Turning Back Time Kang Zhang Describes How His Group Are Battling Age-Related Eye Disease by Swapping Cell Fate

MAY 2018 # 21

Upfront In Practice NextGen Profession VA gains in dry AMD Corneal stigmatism: Should we embrace the How to approach surgery with a RPE patch Taming the irregulars exosome over stem cells? in your early career stages

11 28 – 33 39 – 41 47 – 49

Turning Back Time Kang Zhang describes how his group are battling age-related eye disease by swapping cell fate – and reversing senescence. 18 – 25

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Retinal Bloom This image by David Gamm shows a retina organoid, which mimics the structure and function of the human retina, allowing it to serve both as a platform for the study of disease mechanisms and new therapeutics, but also as a source of cells for transplantation. Gamm’s group uses a variety of stem and progenitor cells in their research to study retinogenesis and retinal degenerative diseases. In September 2017, Gamm and his group’s work was recognized by the National Eye Institute (NEI) as part of their 3-D Retina Organoid Challenge (3-D ROC) with an honorable mention. Credit: David Gamm, Associate Professor of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA. Do you have an image you’d like to see featured in The Ophthalmologist? Contact [email protected]

www.theophthalmologist.com ContentsCoC nttene tst

12 In My View

16 No Smoke Without Fire

03 Image of the Month Upfront 17 Riding the Sea Change

10 Change the Channel, Please! 09 Editorial That’s Life, by Mark Hillen. 11 The Regeneration Game Features

12 When I’m Cleaning Windows 18 Turning back Time The genetic toolbox enables us to 13 Now You See Them, Now do more than correct one gene On ThThee Co Coverver You Don’t at a time. Kang Zhang asks: why not sidestep disease, by

MAY 2018 # 21

Upfront In Practice NextGen Profession What’s the best way 14 Benchmarking the Power List genetically reprogramming cell VA gains in dry AMD Corneal stigmatism: Should we embrace the How to approach surgery with a RPE patch Taming the irregulars exosome over stem cells? in your early career stages

13 15 – 16 42 – 45 48 – 49

Turning Back Time Kang Zhang describes how his group are battling age-related eye disease by swapping cell fate – and reversing senescence. of representing turning 18 – 27 fate, or even better, turning back time back? the clock on senescent cells in

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Editor - Mark Hillen [email protected] Managing Editor - Ruth Steer [email protected] Content Director - Rich Whitworth 36 [email protected] Publishing Director - Neil Hanley [email protected] VP Sales North America - Molly Phillips [email protected] Sales Manager - Abigail Mackrill [email protected] Head of Design - Marc Bird [email protected] Designer - Hannah Ennis [email protected] Digital Team Lead - David Roberts [email protected] Digital Producer Web/Email - Peter Bartley 44 [email protected] Digital Producer Web/App - Abygail Bradley [email protected] 6.6 Audience Insight Manager - Tracey Nicholls 6.0 [email protected] Traff ic & Audience Database Coordinator - Hayley Atiz 5.6 [email protected] 5.0 Traffic & Audience Associate- Lindsey Vickers [email protected] 4.6 Traffic Manager Jody- Fryett 4.0 [email protected] Traffic Assistant Dan- Marr [email protected] 50 Events Manager - Alice Daniels-Wright [email protected] Marketing Manager - Katy Pearson [email protected] Financial Controller - Phil Dale [email protected] Accounts Assistant - Kerri Benson Profession [email protected] In Practice Vice President (North America) - Fedra Pavlou 44 A Question of Capacity [email protected] Chief Executive Officer - Andy Davies 28 Not the Usual Suspects Marty Spencer writes about [email protected] Sheraz Daya shares the secret to how the Seva Foundation is Chief Operating Officer - Tracey Peers [email protected] managing irregular astigmatism: going about adding another Change of address identifying the problem and million sight-saving surgeries in [email protected] tackling it at its source.. developing countries – per year – The Ophthalmologist, Texere Publishing, 125 Varick St, New York, NY 10014. Periodical by 2020. Postage Paid at New York NY and additional mailing offices.

General enquiries 47 How to Approach Surgery in www.texerepublishing.com NextGen Your Early Career [email protected] +44 (0) 1565 745 200 Bobeck S. Modjtahedi and [email protected] 36 Great Minds Look Ahead Eduardo Uchiyama give their Distribution The 2018 Power Listers offer a ten tips for being a better retina The Ophthalmologist North America (ISSN 2398-9270) is published monthly by glimpse of ophthalmology’s future surgeon after you’ve completed Texere Publishing, 125 Varick St, New York, NY 10014. Periodical Postage Paid at New York, NY your fellowship. and additional mailing offices. POSTMASTER: Send address changes to 39 Enter the Exosome Texere Publishing ,125 Varick St, Exosomes are simpler to produce New York, NY 10014 Single copy sales $15 (plus postage, cost available and far easier to administer on request [email protected]) Non-qualified annual subscription cost is than stem cells. Since exosomes Sitting Down With available on request

are all of the “good stuff” stem Reprints & Permissions – [email protected] The opinions presented within this publication are those of the authors cells secrete… Ben Mead asks: 50 Keith Barton, Consultant and do not reflect the opinions of The Ophthalmologist or its publishers, Texere Publishing. Authors are required to disclose any relevant financial are exosomes the answer to our Ophthalmologist, Moorfields arrangements, which are presented at the end of each article, where relevant. © 2018 Texere Publishing Limited. All rights reserved. retinal regeneration needs? Eye Hospital, London, UK. Reproduction in whole or in parts is prohibited. STRIVE TO SEE THE BEST RESULTS POSSIBLE Regular fixed-interval dosing of long-term treatment with anti-VEGFs has been shown to provide better gains and maintenance of vision, compared to PRN or treat-and-extend dosing regimens, in some patients with Wet AMD and DME.1-6

Ask your Regeneron representative what we can do to help ensure patients come in for their scheduled treatment. anti-VEGF = anti–vascular endothelial growth factor; AMD = Age-related Macular Degeneration; DME = Diabetic Macular Edema. References: 1. Heier JS et al. Ophthalmology. 2016;123(11):2376-2385. 2. Rosenfeld PJ et al. N Engl J Med. 2006;355(14):1419-1431. 3. Ho AC et al. Ophthalmology. 2014;121(11):2181-2192. 4. Nguyen QD et al. Ophthalmology. 2012;119(4):789-801. 5. Kaiser PK et al. Ophthalmol Retina. 2017;1(4):304-313. 6. Peden MC et al. Ophthalmology. 2015;122(4):803-808. © 2018, Regeneron Pharmaceuticals, Inc. All rights reserved. 777 Old Saw Mill River Road, Tarrytown, NY 10591 01/2018 US-OPH-13911 That’s Life There will always be people who are left behind Editorial by MedTech advances.

71-year-old white male patient presents with myasthenia gravis (MG), diagnosed from his initial presentation 12 months previously with unilateral ptosis, and Aconfirmed by physical examination and specific antibody testing. Patient commenced neostigmine therapy, but discontinued thanks to an adverse cutaneous reaction to the first dose. He presents today with diplopia, which on examination, is caused by incomitant strabismus in his left, non-dominant eye. For the moment, let’s put to the side the systemic consequences of the MG worsening and the potential treatment options going forward for now. What does it mean for him? If you’re wondering why I’m presenting this case, it’s because the patient is my father. His care from NHS Scotland has been great, but the fact is that he is experiencing first-hand the hard realities of the onset of vision loss. He’s fortunate (enough) for now to be able to drive. As it progresses, he’ll probably be able to drive with a patch over one eye. But this is unlikely to be a permanent solution. He’s very lucky that my mother (who was always a better driver than him!) is able to transport him to cafés, choir, church and the clinic, and he can visit most of his grandchildren with relative ease. And so, his social life remains the same – for now. His life is still pretty normal – but it’s getting harder for him. Let’s assume two things. His MG and vision deteriorate further to the point that his driving license is surrendered, and my mother is needed elsewhere. We’re not at the stage of having Waymo or Uber Level 5 self- driving taxis, so that “co-dependent independence” is gone. Yes, there are taxis, but the cost of those – especially to retirees, quickly adds up. If medical (and potentially surgical – thymectomy) management fails to arrest the rate of his decline, then he’ll be totally reliant on family, mostly my mother, to help him through each day. His healthcare resource use will rise greatly (and it’ll burn my mother out quite quickly too). If, eventually, the systemic symptoms catch up with him, then I know his local hospital staff will do the very best they can for him, until nothing more can be done. Perhaps I have a tendency to put my head in the clouds a little too much – evangelizing about the greatness of technology that’s just coming over the horizon. Sometimes technology can make a huge difference to people’s lives; self-driving cars might help my Dad for a while when they eventually arrive – and I believe they’ll make a huge difference to the visually impaired (and society in general) once they’re established. But sometimes, there’s nothing that can be done, and nothing on the horizon that might bring hope to cling to either. It’s just personal tragedy and societal burden. The saddest thing is, as you healthcare professionals know, it’s also nothing special.

Mark Hillen Editor

www.theophthalmologist.com 10 Upfront

AccordingAccording to Johnstone, the speed Changee tthehe at which the collector channels canca Upfront respond to pressure changes frfrom Channel, PPlease!lease! 0–30 mmHg is “remarkably ffast”a – in Reporting on the the region of 150 ms – andand theret was a innovations in medicine A new OCT-based methodthod letslets “marked synchrony” bbetweenet collector you see aqueous movementment channelschannels and SchleSchlemm’sm canal in non- and surgery, the research in collector channels. Whatat glaucomatousglaucomatous eeyesyes – but in glaucomatous policies and personalities does this mean for glaucomama eyes, this relationshiprel is lost, and that shape the practice specialists – and patients? aqueous momovement is far slower. And of ophthalmology. thethe tetechniquech comes with an additional As a glaucoma surgeon,rgeon, imaimaginegine iiff advantage:advantadvad age: it should be ablable to flag those you could visualize aqueousaqueous outflow in patientspatients with very advancadvancede disease who WWee wwelcome suggestions the trabecular meshworkhwork (TM) with areare unsuitable for Schlemm’sSchle canal- on anythinganyt that’s something like OCT?T? Such information basedbased procedures;procedures; not ononlyly could it spare impactimpactfulful on would help guide yyourour choicechoice patientspatients ffromrom a procedure of procedure, devicece (and thatthat cannot bbenefit them, ophthalmoophthalmology;log placement of the ddevice),evice), butbut it wouwouldld also have the ppleaselease email eedit@d and increase your confidencenfidence addedadded bbenefitenefit of increasing theophthalmolotheophthalmologist.comgi in getting a goodd postpost-- thethe efficacyefficacy o of the MIGS procedural outcome.me. Of proceduresprocedures in those patients course, such a devicee wouldwould whowho can recereceive them. have research applicationsications WhatWhat mmightig the future too, generating greatt insighinsightt bbring?ring? IntIntra-operativer into the pathologies ppresentresent cannulationcannulation combinedc with in many forms of glaucoma,aucoma, OCT-based visualization potentially yieldingng new ofof the trabeculartrabecu meshwork knowledgek about the disease andand collectorcollector channels – thattha could result in earlierearlier – oror even an eentirely non- andannd smarter – interventions.entions. invasive aapproachpp when AtA the recent 2018 thethe technolotechnology is mature AmericanAmer Glaucoma SocietSocietyy enough:enough: pphase-basedhase OCT meeting,meeting Murray Johnston,hnston, toto iidentifydentify aareas of poor a ClinicalClinic Professor atat thethe motion in ScSchlemm’sh canal, UniversityUniversity of Washingtonington occlusionsocclusions iin ostia, and in Seattle ppresented on jusjustt similarsimilar pathology.patho It looks thatthat (1): a ppilot studydy of a likelike it’sit’s onlyonly a matter of time “very“very high rresolution”eso ” OCOCT-T- beforebefore ophthalmicophtha surgeons basedbased imagingimaging methodhod thathatt startstart usingusing this technology to could – in ex vivivov humanuman eyeseyes provideprovide individualizedindividu care for withwith cannulated SSchlemm’semm’s canacanalsls patientspatients witwithh glaucoma.glauc – detect motion in tthehe TM, the dynamic collectorcollector channel enentrancentrance (CCE), and ReferenceReference deepdeep intrascleral collectorcoollectorol channels. 1. M Johnstone et al, “PA03:“PA03: CollectorCol Channel The metethodmethod cocoulduldld also show h CCECCE EntrancesEDillCl Dynamically Close & Open in closure orr ddisruptionisi by MIGS devices Humans as Imaged by OCT: Consideration or approacaapproaches,p hes which could affect in MIGS Selection and Placement?”, AGS distald resistanceresista and, ultimately, the 2018 Annual Meeting, New York City, success of the procedure. March 1st, 2018. Upfront 11

The Regeneration a. Game

Could a successful treatment for dry AMD be on the horizon?

March 2018: the news broke that two patients with severe wet AMD gained vision following implantation of a retinal pigment epithelium (RPE) patch derived from human embryonic stem cells (hESCs) (1). April 2018: a collaborative team from USC Roski Eye Institute and other b. institutions in California, USA, publish Phase I clinical study results showing safety and functionality of their bioengineered RPE implant in patients with advanced dry AMD (2). “So many people suffer severe vision loss due to advanced dry AMD; it is estimated that almost 3 million people in the US will suffer from the condition by 2020,” says Amir Kashani, lead author on the associated paper (2). As no treatment currently exists, the group were inspired to develop an approach to treat geographic atrophy (GA) – one of the main causes of vision loss in dry AMD. Their implant, Figure 1. Scanning electron microscope image of hESC-derived RPE (a) and image of the named the California Project to Cure CPCB-RPE1 implant (b). The implant is comprised of a polarized monolayer of RPE on an Blindness-Retinal Pigment Epithelium ultrathin Parylene substrate that is designed to mimic Bruch’s membrane. Credit: USC Roski Eye 1 (CPCB-RPE1), comprises a polarized Institute (a) and Britney O Pennington (b). monolayer of hESC-derived RPE on a Parylene substrate (Figure 1). After medical need – the treatment of generation of AMD treatments be on subretinal implantation into the area of advanced dry AMD. “To be able to the horizon? GA in four patients, CPCB-RPE1 showed prevent or reverse vision loss in this a stable integration with overlying retinal population would have a major public References tissue, and there were no reported safety health benefit and improve the lives of 1. L da Cruz et al., “Phase 1 clinical study of an concerns (mean follow-up, 260 days). Three millions,” he says. What’s next? “These embryonic stem cell–derived retinal pigment of the four patients maintained vision results are very encouraging and we plan epithelium patch in age-related macular throughout follow-up, with one patient to finish enrollment of about 20 patients degeneration”, Nature Biotechnology, 36, 328–337 sustaining a gain of 17 letter gains to fully demonstrate the safety of the (2018). PMID: 29553577. from day 60, and two patients showing implant, as well as better understand its 2. AH Kashani et al., “A bioengineered retinal improved fixation. potential efficacy,” says Kashani. “This pigment epithelial monolayer for advanced, dry Kashani says their work has the will help us plan for the next trial in a age-related macular degeneration”, Sci Transl potential to address a major unmet larger cohort of patients.” Could a new Med, 10 (2018). PMID: 29618560.

www.theophthalmologist.com 12 Upfront

When I’m Cleaning Windows

Kinoshita’s CEC+ROCK approach to treating corneal endothelial cell dystrophies enters the clinic

If you view the cornea as a window, then you might consider corneal endothelial cells (CECs) as the window cleaner. A single layer that resides at the bottom of the cornea, they keep the cornea clear by transporting fluid and regulating corneal with pseudophakic bullous keratopathy, It’s a small study; more clinical hydration. In a healthy cornea, there are aged between 20 and 90 years, with no validation will be required before this about 2,000 CECs per square millimeter; detectable CECs, a corneal thickness approach can be used routinely (if at in corneal dystrophies, that number starts > 630 μm and a BCVA of 20/40 or worse all). But as Reza Dana noted in his to drop. The CECs respond by spreading received the treatment (4). The primary accompanying editorial in the New out to compensate, but by the time the outcome was, at 24-weeks, a restoration England Journal of Medicine (5), CEC count drops to 400 CECs/mm2, of CEC density to > 500 cells/mm2. At 24 “This study provides clinical proof of they’re overwhelmed. The cornea swells weeks, 11 out of 11 patients achieved this concept regarding the use of cultivated and becomes opaque. – with cell densities ranging from 947 to endothelial cells in the treatment of Shigeru Kinoshita and his research 2833 cells/mm2. The lack of CECs causes corneal endothelial cell dysfunction.” group in Kyoto, Japan, are well known for swelling and opacification; replenishing developing, pre-clinically, a novel approach them, after 24 weeks, reduced not only References to increasing CEC count. They harvest corneal thickness, but also significant 1. N Okumura et al, “Enhancement on primate CECs from a healthy donor cornea, then improvements in BCVA – nine out of corneal endothelial cell survival in vitro by a culture and subculture them ex vivo the 11 experienced a two line or more ROCK inhibitor”, Invest Ophthalmol Vis Sci, (1–3). The cultured cells are recovered and improvement. But the study authors didn’t 50, 3680–3687 (2009). PMID: 19387080. supplemented with a ROCK inhibitor, and just present 24-week outcome data, they 2. N Okumura et al, “ROCK inhibitor converts then injected into the anterior chamber of presented 2-year outcome data too. At corneal endothelial cells into a phenotype capable the eye, having the recipient lie face down this point, the cornea was thicker than at of regenerating in vivo endothelial tissue”, Am J for hours to let gravity (and cell adhesion) baseline in all 11 eyes and each of the 11 Pathol, 181, 268–277 (2012). PMID: do the work of integrating the CECs to the eyes maintained transparency. 22704232. posterior cornea. In rabbits and monkeys, But there’s a safety question. You’re 3. N Okumura et al, “Rho kinase inhibitor enables it worked well, increasing CEC levels, injecting cells into the anterior chamber of cell-based therapy for corneal endothelial and restoring clarity to the cornea. Given the eye, and hoping that leaving the patient dysfunction”, Sci Rep, 6:26113 (2016). PMID: that donor cornea tissue is in short supply, in a prone position for 3 hours will bind the 27189516. what’s nice about this approach is that one new CECs to the cornea. What if some 4. S Kinoshita et al., “Injection of cultured cells with donor cornea could be used to prepare unattached cells go on to block part of the a ROCK Inhibitor for bullous keratopathy”, N CECs for multiple recipients – it’s usually trabecular meshwork? Here, there’s some Engl J Med, 378, 995–1003 (2018). PMID: one donor, one recipient with traditional good news. Only one patient experienced 29539291. keratoplasty procedures. But the real elevated IOP, and this was ascribed to 5. R Dana, “A new frontier in curing corneal question was: could it work in humans? prolonged glucocorticoid use. No uveitis blindness”, N Engl J Med, 378,1057–1058 The answer is yes. Eleven patients or systemic adverse events were observed. (2018). PMID: 29539278. CSF-1 inhibition strips microglia almost Now You See entirely from the retina, leaving just a few cells clustered around the optic nerve. Them, Now Crucially, the loss of microglia doesn’t affect nerve function. And, as Wong notes, You Don’t “If we were to get rid of the microglia while a large, inappropriate immune response Might temporary microglia was happening, we might be able to miss depletion treat inﬂammatory the worst of the inflammation, but still retinal disease? come back into balance at a later point in time. We could hit pause on the immune Microglia are curious cells. They’re the system in the retina in a directed way.” retina’s (and the central nervous system’s) What about when you press the play/ resident macrophages and when infection pause button again? Figure 1 shows the occurs, they’re the first line of defense. answer. Thirty days after stopping the But they’re also central to keeping drug, Wong and his colleagues found that neurons healthy – in addition to looking the microglia had repopulated the retina – for pathogens, they constantly scavenge and by 150 days, they had returned to their for plaques and damaged neurons or normal cell density. “The organization of synapses, always ready to transform into these immune cells is quite elaborate, and reactive phagocytes. But there’s strong all the organization comes right back,” evidence that microglial reactivity is a explains Wong: the returning microglia hallmark of various retinal degenerative first started to regrow in clusters the and inflammatory diseases, including optic nerve head, then gradually, new both rare genetic disorders like retinitis microglia expanded outwards towards pigmentosa (RP) and X-linked juvenile the edges of the retina. Over time, the retinoschisis, and more common cells re-established an even distribution Figure 1. Fundus images of mouse retina after multifactorial retinal diseases such as across and through the various layers being treated with microglia-eliminating drug, AMD, diabetic retinopathy, glaucoma, of the retina. As Wong put it: “We can PLX5622. When the drug was stopped (Day 0), and uveitis. Why? It seems that retinal actually image the eye and watch these nearly all of the microglia had gone, but by Day 7, microglia, in disease states, can remove cells divide and split and migrate as part microglia have started to migrate across the retina, healthy cells too, contributing to vision of the repopulation response.” and by day 10 they have increased in number. loss. Studies have shown inhibiting or But were the new microglia in these Credit: Wai T. Wong, National Eye Institute. removing microglia in retinal degenerative mice fully functional? The researchers disorders can help retain photoreceptors used a photoreceptor light injury model the clinic (not least, showing that this and slow vision loss. But then, they play where photoreceptor cells are damaged approach can actually work in humans). an important role in maintaining a healthy by bright light. The new microglia were The biggest concern about the clinical use retina. So, is their inhibition or removal able to activate and migrate to the injury of such drugs is constraining their effect ultimately bad news in the long-term too? site normally, and the levels of proof these microglia-depleting drugs to the Wai Wong, chief of the US National inflammatory cytokines following light retina – as removal of microglia elsewhere Eye Institute’s Section on Neuron-Glia injury were similar in retinas that contained in the central nervous system represents Interactions in Retinal Disease, and endogenous microglia or repopulated maelstrom of potential side effects that are his team set out to find out more about microglia. Electroretinographic testing best avoided. retinal microglia – and what happens showed that the repopulated microglia to the retinal if you eliminate them (in were able to communicate with and fully Reference mice). To do this, Wong and his team maintain the function of neurons in the 1. Y Zhang et al., “Repopulating microglia restore used PLX5622, a drug that blocks retina (especially when the depletion was endogenous organization and function under the microglial cell survival receptor, short-lived). But significant challenges CX3CL1-CX3CR1 regulation”, Science CSF-1. Over a period of several days, still remain before this approach can hit Advances, 4, eaap8492 (2018).

www.theophthalmologist.com 14 Upfront

The 2018 Power List has landed, and while Benchmarking most of the interest lies with the list, there’s a considerable amount to be learned from the the Power List list. There were a number of questions that we could ask (and answer): Where are the Power The who, what, where and Listers? What do they do? Does one specialty why of this year’s top 100. dominate? What’s the gender balance?

POWER LISTERS BY COUNTCOUNTRYRY

50 47 45 40

) 35 (n 30 Here’s what we found: ers

ist 2255 erl 20 16 There’s a global spread of Power

Powerlisters (n) Pow 1155 Listers. Almost half hail from the US, 10 5 5 and almost four in ten from Europe 2 2 2 2 2 2 5 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 (although the status of the UK’s 16 0 percent as ‘European’ might be up for debate soon). If we go by Power Listers per capita, the top three come out as Switzerland, Singapore then the UK. Let’s examine the 47 Power Listers from the US. Where are they based?

US SSTATETATE By state, we see that California, Pennsylvania, Maryland and Florida come in at 1, 2 and third equal.

SC SSDD AZZ 2% COO 2%2 2% TXX 22% 22% MN CACA 4% 26% MA 44%%

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Let’s cut the data a different way. Which cities are the hottest in the world for Power Listers? Here, we see London leading the pack, followed by Philadelphia and Miami.

Let’s visit gender balance. The first time we ran the Power List Top 100 in 2014, 13 percent of Power Listers were female. Four years later, that statistic is… 13 percent.

While many of those on the list have multiple job titles and affiliations and some work across multiple specialties, we decided to examine what their main “day job” was. What we found was that the vast majority had an academic affiliation – those with the principal job title “President” were relatively few, and of those who did, most were in industry.

What was the most common first name called either Robert Shields or Robert our Power Listers have accomplished in the Power List this year? Robert, Chang, who lives in the United States, great things during their careers. They followed by Thomas, John and David. in the state of California, but somehow have all worked incredibly hard, be it in Surnames were a little more diverse – in London too. the clinic, OR, laboratory, boardroom the only ones that popped up more than This exploration of the Power List or podium, and their achievements once were Chang and Shields. might be a bit of fun, but it’s important deserve to be celebrated – after all, every So, what would the median, to recognize the achievements of every single one of them continues to work composite Power Lister look like? It single person on the list. Irrespective to improve people’s vision each day. would be a man with the title Professor, of their age, race, gender or location, Thanks to you all.

www.theophthalmologist.com 16  In My View

I have discovered a consistent pattern. No Smoke Ninety-nine percent of my new patients In My are unaware of the effect of smoking on Without Fire the eyes, and lack important information on how smoking causes an increased View We need to reinforce the prevalence of eye disease. They are unaware message to stop smoking that visual acuity impairments often occur In this opinion section, at a younger age and in a more expedited experts from across the fashion in smokers. When I explain about smokers having a significantly increased world share a single blood level of carboxyhemoglobin that causes strongly-held view or retinal hypoxia – almost the equivalent of the key idea. smoker partially strangulating him or herself By Alan Mendelsohn, Eye Surgeons – I often hear audible gasps. I wish I had and Consultants, Fort Lauderdale and kept statistics on the number of patients who Submissions are welcome. Miami, Florida, USA came into our office as smokers but no longer Articles should be short, smoke. If I had to guess, the estimate would focused, personal and I don’t smoke. Neither did my parents and hover at the 50 percent mark. We think a very passionate, and may nor do my children. But that’s not enough small percentage stop when they first hear for me: I am on a mission to keep my the message, and others may wait until they deal with any aspect of patients from smoking. And I am looking have heard my ‘doom and gloom’ smoking ophthalmology. for other ophthalmologists to do the same. statistics a few times. The best results take They can be up to 600 It is well known that smoking damages place when a family member is diagnosed words in length and the entire body. The evidence is indisputable with macular degeneration, glaucoma or that smoking causes an epidemic of diabetic eye disease. The most resistant are written in the first devastation, including markedly increased those who have been smoking for decades and person. prevalence of multiple cancers, respiratory still have excellent vision with no posterior and cardiovascular diseases. Inexplicably, segment pathology. They are far less likely to Contact the editor at most people believe their eyesight is stop smoking, assuming incorrectly they are immune from the scourge of smoking. As immune from ocular damage. [email protected] ophthalmologists, we are acutely aware this As a physician, I see my role not only is far from the truth. Smoking is associated as a diagnostician and treatment provider with significantly increased prevalence and but also as an educator. My philosophy is ocular pathology in the three leading causes the more your patients know about ocular of blindness in adults (macular degeneration, health and preventative care, the greater glaucoma, and diabetic retinopathy). Worse your chances of reducing systemic and ocular yet, smokers can be affected at a younger morbidity as well as mortality. I also believe age and more severely than non-smokers. in persistence; if I do not succeed the first Yet many ophthalmologists are hesitant to time, I keep trying as it is part and parcel of bring up the topic of smoking, concerned helping patients save their eyesight. Fellow the patient may not be receptive or will ophthalmologists, I strongly encourage you consider the subject off limits. Others to give the stop smoking push a new try. If may be frustrated by the lack of patient one approach does not work, view it as a action and wary of investing time, effort challenge and use a different one next time. and energy – or they may question whose Track the results, not over months but years, role it is to bring up the hazards of smoking. and watch the numbers plummet. It may not Should it be a topic for a primary physician be dramatic, but it is enough to know that to broach or a social worker? you did your best to change the course of eye In my 30 years as an ophthalmologist, disease in your patients. In My View  17

third, and so on. By doing immediate become widely available, the case for Riding the sequential bilateral cataract surgery, a immediate sequential bilateral cataract cataract surgeon would be taking a net 25 surgery will be even stronger. Sea Change percent reduction in surgical income. If surgical income accounted for 50 percent Challenge 3: Risk management: A shift is happening in of the surgeon’s revenue, and if he or she endophthalmitis prevention. cataract surgery – whether were running a 60 percent overhead, the The final challenge is endophthalmitis we like it or not. Tackling just result would be a 62.5 percent reduction prevention. Though there is a wide three challenges allows us in net income – all for doing an identical range of endophthalmitis incidence, an to build a case for immediate amount of work and assuming the same approved antibiotic for intracameral use sequential bilateral cataract amount of risk. Though this policy may is nevertheless desirable. Haripriya et surgery in the US. make sense for general surgery, where al studied 194,252 patients undergoing a single incision and general anesthesia phacoemulsification and showed a can apply to multiple abdominal or seven-fold decrease in endophthalmitis thoracic procedures, this antiquated in patients receiving intracameral policy need not apply to ophthalmology, moxifloxacin at the end of surgery (1). and should be updated so that efficiency With endophthalmitis rates below 1 in and progress can be made. Without this 1000, the chance of bilateral infection change in policy, no surgeon will be able is less than 1 in a million. With rates By Gary N. Wörtz, Ophthalmic Surgeon, to provide this patient benefit. at 1 in 5,000, that would equate to one Commonwealth Eye Surgery, and Chief case in the US every 8 years. However, Medical Officer, Omega Ophthalmics, Challenge 2: The need for adjustable, ophthalmologists need medicolegal Lexington, KY, USA. exchangeable and upgradeable optics protection from the FDA – assurance As the old saying goes: fool me once that proper indications for the use of The first wave of the aging demographic shame on you, fool me twice shame on these have been clinically vetted, and to of the baby boom generation has been me. The adage implies that being tricked ensure proper manufacturing standards accompanied by a dramatic increase in is only acceptable, if you learn from the have been met. Examples of ophthalmic the demand for cataract surgery. As miscalculation. The same can be said of antibiotics being approved for bacterial cataract surgeons become even busier, cataract surgery. The first surgery can be conjunctivitis while being promoted new strategies for efficiency must be considered a forerunner for the second. entirely for off-label purposes put doctors considered. Having reached the point of If we miss our target in the first eye, at risk if bad outcomes occur. Additionally, diminishing returns, the next paradigm additional measurements and scenario substandard compounding facilities have shift is immediate sequential bilateral planning can help improve the result created batches of drugs with similar cataract surgery. In my opinion, this is in the second eye. With immediate untoward consequences. It’s time for the the change coming in cataract surgery, sequential bilateral cataract surgery, FDA, industry, and doctors to find a way whether we like it or not. Therefore, we we give up the opportunity to judge forward to help protect physicians and must look at the three biggest obstacles the result of the first eye before tackling patients in a responsible way. standing in the way as opportunities for the second cataract. However, with These three challenges can be advancement – and adjust our thinking the new category of exchangeable and met, clearing the way for immediate for the future. adjustable lens platforms from RxSight, sequential bilateral cataract surgery to PerfectLens, Clarvista and others, that become the new standard of care. Challenge 1: The Second Eye is all about to change. No longer will Payment Reduction we need to consult the oracles or crystal Reference It has been said: “No margin, no balls before surgery. In the very near 1. A Haripriya, DF Chang, RD Ravindran, mission.” In the US, physicians future, the visual result of the eye will “Endophthalmitis Reduction with performing multiple surgeries on the be able to be fine-tuned, upgraded or Intracameral Moxifloxacin Prophylaxis: same day are subject to reimbursement even allow for a simplified exchange of Analysis of 600 000 Surgeries”, reduction of 50 percent on the second technology, if the patient is dissatisfied. Ophthalmology, 124, 768–775 (2017). PMID: procedure and 75 percent on the Once exchangeable and adjustable lenses 28214101.

www.theophthalmologist.com 18 Feature

TURNING Back TIME

Gene therapy has traditionally focused on correcting one defect at a time. But what if you could do more with the tools of the trade? How about reprogramming cells to sidestep disease – or turning back the clock on senescent cells in age- related disease? Here’s what we can do today – and what’s on the horizon.

By Kang Zhang www.theophthalmologist.comwwwwwwwwww.th.tththeopeeooopphthththalmalmlmolooollogisggiiisst.ctct.c.comom he Neural Retina Leucine Zipper gene (Nrl) plays rod-mediated vision is actually used – particularly in urban a fascinating role in retinal development. It encodes settings, where artificial light is endemic and most bedside T a transcription factor that acts as a master control tables have a lamp. switch for rod photoreceptor differentiation by regulating So, if you spare the rod, you save the cone? That’s the the expression of important rod-specific genes. These include conclusion most of us have reached and a number of therapeutic the rhodopsin-encoding RHO, and PDE6B – a subunit approaches under investigation are trying to achieve this. In of the cGMP-PDE protein complex, which is essential to some ways, RP is an attractive candidate for gene therapy; the light-mediated neurotransmission in the retina. The interplay eye is accessible, and efficacy is easily tested through imaging, between the various developmental morphogens and signaling eletroretinography (ERG) and even standard visual acuity cascades is nuanced and complex… What you really need to testing, and the genetic defects are well understood. It’s why know is that all photoreceptor precursor cells develop into there are a number of gene therapies currently in Phase I/II cones in the absence of Nrl. But what’s really interesting about clinical trials, with more in preclinical stages. But there are Nrl? Its action is reversible. Inactivate it, and rods become about 200 genes that, if defective, can cause RP – so to treat all reprogrammed and turn into cones. RP patients by gene therapy, we would need as many therapies We’ve known for many years that retinitis pigmentosa (RP) as there are defective genes. Having done an early gene therapy is caused by mutations in genes that are expressed in rods, trial (2) on a rare RP condition caused by a Mertk mutation not cones, and it results in a progressive sequence of rod cell (which has only less than 40 patients in the entire world), and death followed by cone loss. Rod degeneration results in the given what we know about Nrl, its inactivation and cell fate, collapse of the outer nuclear layer (ONL) of the retina, and might there be a better way – one treatment to cure them all? this generates an oxidative, nutrient-deficient environment I wanted to answer two big questions: could we make that is toxic to cones. It’s actually the cone loss that’s the most photoreceptor cells insensitive to inherited mutations by debilitating. Think about it: rods are absent from the all-cone reprogramming them such that they switch from a vulnerable fovea centralis, and it’s hard to find an environment where to an invulnerable state? And could this – potentially universal Feature 21

– RP therapy work in the clinic to preserve cone-mediated, high-acuity daytime color vision? The first hurdle that needed to be cleared in taking this approach was a practical one. It’s all well and good using germline techniques to make conditional Nrl knock-out mice as part of an experiment to understand that gene’s function. But that’s not an approach that can be taken in patients. For a clinically relevant approach, you first need a method capable of inactivating Nrl in post-mitotic cells – and these are notoriously resistant to genetic manipulation. Our approach was to use a homology-independent targeted integration (HITI) strategy based on the revolutionary CRISPR/Cas9 technology. The CRISPR/Cas9 guide RNAs are carefully designed to permit precise sequences of host cell DNA to be excised and replaced with transgene sequences, which we deliver to the cells with a vector based on adeno-associated virus (AAV). In fact, we had already developed an HITI-AAV toolkit and had successfully used it to integrate a transgene (green fluorescent protein) into the DNA of post-mitotic, cultured primary neurons (1). We then went on to use our toolkit on Royal College of Surgeons (RCS) rats, which express a RP- like phenotype (thanks to mutations in the second exon of the Mertk gene). We were able to perform a CRISPR/Cas9- mediated replacement of the mutated gene in three-week-old animals, which not only preserved outer nerve layer (ONL) thickness, but also improved electroretinographic (ERG) responses to light (1), validating a new CRISPR approach Two AAV vectors are employed, one expressing Cas9, and the for gene therapy. other carrying guide RNAs targeting Nrl and Nr2e3. The gRNAS target Cas9 nuclease to genomic Nrl and Nr2e3, resulting in knock-down of these transcription factors. “Could we make photoreceptor cells insensitive to inherited Photoreceptor precursor cells mutations by reprogramming them... from a vulnerable to an invulnerable state?” Nrl

So, we can successfully transfect post-mitotic photoreceptors with our HITI-AAV system. It’s all great work; however, it isn’t cell-fate switching, nor is it the universal RP treatment I’ve proposed. What it did show was that our CRISPR toolkit could work in patients with RP, and that encouraged us to Cones Rods take the first steps towards using cell-fate switching to treat RP. Now, we have developed an HITI-AAV system that

www.theophthalmologist.com 22 Feature

incorporates two guide RNAs targeting Nrl or Nr2e3. You numbers of cone-like cells in the retina (as determined by the already know why we’re targeting Nrl, so why Nr2e3? It’s a presence of the cone cell marker, MCAR), and quantitative key transcription factor that’s activated by Nrl, and in turn PCR demonstrated down-regulation of rod-specific genes up-regulates the rod-specific gene transcription network – and and up-regulation of cone-specific genes. The next step was targeting either or both transcription factors should reprogram to see if our CRISPR-AAV-nrl system worked across multiple rods to cones. murine RP models with different mutations, so we tested it in Rd10 and FVB/N mice. Again, we saw similar, encouraging results. Treated Rd10 mice showed improvements in vision and photopic b-wave amplitude under ERG testing, suggesting that cone function had improved. The treatment also appeared “This approach could provide to preserve cells expressing cone proteins, maintain ONL end-stage AMD patients thickness, and protect S-opsin and PNA expressing cells – cones, in other words. In the FVB/N mouse, treated animals with a new “macula” and showed preservation of mCAR+ cone cells and maintenance of ONL thickness and, again, displayed improved vision and potentially reverse some of their photopic b-wave values. So, another hurdle has been cleared: the data effectively show vision loss.” that our CRISPR genome editing approach can reprogram rods to cone-like photoreceptors in post-mitotic tissues, interrupt retinal degeneration and restore visual function – all in at least two different mouse models of RP. Just like our Mertk work, we first had to demonstrate that Next, we constructed a CRISPR-AAV-Nrl vector to target the system can switch rods to cones in mice. Long story short: the exact same Nrl gene sequence shared by humans and subretinal administration of CRISPR-AAV-nrl at postnatal monkeys, which allowed us to use the same AAV vector in day 7 in wild-type mice resulted in substantially increased both non-human primate (NHP) safety studies and human clinical trials. The preliminary NHP results have been extremely promising: our three-month follow-up data suggest that our approach converts rods to cones in monkeys without any significant toxicity, and we expect to progress to clinical trials later this year.

SEEING THE BIGGER PICTURE The application of rod to cone cellular reprogramming extends far beyond RP; this approach holds the potential to provide a new treatment option for age-related macular degeneration (AMD). People with advanced AMD suffer progressive vision deterioration and loss due to choroidal neovascularization or geographic atrophy, both of which destroy an increasing proportion of cones in the macula. My proposal is that, given the retina contains 200 million rods and 5 million cones, we should be able to employ a cellular reprogramming strategy to switch a patch of rods into cones in a perifoveal area where retina is unaffected by AMD. This approach could provide end-stage AMD patients with a new “macula” and potentially reverse some of their vision loss. For younger people, however, who are at risk of developing AMD but who have not yet progressed to overt damage, a different approach would be required; for these patients, we are investigating a synthetic biology route (Box 1). Feature 23

BOX 1: SYNTHESIS OF SCIENCE AND HOPE stretches of DNA comprising hundreds of kilobases – the affected sequences are too long for conventional gene What do you offer a young patient at high risk of AMD? therapy approaches Historically, very little – but novel options are now offered by • Advances in synthetic biology, however, now allow the the combination of new synthetic biology techniques and the construction of entire chromosomes, or even – in the case increasingly detailed understanding of AMD’s genetic basis. of simple organisms such as yeast – of entire genomes • By combining gene editing and synthetic biology, it may • Nearly 70 percent of AMD cases are associated with just three be possible to excise the entire range of AMD-associated genes, Htra1/ARMS2, CFH and C3 – why not remove any alleles and replace them with normal alleles, in vivo inherited risk by employing gene-directed approaches? • Just a few interventions at the genome level would very • One issue is that AMD risk alleles are spread over substantially reduce the AMD risk for an individual.

What about people with late-stage glaucoma who have lost a significant proportion of their retinal ganglion cells, compromising their optic nerve? Could we address these situations simply by reprogramming neuroglial cells into retinal neurons? There’s some precedent for this concept. “It’s clear to me that cellular We know that Müller glial cells from the retina of non- reprogramming techniques will mammalian vertebrates produce new retinal neurons in response to injury. And we know that these new cells can have a significant therapeutic structurally and functionally integrate with existing visual circuitry, thereby repairing the retina. Mysteriously, however, impact across many disease areas.” mammalian Müller cells appear to have lost this capacity for retinal regeneration. Why? At last, we have at least one answer: it’s due to p53 function (4). By knocking out p53 in mouse Müller glia, we REMEMBER THE VULNERABLE restore their ability to rapidly and efficiently differentiate It’s clear to me that cellular reprogramming techniques will into photoreceptor precursors in culture. Further, these have a significant therapeutic impact across many disease Müller glia-derived progenitors can incorporate themselves areas. And as these techniques rely on modulating the patient’s into the host retina after transplantation, and express own cells, they are likely to be less risky than modalities markers for either retinal ganglion cells (Islet1 and Brn3) or based on exogenous stem cells, where there may be a concern photoreceptors (rhodopsin and IRBP). Importantly – after of tumorigenesis or immune rejection. Add the fact that all, p53 is a classic tumor-suppressor gene – we observed reprogramming therapies are not restricted to genetic subtypes no tumor formation after transplantation of the precursors. and are applicable to very broad range of patients, and we Reprogramming cells isn’t limited to ophthalmology anticipate a broad application of this approach. – there’s a clear rationale for its use in leukemia too. As That said, there will be big challenges getting these kinds of macrophages are not susceptible to the cancer transformation advanced therapies to everybody who needs them. It’s one thing processes associated with the oncogenic mutations that drive to develop a technology that can address a medical need – quite leukemia, we could design a reprogramming strategy that another to ensure that it is broadly accessible to patients at low will treat leukemia by switching malignant leukemic cells cost. There are still many patients with treatable diseases who into benign macrophages. Similarly, cells of glioblastoma go untreated, particularly in rural areas of developing countries. multiforme (GBM) – a very aggressive glial cell lineage Changing this situation may take decades, and will need a tumor – could be switched into a neural cell type in which concerted effort by the global community. It will also require the oncogenes or mutations underlying GBM will no longer the employment of many different tools, not least artificial be effective. intelligence, which I believe will have a key role in allowing

www.theophthalmologist.com 24 Feature

Cell fate – re-determining the predetermined

Disorder Fate switch Therapeutic outcome

RP Rods – Cones Halts the deleterious effects of rod degeneration on the retina

Turn rods into cones in an unaffected AMD Rods – Cones perifoveal area, generating a new “macula”

Knock out p53, de-differentiate Müller glia, Late-stage glaucoma Müller glia – RGCs culture,transplant, differentiate into RGCs

Leukemic cells – Leukemia macrophages Convert malignant cells to a benign cell type Glioblastoma Glial – neuronal cell type

considerable surgical skill. In the future, however, we hope to administer the treatment as an in-office procedure, just like intravitreal injections (but using robotic devices). And maybe one day, we will be able to eliminate the burden of injections altogether. For example, we’ve been working on a topical eye- drop for wet AMD for the last five years, and expect it to move Turning back time into clinical trials in the US and China early next year. Replacing Understand what each component in aging does intravitreal injections with eye-drops would be of great benefit. – and the consequences of manipulating them

“I expect, within my lifetime, to Patient, heal thyself: Wake your own stem endogenous stem cells and see human beings enjoying a direct them to repair damaged tissue in situ. longevity of 150–200 years.”

TURNING BACK TIME IS THE FUTURE In my research, I always try to consider broad themes that are broad patient access to new therapies (for example, by enabling applicable across different areas of medicine. As a consequence, remote diagnosis via smartphones and the Internet). although I work within ophthalmology, I increasingly find Development of simpler and cheaper administration methods that I am thinking outside the eye field. You could say I’m also would help: at present, the best way to deliver reprogramming using ophthalmology as a model to address broad medical therapy to RPE or photoreceptor cells is to inject vector into the needs rather than conditions that are limited to the eye. In sub-retinal space, but this is costly, inconvenient and requires particular, one of my overarching goals is to combat age-related Feature 25

BOX 2: DON’T REPLACE – REGENERATE cells (LECs) • identification of factors (Pax6 and Bmi1) required Will slow, natural lens regeneration relegate current methods for lens epithelial cells (LECs) to participate in lens of cataract treatment to the ‘quick and dirty’ category of care? regeneration • Using this method, we regenerated functional lenses in The Need rabbits, macaques and human infants • Cataracts are normally treated by replacing the occluded • The approach may also restore accommodative power, at least lens with an artificial intraocular lens (IOL) where accommodative loss is mainly due to lens sclerosis • This highly successful procedure normally results in improved vision within a few hours What’s Next? • However, IOL implantation carries a risk of • Modifications to the basic method are in progress: complications, and current IOLs cannot accommodate in • Injection of a 3D-printed scaffold, impregnated with the same way as young crystalline lenses appropriate growth factors, is expected to stimulate and guide LECS during lens regeneration Our Solution • The intent of this device is to decrease the time • We developed a method for regenerating a new lens in required for functional lens regeneration from 6–8 situ (5), which required: months to 2–3 months, improve refractive outcomes, • development of a cataract removal method that and allow customization of the lens’ final form to the preserves endogenous lens epithelial stem/progenitor specific requirements of the patient’s eye

diseases – and perhaps to address ageing itself! Indeed, I believe tissue in situ – another overarching theme of my work. We’ve that if we work out how to stop ocular diseases of ageing – such already seen this happening in cardiac cell regeneration, where as macular degeneration, glaucoma and cataract – we will also you can guide cardiac fibroblasts to differentiate into beating be able to prevent other age-related conditions: Parkinson’s, cardiomyocytes; one day, we will see the same principles used Alzheimer’s, and so on. to address diseases of old age – for example, to reprogram glial But what’s critical to the development of anti-ageing therapies is cells into functional neurons as part of an Alzheimer’s treatment. achieving a full understanding of the biological clock – we were the I foresee a wave of innovative therapies in this field over the next first to identify an epigenetic gene modification mechanism that ten years – and I hope our technique for regenerating lenses (Box drives the ageing process in every single tissue and cell, including 2) is just the first of them! those in the eye. We’ve been working extensively on understanding how this clock ticks – and what makes it tick. In particular, we References have been trying to identify and understand the upstream factors 1. K Suzuki et al., “In vivo genome editing via CRISPR/Cas9 mediated that make the clock run faster or slower, and their downstream homology-independent targeted integration”, Nature, 540, 144–149 (2016). consequences. Ultimately, this research will enable us to devise PMID: 27851729. treatments that inhibit the ageing process – in fact, we have 2. NG Ghazi et al., “Treatment of retinitis pigmentosa due to MERTK mutations evidence to suggest that we can even reverse it! I expect – within by ocular subretinal injection of adeno-associated virus gene vector: results of a my lifetime – to see human beings enjoying a longevity of 150–200 phase I trial”, Hum Genet 135, 327–343 (2016). PMID: 26825853. years. And this extended lifetime would not be burdened by the 3. J Zhu et al., “Gene and mutation independent therapy via CRISPR-Cas9 frailties of age; centenarians would function as though they were mediated cellular reprogramming in rod photoreceptors”, Cell Res 27, 830–833 healthy 40–50-year-olds. (2017). PMID: 28429769. Finally, I believe that the best approach to these age-related 4. JJ Zhao et al., “Induction of retinal progenitors and neurons from conditions is to harness the regenerative power contained within mammalian Müller glia under defined conditions”, J Biol Chem, 289, our own cells and tissues. I am convinced that the next phase of 11945–11951 (2014). PMID: 24523410. regenerative medicine will focus on waking up our endogenous 5. H Lin et al., “Lens regeneration using endogenous stem cells with gain of stem cells and directing them to repair or regenerate the damaged visual function”, Nature, 53, 323–328 (2016). PMID: 26958831.

www.theophthalmologist.comwww.theophthalmologist.com JULY 20, 2018 VANCOUVER, BC, CANADA FOUR SEASONS VANCOUVER

CELEBRATING 10 YEARS OF INNOVATION

UNITING OVER 225 LEADERS IN THE DEVELOPMENT OF GROUNDBREAKING OPHTHALMIC TECHNOLOGIES

WWW.OIS.NET /OIS.NET @OISTWEETS Œ /OPHTALMOLOGYSUMMIT In Practice Surgical Procedures Diagnosis New Drugs

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28–31 Not the Usual Suspects Irregular astigmatism in patients presenting for cataract surgery or RLE can cause the surgeon a lot of grief. Sheraz Daya shares his quarter of a century’s worth of experience of dealing with these “irregulars”, and shows how he deals with such corneas. 28 In Practice

Not the Usual Suspects

The secret to managing irregular astigmatism during cataract surgery? Tackling the problem at its source.

By Sheraz Daya

When people talk about astigmatism and intraoperative aberrometry, the conversation is often made with the assumption that the cornea is normal and regular. When it Figure 1. Disorders of the tear film, or any one of three corneal layers – the epithelium, sub- isn’t normal and regular… well, you have epithelium or the stroma – can all cause irregular astigmatism. a problem. I have been dealing with some pretty difficult corneas for a quarter of a century now, so let me share with you what I have learned over the years. Irregular astigmatism in patients presenting for cataract surgery (or refractive lens exchange; RLE) can have consequences: poor vision. For the surgeon, this is partly because the biometry can be challenging, which makes accurate IOL calculations difficult. Any error results in a refractive miss, causing both the patient and surgeon grief.

At a Glance 17% > 1.0 D difference in keratometric cylinder between two visits. • A lot of talk about astigmatism 0% > 0.50 D in calculated IOL power and intraoperative aberrometry is made on the assumption that the Figure 2. Keratometry cylinder (1). Seventeen percent of hyperosmolar eyes had at least 1.00 D of cornea is normal and regular. But change in keratometric cylinder values between two visits. The hyperosmolar group demonstrates a what if it isn’t? wider variation in keratometric cylinder between visits relative to the normal group (p=0.013). • Biometry becomes far more difficult, as does IOL power To deal with irregular astigmatism, we corneal surface. The epithelium translates calculation. Get it wrong, and first have to understand its cause. to the tear film and, if that is irregular then, there’s grief all round. once again, we have irregular astigmatism. • Understanding the causes of Why corneas become irregular You cannot forget the subepithelial area; irregular astigmatism – and how Let’s look at the cornea systematically from there are conditions that affect this region do you deal with them – is key. front to back. There are five layers and and they also translate right across to the • Here, I offer general principles of three of them are responsible for irregular front surface of the cornea. And then how to manage these ‘irregulars’ astigmatism (Figure 1). The tear film sits there is the stroma; if it is scarred, ectatic and give a few case examples of atop the cornea, and needs to be regular in or abnormal in in terms of shape that may my own. its consistency to provide regularity of the also cause irregular astigmatism. Figure 3. Anterior basement membrane dystrophy – also known as epithelial basement membrane dystrophy, Cogan’s dystrophy or Map-dot-fingerprint dystrophy – results in Figure 5. An eye with keratoglobus, scarring and an extremely thin cornea (left) – and a very irregular astigmatism. unusual topographic map (right).

Figure 4. An example of a sub-epithelial disorder, Salzmann’s nodular degeneration, that causes irregular astigmatism. Other disorders include scarring of Bowman’s layer and Figure 6. Irregular astigmatism: corneal shape. Asymmetric (left) and non-orthogonal astigmatism Reiss-Bücklers corneal dystrophy. (right).

Dry eye Epithelium-induced irregularastigmatism Stromal irregular astigmatism Dry eye is probably the single biggest Figure 3 shows a case of anterior basement Both scarring and ectatic disorders can cause of irregular astigmatism. It’s membrane dystrophy – also known as cause irregular corneal astigmatism from something that cannot be dismissed – epithelial base membrane dystrophy, the stroma. The patient in Figure 5 actually and, in this age of refractive lens exchange Cogan’s dystrophy, map-dot-fingerprint has a combination of both: keratoglobus and refractive cataract surgery, we are dystrophy... Whatever you call it, the with scarring and an extremely thin appropriately giving this topic a great deal irregularity caused in the cornea makes cornea, which has resulted in a very unusual of attention. We all know the causes of accurate calculation very difficult. topographic map. Such patients are not easy dry eye: underproductive, evaporative and to deal with. inflammatory, but remember, an irregular Irregular astigmatism arising from the Corneal shape changes can commonly tear film can exist in asymptomatic patients. sub-epithelium cause irregular astigmatism. They often Tear osmolarity can be used as a measure Salzmann’s nodular degeneration (Figure present as asymmetric bow ties; if they’re of dry eye, and Epitropoulos et al. (1) 4) can also cause problems. Even if the orthogonal, then they are on the correct showed that patients with hyperosmolar degenerative nodule is peripheral, it axis, the cornea is just steeper inferiorly tear film occasionally display great variation can influence central keratometry and than above (Figure 6) – and that’s not bad, in terms of their keratometric cylinder regularity. You may be able to risk because the overall astigmatism is fine – (Figure 2) – plus, their IOL calculations performing a cataract operation on this it’s when they’re non-orthogonal that it’s a varied by 0.5 D in 10 percent of cases. Dry patient – but, if the nodules progress and problem. If you’re going to use a toric lens eye really is not a trivial disorder, and it eventually need removal, you have got a in a non-orthogonal astigmatic patient, certainly does not have a trivial impact on whole new keratometry to deal with; each then the biggest question is: where do I IOL calculations. case needs to be carefully considered. orientate the implant? I shall address this later in this article.

www.theophthalmologist.com The RLE-requesting an acute chalazion in his fellow eye! web developer with My patient was certainly not ready for refractive lens exchange. terrible tear ﬁlms His tear film was streaky, so no surprise by his report of fluctuating This video depicts the eye of a patient vision – which he thought it was from his who came to see me for refractive lens cataracts. There was no way that I was exchange. He was adamant that he wanted going to operate on him until I fixed his trifocal lenses implanted; however, after ocular surface, a process that took about examination, I had to tell him, the bad three months, whereupon we proceeded news “Your tear film is terrible and you with the RLE, successfully implanting have got a whole load of other problems trifocal IOLs. that need attention (punctate epithelial keratopathy and anterior basement Video available at top.txp.to/ membrane dystrophy)!” He even had issues/0518/501.

Some Placido systems are combined with aberrometry systems (such as the Nidek OPD 3, Tracey Technologies’ iTrace and Topcon’s KR1W). They all work in slightly different ways, but all are excellent at providing truly useful information about the surface and overall aberrometry, and by subtracting corneal-derived aberrations from the overall aberrations, internal aberrations can be calculated. Three- dimensional diagnostic instruments (for example, the Orbscan [B+L] with its scanning slit approach or the Scheimpflug- based systems: Oculus’ Pentacam, Ziemer’s Galilei or Visionix’s VX120 family) offer Figure 7. Placido disk-based diagnostic systems are a great way of evaluating the extent of corneal irregularity. shape analysis – elevation, posterior cornea and corneal thickness, which is really useful Diagnostics of Irregular Astigmatism exposure, then they may need to be seen by information when it comes to dealing with We are doctors – and one of the most an oculoplastic surgeon before proceeding the corneal shape. Anterior segment OCT fundamental aspects of the profession to cataract surgery. is now coming into vogue and I suspect will is evaluating patents clinically. A displace some of the current “gold standard” comprehensive clinical evaluation is vital What tools do we have at our disposal, if devices being used. in diagnosing irregular astigmatism, but we suspect there is a problem and want to we do also have a number of diagnostic know the magnitude of that problem? Management strategies instruments available to help us. And First, you need a Placido-based reflective The principles of management are simple: they can also be used to monitor disease topographic system (Figure 7), and there eliminate and reduce corneal irregularity progression (and improvement) of patients. are some great markers devised by Steve by addressing the source of the problem When we look at a patient, going from front Klyce that can be used to flag irregular by either medical therapy (for example, to back; first, we look at the tear film, then corneas: the Surface Regularity Index when the cause is dry eye) or surgical look at the shape, clarity and surface of the (SRI) is used a lot; the Standard Deviation intervention. Follow-up is important; the cornea to see if there is anything that might of (corneal) Power is also a good one. In cornea needs to be evaluated to see how influence things. Next comes a fluorescein Figure 7, the SRI value is colored in red the patient’s eye is progressing. Has the stain to check lid action and the distribution – and that indicates there is something surface got smoother; has the tear film of the fluorescein dye. If patients are not going on with this patient’s eye – anterior improved? Has the surface stabilized? closing their eyelids properly and have basement membrane dystrophy in this case. If a patient presents with dry eye, Figure 8. Anterior basement membrane dystrophy is commonly associated with meibomian gland dysfunction and may be related to inflammation. The pathology is a duplication of the basement membrane. The irregularity it imparts onto the cornea is best removed either by epithelial cell debridement (see the video at top.txp.to/issues/0518/501) or phototherapeutic keratectomy.

results from a duplication of basement membrane, which causes an irregularity you can see on the fundus retroillumination picture (Figure 8). Typically, epithelial debridement (even at the slit lamp) followed by a bandage contact lens is sufficient in such cases – occasionally we’ll add phototherapeutic keratectomy (PTK) – 5–10 μm laser ablation in PTK mode – to promote good healing and adherence. The patient in Figure 8 had quite a high SRI; the OCT-based epithelial maps show the difference between corneal irregularity before and after epithelial debridement (Figure 9). His keratometry changed from 45.71 D to 44.77 D – just over 1 D change Figure 9. The difference epithelial debridement has on corneas with anterior basement membrane dystrophy. – and his irregularity index went from orange and red values to green ones. The cornea became more regular with better potential vision. Six weeks later, these values remained stable, which meant we felt comfortable enough to perform ocular biometry and IOL calculations.

Salzmann’s Nodular degeneration A patient presented for a second opinion to the Centre for Sight for RLE with a refractive error (+8.00 D). He became worried, when he realized his original surgeon was a little hesitant. When I examined him, I saw marked 360° nodular degeneration and an irregular cornea. Salzmann’s Nodular degeneration is caused by hyaline that sprouts out from breaks in Figure 10. Clockwise: the corneal pathology of Salzmann’s nodular degeneration (SND), keratometry, axial Bowman’s layer and goes on to the surface power and HOA maps, and a still from a video of a superficial keratectomy procedure performed on the most (Figure 10). In terms of removal typically extensive SND patient I have ever seen. The video is available at: top.txp.to/issues/0518/501. the edge can be found and elevated and removed as in the image. evaluate the cause and treat it. Once the fluctuating ones. But what about the Postoperatively, he had a smooth regular tear film is stable, biometry and IOL aforementioned corneal disorders? cornea that was steeper; his refraction calculations can be performed with some changed considerably and Figure 11 shows confidence. The key is to proceed from Anterior Basement Membrane Dystrophy his keratometry: he was going to have a stable foundations, rather than highly Anterior basement membrane dystrophy 28.5 D lens placed in his left eye (with flat

www.theophthalmologist.com 32 In Practice

Ks), but after the procedure he only needed a 20 D lens – an 8 D difference (there was a 4.5 D difference in the right eye).

Non-orthogonal astigmatism What causes non-orthogonal astigmatism (Figure 12)? Ectatic disorders like keratoconus mostly, but it can also occur in post-corneal graft patients. So how does one deal with those patients who have got corneal ectasia or keratoconus? I always try and find out from the optometrist what the BSCVA was before the cataract. If it was 6/12 or better I’d probably go ahead and do a Figure 11. Pre- and post-op keratometry of a patient with Salzmann’s Nodular Degeneration who underwent lens calculation and put a toric lens in. If superficial keratectomy. it was less than 6/12, then I’d have to try and find a way to regularize the corneal shape either by use of intracorneal rings (Figure 13) or corneal cross-linking (CXL) with topo-guided PRK. The last resort would be corneal transplantation. Arthur Cummings of the Wellington Eye Clinic, in Dublin, Ireland, shared the details of another case with me – a patient who underwent CXL and topo-guided PRK (Figure 14). He had a pre-op I-S ratio of 52.1 – but, after the procedure, the ratio had reduced to 6.9; similarly, UVCA was 6/60 before surgery, and 6/18 afterward, and – Figure 12. An illustration of a patient with non-orthogonal astigmatism. importantly – the patient was now ready for ocular biometry, lens calculation, and a toric IOL implantation.

Which axis do you use non-orthogonal astigmatism? In Figure 15, the Pentacam shows 73° simulated steepening; the OPD (on refraction) shows in the 90° axis, and on topography, 97°. Which axis does one use? Well, to confound this further, I prefer to use the corneal-derived Z2- derived aberrometry polynomial for astigmatism. We’ve been doing this for quite some time now, and we’ve found that it very accurately averages out the Figure 13. A Ferrara and an Intacs ring (CorneaGen) in the same eye of a patient. actual axis. In this particular case, 102° In Practice 33 Post-op Pre-op I-S ratio 6.9 52.1 SE -2.25 DS -0.75 Cyl 2350 D 3.50 UCVA 6/18 6/60

Figure 14. CXL and topo-guided PRK. Case courtesy of Arthur Cummings. Figure 16. Surface maps and aberrometry of a patient with a prior corneal transplant.

follow those rules, then you needn’t fear irregular astigmatism in cataract surgery: you can embrace it instead!

Sheraz Daya is the Medical Director of the Centre for Sight, East Grinstead, Sussex UK, is a member of The Ophthalmologist’s Power List 2018 Top 100, is internationally renowned for his work in laser eye surgery, lens replacement, stem cell transplantation, corneal transplantation and refractive cataract surgery, and was recently awarded the Fyodorov Medal by the Hellenic Society of Intraocular Implant and Refractive Surgery. Figure 15. Non-orthogonal astigmatism: which axis to use? The Pentacam says 73°; OPD indicates (by He reports that he has consulted for refraction) 90° and (topography) 97°, and the corneal-derived Z2-derived aberrometry polynomial for Bausch + Lomb, Carl Zeiss Meditec, astigmatism (Z2±2 S2±2) indicates 102°! Excellens, LinCor Biosciences, Medicem, Nidek, STAAR Surgical, Scope is the axis that needs to be used. always possible in these types of patients Pharmaceuticals, and Rayner, is an These diagnostic devices can also – and so they need to be counseled in equity owner in Excellens, PRN and provide a good indication of orientation advance about this possibility. Strathspey Crown, has received grant of the toric lens postoperatively without support from Johnson and Johnson Vision, dilation. Figure 16 shows the surface The bottom line and lecture fees from Bausch + Lomb maps and aberrometry of a patient As noted, the principles of managing and Nidek. who had a corneal transplant before I irregular astigmatism cataract surgery had implanted a toric IOL. Before the are actually pretty simple: find the Reference procedure, I had intended to place the source of the problem, address it as best 1. AT Epitropoulos et al., “Effect of tear lens at a 121° axis – but it turned out it as you can, then only proceed to ocular osmolarity on repeatability of keratometry for was actually placed at 127°, giving the biometry, IOL calculations, and surgery cataract surgery planning”, J Cataract Refract patient a residual refraction of 2 D. I when the astigmatism is compatible Surg, 41, 1672–1677 (2015). PMID: always aim for emmetropia – but it’s not with potentially good vision. If you can 26432124.

www.theophthalmologist.com CELEBRATING THREE YEARS OF HUMANITY IN SCIENCE

The Humanity in Science Award recognizes and rewards scientific breakthroughs that aim to have a real impact on humankind’s health and wellbeing.

2015 2016 2017

Peter Seeberger & Andreas Seidel- Waseem Asghar, Assistant Professor Richard Jähnke, Global Pharma Morgenstern, Directors at two at Florida Atlantic University, Health Fund (GPHF), developed and collaborating Max Planck institutes developed flexible sensors for the rapid continuously improved GPHF Minilab in Germany, developed an innovative and cost-effective diagnosis of HIV – and – a “lab in a suitcase,” enabling resource process to manufacture the most effective other infectious diseases – in point-of- poor countries to rapidly identify drugs to treat malaria from plant waste care settings. substandard and falsified medicines. material, air and light.

Nominations will open soon for the 2018/2019 Humanity in Science Award www.humanityinscience.com NextGen Research advances Experimental treatments Drug/device pipelines

36–38 Great Minds Look Ahead he 2018 Power List cadre offer their thoughts on the future of ophthalmology.

39–41 Enter the Exosome Exosomes are simpler to produce and far easier to administer than stem cells. Since exosomes are all of the “good stuff ” stem cells secrete… Ben Mead asks: are exosomes the answer to our retinal regeneration needs?

www.theophthalmologist.com 36 NextGen

In the future, I would Great Minds like to establish cultured corneal endothelial cell Look Ahead “It is injection therapy for bullous exciting keratopathy.” The 2018 Power Listers to see how the Shigeru Kinoshita, Professor and Chair of offer a glimpse of discovery of the Frontier Medical Science and Technology ophthalmology’s future pre-Descemet’s for Ophthalmology, at Kyoto Prefectural layer has evolved University of Medicine, Kyoto, Japan. Ophthalmology is an ever-changing field into direct clinical with a pioneering attitude – it’s why so applications, both from Ten-year goal: “To develop direct evaluation many breakthroughs and innovations our own research but more importantly technology to evaluate corneal biomechanical in medicine and technology are made from research by other independent properties to screen for keratoconus in its in eyecare first. For 2018, we asked groups around the world. We have made earliest manifestations, and predictive the influential leaders making up the new discoveries in relation to this and models for corneal interventions, such as laser Power List for their vision of where other aspects of corneal transplantation, ablation and cross-linking to individualize ophthalmology is heading. which are either in press or submitted to treatment parameters.” reputed journals.” J. Bradley Randleman, Professor of The future of cornea Harminder Dua, Head of the Division Ophthalmology at the Keck School “I’m currently trying to solve the surgical of Ophthalmology and Visual Sciences, of Medicine, University of Southern challenges in Descemet’s membrane University of Nottingham, Nottingham, UK. California, and Medical Director of endothelial keratoplasty (DMEK) Beverly Hills Clinic, USC Gayle and surgery, which is probably one of our most “Corneal transplantation has changed Edward Roski Eye Institute, Los Angeles, difficult surgical procedures in corneal considerably over the last 15 years and CA, USA. transplantation today. The current surgical many of those changes are thanks to approach to DMEK makes it generally technology derived from refractive The future of cataract and inappropriate for complex or high-risk cases, surgery! Microkeratomes enabled refractive surgery where it is needed most – especially as it Descemet’s stripping endothelial “As a profession, our biggest challenge is has the lowest rejection risk. I’m currently keratoplasty (DSAEK), which ended the growing backlog of cataract blindness evaluating a completely new surgical up evolving into DMEK. I expect both in the developing world. Though our approach to this procedure.” procedures will be replaced by therapeutic own patients are beneficiaries of Donald Tan, Professor at the Singapore National modalities, such as corneal cell therapies increasingly sophisticated technology, Eye Centre and Duke-National University of with Rho Kinase inhibitors. Stromal cataract blindness will not be solved by Singapore Medical School, Singapore. substitutes are already in development refractive IOLs and femtosecond lasers. and I expect synthetic corneas will Different innovations that are low tech, become more commonplace. Stem cell affordable, and more easily mastered than At a Glance treatments will have a role, so long as phacoemulsification are needed. Manual • Ophthalmology is an the correct concoction of cytokines and small incision cataract surgery (MSICS) incredibly innovative field – growth factors can be found to get stem is the most important innovation so and often the forefront of cells recruited from the bone far. I work with a group within medical breakthroughs marrow and provide the Iantech, which is devoting • But what’s next, and where necessary repairs required.” resources to developing might the field be heading in Sheraz Daya, Medical the future? Director, Centre for Sight, • We asked members of our 2018 East Grinstead, UK. Power List about the future of cataract, cornea, glaucoma, “I have been pursuing refractive surgery and retina new modalities for corneal • Here, we share their thoughts… and ocular surface disorders. come together with the industry to design our own future in the best interest of we try to make sense of them all!). a low-cost iteration of its our patients.” What I see coming is data increasingly miLOOP that could be used for Florian Kretz, CEO of driving our decision making and MSICS in resource-limited countries. Augenärzte Gerl, Kretz & Kollegen; becoming more integrated; AI-assisted I am also working with a team that is Lead Surgeon, Augentageskliniken Rheine systems pulling together IOP, retinal developing a promising topical medication & Greven; Consultant & Research nerve fiber layer (RNFL)/ ganglion that could prevent or potentially reverse Coordinator of the International Vision cell layer (GCL) analyses with (better cataract formation. A non-surgical way to Correction Research Center Network measures of) visual field function and halt or delay cataract blindness will have a (IVCRC.net), University of Heidelberg; possibly newer variables like outflow far wider global impact than any surgical and CEO of the NGO Augenärzte für die resistance, episcleral venous pressure intervention ever could.” Welt GmbH, Germany. and methods of predicting conjunctival David Chang, Clinical Professor, fibrotic response to surgery. We’ll be University of California, San Francisco, “I believe [the future] will be focused on able to detect smaller rates of change CA, USA. three major areas. One will be for non- and more accurately predict future risk. accommodative patients where the use With this comes tailored management “In lens-based procedures, I believe the of a new generation of IOL will restore of need versus risk which is constantly future lies in the ability to modify the IOL accommodation; the lens capsule will be appraised.” power after implantation, as well as the the key to this technology. The second Dan Lindfield, Consultant Ophthalmologist development of the types of accommodative will focus on the younger patient group and Glaucoma Director, Royal Surrey IOLs. Surgery-wise, the future lies in the and include more advanced – and more County Hospital, Guildford, UK. field of increased precision of surgical customized – corneal-based corrections. procedures given to us by robotic systems The third will be for irregular and “We will move to more remote and lasers. As for corneal refractive unstable corneas, for instance with monitoring of care and will increasingly procedures, I consider refractive keratoconus, which will have access to more effective treatments. index shaping with intra- likely use tissue addition Blindness rates will be greatly reduced.” stromal laser application and in situ molding David Friedman, Professor and Director very promising.” of the cornea with of the Dana Center for Preventive Boris Malyugin, biomaterials.” Ophthalmology, Wilmer Eye Institute, Johns Deputy Director Ioannis Pallikaris, Hopkins Hospital, Baltimore, MD, USA General at S. Founder and Fyodorov Eye Director of the Future goals: “Collaborating with Microsurgery Institute of Vision scientists, industry and regulatory agencies Institution, and Optics, to develop the first neuroprotective agent Moscow, Russia. University of (to protect the optic nerve independent of Crete, Greece. lowering IOP).” “I believe the future Robert Weinreb, Director of the Shiley is now, and there are The future of glaucoma Eye Institute and Hamilton Glaucoma great ideas out there that just “There’s definitely a tide Center, University of California, San have to be filtered and put change. We have so Diego, CA, USA. into clinical practice. The many treatment future is what we make options (some The future of retina out of it, and I believe could say too “Breakthroughs in gene and stem cell it is very important many at the therapy will provide immense opportunity that we, as specialists, moment, as for advancing medical and surgical

www.theophthalmologist.com approaches to eye Engineering, and Integrative Anatomical Outside disease, and fighting Sciences; Director, USC Institute for the OR… degenerative retinal Biomedical Therapeutics; Co-Director, USC “I believe that healthcare disease, while big Roski Eye Institute at the University of will be transformed in data, telemedicine, Southern California, Los Angeles, CA, USA. the next 10 years by the and analytical introduction of AI, in advancements in AI and “Once we have regulatory approval for particular a technique deep learning will enhance [Nightstar’s] gene therapy programs for known as “deep learning”. public health and lift our level of evidence- recessive diseases, we will need to look at I would like ophthalmology based medicine.” other technologies for dominant diseases to be the medical specialty Julia Haller, Ophthalmologist-in-Chief, and we have exciting CRISPR projects leading the way in this regard Wills Eye Hospital; William Tasman in the pipeline.” (and I would like my institution, Endowed Chair, Professor and Chair Robert MacLaren, Professor of Moorfields Eye Hospital, to be playing of Ophthalmology, Thomas Jefferson Ophthalmology at the University of a key role in this). In the short term, I University, Philadelphia, PA, USA. Oxford, UK; and Founder of Nightstar. believe that AI will greatly increase our knowledge of ophthalmic disease using The Future? “Retinal prosthesis implants The future? “Improved recovery of vision imaging techniques that are already widely with much smaller pixels. Ultimately, we after retinal detachment repair, gene available. In the longer term, I think there hope to achieve single-cell resolution, therapy and stem cell treatments.” will be much closer integration between which might restore visual acuity at Stanley Chang, Former Edward S. imaging data and omics data – ‘AI-assisted a level better than 20/80. In addition Harkness Professor and Chairman of science’ will be required to facilitate this.” to photovoltaic restoration of sight, the Department of Ophthalmology and Pearse Keane, Consultant Ophthalmologist, we are working on transplantation K.K. Tse and Ku Teh Ying Professor of Moorfields Eye Hospital, London; of photoreceptors, and the results are Ophthalmology, Columbia University NIHR Clinician Scientist at Institute extremely encouraging!” Medical Center, New York Presbyterian, of Ophthalmology, University College Daniel Palanker, Professor, Department of New York, NY, USA. London, UK. Ophthalmology and Director of the Hansen Experimental Physics Laboratory at Exciting developments? “The increasing We’ve shared only a handful of responses here Stanford University, Stanford, CA, USA. awareness of the importance of neural – for the full Power List and more insight, cell health and not just the amelioration visit www.theophthalmologist. com/ “Argus II is just the beginning. I hope to of exudative manifestations of AMD and power-list/2018. restore color vision and enhance reading diabetes, as well as the consideration of vision so that patients can read small combined therapies to reduce print and watch television. Through neural cell loss.” the support of the California Institute Usha Chakravarthy, Professor, for Regenerative Medicine, I’ve also Ophthalmology and Vision developed a novel minimally invasive Sciences, Royal Victoria stem cell-based treatment, CPCB-RPE1, Hospital (The Belfast Trust) for patients with an advanced form of dry and Queens University of AMD, which is in a Phase I/IIa clinical Belfast, Northern Ireland. trial. The implanted scaffold of RPE are localized, and can function to support and replenish dying photoreceptors of the retina, which would help restore and prevent vision loss in patients with AMD.” Mark Humayun, Cornelius J. Pings Chair in Biomedical Sciences, Professor of Ophthalmology, Biomedical cellular metabolism – had any function Enter the beyond waste management. But today, the evidence suggests that these Exosome humble structures have significant and beneficial effects in terminally Simpler to produce and easier differentiated neural tissues. to administer than stem cell therapies – are exosomes Waste not the answer to our retinal The surge of interest in exosomes over regeneration needs? the last decade was triggered by the demonstration that exosomes contain By Ben Mead functional mRNA and microRNA (1). Furthermore, exosomes can mediate Retinal stem cell therapy works – but the transport of these RNAs to entirely cells aren’t really working in the way different cell types where the exogenous you were promised they would back in messenger is translated into protein, and college. It turns out that they protect the microRNAs modulate endogenous the retina not by differentiating into gene expression. In other words, and replacing damaged neurons, but exosomes enable one cell to modulate to pellet the exosomes, and then wash by rescuing existing, compromised the protein phenotype of another. off the supernatant. This simplicity cells. But how? After this (unprecedented) observation, is one of the great advantages of the Ten years ago, few would have guessed researchers began to postulate functional exosome approach – it’s so much easier that exosomes – small extracellular roles for exosomes. One hypothesis was than isolating specific proteins from cell vesicles that are known to assist the that malignancy-derived exosomes may culture medium. Another advantage is elimination of the by-products of contribute to malignant transformation the stability of the preparation: unlike of previously healthy cells, but a happier cells, which must be maintained at 37°C hypothesis was also made: the therapeutic with appropriate nutrition, exosomes At a Glance potential of exosomes. In heart disease, are stable at -20°C for extended • Until recently, exosomes were for example, the administration of periods (up to a year, according to some thought to function only as waste mesenchymal stem cell-derived exosomes reports). Furthermore, they are easier product excretion vehicles; in fact, mediates a cardioprotective effect similar to administer than cells: dense cell they contain functional molecules to that of the stem cells themselves. Why suspensions are too viscous to easily that can alter the phenotype of use a cell therapy approach – with all the inject, which constrains the number non-cognate cells potential issues of unwanted proliferation, of cells you can administer. Exosomes, • In particular, the ocular differentiation (and de-differentiation) by contrast, can be easily injected in neuroprotective effect of stem cells and migration – when secreted factors huge numbers. Finally, it’s easy to – which depends on preservation give the same effect? This rationale was get robustly quantifiable data with of existing neurons rather than on behind our decision to investigate the use exosomes, whereas cell delivery counts neuroregeneration – is mediated of isolated exosomes for retinal therapy. require guesswork – the vitreous isn’t a by stem cell exosomes great substrate for stem cells, and cell • Current work demonstrates Ways and means survival rates are unclear, even a few this effect in the optic crush Cells expel many extracellular vesicles; hours after injection. model, where exosome-vectored the first step in developing an exosome microRNAs eliminate about two- therapy is to remove all unwanted But does it work? thirds of the RGC death seen in vesicles. Fortunately, this is simply a We decided to investigate the untreated animals question of ultracentrifugation. In brief, therapeutic potential of stem cell • Stem cell-derived exosomes may we expand stem cells in a vat and harvest exosomes in the optic nerve crush form the basis for a novel, cell-free the culture medium; spin it at low speed model (2). This a good model to test neuroprotective glaucoma therapy to remove cell debris; spin at high speed neuroprotective strategies for retinal

www.theophthalmologist.com 40 NextGen

6600

“The great majority 50 m) of exosome- μ 40 * mediated 30

neuroprotection can * be attributed to 2200 * Mean RNFL thickness ± SEM (μm) ( their microRNA 10

component.” 0 IIntactntact OONCNC OONCNC + OONCNC + IIntactntact OONCNC OONCNC + OONCNC + BBMSCMSC FFibroblastibroblast BBMSCMSC Fibroblast ExoExosomessomes ExoExosomessomes ExoExosomessomes ExoExosomessomes ganglion cells (RGCs): traumatizing the Days optic nerve (with a crush) destroys RGCs ppost-ONCost-ONC 0 21 within about three weeks while leaving all other retinal cell types intact. In our study, Figure 1. RNFL thickness in rat eye after optic nerve crush (ONC) and exosome treatment (2). we administered intravitreal injections of Note that ONC eyes lose well over half of the RNFL thickness; in BMSC exosome-treated eyes, the loss is 3×109 exosomes at the same time as the reduced by about 50 percent. Fibroblast exosomes confer much lower protection. crush. Three weeks later, we sacrificed the animals, retrieved the retinal tissue and stained the cells for microscopy. When we compared the number of RGCs surviving 100 in treated and untreated animals, we saw a 90 clear difference: untreated rats lost about retina 90 percent of their RGCs, while treated f 80 rats lost only about 30 percent (Figures 1 70 60 and 2). Furthermore, the exosome-treated per mm o

RGCs maintained function as measured GC 50 R ± SEM by electroretinography (Figure 3). f 40 er o We also investigated the mechanism b 30 by which exosomes might mediate this 20 pronounced protective effect, and found Mean num 10 that down-regulating stem cell microRNA 0 results in exosomes that displayed a reduced Intact ONC ONC + Intact ONC ONC + protective effect (Figure 2). This finding BMSC BMSC Exosomes Exosomes strongly suggests that the great majority of RBPMS Brn3a exosome-mediated neuroprotection can be S attributed to their microRNA component.

Time to translate? Figure 2. Mean number of RGC per mm of retina in rat eye after optic nerve crush (ONC) and Our work indicates that stem cell exosomes exosome treatment. may represent the basis of an entirely new Note that the ONC results in loss of approximately 85 percent of RGCs in untreated rats, but rats treated with therapeutic modality: one that uses stem MSC exosomes lose only about 20 percent of their RGCs. This protective effect is largely eliminated by using cells not as a tissue replacement product, exosomes from stem cells in which microRNA production has been downregulated (2). NextGen 41

But again, the same could be said of 60 whole cell therapies, and so far, there are no data to suggest that these have

50 safety issues related to exosome activity.

μV) Maybe in the future, we will identify

40 the microRNA subset responsible for the * exosome therapeutic effect, and build a

tude ± SEM ( therapy based on that alone. That said, it 30 pli may be simpler to use naturally occurring

R am vesicles, especially given that they are so T 20 easy to isolate, store and administer. * Looking ahead, we envisage exosome- Mean pSTR amplitude ± SEM (μV) pS 10 mediated therapy not just for glaucoma but also for conditions, such as AMD. 0 Identifying all possible applications IntactIntact OONCNC OONCNC + IIntactntact ONC OONCNC + BMSBMSCC BMSBMSCC will require us to address various DaysDays EExosomesxosomes EExosomesxosomes post-ONCpost-ONC 0 21 fundamental questions, such as optimal dosing and required dosing frequency.

And that means there’s plenty to keep us busy! Figure 3. Positive scotopic threshold response (pSTR) in treated and untreated rats after ONC (2). ONC results in a ~70 percent reduction in mean pSTR amplitude in untreated rats; exosome treatment cuts this Ben Mead received his PhD from the loss of function by about half. University of Birmingham (UK) for work on the use of stem cells to treat but as a source of sub-cellular protective the risks, such as retinal detachment, retinal disease and to prevent the death factors that mediate their effect associated with ocular cell therapies. of retinal ganglion cells. Currently, he through the target cells themselves. A possible issue is the fact that is a post-doctoral fellow at the Section Exosomes have similarities to viral and exosomes contain thousands of different of Retinal Ganglion Cell Biology of liposomal gene therapy vectors – but microRNAs, which in theory could the National Eye Institute, Bethesda, are far easier to produce. They are also modulate thousands of different genes MD, USA, where he is investigating extremely straightforward to administer: – a potential source of off-target effects. the neuroprotective potential of stem cell intravitreal injection is already standard factors. His current position is funded by clinical practice and is already received the Marie Skłodowska-Curie by millions of patients a year. Fellowship Scheme There are other reasons to believe that the clinical pathway for exosome- “Given that these References based glaucoma therapies will be 1. H Valadi, et al., “Exosome-mediated transfer straightforward. In particular, stem [stem] cells are of mRNAs and microRNAs is a novel cell therapies are already in trials for the mechanism of genetic exchange between cells”, treatment of retinal disorders, including secreting exosomes, Nat Cell Biol, 9, 654–659 (2007). PMID: glaucoma and optic nerve injury – for 17486113 example, the SCOTS trial (3), which you could say that 2. B Mead and S Tomarev, “Bone marrow- is testing autologous bone marrow stem derived mesenchymal stem cell-derived cells in retinal and optic nerve damage exosomes are exosomes promote survival of retinal ganglion and disease. Given that these cells are cells through miRNA-dependent mechanisms”, secreting exosomes, you could say that already in the Stem Cells Translational Medicine, 6, exosomes are already in the clinic! All we 1273–1285 (2017). PMID: 28198592 are proposing is a more efficient way of clinic!” 3. https://clinicaltrials.gov/ct2/show/ delivering the vesicles – one that avoids NCT01920867

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44–46 A Question of Capacity Marty Spencer writes about how the Seva Foundation is going about adding another million sight-saving surgeries in developing countries – per year – by 2020.

47–49 How to Approach Surgery in Your Early Career Bobeck S. Modjtahedi and Eduardo Uchiyama share ten tips for being a better retina surgeon, after you’ve completed your fellowship. 44 Profession

A Question of Capacity

How Seva plans to add another million sight-saving surgeries in developing countries per year by 2020

By Marty Spencer

A recent paper in the Lancet from the Vision Loss Expert Group (VLEG) conveys sobering data about the projected increase in blindness worldwide over the next 30 years. “Global causes of blindness and distance vision impairment 1990–2020: a systematic review and meta-analysis,” (1) Marty Spencer in the field with Seva.

found that there are 253 million people increase in avoidable vision impairment At a Glance worldwide with vision impairment, by 2050. • Preventable blindness is on the rise including 36 million who are blind and These trends can seem discouraging, globally, according to new data from 217 million with moderate or severe visual but within them is a kernel of hope. the Vision Loss Expert Group; there impairment (MSVI). A full 89 percent of Because so many of the vision-related are clear and specific actions that can visually-impaired people live in low and challenges are treatable or preventable, be taken to change this trajectory middle-income countries. there are clear and specific actions that • Approaching its fortieth The authors of the study estimated that can be taken to change the trajectory. anniversary, Seva Foundation 81 percent of visual impairment (blindness I have volunteered for many years with is increasing capacity in eye care and MSVI combined) is avoidable. In the Seva Foundation, delivering cataract facilities around the world through this case, “avoidable” includes cataract surgery training and technology to its Global Sight Initiative (GSI), and uncorrected refractive error, the two underserved regions of the globe. Groups so that an additional one million conditions included in the World Health like Seva are pioneering cost-effective and people will receive sight-restoring Organization’s Global Action Plan. It sustainable solutions that will bring us surgery every year by 2020. also encompasses trachoma, glaucoma, much closer to a world free of avoidable • Ophthalmologist Marty Spencer, diabetic retinopathy and corneal opacity. blindness, perhaps someday much closer long-time Seva board member, Additionally, the VLEG study than we might imagine. talks about his volunteer work found that the prevalence of visual Seva was founded 40 years ago to with Seva, training local eye care impairment has been dropping over address the problem of preventable and professionals and introducing new the last 25 years, from 4.6 percent in curable blindness. Since that time, the technologies to eye care facilities in 1990 to 3.4 percent in 2015. That’s the foundation has been developing and developing countries good news. But there’s also bad news; perfecting the technological, capacity- • Seva’s cultural competence model the study forecasts that various global building and outreach methodologies of building local capacity where trends, including population increase for delivering sight-saving and sight- cataract surgery takes 15 minutes, and ageing, threaten to overwhelm our restoring services in underserved regions costs $50, and is offered on a sliding existing efforts. Applying the new VLEG throughout the world. Through its Global scale to patients should help local eye data, the International Agency for the Sight Initiative (GSI), Seva plans to care facilities become self-sustainable Prevention of Blindness (IAPB)’s new increase capacity in eye care facilities within 5 to 10 years Vision Atlas (2) projects a threefold around the world so that an additional Profession 45

one million people annually will receive sight-saving surgery by 2020.

A sustainable model GSI pairs established, successful mentor eye hospitals with mentee hospitals in need of training and support. Through this support, one mentee hospital in the GSI network has increased its annual capacity for performing cataract surgeries from 4,000 nine years ago to 10,000 today. If the 94 hospitals currently receiving mentorship match that output – which is a feasible Marty Spencer (top left) training eye care professionals at a Seva partner facility. goal, based on past performance – together they would get us more than halfway to the global goal of one-million additional cataract surgeries a year. There’s cause for more hope. These current GSI mentee hospitals only cover a small portion of the low- and middle- income countries of the world: a handful in Central America and the Caribbean, fewer than ten in Africa, several in Nepal, and the bulk of them in various locations in India. An expansion of this network of mentor and mentee eye hospitals could exponentially increase the number of people receiving eye care. Along with GSI’s hospital network, Seva provides funding, support, and critical capacity-building to eye care centers in numerous locations around the world. This “teach a man to fish” model has proved enormously successful. The locally-run eye Marty (center) with his daughters Laura (left), Chair of the Board of Seva Canada and Justine, a care programs Seva partners with generally volunteer for Seva Canada. become self-sustaining within five to ten years. In many cases, this is done by using local providers aware of and trained in the Nepal. Each lens cost $300 at that time in multi-tier payments systems, where one- latest medical innovations. the U.S., but came free to Seva, enabling third of a facility’s patients subsidize care For example, I introduced manual their partners to offer free cataract surgery for the other two-thirds. sutureless cataract surgery in several to those in need. countries over the past 20 years. Another As IOL technology stabilized, the supply The role of volunteers Seva board member, Dick Litwin, of free lenses dried up, and so Seva and its A key aspect of this model is access to low- introduced the use of intraocular lenses sister organization, Seva Canada, provided cost, but still high-quality, materials and (IOLs) for cataract surgery in India back the impetus for what eventually became techniques. Seva has played a crucial role in the early 1980s. At first, as IOLs were Aurolab. Now the manufacturing division in the development of several innovations going through developmental iterations of Aravind Eye Hospital in Tamil Nadu, in eye care delivery in underserved regions. in the West, Seva obtained the outdated India, Aurolab makes IOLs and other Volunteer ophthalmologists and other eye models – which were still perfectly viable – ophthalmic consumables, such as surgical care providers play a key role in keeping for their partner eye hospitals in India and sutures, pharmaceutical products, surgical

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Changes in the global prevalence of avoidable visual impairment, 1990–2015 and projections to 2020 (2). blades and other equipment. Producing ophthalmologists and other eye care high-quality supplies in-country, with medical professionals with their newly- quality and cost controls, has been a discovered life’s calling of helping people major factor in the spread of free cataract to see. This was certainly the case for me. surgery to people in need. The current My avocation for the past 30 years has cost of sight-restoring cataract surgery been alleviating and preventing blindness Global blindness and visual impairment data 2015 performed at Seva-partner eye camps in developing countries – work that has (Source: IAPB Vision Atlas) and hospitals is only $50 – and that price been extremely meaningful to me. I includes both materials and surgical staff invite everyone working in the field of eye are serving as a hopeful springboard to required to perform the procedure. health to consider contributing their time launch the next phase of the work. We and talents to this global effort. There go forward with a 20/20 vision of a world Cultural competence are myriad opportunities to do so. For where all can see. Adapting teaching and service techniques example, I recently volunteered a week’s to the particular needs and cultures of time training at a center in Latin America Marty Spencer sits on the Board of Directors various developing nations has also and traveled to provide and demonstrate of Seva Foundation and Seva Canada. He contributed immensely to expanding the services in rural Nepal. has received the Governor General’s Medal volume and quality of eye care worldwide. With its global network, volunteer for Volunteers Award from the Canadian When Litwin first traveled to India, the force of ophthalmologists, eye care nurses Government for his commitment and service person he shared those IOL prototypes and other medical professionals, and its to prevent blindness and restore sight around with was Venkataswamy, a founding strong donor base, Seva Foundation is the world. board member of Seva and the force strongly positioned to provide sight- behind Aravind Eye Hospital. At that saving and sight-restoring services to References time, Aravind had already created a more people in more places around 1. SR Flaxman et al., “Global causes of blindness successful model of delivering high- the globe in the decades to come. The and distance vision impairment 1990-202: a volume, high-quality, low-cost eye care challenges, as evidenced by the latest systematic review and meta-analysis”, Lancet in rural regions of India. Seva’s founders data from VLEG, are daunting. But Global Health, 5, e1221–e1234 (2017). PMID: realized this model could be adapted Seva and their governmental and non- 29032195. to different countries in culturally- profit compatriots in the field of reducing 2. International Agency for the Prevention of appropriate ways. global blindness have made enormous Blindness, Vision Atlas, Available at http://atlas. Seva has a long history of connecting strides. Seva’s four decades of experience iapb.org/. Last accessed February 21, 2018. Profession 47

Every young surgeon graduates How to from training with a unique skill set that was cultivated over years Approach of education. However, it is important to remain mindful Surgery in Your of your limitations and biases, while always trying Early Career to improve. We have had the Ten tips for being a better opportunity to learn from retina surgeon, after you’ve skilled mentors as well as completed your fellowship from our own experiences, and we hope our pearls of By Bobeck S. Modjtahedi and wisdom will help you in Eduardo Uchiyama your early career. Although our article is focused onn The beginning of your post-fellowship vitreoretinal surgery, manyany career is fraught with multiple perilous of these lessons can be applieded transitions. Perhaps the most daunting is broadly to other surgeons. You assuming the role of primary surgeon. The will find yourself torn in different first three-to-five years after training can directions in the operating room be thought of as a second fellowship where and some pieces of advice may seem you will: hone your skills as a surgeon and at odds with others; learning the right improve your efficiency, determine what balance of competing instincts is the key approaches work best for you, and define to becoming a good surgeon. your threshold to operate for different conditions. The patients you operate on 1. Learn from other people’s mistakes now will be seeing you for years to come instead of making your own them look weakweak to their newnew – you want to make sure to put yourself The vitreous base is not the only colleagues, andd thoughthough some more in the best position for success, as you will thing that benefits from a little established surgeonsons may not be be reminded of that surgical effort every support – mentorship and support very sympathetic, mostost of your time you examine that retina. will be critical elements to your co-workers are investedd in your success. Sleepless nights and success. Surgeons have two phasesphases anxiety are common features of in life – mentee and mentor. MMostost At a Glance the very common but often under- established doctors are happy to • You are not done with learning after diagnosed Early Surgeon Syndrome take a new physician under their you’ve made it past fellowship (ESS). It may seem cliché, but wing and help guide them. Take • The patients you see operate on being a physician means being a time to identify some mentors at now will be the patients you see lifelong student. Surgery can be your new practice and figure out for years to come – every retina overwhelming, even for seasoned who will be a trusted and safe “no examination will be a reminder of veterans, so do not be afraid to ask judgment” resource. It is important how that surgery went. questions. Your prior mentors will to have someone you can go to for • You need to be mindful of your always be happy to hear from you all the “dumb” questions you might limitations and biases – and and lend their insights – you will be afraid to ask others. It is critical always work to improve yourself always be one of their fellows in to have people you can trust in a as a surgeon their mind, your association with pinch – including those you can call • Here, we share what we’ve them does not end at graduation. from the operating room. learned from our experiences as Many young surgeons are afraid 2. Treat the patient, not the picture early surgeons that asking for help will make It takes skill to know when to operate

www.theophthalmologist.com 488 ProfessionProfo esesssiionn

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Manyny – get the job done andand get it the time to talk to your operating patients consider alll eye donedone right. room staff to let them know what surgeries to be the same, Similarly,Similarly, do not be afraid you plan on doing before the case, so they might expectpect 20/20 to send patients fforor second what to have opened (and what to vision after a chronicronic maculmacula-a- opinionsopinions or ask yoyour colleagues have in the room ready), and how off retinal detachmentchment repairrepair to take on a parparticularlytic you like to run your ship. In the because their next-doornext-door challengingchallenging case.case Patients often operating room, it’s common to neighbor couldld see really wewellll appreciate the opportunityo to feel like you’re in a rush to get the after routinee cataract surgery. get a second opinionop and it can case started – but it is important to For many conditionsconditions – even engender moremor confidence in invest a few minutes to make sure the routinee macular hole oror you because iti shows you have things are set up like you want. epiretinall membrane – patients nothing to hide.h You’ll have more Make sure the microscope is on the need to ununderstandderstand that they surgeries ththan you can count right settings, the foot pedals are may seee better, but the chance in 10 yearyears,s, losing a case in the in the right place, the bed is at the that they willwill seesee perfectly is interest ofof being smart now will correct height, and the patient is remote. If you feell likelike youyou are not mamakeke a difference in the long draped like you want. Small issues making “a pitch” to get a patienttient term. MMost senior colleagues in your setup can cost you far more into the operating room, it’s time to appreciateappreciat an associate that is time later during the case or prove re-evaluate if it is the right surgical conservativeserva in their approach. to be a persistent headache while case or the right surgical patient. 5. Respect the lens, but do not be a slave operating. It is important to plan for At the end of your consultation, to it as many intraoperative possibilities the patient should be asking you to In a competition between the before you head into the operating operate, not the other way around. retina and just about any other part room – have a plan in place for 4. Be willing to take it slow and to take a of the eye, the retina wins. Your every contingency, so you can have step back goal is to fix the retina – the most the appropriate equipment (and ProfessionProfesession 499

mindset)mim nddset)t iinn ththee roroomoomm ttoo smsmoothlymooothly a “win”n” wiwillll bbee fofforr eaeachach susurgery.urggere y.y YouYouu do not want to be one fixfi ttheheh p roproblemoblem a sas so soonon a sas it tita riarisessees case. OnOncece yyouou hithitt thethe of tthosehose ssurgeonsur whose patients – whwwhatata ifif thethe lenslens fallsfalls duringdurinng thethe winn ththreshold,reshold,d yyououu kknownow knknowow tthehe OOR staff’s names by case?cac see? WhWWhatata iiff yoyouu cannotcannot getget thethe youou cancaan comfortablycomfforttably mememory.moryy. SSome patients simply have hyaloidd offff eeasily?asa ily? WWhathah t ifif yyououu lloseoso e enendnd ththee sussurgery.rgere y.y YYou’llouu’ll babadd protoplasmproto and are destined your ILM flap beforeforre cocompletingmpleeting ttheh finfindd yo yourselfourself s staringtaaringn aatt aa to rrequireequ repeat surgery; however, peel? Early in your career, whenhenn yyouro mamacula,cula, vitreousvitrt eous base,base,e oror whwhenen the need for an extra step cases take longer, you should expect a rroroww of llaserasserr aandnd wwonderingondering mamayy be equivocal, lean towards the view to worsen towards the end if iitt lolooksoks gogoodod eenough.nough. IIff yoyouu ovover-treatmente if it increases your of the case – so anticipate in advance araree ththereere to peelpeel ann epiretinalepiretinal pprobability of success (see Tip #7). what to do. You will find the amount memmembrane,mbrranen , yoyouou shshouldn’touuldn’’t obobsessseesss WWhich brings us to… of cornea you scrape is an indirect overerr a stubbornstuubbboro n piecepiece ofo IILMLMM tthathah t 1010.0 Scleral buckles still have a place in measure of your surgical speed – will not comeomme off f rofromm th thee ma macula.cula. detachment repair remember, Viscoat is your friend. You should go ass ffarar aass yoyouu needneed ttoo Do not let anyone tell you Most people want to relax after ensure a good result forfor thethe patient,patientn , otherwise. It seems increasingly finishing a day in the operating without cutting corners. Resistist thethe popular to view the scleral buckle room, but instead invest the time to impulse to make it look perfect as a remnant of a bygone era, think critically about your cases for for the sake of looking perfect – now obsolete due to advances in the day – this works even better if the patient is not going to see how vitrectomy surgery. Although for you can record your surgeries and their retina looks, they only care many detachments a buckle is watch them. Think about places how they see. no longer necessary, it still holds where you could have been more 8. Do not become complacent value in the right context. While efficient, as well as what struggles Avoid being too adventurous in refractive shift, ptosis, and diplopia you encountered and how you the first few months of your career are legitimate concerns when to overcame them, as it will help you – stick to what works best in your comes to scleral buckling, there will plan your future surgeries. hands. Over time, however, you’ll be many cases where you are more 7. Take the easy win want to venture out and try new likely to wish there was one there Invariably, in any surgery, there techniques. It is important to strive than regret putting one on. You will comes the critical juncture of when for continued improvement and often hear colleagues say they think to decide you are done. This can growth – the best surgeons are not they can “get away” or “get by” with be a struggle for young surgeons. doing the same thing they were 20 just a vitrectomy. Focus instead on There is a balance between doing years ago. Take advantage of high- how to “get it right.” a limited core vitrectomy and a quality surgical videos available few dozen spots of endolaser for online and even reach out to Bobeck S Modjtahedi is a vitreoretinal a diabetic vitreous hemorrhage authors for advice – most of them surgeon at the Southern California and meticulously shaving the love passing on additional thoughts Permanente Medical Group (SCPMG) in vitreous base for an epiretinal and helping you employ their Baldwin Park, CA, USA. He was voted membrane. The longer you are in techniques. Check in frequently #6 on The Ophthalmologist ‘Rising Stars’ the eye, the greater the likelihood with your former co-fellows and Power List 2017. He can be reached by that something could go wrong; contemporaries to see how their email at [email protected]. Eduardo however,ho there is an important surgical approaches are evolving. In Uchiyama is a uveitis specialist and trade-offtrade-off to consider, though a few years, you should be giving vitreoretinal surgeon at Retina Group some are ffondond of saying “the tips to your old fellowship mentors of Florida in Ft Lauderdale, FL. He enemy of good is perfect”pe it can on how you have expanded on is also an Affiliate Assistant Professor be equally true that “the“the eenemy of their methods. of Clinical Biomedical Sciences at the goodgood is ‘good enough’.” FindingFinding 9. Your best chance to fix a problem is the Charles E. Schmidt College of Medicine, the balance is one of the hardestharde first time Florida Atlantic University, Boca Raton, parts of the “art” of surgery,surgery, butb The probability of success falls FL, USA. He can be reached by email at ultimately you have to lealearnrn what exponentially with each successive [email protected].

www.theophthalmologist.com Mr. Fix-It Sitting Down With... Keith Barton, Consultant Ophthalmologist, Moorfields Eye Hospital, London, UK Sitting Down With  51

What has been your most later, and it is exciting to see how they’ve successful collaboration? grown and how they will continue to grow. “John Dart taught Without a doubt, working with Don This year we will host our first Retina Budenz; we’ve had enormously successful Forum on September 19 (the evening me that surgeons collaborations dating back more than before EURETINA). 20 years. I owe the majority of my H-index can actually be very to Don’s relentless hard work in research. What are the highlights of your career? We started working together in 1996 There have been many. Being asked to logical, scientific with the first use of amniotic membrane manage glaucoma in patients attending transplantation in glaucoma surgery, Moorfields’ burgeoning uveitis clinics and, contrary to initially in rabbits and subsequently in a first springs to mind; I had an instant human randomized controlled trial. After referral base of largely young patients – the popular belief, that, we collaborated – or rather, Don did majority of whom required surgery. One all the work and I helped! – in the ABC of the biggest moments was convincing sometimes even study (which we co-chaired), the Tema Eye Pharmacia in 1999 to bring the Baerveldt Survey and the Tema Eye Survey II. In Glaucoma Implant to the UK. For context, think a lot.” between, we were both investigators in the my Moorfields clinic had become a bit of TVT and PTVT studies. Parenthetically a “bleb-repair shop”, with endless streams (and outside of Ophthalmology), Don’s of patients returning for more and more Lightman, who told me early on that I should wife, Sue, rescued my 19-year-old son from trabeculectomy bleb fiddlings, revisions, be at a tertiary referral center and helped a crack house in Chapel Hill! repairs... Having access to the implant kick-start my career in uveitic glaucoma. John meant that we glaucoma surgeons finally Dart taught me that surgeons can actually Wait, what? had access to something that could control be very logical, scientific and, contrary to Yes. Four years ago, Don hooked my patients’ IOP with a high level of efficacy popular belief, sometimes even think a lot. would-be medical student son up with in complex surgical cases. Crucially, he taught me not to be scared of a summer job in an HIV immunology Being part of the TVT, ABC and complex cases. Finally, Roger Hitchings, lab in North Carolina, where he spent PTVT studies was also privilege, as I was who gave me a consultant job, encouraged a few months “growing brain cells on able to help contribute to the generation of my entry into complex surgical glaucoma, cover slips,” as he told his mother. Said a firm evidence base for the role of aqueous inspired and encouraged my international son found himself accommodation using shunts in glaucoma surgery. Then there’s career and, probably the greatest compliment, the highly reputable “Craigslist,” but my involvement in the MIGS boom; graciously permitted me to look after his started grumbling about his party-animal watching glaucoma surgery – a field in private patients on his retirement. housemates. The night of our first Asian which I have toiled for years – suddenly Ophthalmology Futures Forum in Tokyo, become hot and sexy, with a feeding frenzy What drives you? at midnight (after a lot of wine), I received of commercial interest, has been incredible. Caffeine, patient’s appreciative comments a call from him: he wanted to get out It’s been quite a ride these past few years! after controlling the pressure in seemingly immediately. His housemates were always impossible cases, training surgical fellows high on various substances, they partied all Who do you consider your mentors? and teaching them not to shy away from night every night, they never locked the My first in medicine was Desmond complex cases, like John and Roger did doors, and so on… Sue, with 30 minutes Archer, retired Chair of Ophthalmology for me. Caffeine again. And the pursuit notice, organized an actual SWAT team, at the Queen’s University of Belfast, a of something that is at least as effective who swooped in and transferred him (with charismatic figure who by the early-to- as the Baerveldt Glaucoma Implant, that all his stuff) to Chateau Budenz, where mid 1980s had built one of the most is at least as predictable as femtosecond he remained! impressive ophthalmology departments laser-assisted cataract surgery, that Back to collaborations: a fruitful one of in the UK and who inspired me to take doesn’t require Heath-Robinsonian a different nature has been with Kuldev up ophthalmology. Then there was James systems of occluding sutures to prevent Singh and the Ophthalmology Futures McGill in Southampton, who told me early hypotony, and that doesn’t risk Forums, which we first launched in 2012. in no uncertain terms in 1989 to apply to endothelial cell loss, later erosion or Six European and three Asian Forums Moorfields. After James, there was Sue double vision.

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