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JANUARY 2014 Upfront Why Put Pancreatic β-Cells in the Aqueous Humor? 10 In Practice Marc Muraine’s deft DMEK packs a punch 24 – 27 NextGen e future of gene therapy in ophthalmology 38 – 39 Profession Six Strategies to Stimulate Resident Learning 46 – 48 # 04 VEGF e Jekyll and Hyde of the Adult Eye 16 – 21

The Jekyll and Hyde of the Adult Eye

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January 2014

UpfrontWhy Put Pancreatic β-Cells in the Aqueous Humor? 10

In PracticeMarc Muraine’s deft DMEK packs a punch

24 – 27

NextGenThe future of gene therapy in ophthalmology

38 – 39

ProfessionSix Strategies to Stimulate Resident Learning

46 – 48

# 04

VEGFThe Jekyll and Hydeof the Adult Eye16 – 21

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Feature

16 VEGF Has Physiological as Well as Pathological Functions Magali Saint-Geniez and Patricia D’Amore review the role of VEGF in the normal adult eye. It does more than promote neovascularization… and chronic blockade may have unintended consequences.

In Practice

24 DMEK: Simplified, Deftly Marc Muraine describes his novel method of preparing DMEK grafts. It uses a punch but doesn’t lay a finger (or forceps) on the corneal endothelial cells.

28 Novel Refractive Intracorneal Procedures for Keratoconus Francisco Sánchez León reports his experience of intracorneal ring segment and phakic IOL implantation for patients with keratoconus and high myopia.

03 Online This Month

07 Editorial Cost: The Final Frontier By Mark Hillen

08 Contributors

On The Cover

Jekyll and Hyde theme createdusing a poster from the 1880s.Background illustration byRachael Tremlett.

Upfront

10 Keeping an Eye on Diabetes 10 20/200 drivers

11 Dropper Bother 12 Retinal Visualization of Schizophrenia

14 Not All Big Pharma Loves Ophtho

15 Seeing What’s Behind the Camera

Contents

January 2014

UpfrontWhy put pancreatic β-cells in the aqueous humor? 10

In PracticeMarc Muraine’s deft DMEK that packs a punch

26 – 28

NextGenThe future of gene therapy in ophthalmology

35 – 37

ProfessionMarket your practice with that premium polish

40 – 41

# 04

VEGF:the Jekyll and Hydeof the adult eye.16 – 20

0114 TOP.indd 1 14/01/2014 16:16

16

50

30 Practical Pearls and Possible Pitfalls for the General Cataract Surgeon Top ten tips from David Kent to give patients the best possible refractive outcomes.

NextGen

36 Gene Therapy Clinical Trials We’ve seen gene therapy hitting the clinic, but not for eye disease – yet. How close are we? By Irv Arons and Mark Hillen. 38 Integrin Blockade as a Retinovascular Therapy David S. Boyer introduces ALG- 1001, a drug that targets integrins for the treatment of wet AMD and posterior vitreous detachment.

Profession

44 Re-Engineering Healthcare Jim Taylor offers a solution to the “perfect storm” enveloping healthcare today.

46 Six Strategies to Stimulate Resident Learning Karl C. Golnik gives his top tips on residents learn from your instruction more effectively.

Sitting Down With

50 Carrie MacEwen, Consultant Ophthalmologist at Ninewells Hospital, Dundee, Scotland, and President-Elect of the UK Royal College of Ophthalmologists.

Erratum (Issue 3, p24): Per the article ‘Loss of Traction’, please note that the non-US commercial

rights holder for ocriplasmin (Jetrea®) is Alcon.

ISSuE 04 - January 2014

Editor Mark Hillen

[email protected]

Editorial Director Richard Gallagher

[email protected]

Graphic Designer Marc Bird

[email protected]

Managing Director Andy Davies

[email protected]

Director of Operations Tracey Peers

[email protected]

Publishing Director Neil Hanley

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Audience Development Manager Tracey Nicholls

[email protected]

Digital Content Manager David Roberts

[email protected]

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ISSN 2051-4093

24

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Our NextGen section predicts what clinical practice might look like in five-to-ten years’ time. In this issue, we look at the status of gene therapy for the treatment of ophthalmic disease; in the previous issue, we did the

same thing for stem cell therapy. The signs on both these frontiers of medicine are promising,

and although their introduction has been “only 5–10 years away” for as long as I can remember, this time many of the problems that had stymied development appear to have been overcome. We have even witnessed the first European regulatory approvals for a gene therapy-based treatment: in October 2012, the European Medicines Agency approved alipogene tiparvovec (Glybera), a gene therapy that compensates for lipoprotein lipase deficiency.

Ironically, once functional gene and stem cell therapies are approved, they may still fall at the biggest, and final, hurdle: affordability.

In some cases, a single application of gene therapy might confer a cure. It’s a cure that has taken decades of eye-wateringly expensive research, development and clinical evaluation to make. All that has to be paid for. In alipogene tiparvovec’s case, where the market is small – just a few hundred patients worldwide – the per-patient treatment charges may be pitched as high as US$1.6 million/ €1.25 million.

The market size for most of the ophthalmic diseases currently under investigation for stem cell and gene therapies is orders of magnitude greater so per-patient costs might be expected to be orders of magnitude lower, right? Wrong! Economists tell us that the value of a product is simply what people are prepared to pay for it. The question is, is there a sweet-spot? Will there be a price for gene and cell treatments that will be affordable to those who manage healthcare budgets; that will satisfy the companies that have finally realized the promise of a new category of medicines; and that will be palatable to the general public, who will rightly pore over all aspects of these new therapeutics? Getting these negotiations right is one of the major factors Jim Taylor alludes to when he describes the challenge facing global health care as “the perfect storm” (see page 45).

Vision is precious as its impairment is profoundly disabling; the value of an effective treatment or cure to patients – and to society – is great. What impact this will have upon the price on these agents once available remains to be seen.

Now is the time for ophthalmologists to start thinking about this. What would you be prepared to spend on a novel gene therapy agent to improve your sight? To restore sight from blindness? What should our health insurers, whether private or public, be prepared to pay?

Mark HillenEditor

Editor ia lCost: The Final FrontierGene therapy for ocular disease will soon be available. Stem cell therapies too. They may be able to cure the currently untreatable, but at what price? And will anyone pay it?

Reference1. J Whalen, “Gene- Therapy Approval Marks Major Milestone”, Wall Street Journal, November 2nd, 2012. http://online.wsj. com/news/articles/SB10 001424052970203707 60457809509194087 1524

Contr ibutors

Magali Saint-Geniez and Patricia D’AmoreMagali is an Assistant Scientist at the Schepens Eye Research Institute, and an Assistant Professor of Ophthalmology at Harvard Medical School. Her research interests focus on the development of new strategies for the characterization and treatment of retinal degenerative diseases such as AMD. Magali also enjoys directing educational videos like “Can Treat This,” that tell the story of how to treat AMD (see http://top.txp.to/damore/amd).

Patricia holds many learned positions at Harvard Medical School, including Director of Research at the Schepens Eye Research Institute; Vice Chair of Basic Research in Ophthalmology; the Charles L. Schepens Professorship of Ophthalmology; Professor of Pathology, and Co-Director of the AMD Center of Excellence. Patricia participates in the Susan G. Komen 3-Day, 60 miles walk. To date, she’s completed eight walks, totaling 480 miles in the process, plus another 1,500 miles in training. Read Magali and Patricia’s feature on the role of VEGF in the adult eye – and its implications for chronic use of anti-VEGF therapies on page 16.

Marc MuraineStruck by the eye’s beauty and complexity early in life, Marc Muraine decided to devote himself to a career in ophthalmology in his fifth year at high school. Marc is now a Professor and Chief of the Ophthalmology Department at Rouen University Hospital, where he specializes in corneal transplantation, overseeing 15–20 such transplants per week. While doing so, he came upon an idea for an easier way to prepare DMEK grafts. On page 24, Marc explains his new, simplified method for preparing corneal grafts for DMEK surgery, and his surgical technique.

Karl Golnik Twenty years after his MD degree, Karl Golnik obtained a Master’s Degree in Education. He puts this to use as Director for Education for the International Council of Ophthalmology, President of the Joint Commission an Allied Health Personnel in Ophthalmology, and Chair of the Pan-American Association of Ophthalmology’s Resident Education Committee. Karl is Professor of Ophthalmology, Neurology and Neurosurgery at the Cincinnati Eye Institute and the University of Cincinnati, and Professor of Ophthalmology at the University of Louisville. Read Karl’s article on stimulating resident learning on page 46.

David KentDavid Kent’s principal interests are retinal repair and regeneration, retinal pigment epithelial cell biology, and Wexford hurling (is an outdoor team game of ancient Gaelic and Irish origin, thought to be the world‘s fastest field team game). David is a consultant ophthalmic surgeon & retina specialist, Aut Even Hospital, Kilkenny, Ireland and Barringtons Hospital, Limerick, Ireland a researcher at the University of Liverpool, UK, and a visiting professor at Florida University. His top tips, pearls and pitfalls for toric IOL placement can be found on page 30.

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Keeping an Eye on Diabetes Transplanting pancreatic Islets of Langerhans into the ocular anterior chamber of the eye allows researchers to effectively monitor β-cell function.

When the demand for insulin is high – such as during prolonged periods of excess food consumption or when insulin resistance occurs – the number of β cells increases. This plasticity is essential for normal blood sugar levels to be maintained; diabetes results from its dysfunction.

Assessing the state of β-cells in vivo would provide valuable information on the function of the cells and on disease state of patients with insulin resistance or diabetes. However, it is difficult to assess these cells, given their location: non-invasive imaging techniques like ultrasound or magnetic resonance imaging are inadequate, and biopsies are invasive and give only a snapshot of what’s going on.

Now, a new approach has been proposed by Per-Olof Berggren, a Professor of Exper imental Endocrinology at Sweden’s Karolinska Institutet and Erwin Ilegems, researcher at the Rolf Luft Research Centre for Diabetes and Endocrinology, and their colleagues. Their solution is to transplant Islets of Langerhans into the anterior chamber of the eye. The work, for now, is being conducted in mice (1).

“We’ve made the cells optically accessible by grafting a small number of ‘reporter islets’ into the eyes of mice, which allows us to monitor the activity of the pancreas just by looking into the eye,” says Berggren. “We’re now able to really study the insulin-producing β-cells in

detail in a way that wasn’t possible before.”“The transplanted islets can be

visualized repeatedly over a period of months. During this time, the functional and morphological changes that occur in them that are identical to those occurring in the pancreas,” says Ilegems.

“We’ll be using the system to identify new drug substances that regulate β-cell plasticity and function,” Berggren adds. “In the future we may develop reporter islets in humans in order to find unique, tailored treatment principles, to measure the effects of personal medication, or to diagnose problems with the pancreatic islets.”

So don’t be too surprised when you perform ophthalmoscopy in a decade’s time if you see bits of the body that shouldn’t really be there. The principle may also work with other cell types too – so it may be that a whole diagnostic panel of disease-marking cells could await your examination. MH

Reference1. E Ilegems, A Dicker, S Speier, et al., “Reporter islets in the eye reveal plasticity of the endocrine pancreas”, PNAS, Epub ahead of print.

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

We welcome suggestions on anything that’s impactful on ophthalmology; please e-mail [email protected]

Upfront10

20/200 DriversAmericans love their cars and in many places you’re virtually stranded if you don’t drive. So does vision loss stop elderly Americans from driving?

For many people in the USA (and elsewhere), a car is essential to live a normal life: it represents independence. Studies have shown that elderly people who have their ability to drive limited or removed experience “increased dependence, reduced accessibility to healthcare and higher mortality.” This

prompted Sabyasachi Sengupta and colleagues at the Wilmer Eye Institute in Baltimore, MD, USA to ask if elderly Americans with central vision loss are tempted to continue driving and, if they are, under what conditions. Do they restrict their driving? If another driver is available, do they let that person drive?

The evaluation questionnaire was completed by sixty-four patients with bilateral vision loss (<20/32 in the better eye) or severe unilateral vision loss (<20/200) from age-related macular degeneration (AMD), and fifty-eight normally-sighted controls (with glaucoma), aged between 60 and 80 years (1). Driving limitations were specified by the investigators as: restricting their driving to the neighbourhood or familiar areas; reducing the frequency or distance of driving, or not driving when it’s at night or in the rain.

What they found (Figure 1) was that most patients with AMD continue to drive; indeed only one-fourth of

patients with AMD-related central vision loss reported ceasing driving altogether. However, an increasing proportion of patients restricted their driving as their vision and contrast-sensitivity worsened. The patients were generally willing to let others drive when possible and they did restrict where, when and how far they drove. The authors write that it “appears that patients adjust to central vision loss by altering their driving habits, rather than ceasing driving altogether.”

Thus, patients maintain their quality of life for the longest possible time, but whether their actions strike a fair balance between safety and independence is another matter entirely. MH

Reference1. S Sengupta, SW van Landingham, SD Solomon, et al., “Driving Habits in Older Patients with Central Vision Loss”, Ophthalmology (2013), Epub ahead of print.

Upfront 11

Figure 1. Driving habits of current drivers with and without age-related macular degeneration – proportion of patients who will drive (per charted parameters). * p<0.05; †States of Maryland, Delaware, Pennsylvania, Virginia and Washington DC.

Dropper BotherThe UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) issues a safety alert for Cosopt preservative-free single-dose eye drops

The merits of preservative-free eyedrops are well known. They must be packaged in single-dose containers, however, and that introduces potential problems. At lease it has done for preservative-free formulations of the glaucoma medication, dorzolomide hydrochloride/timolol maleate (Cosopt). Since a new dropper design was introduced in July 2013, the MHRA has received 69 complaints, ranging from scratches to the cornea to “difficulty in administration of the drops onto the eye” (1).

The culprit appears to be the wings that extend from the pipette tip, and the small bits of plastic that remain on the tip after the pipette is opened. Some patients find it difficult to use the pipette, increasing the risk of eye injury.

A new dropper with an improved design will be introduced soon, but in the meantime, the MHRA notes that “patients who are currently using this product may be experiencing problems administering their eye drops, and may benefit from additional education in the safe self-administration of eye drops.” The agency has requested that UK-based eyecare professionals “report any problems via the Yellow Card Scheme (an online reporting system for suspected side effects), specifying which presentation was involved.” MH

Reference1. Medicines and Healthcare products Regulatory Agency, Drug Safety Update, 7(5), S2 (December 2013); http://www.mhra.gov.uk

Retinal Visualization of Schizophrenia OCT imaging visualizes retinal nerve fiber layers and the thickness of the macula; abnormalities in either can predict the stage and duration of schizophrenia.

Patients with schizophrenia exhibit a progressive reduction in brain volume as the disease advances. From the very first schizophrenic episode, during the prodromal phase and even in those with a high genetic risk of developing the disease, volume deficits in grey matter are detectable.

When researchers at the Department of Ophthalmology at the University of Malaya, in Kuala Lumpur, Malaysia, decided to see if these abnormalities could be visualized in the retina by spectral-domain optical coherence tomography (SD-OCT) they found that, relative to age-matched controls, patients with schizophrenia exhibited significant thinning of the retinal nerve fiber layer (RNFL) and the macula;

overall macular volume was reduced too. The study revealed significant inverse correlations between the duration of schizophrenic illness and peripapillary RNFL thickness (r=–0.36), macula thickness (r=–0.38), and macula volume reduction (r=–0.36).

The authors concluded that “SD-OCT can be a useful tool for diagnosis and monitoring the progression of this disease.” As we’ve previously reported, the retinal vasculature can also predict the status of systemic diseases like diabetes [0113-301] – even without injecting β-cells from the Islets of Langerhans into the anterior chamber (this issue). It seems that either ophthalmologists will increasingly assess non-ophthalmic disease states in patients or that the practitioners of other specialties will soon be investing in imaging equipment that was once solely the domain of eye care specialists. MH

Reference1. WW Lee, I Tajunisah, K Sharmilla et al., “Retinal nerve fiber layer structure abnormalities in schizophrenia and its relationship to disease state: evidence from optical coherence tomography”, Invest Ophthalmol Vis Sci., 54(12), 7785–92 (2013).

FUNDUS IMAGING WITH AUTOFLUORESCENCE “With the extra feature of fundus autofluorescencephotography we have discovered retinal changeswe have not seen before and which makes us learnmore about retinal changes and diseases every daywe use the Canon retinal cameras.” Rune Brautaset BSc (Hon), MPhil, PhD, Associated professor, and Head of Unit/Director of Studies, Unit of Optometry/Optometry Education, Karolinska Institutet, St Erik’s Eye Hospital, Stockholm, Sweden

http://www.canon-europe.com/Medical/Eye_Care/FAF

Canon.indd 1 16/01/2014 16:23

Will Eye Bling Take Off?The media have been building up “eyeball jewelry” as a potential craze, but the evidence suggests otherwise

Late last year, widespread media coverage was given to a 25-year old woman from New York, Lucy Luckayanko, who had a heart-shaped platinum implant placed just under her conjunctiva via a tiny, self-sealing incision. She was the first person to undergo the “Safesight Jewelry” operation, performed by “entrepreneur ophthalmologist” Emil Chynn of Park Avenue Laser Vision in New York City. Column inches were given over to the likelihood that eyeball jewelry craze would become a “raging new fashion trend” that would sweep America’s affluent twentysomethings. The American Academy of Ophthalmology issued a warning to consumers about the associated dangers.

The impact of the story remains to be seen, especially as the New York case is not a first. Back in early 2004, in The Netherlands, the ‘JewelEye’ platinum heart implant was offered by two eminent Dutch ophthalmologists, Gerrit Melles and Bob Ververs (of Descemet membrane endothelial

keratoplasty fame). It too made a (brief ) impact on the world’s media. But it never took off as a trend.

We spoke to Jannemiek Sonneveld, the second person to receive a JewelEye implant. “In 2004 there was a lot of media attention with similar responses as now,” she says. “Any treatment with eyes sounds scary. My opinion is that people tend to overreact.”

Sonneveld’s motivation for having the implant was surprising. “I am not a person who has piercings or tattoos,” she told us, “it was my professional passion for eyes that led me to have the procedure. I am an optometrist, so I knew what to expect and that the risks would be minimal.”

Hearteningly for prospective eye bling aficionados, Sonneveld still has the little platinum heart in her eye, and reports that she “has never experienced any problems at all.” Less heartening, however, is that, far from being eye-catching, “hardly anyone notices that I wear a heart on my eyeball.” For Jannemiek that is not an issue, as she “never meant to attract attention with it; it is just something for me.”

It seems unlikely that many people who would be prepared to spend thousands of dollars to have jewelry inserted into their eye would be satisfied with “hardly anyone” noticing it. To the great relief of ophthalmologists, it’s unlikely that eye jewelry will become a major fashion trend. MH

Upfront14

Not All Big Pharma Loves OphthoWhile other pharmaceutical companies are buying into ophthalmology, Pfizer is heading for the hills

In recent issues we’ve reported on the increasing number of the liaisons between the pharmaceutical industry and ophthalmology. But it’s not all plain sailing. Lpath, a San Diego, California-based biotech firm is currently developing a therapy for wet age-related macular degeneration (AMD) called iSONEP. Pfizer had an exclusive option for a worldwide license to develop and commercialize iSONEP but Lpath recently received notification that the world’s biggest pharmaceutical company wants to divest its commercial interests in ophthalmology, including its exclusive option on iSONEP.

Why might Pfizer be withdrawing from ophthalmology? Eight years ago, the company had petaganib (Macugen), the first anti-VEGF therapy to be approved by the FDA for the treatment of wet AMD. They had a thriving ophthalmology section to support, develop and market their groundbreaking drug. Then Genentech/ Novartis brought out ranibizumab. Petaganib slowed VA decline in patients, but could not stop it. When used appropriately, ranibizumab could, and so Pfizer saw its drug’s market share drop into single digit percentages. Was this the turning point that dulled the luster of ophthalmology for Pfizer? MH

Upfront 15

Seeing What’s Behind the CameraThe pupil of the eye is dark, and the cornea highly reflective – it acts as a mirror. Combine this with high resolution photography, and you get a whole new vista.

Sherlock Holmes observed that “There is always a man at a wedding who is not in any photograph” – the photographer. This brilliant deduction may have helped him identify a murderer, but today the task would be easier. Because the photographer is in the picture.

As psychology researchers Rob Jenkins and Christie Kerr have demonstrated (1), the advent of high-resolution digital photography means that incredible amounts of detail are captured in every photograph taken. Jenkins and Kerr exploited this, taking passport-style photographs of a person in the presence of four other people (plus the photographer) out of shot. The photos were taken at a resolution of 39 megapixels, then the eye of the subject was zoomed in on, and that image was presented to study participants. The participants were either familiar or unfamiliar with the faces of the people who had been in the room when the photo was taken.

Study participants were asked to identify the faces in the image against a series of portrait photographs – “foil” photographs were also used to increase the difficulty of the task. Success rates were seventy-one percent in those unfamiliar with the faces, which rose to eighty-four percent with familiar faces.

Jenkins and Kerr wrote, “Corneal

reflections can reveal surprisingly rich information about the social environment,” noting that “these bystander images were not merely informative about facial appearance, they were properly identifiable to viewers who knew the faces.” Given that one company produces a smartphone with a 41 megapixel sensor already, it’s likely that many people will be carrying a camera in their phone that’s capable of showing not only the subject of the

photograph, but also the photographer. The implications for crime investigation – and privacy – are substantial. MH

Reference1. R Jenkins, C Kerr, “Identifiable Images of Bystanders Extracted from Corneal Reflections”, PLoS ONE, 8(12), e83325 (2013).

Video

http://top.txp.to/zoom

VEGF has Physiolgical as well as Pathological Functions

V ascular endothelial growth factor (VEGF, also known as VEGFA) was originally identified in 1989, as a protein that could stimulate the proliferation of vascular endothelial

cells (1). The earliest VEGF studies focused on the fact that it appeared to be involved in the induction and maintenance of tumor vascularization. At around the same time, another research group, spurred by the observation that tumor blood vessels are excessively leaky, discovered a protein that could induce vascular permeability, and called it vascular permeability factor (2). In fact, most new blood vessels – with the apparent exception of those formed during development – are particularly permeable. The gene sequences of both molecules were determined in 1989, and it was discovered that the proteins that mediated these two activities – angiogenesis (capillary growth) and permeability – were actually the same, and ever since it has been referred to as VEGF (3).

Later, VEGF was found to be critical for vascular development. Its genetic deletion – even the deletion of one allele – from mice was catastrophic. It resulted in very early embryonic lethality, characterized by the absence of yolk sac vasculature and failure to form an aorta. Other work demonstrated that VEGF was involved in wound healing and the normal angiogenesis associated with reproduction – such as in the formation of the corpus luteum and the placenta. Blockade of VEGF, or of its primary signaling receptor VEGFR2, was shown in experimental models to suppress tumor growth. This observation stimulated great excitement regarding the possibility of a “magic bullet” that could inhibit primary tumor growth as well as prevent the formation of metastases.

These events were followed by studies in the late 1990s that demonstrated an association between levels of VEGF in the aqueous of patients, and active angiogenic ocular pathologies – including proliferative diabetic retinopathy, wet age-related macular degeneration and retinopathy of prematurity. Perhaps for these reasons, little thought was given to the possibility that VEGF might play a role in the adult that was not associated with vascular pathology.

The Many Lives of VEGFIn 2006, purely for the reason of scientific curiosity, we decided to examine VEGF levels in various tissues of adult mice. We were surprised to find that virtually all tissues had some – or many – types of cells that produced VEGF. As these were normal adult tissues, the VEGF was being expressed in the absence of any active angiogenesis. This prompted the question: What was the function of the VEGF being produced in adult tissues? We started to wonder whether there might be a role for VEGF in the adult that was unrelated to angiogenesis.

There were, in fact, already clues suggesting roles for VEGF in the adult that were distinct from angiogenesis, including two clinical examples where the actions of VEGF were being blocked. One was a pathology of pregnancy, preeclampsia, the early stages of which are characterized by hypertension and proteinuria. It had been shown that the plasma of severely preeclamptic woman contains particularly high levels of soluble FLT1 (FMS-related tyrosine kinase 1, also known as soluble VEGFR1). Soluble FLT1 contains the extracellular (that is, ligand-binding) portion of a high affinity VEGF receptor. As FLT1 circulates, it sequesters free VEGF, preventing it from binding to its receptor; in effect, neutralizing VEGF. The study showed that symptoms of preeclampsia could be replicated by administering soluble FLT1 to pregnant rats, demonstrating that VEGF neutralization played a central role in the pathogenesis.

Further evidence came from patients with cancer who received intravenous anti-VEGF antibody (bevacizumab) as a form of adjuvant chemotherapy. The circulating antibodies mopped up not only tumor-derived VEGF, but also any other available VEGF, thereby neutralizing the action of VEGF systemically. Interestingly, the primary side effects of bevacizumab were (like preeclampsia) proteinuria and hypertension. Thus, it was clear that VEGF was, indeed, playing a role in the adult that was unrelated to its ability to stimulate new blood vessel growth.

The biological basis for the proteinuria associated with systemic VEGF neutralization is now known. Our earlier work revealed that kidney podocytes (an epithelial cell that lies in very close proximity to the glomerular capillaries) express

Feature 17

Growing evidence for the key role played by VEGF in the normal adult eye now demands that ophthalmologists give careful consideration to the use of anti-VEGF therapies. While these agents are highly effective for the treatment of ocular neovascularization – particularly as an

anti-permeability factor – it may also interfere with the normal functions of VEGF in the eye.By Magali Saint-Geniez and Patricia A. D’Amore

high amounts of VEGF. The glomerulus, like many filtrating organs and tissues (such as the ciliary body or the pancreas) is comprised of capillaries that are fenestrated (that is, have pore-like structures that maximize the exchange between blood and tissues). It has since been demonstrated by a number of researchers that all fenestrated capillaries are dependent on a local source of VEGF – virtually always epithelial cells – that is essential for the maintenance of both the fenestrations and the fenestrated capillary endothelium itself.

VEGF in the Normal EyeMotivated by these clinical observations and by the knowledge that VEGF is ubiquitously expressed in adults, we set out to understand what role VEGF might play in the adult eye under normal conditions. As we had already observed VEGF production in most ocular tissues – the retina, the lens and the ciliary body (4–6) – we suspected that VEGF blockade would have effects in the normal adult eye.

The retina has many VEGF-expressing cells, including pericytes and astrocytes in the ganglion cell layer, Müller cells, and the retinal pigment epithelium (Figure 1). However, the fact that cells in the retina produce VEGF is, of itself, not evidence that VEGF has a function: we needed to know if the VEGF receptor was also expressed. Using a variety of methods, we demonstrated that a number of cells in the retina express VEGFR2, the primary signaling receptor for VEGF (Figure 1). These include the capillary endothelium of the retina, choroid and the ciliary body, Müller cells and, most surprisingly, photoreceptor cells. The concurrent presence of cellular sources and targets of VEGF strongly suggested that this factor could be involved in the maintenance of the retina’s integrity and/or its function.

To investigate this in an experimental system, we intravenously injected into mice adenovirus that expressed soluble FLT (the culprit in preeclampsia). Adenoviruses primarily lodge in the liver, effectively becoming a factory for the production of soluble FLT and leading to systemic VEGF neutralization, which enabled us to study the impact of VEGF neutralization on various tissues.

When we looked at the histology of the retina after two weeks of VEGF neutralization, we found that many cells in the inner and outer nuclear layer showed signs of damage and cell death. Further examination at 28 days revealed a significant thinning of the retina (Figure 2) and vision loss, indicated by a reduction of the electroretinograph a- and b-waves. These observations were consistent with the pattern of expression of VEGF and its receptor, with VEGF derived from Müller cells likely acting as a survival factor not only for Müller cells themselves, but also for the neighboring photoreceptors – VEGF appeared to signal

in both an autocrine and paracrine manner. This hypothesis was supported by additional tissue culture studies, in which we demonstrated that freshly isolated photoreceptors cultured in low nutrient media die unless they are protected by the addition of VEGF.

Using the same SFLT-1 overexpression mouse model, we went on to examine the effect of VEGF blockade on the ciliary body (6). Located in the anterior segment, the ciliary body produces the aqueous humor and mediates lens accommodation. Each ciliary process consists of centrally located fenestrated capillaries overlaid with a double layer of epithelium, an inner pigmented epithelium and an outer non-pigmented epithelium. We determined that VEGF is produced by the pigmented epithelium, whereas VEGFR2 is expressed by the fenestrated endothelium and the non-pigmented epithelium. Consistent with this expression pattern, ciliary bodies from mice with systemic VEGF neutralization suffered from degeneration of the non-pigmented epithelium and the capillaries. These changes included the appearance of vacuoles (a possible sign of autophagy), thinning of the epithelium, loss of capillary fenestrations, and the appearance of microthrombi. This degeneration was associated with impaired ciliary body function, as evidenced by a decrease in intraocular pressure. These observations parallel what is observed in the choroid plexi in the brains of mice that had been subject to VEGF blockade (7). Like the ciliary body, the choroid plexus is a secretory tissue – the site of cerebral spinal fluid production – and is comprised of a core of fenestrated capillaries covered by VEGF-producing epithelial cell layers.

We also investigated the function of the VEGF that is produced by the retinal pigment epithelium (8). Once again, we demonstrated that the retinal pigment epithelial cells, along with the endothelial cells of the underlying choriocapillaris, express VEGFR2. This pattern of expression indicated that VEGF might act in an autocrine manner on retinal pigment epithelial cells and on underyling choriocapillaris endothelial cells by paracrine signaling. To test whether the VEGF from the retinal pigment epithelium was important for maintenance of the choriocapillaris, we used a mouse model in which the form of VEGF produced by the retinal pigment epithelium could not effectively reach the choriocapillaris endothelial cells but would still be able to act on retinal pigment epithelial cells.

To understand how this was accomplished it is important to know that VEGF in the mouse is produced as three isoforms of different molecular weights (they all come from the same gene and are produced by alternative splicing). The longest isoform (referred to as VEGF188) is highly charged so cannot easily diffuse away from the pigment epithelium after it is secreted. Retinal pigment epithelial cells do not normally make

Feature18

any VEGF188. Instead they make the more diffusible forms, VEGF120 and VEGF164. This makes sense if VEGF needs to reach the choriocapillaris on the other side of Bruch’s membrane. We genetically engineered mice so that the pigment epithelium could make only VEGF188. These mice exhibited age-dependent degeneration of both the retinal pigment epithelium and the choriocapillaris; by the time the mice were 18 months old (equivalent to old-age in humans), degeneration of the retinal pigment epithelium and a loss of the choriocapillaris and photoreceptor cells could be observed. The changes in the retinal pigment epithelium of the choroid in the mice were not unlike those seen in human geographic atrophy.

Implications for Anti-VEGF TherapyWhat do these experimental observations mean for the use of intravitreal anti-VEGF? It is important to point out that the results described above were obtained in experimental models that involve a continuous and high-level blockade of VEGF. This contrasts with the clinical situation, where the anti-VEGF antibodies injected intravitreally are cleared relatively quickly: the reported half-lives are 5.6, 3.2 and 4.8 days for bevacizumab, ranibizumab and aflibercept, respectively. In addition, anti-

VEGF treatments are administered only every 4–12 weeks. Thus, in the clinical situation, VEGF neutralization may be complete in the short-term, but the antisera are cleared and the neutralization does not persist so, meaning that levels of both normal and pathologic VEGF are restored.

The restoration of physiologic VEGF in anti-VEGF-treated patients likely accounts for the fact that the undesired side effects are few (or take a long time to appear). Pathologic VEGF is similarly “reestablished” – that’s why the vessel leakiness and vision loss returns – necessitating periodic retreatment with anti-VEGF therapy.

Our findings in mouse models do, however, raise questions about chronic intravitreal anti-VEGF treatment (Figure 3). There is increasing evidence that long-term therapeutic VEGF neutralization may have undesirable side effects. The loss of photoreceptors – and vision – in patients treated with anti-VEGF agents in the absence of choroidal neovascularization (CNV) has led to speculation that the these drugs may interfere with the neuroprotective actions of VEGF, as predicted and supported by the studies described above (9). In addition, spectral domain optical coherence tomography (OCT) studies performed after six and 12 months of anti-VEGF treatment

Sources of VEGF VEGF targets

Ganglion cells

Endothelial cells

Müller cells

Photoreceptor cells

Retinal pigmentepithelium

Choroidal vessels

Astrocytes

Pericytes

Müller cells

Retinal pigment

epithelium

Figure 1. Cellular sources and targets of VEGF in the normal adult retina. In the adult retina and under normal conditions, VEGF is expressed by various cells types including pericytes, astrocytes, Müller cells and retinal pigment epithelium (left panel). Cellular targets of VEGF, that is cells expressing the primary signaling receptor VEGFR2, include the retinal and choroidal vessel endothelium, the ganglion cells, the Müller cells, the photoreceptors and the retinal pigment epithelium (right panel). This pattern of expression suggests that VEGF signaling may be important for the maintenance and function of the vascular, glial, neuronal and epithelial components of the adult retina.

Illustration by Rachael Tremlett

revealed “significant thinning of the choroid, whereas control eyes showed no reduction in the choroidal thickness over six months” (10). Similarly, thinning of the nerve fiber layer has been detected following anti-VEGF treatment (11). This is of particular concern for the subset of patients with AMD also affected by glaucoma for which the nerve fiber layer is already vulnerable.

There are also a number of reports documenting sustained elevations in intraocular pressure following intravitreal anti-VEGF treatment, which appear to be associated with more frequent injections. The mechanisms underlying this effect have not been elucidated; however, it is consistent with our observations of the effect of VEGF blockade on the integrity of the ciliary body.

Clearly, the availability of anti-VEGF therapy for a variety of ocular pathologies characterized by edema and/or neovascularization has been life changing, for both patients and clinicians. However, these recent observations indicate that the additional, physiological, roles of VEGF in the eye must be considered. Treatment regimes that are driven by need – that is, pro re nata (PRN) – would seem to be preferable to scheduled monthly treatments. Our data also caution against any move towards continuous release of anti-VEGF agents: total VEGF blockade would shut down physiological VEGF and is unlikely to be ideal. The goal should clearly be to target the pathological VEGF while sparing the physiological.

Magali Saint-Geniez and Patricia A. D’Amore are at the Schepens Eye Research Institute, Massachusetts Eye and Ear Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

References1. DW Leung, G Cachianes, WJ Kuang, et al., “Vascular endothelial growth factor is

a secreted angiogenic mitogen”, Science, 246(4935), 1306–9 (1989).2. DR Senger, SJ Galli, AM Dvorak, et al., “Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid”, Science, 219(4587), 983–5 (1983).3. PJ Keck, SD Hauser, G Krivi, et al., “Vascular permeability factor, an endothelial cell mitogen related to PDGF”, Science, 246(4935), 1309–12 (1989).4. ASR Maharaj, M Saint-Geniez, AE Maldonado, PA D’Amore, “Vascular endothelial growth factor localization in the adult”, Am J Pathol., 168(2), 639–48 (2006).5. M Saint-Geniez, ASR Maharaj, TE Walshe et al., “Endogenous VEGF is required for visual function: Evidence for a survival role on Müller cells and photoreceptors”, PLoS One, 3;3:e3554 (2008).6. KM Ford, M Saint-Geniez, TE Walshe, PA D’Amore, “Expression and role of VEGF-A in the ciliary body”, Invest Ophthalmol Vis Sci., 53, 7520–7527 (2012).7. ASR Maharaj, TE Walshe, M Saint-Geniez, et al., “VEGF and TGF-β are required for the maintenance of the choroid plexus and ependyma”, J Exp Med., 205(2), 491–501 (2008).8. M Saint-Geniez, T Kurihara, E Sekiyama, et al., “An essential role for RPE- derived soluble VEGF in the maintenance of the choriocapillaris”, Proc Natl Acad Sci USA, 106, 18751–6 (2009).9. PJ Rosenfeld, H Shapiro, L Tuomi, et al., “Characteristics of patients losing vision after 2 years of monthly dosing in the phase III ranibizumab clinical trials”, Ophthalmology, 118, 523–530 (2011).10. L Branchini, C Regatieri, M Adhi, et al., “Effect of intravitreous anti-vascular endothelial growth factor therapy on choroidal thickness in neovascular age-related macular degeneration using spectral-domain optical coherence tomography”, JAMA Ophthalmol., 131, 693–694 (2013).11. M Martinez-de-la-Casa, A Ruiz-Calvo, F Saenz-Frances, et al., “Retinal nerve fiber layer thickness changes in patients with age-related macular degeneration treated with intravitreal ranibizumab.” Invest Ophthalmol Vis Sci., 53, 6214–621 (2012).

Figure 2. VEGF neutralization causes photoreceptor loss in mice. Mice expressing high level of soluble FLT1 (right) for four weeks showed significant thinning of the retina (yellow arrows), particularly of the outer nuclear layer (ONL, white arrows), compared to control mice (left). Bar is 50µm.

Control VEGF Neutralization

Feature 21

Figure 3. Cellular targets and potential side effects of anti-VEGF therapies in AMD. By blunting the neovascular process and reducing the retinal edema, anti-VEGF therapies are able to efficiently block disease progression and improve visual function of patients with wet AMD. However, anti-VEGF treatments are not specific to the pathological processes and may also neutralize physiological VEGF signaling on other retinal targets cells (ganglion cells, Müller cells, photoreceptors, retinal pigment epithelium and choriocapillaris endothelium). Long-term blockade of normal VEGF pathways may induce retinal cell dysfunction and/or death, leading to serious deleterious effects such as worsening of disease and visual loss.

Ganglion cell dysfunction/loss• Visualfieldchange• Opticnervedamage

Müller cell dysfunction/loss• Retinalswelling• Neuronalcelldeathandvisionloss

Photoreceptor cell loss• Visionloss

Retinal pigment epitheliumdysfunction/loss

• Geographicatrophy

NeovascularizationSubretinal edema

Choriocapillaris atrophy• Geographicatrophy

Cellular target of anti-VEGF therapies

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InPracticeSurgical Procedures

DiagnosisNew Drugs

28-29DMEK: Simplified, DeftlyDMEK that packs a punch, but doesn’t lay a finger (or forceps) on the corneal endothelial cells.

30-33Novel Refractive Procedures for KeratoconusIntracorneal ring segment and phakic IOL implantation for patients with keratoconus and high myopia.

24-27Ten Tips for Toric Lens ImplementationPractical pearls and possible pitfalls for the general cataract surgeon

DMEK Simplified, Deftly A novel method for preparation of Descemet membrane endothelial keratoplasty (DMEK) grafts is here. It uses a punch but doesn’t lay a finger (or forceps) on the corneal endothelial cells.

By Marc Muraine

The availability of corneal tissue, as with other organs for transplantation, relies on the goodwill of people to bequeath them for use after their death. Numbers are finite; this is a precious resource.

For a number of diseases, such as Fuchs’ dystrophy, bullous keratopathy (or the failure of previous penetrating keratoplasty), the current standard of care is endothelial keratoplasty, where the patient’s diseased corneal endothelium is replaced with an endothelial graft. Two major techniques for the preparation of such grafts have been developed: Descemet Stripping Automated Endothelial Keratoplasty (DSAEK) and Descemet Membrane Endothelial Keratoplasty (DMEK). Although DSAEK is relatively simple to perform, the transplant retains the stroma and

Descemet’s membrane, which can distort vision after implantation. DMEK utilizes only the endothelium from the donor cornea which, once grafted, reproducibly gives good visual outcomes. However, the preparation, manipulation and placement of a DMEK graft is particularly challenging to learn and perform.

I sometimes found it difficult to perform this surgery because of the risk of tearing the Descemet’s Membrane, when we have to hold the membrane with forceps. Furthermore, traditional DMEK is performed under balanced salt solution (BSS) – the “SCUBA” technique – which has one big problem: once the detachment has been performed, the graft always rolls up with the endothelium to the outside. That’s because every time you leave the tissue free in solution, it spontaneously does this. It makes placement of the graft within the anterior chamber much more difficult than if the endothelium was on the inside of the roll. It was clear to me that matters needed to be rethought.

Punch It OutThe first change that I made was to the circular trephination of the donor tissue. When I first started doing this dissection ten years ago, I did so by placing an air bubble in the stroma. This detached the tissue of interest from the endothelial-side components. Following this I performed circular trephination. I wanted to find the real plane between the Descemet’s membrane and the stroma, but it was difficult to obtain this planal dissection every time; the dissection was often within the stromal layers.

Sometimes when I performed this superficial trephination it wasn’t successful over the entire 360°. However, far from being an issue, this incomplete trephination led to improvements. In the area where trephination was unsuccessful, if I could detach the Descemet’s membrane from right to left

I had the plane of dissection outside the section; I could enter in the middle of the cornea very easily at this point. To do this deliberately, I simply broke the circular trephine’s blade over 30°. The technique was published in the American Journal of Ophthalmology in 2013 (1).

However, homemade broken blades aren’t ideal for use in corneal surgery. Sometimes it’s difficult to break the circular blade to obtain the 330° section of the Descemet’s membrane. And when you are using a broken blade you can’t press too hard, in case you perforate the lot. So I wondered if it was possible to design a punch, where the blade was missing over 30° and where there was a stop at around 300 µm, so that even if it was pressed hard on the top of the endothelium, it didn’t perforate the entire circle. That would reproducibly, section the Descemet’s membrane at 330° (Figure 1).

Sunny Side UpOnce punched, the donor cornea is placed endothelial side up in an artificial chamber, sealed, and the area that was punched is stained with Trypan blue (Figure 2). The graft is then protected by methylcellulose, and the Descemet’s membrane between trephination and limbus is peeled back with forceps, leaving an upside-down flap at the hinge (that is, the 30° region is not punched out). Manual dissection under the hinge flap is performed and is extended 1 mm into the graft area, initiating a delamination plane and permitting hydrodissection of the Descemet’s membrane until it is completely detached. This is a difference to the SCUBA approach. The dissection is not under BSS when we perform the separation of the Descemet’s membrane – at all times, it is in contact with the underlying stroma, which has implications later in the procedure. The hydrodissection has another advantage

At a Glance• DMEKcornealgraftdissectionand anterior chamber placement methods are hard to learn and difficult to perform • Asimplerprocess,fromdissectionto placement, is proposed • Visualoutcomesareequivalenttoother DMEK methods • Thistechniqueavoidstouchingthe endothelium during the dissection, which kills cells

In Pract ice24

Figure 1. The Muraine technique. (a) Place the punched donor cornea on the artificial chamber, inflate and close the valve to stabilize the chamber and reverse the cornea – the endothelium now faces upwards. (b) On both sides of the zone where Descemet’s membrane was not cut, the peripheral endothelium can be easily detached with a spatula or Troutman forceps to create a small, easily-lifted flap; (c) The jaws of a pair of Troutman forceps are slipped under the flap to ensure the correct detachment of the Descemet membrane over a length of 2-3 mm. (d) Hydrodissection with a 27 gauge cannula mounted on a syringe filled with balanced salt solution (BSS) detaches the endothelium. (e-f) The endothelial graft is folded over itself, with the endothelium towards the interior into a “burrito” shape, with the aid of the 27 gauge cannula. (g) The Descemet membrane graft, rolled up with the endothelium on the inside, is then placed into an IOL injection cartridge chamber.

In Pract ice 25

a b c

d e

f g h

In Pract ice26

Figure 2 (a). The Muraine Punch (Moria Surgical, Antony, France). (b) Close-up view.

a

b

In Pract ice 27

over the SCUBA technique; the surgeon is not peeling to separate the endothelium from the stroma at this point, reducing the risk of tearing.

After protecting the membrane with a small amount of methylcellulose, the surgeon uses a 27 gauge cannula to separate the entire Descemet’s membrane and then to lift the membrane and fold to the center – into a burrito-like shape, with the endothelium to the inside of the burrito. All that’s then left to do is fill an intraocular lens (IOL) cartridge with corneal storage medium, place the membrane burrito into the cartridge, insert the graft into the anterior chamber with the endothelium facing the iris – much like you would do with a DSAEK graft – and inject BSS to unfold the graft, centering the graft with an air bubble to maintain it in position.

This is the point where the approach to dissection pays off. When we unfold the roll, the endothelium is on the inside (Figure 3), because the section was not under BSS when the Descemet’s membrane is being separated. This means that it’s far easier to unfold the graft in the anterior chamber.

Avoiding Death GripsEvery time a surgeon touches the endothelium during the SCUBA technique, cells are lost. Using the dissection technique described above,

the surgeon works underneath the Descemet membrane, never touching the endothelium. Theoretically, at least, this approach spares cells, resulting in more robust grafts. I have not personally performed any comparative studies but an American team from the Lions VisionGift facility in Portland, OR, USA compared the SCUBA technique and my system, and they found a difference. I prefer that others have done it because I may have a personal interest in such questions.

Is Easier Better?This technique is easier than regular DMEK. Visual recovery is the same, because with both techniques, you only have Descemet’s membrane and endothelial cells. Surgeons who are proficient in SCUBA-technique DMEK can routinely and reproducibly achieve similar surgical success rates as are achieved with my technique. However, it can take a long time to get there; the SCUBA technique learning process with technique is strenuous.

I presented a paper at the European Society of Cataract and Refractive Surgeons meeting in Amsterdam in October 2013, reporting on when I asked two of my residents who had never performed DMEK or any similar dissection before to perform the corneal dissection using this new approach (2). I

sat beside them and explained step-by-step how to perform the procedure, and in 14 out of 16 cases they successfully isolated the graft on their first dissection. This clearly demonstrates that it’s easier to do it with this system.

One additional benefit of a simple, highly reproducible and easy-to-learn technique for DMEK graft preparation is that more ophthalmologists are likely to learn it. This increases the availability of a corneal graft procedure that provides excellent visual outcomes, but that has, to date, been limited to a small number of experienced surgeons. For those with corneal diseases like Fuchs’ dystrophy or bullous keratopathy, that’s great news.

Marc Muraine is Professor of Ophthalmology at CHU de Rouen, Hôpital Charles Nicolle, Rouen, France.

References1. M. Muraine, J. Gueudry, Z. He, S. Piselli, et al., “Novel technique for the preparation of corneal grafts for Descemet membrane endothelial keratoplasty”, Am J Ophthalmol, 156(5), 851–9 (2013).2. M. Muraine, D. Toubeau, J. Gueudry, S. Lefevre, “Simple novel surgical device to facilitate preparation of endothelial grafts for DMEK”. Free paper presentation, presented at the XXXI Congress of the European Society of Cataract & Refractive Surgeons, Amsterdam, October 8th, 2013.

Figure 3. (a) Insertion of the graft into the anterior chamber with the endothelium facing the iris. (b) Injection of BSS to unfold the graft. (c) Unfolded graft in situ.

a b c

In Pract ice28

Ten Tips for Toric Lens Implantation Practical pearls and possible pitfalls for the general cataract surgeon

By David Kent

Globally, cataracts are responsible for just over half of all cases of blindness and cause severe disability (1). In the US, more than half of all people aged 80 years or older will have a cataract (2) – and treatment costs in 2004 were estimated to be $6.8 billion (3).

Having said all that, today’s cataract surgery is normally straightforward to perform, and restores good vision almost immediately. Cataract surgery also provides an opportunity for surgeons to correct astigmatism at the same time as removing cataracts, by replacing the crystalline lens with a toric intraocular lens (IOL). However, for toric IOLs to work optimally, they require rotation to be on-axis with the patient’s astigmatism – even slight misalignments can have big impacts upon refractive outcomes (4).

Here’s what I do to ensure that my patients receive the best possible refractive outcomes after surgery.

David is a consultant ophthalmic surgeon & retina specialist, Aut Even Hospital, Kilkenny, Ireland & Barringtons Hospital, Limerick, Ireland, a researcher at the University of Liverpool, UK, and a visiting professor at Florida University.

Tip 3: Avoid AnesthesiaDo not instill local anesthetic into to the eye prior to performing

k readings. This disrupts the corneal epithelium and causes the cornea to dry out – a source of error in k readings. Don’t perform

applanation tonometry either, another potential source of k value errors. It is the quality of the tear film that ensures accuracy.

Tip 2: Variance Is A Red Flag

Beware marked differences in k values between a patient’s

eyes unless there is an obvious cause such as amblyopia or

corneal pathology. Repeat if necessary.

Tip 4: Get Your BearingsMark the three and nine o’clock positions of eye with a

fine tipped marker, with the patient sitting up to eliminate cyclotorsion.

Tip 1: X Marks The Axis On the operating table, mark the axis of alignment either before surgery or after removal of cataract and stabilization of the chamber. This is important if your view of the lens markings is impeded by pupillary constriction during the procedure or exuberant corneal hydration when sealing the section at the end of the procedure.

Tip 6: Read, And Read AgainTo ensure precision for lens calculation, obtain several readings.

Repeat on different days if measurements are variable; this is especially important in the presence of high degrees of corneal astigmatism.

Tip 5: Look To The LightMake sure the patient is looking at the operating microscope light to remove the effects of parallax.

Tip 7: Incisive IncisionsWhen making the corneal incision, ensure accurate placement in the normal corneal

meridian based on your audited results.

Tip 10: OVD: Out, Out, Out!To ensure complete removal of the ophthalmic viscosurgical device (OVD), drop the bottle and use a low vacuum when the tip of the irrigator/aspirator (I/A) is behind the IOL.

Tip 8: Soft Shell ShuffleIn the Arshinoff Soft Shell technique, you

partially fill the bag with OVD whilst completely filling the rest of the chamber prior to lens insertion. Fill the remainder of the bag with balanced salt solution (BSS) beneath the

OVD, then inject the IOL. With this technique virtually all the OVD is anterior to the IOL and removal is rapid and complete with I/A.

Tip 9: Successful CompletionFollowing removal of OVD ensure that the IOL is in the correct axis. Redial into correct position if

necessary. Next, ensure adequate chamber stabilization with stromal hydration of the corneal section. It is the combination of complete OVD removal and chamber

stabilization that ensures rotational stability of the IOL. Remember not to mask the lens markings with your stromal hydration when sealing the section. Finally,

inject intracameral cefuroxime via the paracentesis and make a final check that the lens is ‘on axis’.

References1. World Health Organization, “Prevention of Blindness and Visual Impairment: Priority Eye Diseases”. http:// www.who.int/blindness/causes/priority/en/index1. html; accessed December 16, 2013. 2. Prevent Blindness America/ National Eye Institute, “Vision Problems in the U.S.: Prevalence of Adult Vision Impairment and Age-Related Eye Disease in America” (2008). http://www.preventblindness.net/ site/DocServer/VPUS_2008_update.pdf; accessed December 16, 2013.3. Rein, P Zhang, KE Wirth et al., “The economic burden of major adult visual disorders in the United States.” Arch. Ophthalmol, 124(12), 1754-60 (2006).4. H Jin, IJ Limberger, A Ehmer, et al., "Impact of axis misalignment of toric intraocular lenses on refractive outcomes after cataract surgery", J Cataract Refract Surg. 2010, 36(12), 2061-72 (2010).

In Pract ice30

A Novel Refractive Procedure for Keratoconus Intracorneal ring segment and phakic IOL implantation: a refractive solution for patients with keratoconus and high myopia

By Francisco Sánchez León

The last decade has seen a seismic shift in the treatment of keratectasia and keratoconus. Where spectacles, contact lenses, and penetrating

keratoplasty for advanced keratectasia were the only treatment options available, today we have a variety of techniques at our disposal, including corneal crosslinking, intracorneal ring segments (ICRS), topography-guided photoablation, deep anterior lamellar keratoplasty (DALK), and phakic intraocular lenses/implantable collamer lens (pIOLs/ICL). Recently, I have started to combine two of these techniques, ICRS and ICL implantation. I have found that this creates a highly effective refractive intervention for the treatment of patients with keratoconus and high myopia.

The purpose of combining these procedures is twofold. One, the ICRS enables corneoplastic corneal remodeling: the surgeon remodels the

cornea to improve the appearance of corneal topography. And two, to reduce astigmatism – without using invasive procedures such as penetrating keratoplasty or lamellar transplants. I tend to use ICLs or pIOLs to manage the high spherical error of refraction that is present in many patients with keratoconus.

Deciding Which Procedure to UseThere’s a multitude of treatment options for keratoconus, and choosing the right one depends on any number of product and patient factors, and can be difficult. In my clinic, we follow a decision tree (Figure 1) to determine the best course of treatment. In patients with stable disease, no scars and an acceptable level of visual acuity (VA), we use contact lenses and

At a Glance• Adecadeago,keratectasiatreatment required heavy-duty surgery• Today,mostcasescanbetreatedwith corneal remodeling techniques in combination with refractive interventions• Thecombinationofintracornealring segments and phakic IOLs is a viable option for correcting corneal irregularities and large refractive errors in keratoconus patients • Thechoiceoftechnique(s)tousevaries by a number of patient factors and the surgeon’s experience

spectacles. In patients with very low VA and scars, DALK is our preferred mode of treatment, and we can perform both traditional DALK and femtosecond laser-assisted DALK. We favor the use of corneal crosslinking in patients with mild disease progression and acceptable VA. For those with progressive disease with low VA and irregular astigmatism – but without scarring in the central cornea – we use contact lenses, ICRS, pIOLs, and laser treatment, either individually or in combination.

I find that the combination of ICRS

implantation with a pIOL provides a reliable keratoconus treatment option, while simultaneously correcting large refractive errors. To do this, I first implant the ICRS to control the keratectasia and reduce the cylindrical error; six months later, once the refractive results of the eye have stabilized, I implant a pIOL or ICL to correct the spherical error. One advantage of this approach is that it can predictably correct large spherical and cylindrical errors. Furthermore, patient recovery is a relatively speedy six months, compared to the 18-month

recovery period that’s typically required after DALK surgery.

The efficacy of this sequential approach was illustrated by one of my patients who presented with pre-operative best corrected visual acuity (BCVA) of 20/50 and a refraction -8.00 sph -8.00 cyl × 45° in his left eye. I first implanted a 90° 300 µm ICRS and six months later implanted the pIOL. Six months after the second procedure, the patient’s refraction in that eye had improved to +1.00 sph -1.00 cyl × 50° and his BCVA was 20/40 (Figure 2).

In Pract ice 31

Figure 1. Keratoconus decision tree to determine the best course of treatment.

No Progression Acceptable VA

No scans

Contact Lenses Intracorneal ring segments Phakic intraocular lenses Femtosecond laser

Unacceptable VAScars

Mild progressionAcceptable VA

ProgressionUnacceptable VA

No ScarsIrregular astigmatism

CXL, corneal cross-linking; DALK, Deep anterior lamellar keratoplasty; VA, visual acuity

Although the same approaches used in eyes without ICRS can be used to calculate pIOL power after ICRS implantation, some special considerations are necessary in keratoconic eyes. We recommend that toric pIOLs are used in cases where the refractive and keratometric cylinders are in agreement and the axis of astigmatism from the refractive and keratoconus cylinders agree. In cases where the refractive and keratoconus cylinders diverge, we suggest treating only the high spherical myopic component of the refraction, hence we recommend that spherical IOLs are used. For any pIOL implantation, patients must have an anterior chamber depth of at least 3 mm and keratometry <55 D. If keratometry is >55 D, the IOL calculations become less predictable.

Clinical ExperienceTo determine the efficacy of this combination approach, I performed a study on the visual outcomes of keratoconus patients with large refractive errors who received the Keraring ICRS followed by implantation of the AcrySof CACHET anterior chamber pIOL. The patients included in the study had keratoconus, contact lens intolerance, clear corneas, maximum keratometry (K) reading <55.0 D, minimum K reading >40.0 D, and a minimum corneal thickness of 400 mm. All patients received the ICRS followed by an anterior chamber pIOL six months later. I implanted both the SI5 and SI6 Kerarings ICRSs in this study using the IntraLase femtosecond laser (Abbott LaboratoriesMedical Optics, USA) to create the tunnels for implantation. My rule of thumb with ICRS implantation is to have at least eighty percent corneal thickness

In Pract ice32

Figure 3. Keraring SI6 IntraLase iFS 150Hz parameters.

Inner Diameter 6.0 mm

Outer Diameter 6.8 mm

Ring energy: 1.5 μJEntry cut energy: 1.3 μJ

Depth in cornea 80% at 5.5 mm

Incision axis at steepest meridian

Entry cut length: 1 mm

Figure 2. Visual outcomes in one patient with sequential implantation of the Keraring followed by AcrySof CACHET.

Bioptic Procedures90° x 300 μm + AcrySof Cachet

Pre: BCVA -8.00 / -8.00 x 45°= 20/50Post BCVA +1.00 /1.00 x 50°= 20/40

Figure 4. Corneal topography of a patient who underwent ICRS implantation followed by pIOL implantation. Left panel pre-op, right panel post-op.

Pre BCVA 20/60 Post UCVA 20/30

at the site of implantation. In order to achieve better refractive results, I find it is necessary to make very tight tunnels. For the SI5, I use tunnels of inner diameter 4.8 mm and outer diameter 5.3 mm, whereas for the SI6, which is slightly larger, I use an inner diameter of 6.0 mm and an outer diameter of 6.8 mm and I make my incision on the steepest meridian (Figure 3). With the IntraLase, I manage to make precise tunnels within five to eight seconds.

This study included 10 patients. The average pre-operative mean sphere in the group was -12.10 D ±4.48 D, (range -6.00 D to -21.50 D). The mean cylinder was -4.90 D ± 1.68 (range -2.50 D to -7.50 D); and spherical equivalent was -14.54 ± 4.25 (range -9.00 D to -24.00 D). Six-months after the pIOL was implanted, and 12 months post-operatively, mean sphere,

cylinder, and spherical equivalent were 0.57 ± 0.91 D (range +2.00 D to -1.00 D), -1.23 ± 1.28 D (range -0.75 D to -2.50 D), and -0.15 ± 1.05 D (range +0.75 D to -2.25 D), respectively.

The improvement in refractive results also led to an increase in visual acuity. Shown in Figure 4 is an example of a patient who had pre-operative refraction of -20.50 sph -4.50 cyl x 35° and pre-operative corrected distance visual acuity of 20/60. After the two procedures, his refractive results improved to -0.50 sph -0.75 cyl x 10° and uncorrected distance visual acuity improved to 20/30.

The last decade has seen a vast improvement in techniques for the treatment of keratectasia. Whereas penetrating keratoplasty and DALK used to be the most commonly used techniques for the treatment of keratectasia 10 years ago, today,

these approaches are recommended only in advanced cases with central corneal scarring. The preference today is instead to remodel the diseased cornea using techniques such as corneal ICRS, crosslinking and thermokeratoplasty in combination with refractive procedures like pIOLs or customized photoablation. Indeed, the choice of modality used to treat any given patient will depend on a variety of factors, including patient parameters and surgeon’s experience. However, the combination of ICRS and pIOLs should be considered as a viable option for correcting corneal irregularity and large refractive errors in patients with keratoconus.

Francisco Sánchez León is the Medical and Scientific Director of the Novavisión Laser Center in Naucalpan de Juárez, Mexico

In Pract ice 33

NextGenResearch advances

Experimental treatmentsDrug/device pipelines

36-37Gene Therapy Clinical TrialsWe’ve seen gene therapy hitting the clinic, but not for eye disease – yet. How close are we?

38-40Integrin Blockade as a Retinovascular TherapyALG-1001 is a new drug with a new mode of action. What promise does it hold?

NextGen36

What ocular diseases?

What gene is being inserted?

Leber Hereditary Optic Neuropathy, 1

Stargardt Disease, 1

Choroideremia, 1

MERTK-associated retinal

disease, 1

Retinitis Pigmentosa/

Usher Syndrome, 1

Retinitis Pigmentosa, 1

Retinal degeneration, 1

Macular degeneration, 3

Leber Congenital Amaurosis, 7

MY07A, 1

ND4, 1

REP1, 1

sFLT01, 2

ABCR, 2

hMERTK, 1

hPEDF, 1

hRPE65v2, 3

hRPE65, 5

Who is funding these trials?

Academia 9Biotech 4

Academia/Biotech 1Academia/Government 1

Government 1 Pharma 1

Phase III 6%

Gene Therapy Clinical Trials The EMA approved the first gene therapy agent in 2012 – for lipoprotein lipase deficiency. Might gene therapies for ophthalmic disease reach the wards any time soon?

By Irv Arons and Mark Hillen

What phase are the trials at?

Phase I 47% Phase I/II 47%

Retinal degeneration

Macular degeneration

Stargardt disease

Leber Hereditary Optic Neuropathy

MERTK-associated retinal disease

Leber Congenital Amaurosis

Choroideremia

Retinitis Pigmentosa/ Usher Syndrome

Retinitis Pigmentosa

No safety problems have been reported in any the trials conducted to date and some of the more advanced studies have reported improvements in vision. But questions remain. Will gene therapy deliver a permanent cure or something less? What diseases can it treat? All of the currently ongoing trials are for posterior segment diseases – can anything be done for anterior segment disorders? And what will it cost per patient? Alipogene tiparvovec treatment may cost as much as $1.6 million per patient (4) but the extent of its worldwide market numbers in the hundreds – this is whole orders of magnitude smaller than potential market size of the ophthalmic diseases currently under investigation. What’s

interesting is that again, in general, Big Pharma aren’t funding the trials; it’s academic centers and biotech firms that are – and it’s likely that pharmaceutical companies will acquire or license the successful agents and market them; an expenditure they expect to recoup.

Whatever the eventual costs are, it looks like we may see the first gene therapies for ophthalmic diseases within the next 5–10 years. If these interventions are successful, that’s something to celebrate.

References1. European Medicines Agency, “EPAR summary for the public. Glybera (alipogene tiparvovec)”, October 25th, 2012. http://www.ema.europa. eu/docs/en_GB/document_library/EPAR_-_

Summary_for_the_public/human/002145/ WC500135474.pdf2. Human Stem Cells Institute Press Release, “HSCI receives approval to market Neovasculgen – the first Russian gene-therapy drug for treatment of peripheral arterial disease”, December 7th, 2011. http://eng. hsci.ru/news/press-relizy/hsci-receives- approval-to-market-neovasculgen-the-first- russian-gene-therapy-drug-for-treatment-of- peripheral-arterial-disease3. S Pearson, H Jia, K Kandachi, “China approves first gene therapy”, Nat Biotechnol., 22(1), 3-4 (2004).4. J Whalen, “Gene-Therapy Approval Marks Major Milestone”, Wall Street Journal, November 2nd, 2012. http://online.wsj.com/ news/articles/SB1000142405297020370760 4578095091940871524

Was blinding performed?

2014 2015 2016 2017

Trial primary completion dates

2026

Date passed; no data yet published

What age groups?C

hild

/Adu

lt 18

%

Adult/Senior 41%

Child/Adult/Senior 41%

Which vector is

being used?

Equi

ne in

fectio

us

anem

ia vir

us

76%

Sim

ianim

mun

odefi

cienc

yvir

us

6%Ade

no-a

ssoc

iate

d vi

rus

18%

Single-blind 1

Open-label 16

Integrin Blockade as a Retinovascular Therapy A new drug, ALG-1001, that blocks the transmembrane receptors that cells use to attach to their surroundings, has the potential to treat a range of retinovascular diseases

By David S. Boyer

The role of vascular endothelial growth factor (VEGF) in retinovascular diseases is well understood. VEGF inhibitors such as bevacizumab, ranibizumab and aflibercept have revolutionized treatment of these diseases over the past decade, but there remain many patients who don’t respond adequately to anti-VEGF therapy. The blockade of a different set of molecules, the integrins, may hold the key to resolving these therapeutic challenges. Integrins are surface receptors that regulate the interaction of cells with other surrounding cells and tissues. They

play important roles in cell adhesion, proliferation, shape and motility.

Allegro Ophthalmics’ ALG-1001 is the first drug of a new therapeutic class: integrin peptide therapy. The drug targets integrin receptors at multiple sites. Integrins αvβ3, αvβ5, and α5β1 have been shown in the literature over the past 20 years to be closely associated with both pre-retinal neovascularization (as seen in diabetic retinopathy and macular edema) and choroidal neovascularization (as seen in wet macular degeneration). ALG-1001 specifically inhibits these receptors’ effects on angiogenesis. For example, it can inhibit further growth of abnormal blood vessels, turn off production of new blood vessels, and cause leakage from existing neovascularization to dry up. Furthermore, ALG-1001 activity in binding the integrin α3β1 receptor sites at the vitreoretinal interface facilitates the release of cellular adhesion between the vitreous and the retina, inducing posterior vitreous detachment (PVD).

Integrin peptide therapy operates by a mechanism of action that is different from

that of anti-VEGF agents (Figure 1). If we imagine neovascularization as a factory that produces blood vessels, anti-VEGF drugs act as a signaling switch that tells the factory’s machinery to shut off. Inhibition of the integrin pathway is more akin to sabotaging various pieces of machinery – so that even if they are turned on, they can no longer function properly. All the machines downstream in the manufacturing process are starved of product to work on. So in the eye, integrins on the “bud” or leading edge of an existing blood vessel may be prevented from initiating the proteolytic changes that break down surrounding tissues and permit tissue penetration by the new blood vessel. Because of their different mechanisms of action, the integrin and VEGF pathways likely offer complementary – and potentially synergistic – approaches to tackle pathological angiogenesis in the retina.

Early and Mid-Phase Trial ResultsClinical trials of ALG-1001 are progressing in several therapy areas

At a Glance• Integrinsmediateretinal neovascularization and form part of the link between the vitreous and the retina• Integrinantagonismoffersan attractive new therapeutic target • Anintegrinantagonist,ALG-1001,is currently undergoing clinical evaluation for the treatment of wet AMD, DME and VMT• ALG-1001hasthepotentialto complement and/or replace current therapies

NextGen38

Figure 1. The differential effects of inhibiting VEGF and integrin.

where the compound has the potential to complement or replace current therapies, including wet age-related macular degeneration (AMD), diabetic macular edema (DME), and vitreomacular traction (VMT). What has been most encouraging in the initial results from these trials is that they have demonstrated a high degree of efficacy and a long duration of action.

Wet macular degenerationA high bar for treatment of wet AMD has been set by anti-VEGF drugs; in most cases, they work. However, one of the major challenges with current therapy is the frequency of injections required. They are unpopular with patients, and consume healthcare resources and the time of the patient. Additionally, a sizeable number of patients either do not gain functional vision following anti-VEGF therapy or respond initially but, over time, continue to develop fibrosis and an enlarging central vision defect. The questions for integrin therapy are:

• Willitworkatleastaswellas existing therapies?• Willthedurationofeffectbelonger

than current therapeutic options?• Canitimproveoutcomesinpatients

currently plateaued or unresponsive to existing therapies?

Allegro performed a phase Ib/IIa monotherapy study that was designed primarily to evaluate the safety and optimal dosage of ALG-1001. The drug was administered to twenty-two patients with wet AMD. Patients received three monthly injections of ALG-1001 (at doses of either 2.0 mg or 3.2 mg) in monotherapy after a six-week washout period from anti-VEGF therapy, and were then followed-up for four months, off-treatment. The higher dose provedmoreeffective,soa5.0mgdose,forwhich

data are still being collected, was added to the study.

The peak average improvement in best-correctedvisualacuity(BCVA)withthe3.2mgdosewas 5.2 letters (Figure 2).This was accompanied by a 30 percent mean improvement in central macular thicknessmeasuredonOCT.Thegainswere maintained throughout the four months of follow-up, and as long as six

months in some subjects, implying that there is a long-acting aspect to this drug which could reduce treatment burden.

Allegro have received clearance to commence a larger phase II wet AMD study, expected to begin this year. If this kind of efficacy is confirmed, integrin peptide therapy may be useful in combination with anti-VEGF therapy early in the treatment course, then as

NextGen 39

Figure2.PhaseIb/IIaWetAMDClinicalTrialefficacy:improvementinBCVA(ETDRSletters).

Figure3.PhaseIDMEClinicalTrialefficacy:improvementinBCVA(ETDRSletters).

quarterly-injection monotherapy for longer-term maintenance.

Diabetic macular edemaDiabetic retinopathy is a complex disease in which a number of pathogenic pathways are implicated. Despite the success of ranibizumab in the RIDE/RISE trials and aflibercept in the VIVID/VISTA-DME trials, it is reasonable to expect that a combination of therapies will ultimately prove to be most effective against this multifactorial disease.

Fifteen subjects with DME were enrolled in an initial safety (phase I) trial for ALG-1001. These were not straightforward, naïve-to-treatment cases. Rather, many were subjects with end-stage DME refractory to repeated anti-VEGF treatment. After a 90-day washout period, the 2.0 mg dose was given monthly by intravitreal injection for three months, followed by three months of (off-treatment) follow up. The safety profile was excellent, with no patients losing vision and no serious adverse events.

Slightly more than half the patients improved to functional visual acuity (20/40 to 20/60) in this monotherapy trial (Figure 3). As in the AMD study, there was a corresponding improvement in central macular thickness and the improvements were maintained for the duration of the study – which in this case included a three-month off-treatment period. A phase Ib/IIa DME trial in which subjects are treated with a combination of ALG-1001 and anti-VEGF agents in comparison to anti-VEGF alone is underway.

Vitreomacular tractionAn additional endpoint in the phase I DME study was posterior vitreous detachment (PVD), observed by video B-scan. Six of the 11 patients in that study who had no or partial PVD at baseline developed total PVD by day 90 (Figure 4). This is very encouraging and not altogether surprising, given that ALG-1001 is known to inhibit the integrin α3β1 receptors associated

with the attachment of the vitreous extracellular matrix to the retina.

Currently, ocriplasmin is available for the treatment of symptomatic vitreomacular adhesion but it does not usually create a full PVD, particularly in cases with larger areas of adhesion. It would be a boon to the retinal community if the success rate of medical therapy could be increased without any impact on safety; this could help more patients avoid the risk of surgical vitrectomy.

Investigators are currently enrolling 60 subjects in a phase II, double-masked, randomized, placebo-controlled study to evaluate the efficacy of ALG-1001 in resolving VMT. If all goes well, the company hopes to move quickly into phase III trials, as ALG-1001 for VMT may fill a significant unmet need and offer the shortest regulatory path of all the indications sought for this drug.

All of these trials are still in the early stages, but integrin peptide therapy has progressed from initial molecule discovery to phase II clinical trials rapidly and with encouraging results to date. If we continue to see good efficacy and duration of effect in the larger phase II and phase III studies, particularly with a dose-escalating response, I feel confident that ALG-1001 will have a significant place in our treatment armamentarium.

Dr. Boyer is co-founder of the Retina Vitreous Associates Medical Group, in Los Angeles, California and is a leading investigator for various national clinical trials on retinal diseases and an advisor for multiple research, educational and charitable institutions. Dr. Boyer is a member of Allegro’s Scientific Advisory Board and is an equity owner in Allegro. He also serves as a consultant to Genentech and Regeneron.

NextGen40

Figure 4. Posterior vitreous detachment in a subject enrolled in the phase I DME clinical trial for ALG-1001 who received the 2.0 mg dose.

Five x first prizes of flights,

accommodation and delegate fees for

AAO 2014

Sponsorship for these travel awards, including funding for travel, accommodation, and registration, is kindly provided by Alimera Sciences Limited.

More Details

Overleaf

Travel Award

Closes Soon

With Diabetic Macular Edema (DME) increasing in prevalence, a major question facing ophthalmologists today is how to manage insufficiently responsive, long-term cases. There are treatment options, but when should a patient be considered unresponsive? What diagnostic criteria provide useful categorization of the patient population? What readouts of responsiveness to therapy are most reliable?To help stimulate discussion of best practice within the community, The Ophthalmologist is organizing a competition for Case Study reports that address DME management. The five leading entries will be published as part of a feature in the print edition The Ophthalmologist, and the authors will be invited to attend the 2014 Annual Meeting of the American Academy of Ophthalmology, to be held in Chicago, October 18–21, as our guests. Flights, accommodation and delegate fees will be covered.The ten best submissions will be published online at: www.theophthalmologist.com.Case reports should include relevant positive and negative findings from history, examination and investigation, and should include clinical photographs.The closing date for submission is March 31, 2014. Full information on how to submit your entry can be found at www.theophthalmologist.com/travel-awardSubmit your Case Study today and help the ophthalmology community to identify and manage patients with DME.

Enter online at:theophthalmologist.com/travel-award

Sponsorship for these travel awards, including funding for travel, accommodation, and registration, is kindly provided by Alimera Sciences Limited.

Case Studies will be judged by a panel of experts based on:

Initial Diagnosis of DME• Howadequatelythepatient’sinitial DME was characterized• Whatcharacteristicschangedto warrant an intervention

Long-term Management of DME• Whatmanagementstrategieswere employed before and after the patient was diagnosed • Characterizationofthepatient’s response and subsequent lack of response to therapies

Progression of DME • Considerationsmade–and treatment strategies employed – in the management of patients who failed to sufficiently respond to current therapies• Criteriageneratedthatmightenable easier or better diagnoses of subsequent patients as being insufficiently responsive to current therapies• Recommendationsforaphysician treating a patient presenting with an identical case

Management of Side Effects• Cerebro-orcardiovascularsideeffects• Cataractextraction• Assessmentofpatientforsteroid- induced changes in intraocular pressure• Recommendationstoensure intravitreal steroids are used appropriately, safely and effectively

How do you identify & manage long standing refractory DME?Share your knowledge and win a trip to Chicago to attend AAO 2014

Travel Award

44-45 Re-engineering HealthcareJim Taylor offers a solution to the “perfect storm” enveloping healthcare today.

46-48 That’ll teach themSix strategies to stimulate resident learning.

ProfessionYour career

Your businessYour life

Profession44

Profession 45

Re-engineering Healthcare Change is hard – and major change even more so – in large part for one simple reason: as Leo Tolstoy once advised, “Everyone thinks of changing the world, but no one thinks of changing himself.”

By Jim Taylor

For all of us associated with healthcare, it should be apparent that our world is on the cusp of a significant change. I am not talking about the usual incremental shifts or isolated disruptions. I am referring to real and disruptive sea change that will continue for a decade or more. In fact, we are facing a perfect storm in global healthcare, and one that will impact clinicians, insurers, and industry… and ultimately the patients we all work to serve. The factors creating this storm are well recognized:

• Ademographicshifttorapidly aging populations in Europe, the US and parts of Asia• Theeconomicadvancementin

emerging economies in Asia and Latin America• Thegloballyintensefinancial

and budgetary pressures faced by seemingly indecisive or dysfunctional governments• Ashortageoftrainedclinicians

across virtually all disciplines• Theavailabilityandcostsassociated

with ongoing advances in medical technology

Ironically, we now have far more

capability to prevent or attack disease than ever before, but we will have far fewer resources per capita to employ those technologies or to develop others.

It will not be possible to survive this storm by simply working harder or trying to do more with less. Those approaches are doomed to fail. Already we can see the stress cracks forming, as government-provided resources are slashed, as centralized planning and control methods falter under their own weight, as the impending shortage of trained clinicians becomes apparent, and as patient needs and demands escalate.

Fortunately, there are methods for dealing with such crises; approaches that have evolved across organizations facing tectonic shifts of their own. These methods, labeled “business process engineering” or simply “re-engineering”, focus first on defining the desired outcomes while recognizing and accepting the external realities and constraints. Their aim is not to reduce costs or cut headcount (that wonderfully benign phrase for terminating real people’s employment). The focus is on taking positive action rather than allowing natural forces to dictate outcomes. One proponent, Minder Chen, has described re-engineering as “The fundamental rethinking and radical redesign of core processes to achieve dramatic improvements in critical performance measures such as quality, cost and cycle time.” The key elements of re-engineering are to:

• Organizearoundoutcomes• Engagethepeopledoing

the work to identify key processes and priorities• Integrateinformationprocessing

work into the real work

• Treatdispersedresourcesasthough they were centralized• Linkparallelactivities• Putdecisionpointswherethework

is performed• Captureinformationonceandat

the source

This approach is ideally suited to the challenges faced across healthcare. I previously initiated the complete re-engineering of a 100 year old company with legacy processes and IT systems, proud and skilled employees, and in a highly regulated field associated with life support technologies. The prospects for disruptive change seemed somewhere between impossible and delusional, but there was no alternative. Three years later, the goals had all been substantially exceeded by teams of employees who started first with skepticism; morphed into caution and hope; and eventually became passionate owners of the new reality that they themselves had created. The process works, and there is simply no other approach to successfully react when the ground we have long stood upon has rapidly shifted under our feet; and with new realities that are no longer consistent with the “ways we have always done things.”

We face harsh realities and what might appear to be insurmountable obstacles in the years ahead, but this is the perfect opportunity for meaningful and disruptive change, with improved patient outcomes as our unifying cause. How do we get there? To quote St Francis of Assisi, we must “Start by doing what is necessary, then what is possible, and suddenly you are doing the impossible.”

Jim Taylor is CEO of Oraya Therapeutics, Newark, CA, USA.

Profession46

Six Strategies to Stimulate Resident LearningAcademic ophthalmologists are expected to be effective teachers but receive little or no instruction on teaching methodology. Our goal should not be to teach; rather, for the student to learn what is needed. These tips will improve your effectiveness.

By Karl C. Golnik

1. Apply “Adult Learning Principles” The most important principles to keep in mind when teaching residents are summarized in four principles: relevance, goals, active involvement and respect. These principles form the basis for the other five strategies.

Adults must believe what they are being taught is relevant to their immediate future. If they do not, they simply will “turn off ” and not learn the material.

The resident must believe that the learning will lead to some goal, perhaps passing their board examination or becoming a competent surgeon. Sometimes you should reinforce the relevance of the material and exactly what goal will be achieved.

Adults must be actively involved in their learning. A straight lecture with passive participants results in poor learning retention. Lectures can be designed for improved effectiveness and alternatives to faculty lectures should be encouraged. These could

include residents giving the lectures themselves, case studies with group discussion, case studies with online discussion (as simple as email!), literature searches, etc.

Finally, adults should be treated with respect. I call this the “positive learning environment”. You should encourage active discussion and questioning to enhance learning. Teaching activities should be positive, motivating and aimed at increasing confidence, never punitive or intimidating. A poor learning environment inhibits effective learning.

2. Perform a “Needs Assessment”All too often, we assume what a resident knows based on their post-graduate year of training or progress through the training program. It is important to ascertain where the resident is in mastery of the material. A “needs assessment” determines the level of knowledge or skill an individual resident possesses. This may be achieved by simply asking several questions, observing skill during a procedure or reviewing past evaluations.

The needs assessment will help you teach at a level appropriate to the learner. If you teach at too low a level, the material will not be relevant and is a waste of time; if you teach at a too advanced a level, the resident may have difficulty with the concepts or skills, and learning will be adversely affected. Performing and acting upon a needs assessment will ensure that the material is relevant.

3. Provide “Goals and Objectives”Adults need to feel that their learning leads to a goal, so you shouldn’t keep this goal a secret! Tell the learner from the outset what you expect, whether you are lecturing or teaching in clinic

or operating room. The goal of the teaching intervention can be thought of as the big picture of desired learning.

Objectives are more discreet, measurable items that can be considered the goal’s building blocks. If you achieve the objectives, the goal will be met. For example, prior to a clinic teaching session, I might tell a first year resident, “Today, I want to be sure that you are able to detect a relative afferent pupillary defect and describe its significance.” This is the goal of the teaching intervention. To reach this goal, objectives might be that resident should be able to:

1. Recite the anatomy of the

pupillary light reflex2. Perform a swinging flashlight test3. Identify a relative afferent

pupillary defect in at least three patients.

By providing these simple goals and objectives you establish a framework for learning and testing. The resident will have a clear understanding of what you deem to be important.

4. Improve Lecture EffectivenessThe formal lecture is still widely used to impart information to residents. Unfortunately, learning retention is very poor when students passively listen.

You should be providing goals and objectives at the beginning of every lecture to orient the student and let them know what they should be getting from it. Ideally, you should also get the audience thinking and involved, perhaps by using a case study, pre-test, or by asking a stimulating question. These approaches orient and engage the audience.

The difficult part is maintaining attention in the body of the lecture –

Profession 47

adults lose attention after just 10 minutes of passive listening. This is where interactivity should play a role. Frequent questioning of the audience, using case studies, brainstorming, varying audiovisual aids and emphasizing relevance will help keep the audience attentive and participating.

To wrap up the lecture, be sure to have a conclusion that summarizes the key points. Post-testing is also valuable as both you and the students will see that learning has occurred (hopefully!).

5. Give Good FeedbackFeedback may be formative or summative. Formative feedback can be thought of as behavior modification – you are trying to change bad habits and reinforce good behavior. Another word for formative feedback is teaching! Summative feedback is the grade on a test or whether one has passed or failed a rotation.

From a teaching standpoint, formative behavior is crucial for improving knowledge and skill. Good formative feedback should be timely: if your dog pees on the rug, you don’t scold your dog a week later – you do it right away or the dog doesn’t know why they are being scolded! It should also be frequent, specific (hopefully based on first-hand data) and should be designed to improve performance. Terms such as “good case” or “you are not doing right” are not helpful as the resident doesn’t know what was good or how to “do it” right. Be specific about what exactly was good about how the case was done. Tell the resident exactly how to do it right.

Good feedback should point the resident in the right direction and improve performance. Remember that feedback should be used not only to help the struggling resident improve

but to make a good resident great. You should use formative feedback every day!

6. Use a RubricI define a rubric as an explicit set of criteria used to assess a particular skill. This provides you with a tool that can help you to give timely, specific, structured feedback. Rubrics can be used to assess virtually any skill including piano playing, lecturing, and surgical procedures.

Good rubrics consist of three parts: dimensions, for example, steps of a surgical procedure; levels, for example, scores of 1 through 5, or novice to expert; and descriptors, that is, what it means to perform at a certain level for any of the dimensions. Valid and (sometimes) reliable rubrics have already been published for ophthalmic patient examination (1,2), phacoemulsification (3,4), small incision cataract surgery (5), strabismus surgery (6) and the lateral tarsal strip procedure(7).

Rubrics should be given to the resident in advance so that they serve as both a teaching and assessing tool. The resident can read the rubric in advance to learn what is required to be competent in various stages of the procedure. The rubrics should be completed by you immediately after the case and then reviewed with the resident to provide that structured, timely and specific formative feedback described above. Additionally, the rubric allows you to more objectively assess the resident’s performance, allowing areas of deficiency to be identified and remediated.

In summary, we should always strive to improve our teaching effectiveness, with the goal of stimulating resident learning. Utilize adult learning principles in your teaching and try

using some of the strategies described. Good Luck!

Karl C. Golnik is Director for Education of the International Council of Ophthalmology and Professor, Department of Ophthalmology, University of Cincinnati and the Cincinnati Eye Institute, OH, USA.

References1. K Golnik, L Goldenhar, J Lustbader, J Gittinger, “The Ophthalmic Clinical Evaluation Exercise (OCEX)”, Ophthalmology, 111, 1271–1274 (2004).2. KC Golnik, L Goldenhar, “The Ophthalmic Clinical Evaluation Exercise (OCEX): Interrater reliability determination”, Ophthalmology, 112, 1649–54 (2005).3. KC Golnik, H Beaver, V Gauba, et al., “Cataract Surgical Skill Assessment”, Ophthalmology, 118, 427, e1–5 (2011). 4. KC Golnik, H Beaver, V Gauba, et al., “Development of a new valid, reliable, and internationally applicable assessment tool of residents’ competence in ophthalmic surgery”, Trans Am Ophthalmol., 111, 24–33 (2013).5. KC Golnik, A Haripriya, H Beaver, et al., “Cataract Surgical Skill Assessment”, Ophthalmology, 118, 2094.,e2 (2011). 6. K Golnik, WW Motley, H Atilla, et al., “The ophthalmology surgical competency rubric for strabismus surgery”, JAAPOS, 16, 318–321 (2012).7. KC Golnik, V Gauba, GM Saleh, et al., “The Ophthalmology Surgical Competency Assessment Rubric for Lateral Tarsal Strip Surgery,” Ophthal Plast Reconstr Surg., 28, 350–354 (2012).

Profession48

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Sitting Down With Carrie MacEwen, Consultant Ophthalmologist at Ninewells Hospital, Dundee, Scotland, and President-Elect of the UK Royal College of Ophthalmologists

Right place, right time

What is your vision for the Royal College of Ophthalmologists under your Presidency?One of my main objectives is to engage with the College members fully in order to maximize their varied skills and expertise for the benefit of ophthalmology and to encourage as much participation as possible. I’d also like to improve the understanding of what the College does and does not do. It is really busy with day-to-day work that ensures that the standards within ophthalmology are maintained, through training, assessment and professional standards revalidation.

As far as vision is concerned, it is important that we continue to promote the value of the ophthalmologist within healthcare. There’s a risk that people look at the cost of things, but don’t actually look at the value. Ophthalmologists are well-trained professionals, who can make decisions and are good value. Maybe they cost a bit more than other individuals in certain settings, but at the end of the day, it does translate into better overall performance for the patient. We have to keep ensuring that people are aware of who we are, what we do, and that we do it very well and efficiently.

How hard is it convincing health care managers that paying for the experience of ophthalmologists gives best value?It’s difficult. And of course we need and want to work with optometrists, orthoptists and ophthalmic nurses to make sure that together we provide a package that is appropriate for individual patient care, rather than trying to hive everything off into individual silos, which is not going to work well. Teamwork is the key, with clear pathways and communication.

Your predecessor, Harminder Dua, said

that UK-based ophthalmologists have such a heavy workload that it’s hard for them to find the time to do their continual professional development. Is that something that the College can help with?Well it is a concern that we’re all working so hard just to stand still. In isolation, it’s difficult to make a change, but we are working through the Academy of Colleges and we all stand together: all registrars require to be trained, and in order to do that properly, it takes time.

Consultants’ job plans must reflect this too. We must get rid of this 1SPA (Supporting Professional Activities) situation – the so-called 9-in-1 contract. There must be adequate SPA time, for people to not only do their continuing professional development, but also to train people. If we can stick together across specialties and emphasize the importance of this aspect of our work, hopefully people might begin to pay attention.

You’ve had some additional interesting roles, including serving as the Rugby World Cup’s ophthalmologist. How did that come about?Well, I’ve always been interested in sports medicine, and I’ve published in that area – mainly on eye injuries.

When the Faculty of Sport and Exercise Medicine was being created, the Royal College of Ophthalmologists was asked to nominate a representative on their council, and that, fortunately, was me. So when they needed an ophthalmologist for the World Cup, lo and behold, they got me. Sitting in the stadium next to the All Blacks: wonderful!

You are also a founder member of the British Ophthalmological Surveillance Unit. What impact has it had?It’s an extremely powerful tool that picks up a lot of detail about rare conditions and how they are managed, with a robustness that just can’t be obtained any other way. Miles Stanford, Professor of Clinical Ophthalmology and Guys and St Thomas’ Hospital in London set it up; I just happened to be called in as I had done quite a lot of epidemiology, and they needed somebody from Scotland. It’s also a good way of training junior doctors in aspects of medical research; it educates them in ethics regarding questionnaires, for example.

So can you give us a snapshot of your average working day?I’m at work by about eight o’clock. I do some admin and e-mails; see any inpatients on the ward; maybe I’ll do some teaching; see pre-ops or laser patients, then do a clinic. The clinics are usually fairly lengthy and very oversubscribed. I’ll get home at about seven o’clock hopefully and do some research or admin once I’ve had a couple of hours of relaxation with my husband and children, if they’re at home.

How would you characterize your management style?It’s working with people, allowing them to take on responsibility to a level they’re comfortable with, and being prepared to support them all the way down the line.

Sitt ing Down With 51

“As far as vision is concerned, it is important that we continue to promote the value of the ophthalmologist within healthcare.”

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