtosecond lasers • Normal femtosecond laser surgery bicrystal mechanics that we’ve previously not to cut tissue, but to strengthen it by employs a highly-focused beam, worked on – but good things happen when inducing crosslinks. resulting in a high-density plasma you embrace new concepts and think outside How does this work? Normally, surgical that creates pressure waves, which the box. In fact, our open-minded approach use of femtosecond lasers relies on ‘avalanche can disrupt corneal biomechanics and helped us make a key discovery: a loosely- ionization,’ where multiple photons ionize a cause post-surgical complications focused laser beam can non-invasively substrate molecule; the freed electrons hit • By contrast, a loosely-focused modulate corneal geometry and stably alter electrons associated with other molecules, femtosecond beam creates a low the eye’s refractive power. thereby ionizing other molecules and density plasma (LDP) that does not liberating more electrons, and so on. The generate damaging pressure waves Clouds not avalanches cascade effect requires the electron cloud • We have discovered that LDP, by I am a mechanical engineer by training, and to reach a critical density such that all the ionizing water and creating oxygen have always been fascinated by the plasma incoming photons from the laser pulse are free radicals, creates crosslinks in physics of ultrafast lasers. In retrospect, this absorbed by electrons, thus creating a dense corneal proteins and thereby alters turned out to be the perfect background plasma. Being under pressure, however, corneal geometry in a modulatable, to kick-start our investigations into the the plasma expands and creates damaging predictable way adjustment of corneal biomechanics. shock waves and cavitation bubbles. Hence, • Results from animal models Nevertheless, making progress in this field normal femtosecond laser operation allows suggest that our LDP approach required a great deal of time and effort; for the surgeon to cut a flap in the cornea but could be the basis of safer, non- example, once we’d found that a loosely- also causes unwanted damage, and may lead invasive, permanent vision focused laser beam strengthened the cornea, to post-surgical complications, such ectasia correction procedures suitable for we had to go back to first principles and do and corneal weakening. virtually all patients. some very basic science to figure out what By contrast, our approach involves NextGen 37

principle studies in enucleated porcine over this period. And that’s exactly what eyes and in rabbit eyes in vivo (see ‘Plasma we expected; remember that we are creating physics for configuring corneas’). For the in covalent bonds, which are difficult to break. vitro porcine eye studies, we removed the Therefore, as long as there is no significant epithelial layer, not because our approach collagen turnover, the refractive power requires it, but because abattoir-sourced changes we achieve should persist. eyes often have superficial damage that We are very pleased with our data so far, can interfere with imaging. We didn’t need but we’d also be delighted to work with to remove the epithelial layer in the rabbit anyone who wants to try replicating our animal models. Indeed, a big advantage of results; we all have a duty to make sure that our method is that it is truly non-invasive. our data are valid. After all, we want to The results from these animal studies are develop a treatment that works every time highly promising. In enucleated porcine – 85 or 90 percent success rates are not good eyes, LDP-mediated corneal flattening enough. Excellent outcomes, every time: (as would be used for the treatment of that’s our goal. myopia) changed refractive power by about 12 percent (~ 5.11 diopters) during the Future focus initial 8 hours. After 24 hours of recovery, Currently, we are moving ahead in two refractive power stabilized at ~92 percent major directions: basic research and clinical (~3.45 diopters) of the initial level. In LDP- development. The former will include mediated corneal steepening (as would be extensive parametric studies to ensure that used for the treatment of hyperopia), the we know exactly what is going on during refractive power of enucleated porcine eyes LDP treatment of the cornea. And however modulating the power and focus of the increased gradually for 12 hours before many samples the power analysis tells me laser beam such that there are enough stabilizing. In no case was there evidence I should do, I will always multiply that by photons to create an ionization cloud, but of laser-induced thermal denaturation or five! It upsets the statisticians, but my view not enough for avalanche ionization and other tissue damage. Additionally, we have is that you only need to mess up once to lose dense plasma formation. The resulting very new and exciting – albeit preliminary credibility. In addition, we are developing low density plasma (LDP) does not – observations regarding LDP treatment a model that treats crosslinks as external generate shockwaves, and therefore and keratinocyte populations. load, and developing equations relevant does not damage biological tissue in In rabbit eyes in vivo, we observed to this; the aim is to fully understand the the same way as a high density plasma. a relative change in effective refractive cornea’s viscoelastic response to the LDP Importantly, however, the LDP ionizes power of ~1.94 diopters for treated eyes procedure. This knowledge should enable water molecules, thereby generating (the difference between porcine and rabbit us to precisely tailor LDP treatment to oxygen free radicals which react with eyes in the refractive change achieved each patient. Treating crosslinks as a load corneal proteins, creating crosslinks that is expected, as the two species have very has not been done before, at least not to strengthen the cornea in the precise area different corneal geometries). Treatment my knowledge – so there’s enough work covered by the laser. The ability to target of live rabbits was not associated with the for two PhD theses! We are also looking crosslink induction to very small volumes wounds or wound-healing responses seen at longitudinal studies on the nature of the of corneal tissue allows us to precisely and in refractive surgery. Equally, there was no crosslinks generated by LDP. predictably modulate corneal geometry. evidence of thermal damage, such as edema With regard to clinical trials, we are or endothelial cell detachment; microscopy working hard on developing suitable Correction without cutting after sacrifice suggested that treated eyes device prototypes and procedures. I’d Once we had shown that we were creating were no different from controls. Some of hope to be in human trials by the end of crosslinks that strengthened the cornea, I our treated rabbits have now been followed the year, certainly some time in 2019. We knew we’d found something important: up for seven months; data suggest that the are already talking with potential partners a new therapeutic approach that could refractory power change is stable, and about clinical trials in Europe – people have be tailored to different patients’ needs. confocal imaging indicates that the eyes been very enthusiastic whenever we present Our next step was to conduct proof-of- show no significant structural changes this work. In particular, we are optimizing

www.theophthalmologist.com 38 NextGen

Plasma physics induced corneal flattening (n=15; matched with 10 controls) for configuring • Treatment of ring-shaped area corneas induced corneal steepening (n=13; matched with 10 controls) • A separate control study was Porcine eyes: undertaken to evaluate any effects of experimental set-up itself (n=12) • Fresh eyes (~2 hours old; n=60) • After treatment, refractive were mounted in a chamber that power was measured hourly over permits control of IOP 24 hours • Epithelia were removed because • After 24 hours, corneas were of abattoir-associated damage that cultured for one week to assess Clear benefits would interfere with imaging stability of crosslinking The theoretical advantages are profound. • A coverslip was applied to Firstly, being non-invasive, our technique is press the cornea into a single plane Rabbit eyes: preferable to standard surgical approaches and thereby allow consistent delivery to vision correction. Furthermore, our of laser energy over the treated area • Mainly as above, but modified approach is gentler than other crosslinking • The laser was applied in a to accommodate live animal (for methods: we do not need to peel off the boustrophedon pattern; successively example, the coverslip arrangement keratocytes, and we don’t need to risk deeper ‘treatment layers’ permitted addition of drops to keep damage to keratocytes and epithelial were achieved by consecutive eyes moist) cells by applying UV light, as required in applications at increasing depth • Epithelium left in place standard crosslinking. Secondly, unlike (50 µm increments) • Treated area of 5 mm diameter standard surgical procedures, our method • Treatment of square 5 mm by • Followed up at 24 hours, 7 days, will be applicable to ‘difficult’ patients; 5 mm, over the center of the eye, then weekly up to 3 months for example, older individuals, patients with thin corneas, people with dry eye syndrome, and those with abnormal corneas. Thus, we hope that many people who are currently ineligible for refractive the procedure so that it is at least on a par surgery could be treatable by our method. with LASIK with regard to treatment I firmly believe that LDP could be the time; everyone would prefer a 5 minute start of a new standard of care in permanent procedure to a 40 minute procedure. We vision correction. also intend to modify the LDP procedure so that it is applicable to other conditions, Sinisa Vukelic is a Lecturer in Discipline at including keratoconus, which is the Columbia University, New York, NY, USA. condition we were originally targeting His laser research interests lie in laser induced before our ophthalmological colleagues mechanical deformation, single crystal steered us towards refractive surgery. In and bicrystal micromechanics and strain fact, keratoconus is a great opportunity, gradient plasticity, structural modification given that the current standard of care of transparent dielectrics and laser imaging requires ‘epithelium-off’ crosslinking. and diagnostics. Our ‘epi-on’ approach would remove many risks, and could represent a Reference significant advance. 1. C Wang, et al., “Femtosecond laser crosslinking of We are also looking at applications the cornea for non-invasive vision correction”, beyond ophthalmology; for example, Nature Photonics, https://doi.org/10.1038/ applying LDP to articular cartilage in s41566-018-0174-8. osteoarthritis has given us some fantastic results, and we have now received NIH lllustrations by Andy Potts for Vukelic Group grants to further pursue this. and Clarity Vision Technologies Navigating the Long Road

How lessons learned from a uveal melanoma cluster may present a roadmap for a team approach – and how ophthalmologists can ensure optimal care for patients

By Kathleen Gordon and Jonathan S. Zager

In 2014, the small town of Huntersville Thomas Jefferson University Hospital, initial diagnosis of uveal melanoma in North Carolina garnered international to analyze this ocular melanoma cluster, generally falls to an optometrist or attention after a news station revealed and determine how best to offer patients ophthalmologist when a patient presents that the town of 50,000 was experiencing the treatment and support they need. with blurred vision or flashes of light. The an unusually high number of uveal Ultimately, the disparate nature of tumor may also be found during a routine melanoma cases. For an exceedingly these cases helped bring to light the dilated exam and the patient may have rare disease – which generally has a challenges of ensuring that patients with no symptoms. Many assume that once a prevalence of six to eight people out uveal melanoma – who often have a diagnosis is made, a patient is referred to of every million per year (1) – the 12 lengthy disease progression – have access an oncologist, who undertakes any future cases found in the town over a 10-year to appropriate immediate and long-term care. The reality is that because uveal period certainly raised concern. After medical care. Most significantly these melanoma is so rare, a patient who has securing $100,000 in state grants, local events have reinforced the pivotal role been diagnosed with the cancer may have legislators were able to assemble a panel ophthalmologists play in their patients’ to travel 100 miles or more to work with of experts – including ophthalmologists short- and long-term care – and the an ocular oncologist who is familiar with and oncologists – at the University of importance that all ophthalmologists the illness. Once treatment of the primary North Carolina, Duke University and remain abreast of the latest and upcoming tumor is complete, surveillance for treatment options for patients with uveal metastatic disease may be variable. Many melanoma and metastatic uveal melanoma. patients prefer to be monitored close to At a Glance home. Some will educate themselves • Uveal melanoma is a systemic Understanding uveal melanoma about their risks for metastatic disease illness that requires long-term Uveal melanoma is the most commonly through advocacy organizations, such monitoring and care diagnosed intraocular malignancy in as the Ocular Melanoma Foundation • Ophthalmologists play a pivotal adults. In most cases, it develops from the (OMF). Unfortunately, many patients role in multidisplinary teams for the pigmented cells of the choroid, but it can will mistakenly believe that once the short- and long-term care of patients also develop from the pigmented cells of tumor – which was localized to the eye with the disease the iris and ciliary body. In general, uveal – is treated that they are cancer-free and • Ophthalmologists can further aid melanoma presents most commonly in no longer need to see an oncologist. But patients by understanding the older patients, with a higher incidence in nearly half of all patients who develop advancements that are currently men (2). The Huntersville cluster bucks uveal melanoma will go on to suffer from being made in uveal melanoma and this trend. Among the initial 12 identified metastatic disease (1). In some cases, metastatic uveal melanoma individuals, nine were female and six patients may not experience progression • Lessons learned in the Huntersville were younger than 30 when they were of the disease for as many as 15 years after North Carolina uveal melanoma diagnosed. the initial diagnosis (3). Anecdotally, care cluster may present a roadmap for a Uveal melanoma has an overall teams who provided initial treatment to care-team approach to the disease. mortality rate of about 50 percent. The uveal melanoma patients report that

www.theophthalmologist.com 40 NextGen

they often don’t hear that a patient had enucleation is the preferred approach, developed metastatic disease and passed but some physicians have achieved fairly away until years after. Not only does this good results and comparable survival leave care teams wondering whether the rates treating them with proton beam managing care. Here, we overview just patient received regular monitoring, but it radiation therapy (4). some of the options that are currently also keeps clinicians from gathering vital But given that approximately one under investigation. data that can help improve care for other out of every two patients will go on patients – an essential step for a cancer as to develop metastatic disease – the AU-011 for primary uveal melanoma rare as uveal melanoma. leading cause of death among patients AU-011 is an investigational therapy for As uveal melanoma is a systemic with uveal melanoma (5) – treating the the primary treatment of uveal melanoma. disease rather than just an ocular one, primary tumor is only the first step, and The therapy – in development by Aura it is crucial to surround patients with patients require routine surveillance to Biosciences – requires an intravitreal a multidisciplinary team (MDT) of monitor for tumor spread. Metastatic injection of a novel recombinant clinicians – including an ophthalmologist uveal melanoma often involves hepatic papillomavirus-like particle (VLP) and a medical oncologist – to monitor metastases, which can occur in as many that selectively binds to heparan and treat the patient over the long- as 93 percent of patients with metastatic sulfate proteoglycans on the surface of term. In urban areas, these teams may disease (6). Median survival after liver the tumor cells, and is conjugated to a be conveniently working at the same involvement is poor, often ranging from phthalocyanine photosensitizer, IRDye hospital – as they are at the University 4 to 6 months, with a one-year survival 700DX (8). When activated by a near- of North Caroline and Moffitt Cancer of only 10-15 percent (5). Surgical infrared light, IRDye 700DX produces Center – and so may meet patients and resection, however, offers limited success reactive oxygen species that disrupt the discuss treatment strategies together. But because of the classic miliary spread of membranes of bound cells, inducing patients in more rural areas may rely on the metastases in the liver. In fact, only tumor necrosis. their local hometown ophthalmologists a small number of patients have enough In a preclinical study, treatment who they see on a regular basis to help healthy liver tissue uninvolved by tumor with AU-011 yielded extensive tumor them understand their treatment options remaining for this to be an option, which necrosis in a rabbit xenograft model of and assess next steps. For these patients, is why effective therapies are crucial. uveal melanoma; three out of 10 animals MDTs may need to come together Although several treatment options experienced complete tumor response from unaffiliated institutions and meet have come to market in recent years and after treatment with activated AU-011 electronically. In either case, it is critical improved overall survival of patients with (9). AU-011 shows high affinity for for all team members to understand the metastatic cutaneous melanoma (such as tumor cells while not binding to healthy diagnostic and treatment options available ablation, embolization, targeted therapy epithelium, and so should selectively to a patient, and ophthalmologists – and immunotherapies) (7), the treatment destroy uveal melanoma cells while regardless of specialty – play a pivotal landscape for metastatic uveal melanoma sparing the adjacent retina; in a rabbit role in the care of patients. has remained relatively unchanged. The orthotopic model, tumor treatment was lack of effective therapies has resulted in found to spare the retina and adjacent Approaches to treatment a poor prognosis for patients. ocular structures (10). Phase Ib trials Patients who present with primary tumors Fortunately, recent advancements commenced in 2017 and are expected to can often be successfully treated with local have been made in the treatment of enroll a total of 12 patients. Although radiation therapy and ablative treatments. primary uveal melanoma, as well as the clinical development of AU-011 is Depending on the size and location of detection and treatment of metastatic early and the treatment is currently the melanoma, it might be possible to uveal melanoma, which could experimental, should it prove effective retain some vision using these treatment potentially offer new options for both in targeting primary uveal melanoma, approaches. For large melanomas, patients and the extended medical team it could become a valuable primary NextGen 41

treatment option for patients whose disease is identified early.

Detecting metastatic potential Though it has not been clinically proven, it is believed that if metastatic disease could be diagnosed early – and thus tumors treated when they are smaller – it could improve long-term survival of patients with metastatic uveal melanoma (10). DecisionDX-UM (Castle Bioscience), a gene expression profile test available since 2009, and the follow-on DecisionDX-PRAME test, which was launched in 2016, were designed with early diagnosis in mind. The DecisionDX-UM test evaluates the expression patterns of 12 select genes Patient before (top) and after (bottom) PHP treatment with melphalan hydrochloride. The white in tumor samples, as well as three control arrow shows the hepatic metastasis after treatment. Credit: Jonathan Zager. genes shown to be unchanged in uveal melanomas (11). Based on the results, patients should receive a work up every 3 (15). Another Phase II trial, led by Columbia tumors are classified as Class 1A (low to 6 months. University, is recruiting patients at five risk), Class 1B (intermediate risk) or different centers on the East Coast and in Class 2 (high risk). Clinical studies have Adjuvant therapy to stave off the Midwest, and is investigating crizotinib shown the test is 97 percent successful metastatic disease as an adjuvant therapy for uveal melanoma in determining whether patients In recent years, researchers have started (ClinicalTrials.gov, NCT02223819). fall into Class 1 or Class 2 (12). But looking at whether cytotoxic and Crizotinib, a tyrosine kinase inhibitor that is although Class 1 tumors are lower risk, immunotherapy regimens – both alone currently approved for the treatment of non- metastatic disease is still a possibility. To and in combination – could be applicable small cell lung cancer, has been shown to address this, DecisionDX-PRAME was as adjuvant therapy in patients shown significantly reduce metastasis in a murine developed. PRAME – or preferentially to be at high risk for metastatic disease. model of metastatic uveal melanoma (16). expressed antigen in melanoma – is a Currently, several clinical trials are Other strategies being investigated as cancer antigen gene that can be increased underway in the USA to evaluate adjuvant adjuvant therapies include dacarbazine in some types of cancer. A study published therapies. One such Phase II trial, and interferon-alfa (ClinicalTrials.gov, by researchers at the Bascom Palmer Eye occurring at Thomas Jefferson University NCT01100528), ipilimumab and nivolumab Institute showed PRAME to be a strong in Pennsylvania, is evaluating the use (ClinicalTrials.gov, NCT01585194) and a indicator for metastatic disease in patients of sunitinib malate or valproic acid to dendritic cell vaccine (ClinicalTrials.gov, who had been previously classified as prevent metastasis of uveal melanoma NCT00929019). With these trials in early having Class 1 uveal melanoma (13). (ClinicalTrials.gov, NCT02068586). stages, use of adjuvant therapies for uveal Not all patients will want to undergo Sunitinib malate is a tyrosine kinase inhibitor melanoma is still several years off. this type of genetic testing, but such that may prevent metastatic progression information adds an important element through inhibiting c-Kit and receptors, Liver-directed therapies for to the management of patients. Current including VEGFR (14). Valproic acid is a metastatic disease guidelines recommend that low-risk histone deacetylase inhibitor that may lower Once uveal melanoma has metastasized patients receive a systemic work up the risk of metastasis by altering the gene to the liver, a limited number of treatment every 6 to 12 months, whereas high-risk expression profile in uveal melanoma cells options are available – particularly for

www.theophthalmologist.com 42 NextGen

those diagnosed at an advanced stage. PHP with melphalan hydrochloride team in the identification and treatment As such, liver-directed therapies are in (18). The largest study conducted to date, of the disease, as is the practice at major use and under investigation, including the analysis included 51 patients who centers such as the University of North embolization and percutaneous hepatic received a total of 134 treatments. Of Carolina and Moffitt Cancer Center. perfusion (PHP). Embolization involves those, 49 percent achieved a partial (43.1 The Huntersville North Carolina uveal the targeted destruction of tumor cells percent) or complete hepatic response (5.9 melanoma cluster, while tragic, may through radiation or chemotherapy, percent). The disease stabilized for at least become a case study highlighting the whereas PHP is a targeted whole organ three months in 33.3 percent of patients. potential that exists when medical care therapy for the liver. The PHP procedure Median overall PFS and hepatic PFS teams work in concert. Future uveal is a three-step process that i) isolates was 8.1 and 9.1 months respectively, with melanoma patients in the Huntersville the liver from the circulatory system, ii) median overall survival of 15.3 months. area have the benefit of an educated administers a high dose of chemotherapy The Moffitt Cancer Center is the lead and coordinated medical community, for 30 minutes before iii) filtering out site in the US for the Phase III clinical and their long-term survival may the chemotherapeutic agent from the trial of Delcath Melphalan/HDS, with benefit greatly. blood exiting the liver to reduce systemic select trial sites throughout the US In North Carolina, Florida and exposure and minimize many of the and Europe also involved and actively nationwide, ophthalmologists have been side effects inherent to the drug. PHP enrolling patients (ClinicalTrials.gov, identified as one of the most vital players is a minimally invasive procedure that is NCT02678572). If the treatment receives repeatable, with patients being treated as approval, it could represent a huge step many as eight times in early clinical trials. forward in the treatment of metastatic A retrospective analysis comparing uveal melanoma. “Ophthalmologists liver-directed therapies has demonstrated that radioembolization with yttrium-90 Traveling the long road together have been (Y90) and chemoembolization had a Uveal melanoma can be difficult to treat, median progression-free survival (PFS) especially when it progresses to metastatic identified as one of of 54 days and 52 days, respectively disease. Thankfully, new advancements (17). By contrast, PHP with melphalan are in development or on the market the most vital hydrochloride (Delcath Melphlalan/ that might help the fight against the HDS) demonstrated a significantly disease. But for these advancements players on the higher PFS of 245 days (P=0.03 versus to make a meaningful impact on the Y90 and chemoembolization). Median long-term survival of patients with care team” overall survival with PHP was also uveal melanoma, the care communities longer at 608 days compared with Y90 (oncologists, ophthalmologists and (295 days) and chemoembolization (265 advocacy partners) must remain educated days) (P=0.24). An even more recent about the diagnostic and treatment retrospective analysis of outcomes data of options, and be vigilant about long- patients with metastatic uveal melanoma term patient monitoring. The key is to has further supported the potential of involve all members of a patient’s care NextGen 43

on the care team, as they are often the Disclosures: Zager reports he has 9. PT Logan et al., “Assessment of the activity of physician with the most sustained patient received research and grant support, and different AU-011 doses in a xenograft uveal contact. As the gatekeepers to uveal Medical Advisory Board participation, melanoma model. Invest Ophthalmol Vis Sci, melanoma patients, they are essential for Delcath Systems. 57 (2016). Abstract 4111 in identifying disease early, treating the 10. S Kaliki and CL Shields. “Uveal melanoma: primary tumor, educating the patient References relatively rare but deadly cancer”, Eye, 31, about potential options available to them 1. P Jovanovic et al., “Ocular melanoma: an 241-257 (2017). PMID: 27911450. and stressing the importance of ongoing overview of the current status”, Int J Clin Exp 11. MD Onken, et al., “An accurate, clinically surveillance. And because metastatic Pathol, 6, 1230–1244 (2013). PMID: feasible multi-gene expression assay for disease can happen years after the initial 23826405. predicting metastasis in uveal melanoma”, J diagnosis, ophthalmologists play a critical 2. K Mahendraraj et al., “Trends in incidence, Mol Diagn, 12, 461–468 (2010). PMID: role in reinforcing the need for monitoring survival, and management of uveal 20413675. and testing well after many patients may melanoma: a population-based study of 7,516 12. JW Harbour and R Chen. “The DecisionDx- think it’s necessary. Uveal melanoma has patients from the Surveillance, Epidemiology, UM gene expression profile test provides risk a long treatment path – and all caregivers and End Results Database (1973–2012)”, stratification and individualized patient care should be involved in making sure that Clin Ophthalmol, 10, 2113–2119 (2016). in uveal melanoma”, PLoS Curr, 5 (2013). patients and clinical teams stay on course. PMID: 27822007. PMID: 23591547. 3. F Spagnolo et al., “Uveal melanoma”, Cancer 13. MG Field et al., “PRAME as an independent Jonathan Zager is Professor of Surgery Treat Rev, 38, 549–553 (2012). PMID: biomarker for metastasis in uveal melanoma”, in the Cutaneous Oncology and Sarcoma 22270078. Clin Cancer Res, 22, 1234–1242 (2016). departments, and a Senior Member at 4. B Weber et al., “Outcomes of proton beam PMID: 26933176. the Moffitt Cancer Center, Tampa, FL, radiotherapy for large non-peripapillary 14. ME Valsecchi et al., “Adjuvant sunitinib in USA. He is also the Chair of Graduate choroidal and ciliary body melanoma at high-risk patients with uveal melanoma: Medical Education and Associate Chief TRIUMF and the BC Cancer Agency”, Ocul comparison with institutional controls”, Academic Officer. Zager is a member of Oncol Pathol, 2, 29–35 (2015). PMID: Ophthalmology, 125, 210–217 (2018). the editorial board for the World Journal 27171272. PMID: 28935400. of Surgical Oncology and Annals of 5. PR Pereira et al., “Current and emerging 15. S Landreville et al., “Histone deacetylase Surgical Oncology, and has published treatment options for uveal melanoma”, Clin inhibitors induce growth arrest and more than 220 articles and book chapters, Ophthalmol, 7, 1669–1682 (2013). PMID: differentiation in uveal melanoma”, Clin and presented over 300 talks at national 24003303. Cancer Res, 18, 408–416 (2012). PMID: and international surgical and 6. Collaborative Ocular Melanoma Study Group. 22038994. oncology meetings. “Assessment of metastatic disease status at death 16. O Surriga et al., “Crizotinib, a c-Met in 435 patients with large choroidal melanoma inhibitor, prevents metastasis in a metastatic Kathleen Gordon is a medical director at in the Collaborative Ocular Melanoma Study uveal melanoma model”, Mol Cancer Ther, 12, IQVIA (formerly Quintiles) and has a (COMS): COMS report no. 15”, Arch 2817–2826 (2013). PMID: 24140933. volunteer faculty position at the University Ophthalmol, 119, 670–676 (2001). PMID: 17. AM Abbott et al., “Hepatic progression-free of North Carolina, Chapel Hill, NC, 11346394. and overall survival after regional therapy to USA. In addition, she serves as the 7. SF Hodi et al., “Improved survival with the liver for metastatic melanoma”, Am J Clin president of the North Carolina Society ipilimumab in patients with metastatic Oncol, 41, 747–753 (2018). PMID: of Eye Physicians and Surgeons. Prior to melanoma”, N Engl J Med, 363, 711–723 28059929. joining IQVIA, Gordon was a practicing (2010). PMID: 20525992. 18. I Karydis et al., “Percutaneous hepatic ophthalmologist and an Associate Professor 8. R Kines et al., “An infrared dye-conjugated prefusion with melphalan in uveal melanoma: with the University of North Carolina, virus-like particle for the treatment of primary a safe and effective treatment modality in an Chapel Hill. She is a board-certified uveal melanoma”, Mol Cancer Ther, 17, orphan disease”, J Surg Oncol, 117, 1170–1178 ophthalmologist and a Fellow of the AAO. 565–574 (2018). PMID: 29242243. (2018). PMID: 29284076.

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46–49 Overcoming the Mountain of Global Blindness Geoff Tabin on why he co-founded the Himalayan Cataract Project, and what he hopes to achieve in the coming years. Photo by Ace Kvale. 46 Profession

were blind, the figure now stands at less than systems throughout the world. Overcoming three per thousand – the same as the West. My focus was already on global health And all it took was a five-minute procedure. by the time I matriculated at medical the Mountain of If the poorest country in south Asia can school. As it turned out, I wasn’t done eradicate preventable blindness, others with climbing just yet. I was asked to join Global Blindness can too. By establishing a top-to-bottom the first American climbing expedition to system based on compassionate capitalism Tibet. Together, we would attempt the last The story behind the – where paying patients subsidize surgery unclimbed face on Mount Everest. How Himalayan Cataract Project – to keep costs low – it is possible to provide could I say no? the NGO eradicating blindness, a high standard of care in even the poorest I was applying for leave of absence from one country at a time. places. That’s what HCP is all about. We medical school when I got the phone empower local people to take control of their call that would change everything. After By Geoff Tabin healthcare. We train doctors, nurses and making sure I was Geoff Tabin, the man technicians at every level, from the primary on the other end said, “You’re probably Nepal is the only large, low to moderate health care workers to a subspecialty trained the dumbest person ever accepted into income country in the world that has reversed ophthalmologists. We know surgeons in Harvard Medical School.” His name was its incidence of blindness, and I’m proud to developing countries are constrained by lack Dr. Michael Wiedman, and he was on the be part of the reason why. Back in 1995, I of equipment, so we try to make sure our committee reviewing request for leaves of co-founded the Himalayan Cataract Project partners are as well-equipped as possible. absence. “There’s no way that you would (HCP) with Nepali ophthalmologist Dr. ever get a leave of absence to go climbing,” Sanduk Ruit. When we started, there were In the beginning… he said. “Anybody with the intelligence more than 250,000 people bilaterally blind HCP came about almost by chance. Back to get into this school should know that from cataracts in the Himalayas, with 60,000 in my early 20s, I was lucky enough to if you apply to do research, Harvard will more people going blind every year. Nepali receive a Marshall Scholarship to study give you credits.” It turned out he was surgeons were performing a few thousand philosophy at Oxford University in the UK. interested in the effects of high altitude on cataract surgeries a year, but even fewer were At that point, I’d already been accepted retinal physiology, specifically high altitude being performed in Tibet, northern India, to medical school in the US. If it weren’t retinal hemorrhaging as a prognosticator West Bengal, Sikkim or Bhutan. Today, for the scholarship, I would probably be of cerebral edema. He said: “Let’s forget the number of cataract surgeries performed an orthopedic surgeon somewhere doing about your leave of absence and talk about in Nepal has risen to more than 350,000 a sports medicine. My time at Oxford gave our research project.” So we did. year. Where once, nearly one in 100 people me time to think about what I wanted to do, and I became interested in the moral Climbing high paradigm behind healthcare delivery, In 1983, while researching under At a Glance and the disparity in access to healthcare Wiedman, my team and I made the first • The Himalayan Cataract Project between countries around the world. successful climb of the east side of Everest. (HCP) was co-founded by Geoff Oxford had a number of endowed funds, It’s still the only route done with only local Tabin and Sanduk Ruit in 1995 including the A C Irvine Travel Fund that support. It’s very technical – more than any • Aiming to tackle avoidable provided resources for students to enjoy a other path up the mountain – and it’s never blindness, the organization began strenuous mountaineering holiday abroad. I been repeated. its work in Nepal and has since had always been sporty. I played university After finishing medical school, I had the expanded throughout South Asia tennis and skied from an early age, but I opportunity to work as a general doctor and Sub-Saharan Africa became fanatical about climbing. With the at one of the hospitals in Nepal that Sir • Geoff Tabin tells the story of setting help of the fund, I more or less spent half Edmund Hillary, one of my heroes, had up HCP, and how it all began with the year on a paid climbing holiday, scaling established. Many of the problems I a philosophy degree and conquering big walls in Afghanistan, New Guinea and faced were public health issues, problems the world’s highest mountain Africa. The opportunity to climb in Asia of poverty. I watched children dying of • Tabin also shares his view on and Africa allowed me to witness firsthand diarrhea and pneumonia and things that how worldwide blindness can be the consequences of extreme poverty on would be so easy to treat in the Western eradicated. health, and the disparity in healthcare world. Then I saw Dutch ophthalmologist Geoff Tabin with a patient who had received sight-restoring cataract surgery in Kalimping, India. Photo by Ace Kvale.

HCP Co-Founders Sanduk Ruit and Geoff Tabin with patients at a high volume cataract outreach in Dolakha, Nepal. Photo by Michael Amendolia. Geoff Tabin with a cataract patient in South Sudan. Photo by Jordan Campbell.

Dr. Jan Kok and his team perform cataract with top honors and won a full scholarship my fellowship under Dr. Hugh Taylor, surgery. It was mind-boggling. Before to one of the best medical schools in India. the world authority on river blindness and they came, blind people just waited to Upon seeing the level of blindness in trachoma. It wasn’t until my fellowship die. They accepted that you get old, your his home country, he re-trained as a micro that I met Sanduk and everything began hair turns white, your eyes turn white, and surgeon in the Netherlands with Jan Kok to fall into place. He had already set up then you die. In an agrarian economy like – the same doctor I saw perform cataract this amazing system of delivery, taking the Nepal, blindness was a burden for the surgery in Nepal – and also completed best cataract care in India and applying it whole family. Often children would leave a fellowship in Australia with Dr. Fred to Nepal. I was blown away. I finished my school to take care of a blind parent or Hollows. It was the late 1980s when he fellowship and moved to Nepal to work grandparent. But all it took was a small returned to Nepal. with Sanduk. That’s when HCP was born. operation to bring these people back to life. At this time, even the least expensive I’d never seen anything in medicine ignite IOLs were cost-prohibitive for the Going above and beyond such unbelievable joy. It’s hard to express developing world. Sanduk had the genius During our first cataract outreach the happiness that a totally blind person to team up with his mentor Fred Hollows together, we restored sight to 224 feels when they are able to see again. and his eponymous foundation to raise the people in three days. Sanduk did 201 I knew I could make a difference. funds to start the first low-cost IOL factory surgeries, while I did 23. The results I wanted to teach people to perform in the world, in Kathmandu, instantly were incredible. About 80 percent of our cataract surgery and immediately sought a reducing the cost of the lenses from $200 patients could see well enough to be able residency in ophthalmology. What I didn’t to $4. In doing so, he transformed the to pass the American driving test one know then was that the real genius behind economy of global cataract surgery – a day after surgery. With Sanduk’s cataract anything that I’d be able to accomplish in procedure that would cost $3,000 in the outreach system, a single doctor in Nepal the future was also in Nepal – my HCP United States now cost $20 in Nepal. can provide more than 100 sight-restoring co-founder Sanduk Ruit. Sanduk grew up I heard Fred Hollows lecture in the cataract surgeries in a single day. in a hill village in Nepal four days’ walk second year of my residency. I was so Unfortunately, people in rural Nepal from the nearest road, with no electricity or impressed by him that I decided to do didn’t know they could have their sight running water. At eight years old, his father my corneal fellowship in Australia. restored – they had to be told. And so our walked him all the way to Darjeeling, India Unfortunately, Fred died of cancer before mission transformed. Instead of simply to attend school. He went on to graduate I had chance to start, so I ended up doing teaching doctors, we created an entire Profession 49

system of care. We established primary eye partners. We give them the resources they When we started out in Nepal, about 80 care centers throughout the hills of Nepal, need to do things on their own. We build percent of blindness was due to cataracts. which referred patients to larger regional their skills, provide them with equipment It meant if your dad was blind, you carried cataract centers. We expanded upon our and never show them anything they can’t him for two days to see a facility and four now full-service tertiary eye hospital, the replicate themselves. Talented individuals out of five times he would come back with Tilganga Institute of Ophthalmology, in often go abroad to get a better income, but his sight. Those are pretty good odds. Kathmandu. Sanduk also had the brilliant Sanduk has been incredible at identifying Good enough that people will come back idea of introducing training programs for young people who are passionate about and actively seek care. But if we played nurses, ophthalmic assistants, ophthalmic staying in their own country. In fact, out that same scenario in Africa, things technicians and residents – making us the we’re currently in the process of providing would be different. The continent has more first hospital in Nepal to develop a full fellowships in India, Nepal and America glaucoma, more infectious blindness, and ophthalmology residency program. for promising ophthalmologists. more retinal blindness than Nepal. Even people with cataracts often have glaucoma On the move or corneal scarring from trachoma. Today, our work is no longer limited to Suddenly, the odds of a miracle aren’t so the Himalayas despite our name. We run high. Half of the people who take two days training sessions throughout the developing “The truth is there off from work to carry dad to the doctor world – from Asia to sub-Saharan Africa. won’t get cured. Walking another two We currently have programs in Ghana, are very few public days home to hungry kids and a father who Ethiopia and Rwanda, and initiatives in is still just as blind as he was when you left Tanzania. One of the biggest problems health problems we doesn’t incentivize you to proactively visit in Africa is access to care. There are the clinic. So that’s what we’re working on no neuro-ophthalmologists or uveitis can’t overcome” right now, a way to transpose and develop specialists in East Africa – or West Africa, a sustainable system of care to the poorest for that matter. In Ethiopia, there’s one of the poor. ophthalmologist for every 1,000,000 people – and even that figure is deceptive. And it’s a good thing we are, because the Still climbing Of the 130 ophthalmologists in the country need for comprehensive eye care continues to The goal may appear to be unreachable, of 105,000,000 people, 30 are either grow. In India, the standard of cataract care but the truth is that there are very working with NGOs or not doing active has become so great that the upper middle few public health problems we can’t surgery, while 60 live in the capital, Addis class are now paying for surgery before they overcome. Blindness can be reversed Ababa, which leaves 40 ophthalmologists lose their sight – leaving the destitute blind – it happened in Nepal, it happened in to serve the rest of the population – several behind. To understand why that is such a Bhutan, and it can happen elsewhere million people each. You don’t have to be huge problem, think of it on a global scale. too. All we need is funding. We could a mathematician (or ophthalmologist) to If we were to only operate on blind people, eliminate avoidable blindness on the know those numbers aren’t good. we would need to perform about 16,000,000 planet for the cost of what America To that end, our Ethiopian training cataract surgeries. But if we were to operate spends every month on war. Just think program is geared towards high-volume at the 20/100 level, it’s suddenly 60,000,000. about that – two and a half billion cataract surgery, equipping doctors with And of those extra 44,000,000 people, many dollars could restore sight to every single the necessary skills and equipment to deal have the means to pay. Imagine if we start person who is blind from cataracts. It with 1,000 cases a week. As in Nepal, we operating at the level we do in America, would take $100,000,000 to change the are still having to reach out to patients. And 20/60, or England, 6/18 – that number arc of blindness in Africa. Our website, although this works for now, we are working would be eight times higher. Now think which we got by luck, is cureblindness. with local partners and the Ministry of of India again. There are many people who org – and that’s really what we’re trying Health to establish permanent healthcare have a little trouble seeing their computer or to do. Help us do it. If you are interested sites to make truly lasting change. driving at night, and they’re willing to pay in being part of the Himalayan Cataract HCP doesn’t just visit a place, perform a to make that go away. Paradoxically, as the Project by donating your time or money, few surgeries, then leave. We want to make quality of surgery has improved, less of the email [email protected]. Together, a lasting impact, and we do that by finding surgery is going to the blind. we can do great things.

www.theophthalmologist.com Doing Right by Everyone

Sitting Down With… Elizabeth Yeu, Assistant Professor at Eastern Virginia Medical School and Cornea, Cataract and Refractive Surgeon with Virginia Eye Consultants, VA, USA Sitting Down With  51

What led you to ophthalmology? gentlemen. It was a huge deal for me to Do you struggle to balance work and As cliché as it sounds, I’ve wanted to be train under them, but to be colleagues motherhood? in medicine since I was four years old. of theirs? That’s a sincere highlight. Absolutely! The struggle lies in doing My mother actually discouraged me They also taught me that it’s all in right by everybody. It’s really exciting from going down the more traditional the details. Between the exposure, to be involved with extracurricular academic route and encouraged me to the expertise and all that they have opportunities, whether that’s explore different interests, but I was contributed to the field, both Doug volunteering or working with industry drawn to the humanism of medicine. and Steve are the quintessential on innovations, but you get to a point clinician scientists. when some of these opportunities collide When did you know you’d made the with family commitments. It goes back right choice? Do you have any other “heroes?” to not rushing in too quickly and saying I can honestly say that going into Dick Lindstrom to me is in a different “yes!” to everything. I want to do right residency was that awakening for me. realm. I respect him for his continual by those I say yes to! There was no hands-on OR experience commitment to ophthalmology, to I gave myself a goal: by the time my during medical school, so I was anxious driving innovation and to putting his children are 10, I need to be around about my potential as a microsurgeon. money where his mouth is. I recently more, because shaping their adolescence Residency was the “a-ha!” moment learned that he was one of the inventors is the biggest responsibility I have, aside when I knew I’d found my calling. It of Opti-Sol, the storage media that from my responsibility to my patients. was where so much of my life began. I we’ve used for decades with corneal met my husband during residency, and transplantation, which is tremendous Outside of ophthalmology, what was able to connect with a profession – in itself. More than that, he donates all makes you happy? and a career – that made me feel alive. of the royalties to different eye banking My family is the big one! But I also It was hugely impactful. associations. To have someone like Dick meditate and do yoga. I make sure I take Ophthalmology is such a unique reinvesting funds just to create better time to refuel. You can’t give to others if blend of medical and surgical care, it technology in the realm of cornea is you don’t center yourself spiritually and really encompasses the joys of being invaluable. Can you imagine a time mentally – something I didn’t recognize able to positively impact our patients, when we’re able to inject endothelial the importance of 10 years ago. and maintain relationships with them cells or potentially 4D print ocular at the same time. And, unlike other tissue? Cornea as a field has been What advice would you give to your fields of medicine, morbidity is pretty relatively stagnant in therapeutic younger self? low. I knew I couldn’t desensitize advancements. We have been doing Don’t rush the process. If there are tough myself from taking care of very it the same way with transplantation decisions that need to be made – and sick patients. for decades more or less! And we may there will be many, both personal and have continued, were it not for someone professional – don’t rush them. Step What are the highlights of your like Dick. back, enjoy each success and learn from career so far? each failure. Ever since I was little, There are two that come to mind. How are you finding motherhood? I’ve rushed, rushed, rushed. I entered The first occurred very early on in my It’s a “hat” that I’m still growing school at the age of four, graduated from career – my fellowship training and accustomed to! My kids are five and high school at 17, and entered medical then faculty position at the Cullen seven and that’s happened in the blink school at 20. It was great to have those Eye Institute at the Baylor College of the eye. Though I know each stage opportunities, but I’ve come to realize of Medicine. My four colleagues, of motherhood is a challenge in itself, I there is so much to enjoy in the present including Doug Koch and Steve try to sit back and enjoy each moment, because time goes by so quickly. Pflugfelder, truly covered the breadth tame my impatience and anxieties, We should all aspire for greatness, of the anterior segment sub-specialty, while putting every effort into making setting slightly unrealistic goals that push from complex lens-based surgeries sure I do a great job. We must strive us beyond our comfort zones.Whether through corneal and external disease to be the best people we can be, but we’re teaching residents or committing management. Not only are they experts we shouldn’t beat ourselves up over to research, we are all helping patients within our field, but they are also real the failures. and bettering our field.

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INDICATIONS AND IMPORTANT SAFETY INFORMATION FOR THE CATALYS ® PRECISION LASER SYSTEM Rx Only INDICATIONS: The OptiMedica® CATALYS® Precision Laser System is indicated for use in patients undergoing cataract surgery for removal of the crystalline lens. Intended uses in cataract surgery include anterior capsulotomy, phacofragmentation, and the creation of single-plane and multi-plane arc cuts/incisions in the cornea, each of which may be performed either individually or consecutively during the same procedure.CONTRAINDICATIONS: Should not be used in patients with corneal ring and/or inlay implants, severe corneal opacities, corneal abnormalities, significant corneal edema or diminished aqueous clarity that obscures OCT imaging of the anterior lens capsule, patients younger than 22 years of age, descemetocele with impending corneal rupture, and any contraindications to cataract surgery. IMPORTANT SAFETY INFORMATION: Mild petechiae and subconjunctival INVISIBLE LASER RADIATION AVOID EYE OR SKIN EXPOSURE TO hemorrhage can occur due to vacuum pressure of the suction ring. Potential complications and adverse events include DIRECT OR SCATTERED RADIATION CLASS 4 LASER PRODUCT any of those generally associated with cataract surgery. CAUTION: Should be used only by qualified physicians who have Yb Laser: Laser Class 4/IV

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