The Capsulotomy: from There to Where?

Home , Albrecht von Graefe, Capsulotomy, Ophthalmoscopy, Trifocal lenses

JUNE 2017 # 42

In My View NextGen Profession Sitting Down With Presbyopia correction in Dry eye: how the humble Louis Pasquale believes it’s Innovator extraordinaire, younger patients – what’s best? eyedrop is evolving time to redefine POAG Sean Ianchulev

17 36 – 38 42 – 45 50 – 51

The Capsulotomy: From There to Where?

A tale of jealousy, rivalry and pride… The unfolding story of the capsulotomy over time 18 – 27

www.theophthalmologist.com It’s all in

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In a Micropig’s Eye This Wellcome Image Award winner depicts a 3D model of a healthy mini-pig eye. A contrast agent, µAngiofil, was injected into the microcirculation of the eye to allow visualization of the tiny vessels – the images were then transferred to a 3D model and printed. “The image displays the incredible vascular network of a healthy minipig’s eye,” says Peter Maloca, one of the creators of the image. “Our findings should contribute to better understanding of how the circulation is important in diseases like diabetic retinopathy or in ocular tumors. And as an image, it’s amazing to look at just how wonderful an architect nature is,” he adds. Image courtesy of Peter Maloca, University of Basel, Switzerland, and Moorfields Eye Hospital, London; Christian Schwaller, Ruslan Hlushchuk, and Sébastien Barré

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www.theophthalmologist.com Contents

03 Image of the Month Upfront In My View

10 Dropping the Needle 16 When is it best to operate for 09 Editorial congenital glaucoma? Nader The Big News Is Big Data, 11 Business in Brief Bayoumi discusses what’s by Mark Hillen. known, and explains why at 12 No More Playing Pirate? his clinic, they only operate in patients over two months of age. 13 Mind the Gap On The Cover 17 Günther Grabner shares why

JUNE 2017 # 10 14 CLARITY Achieved he believes that solutions of

Upfront NextGen Profession Sitting Down With Presbyopia correction in How the humble eyedrop Louis Pasquale on why it Jules Stein Institute founding younger patients – what’s best? is evolving for dry eye is time to redefine POAG father, Bradley Straatsma

17 38 – 40 42 – 45 50 – 51 An artistic representation of some of the corneal plane, such as The Hubble Telescope of the Eye

The quest for truly non-invasive ocular biomechanical measurements 18 – 27 the key events in the history of the 15 Survival Scar presbyLASIK and corneal caspulotomy, combined with some inlays, are best for younger www.theophthalmologist.com devices of the near-future. patients with presbyopia. START HERE

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The Ophthalmologist Smartfield Perimeter 210x266 e 05.17.indd 1 22.05.2017 18:13:45 New OCULUS Smartfield ISSUE 42 - JUNE 2017

Editor - Mark Hillen [email protected] Associate Editor - Ruth Steer [email protected] Associate Editor - Nick Miller [email protected] Content Director - Rich Whitworth [email protected] Editorial Director - Fedra Pavlou [email protected] Publishing Director - Neil Hanley [email protected] Sales Manager - Abigail Mackrill [email protected] VP Sales North America - Scott Schmidt [email protected] Head of Design - Marc Bird [email protected] Junior Designer - Hannah Ennis 50 [email protected] Digital Team Lead - David Roberts [email protected] Digital Producer Web/Email - Peter Bartley [email protected] Digital Producer Web/App - Abygail Bradley Feature [email protected] Audience Insight Manager - Tracey Nicholls [email protected] 18 The Capsulotomy: From Audience Project Associate - Nina Duffissey There to Where? [email protected] Traffic and Audience Associate - Lindsey Vickers Richard Packard takes a journey Profession [email protected] Please note: The availability of the products and features may differ in your country. Please note: The availability of the products and features may differ in your country. Specifications and design are subject to change. Please contact your local distributor for details. through time, recanting the Traffic and Audience Associate - Jody Fryett [email protected] history of how the capsulotomy 42 Redefining POAG Social Media / Analytics Associate - Ben Holah has evolved and exploring where Primary open angle glaucoma [email protected] Events Manager - Alice Daniels-Wright it may go in the years to come... (POAG) has been a source of [email protected] confusion for many specialists Marketing Manager - Katy Pearson over the years… Louis Pasquale [email protected] Financial Controller - Phil Dale shares why it is time for the [email protected] In Practice disease to be redefined. Accounts Assistant - Kerri Benson Welcome the Youngest Member [email protected] Chief Executive Officer - Andy Davies 30 Single Incision: 46 B alancing the Cost of Success [email protected] Chief Operating Officer - Tracey Peers to the OCULUS Perimeter Family – Multiple Advantages and Failure [email protected] For patients with open- Ian Catchpole shares his story Change of address angle glaucoma, stab incision on working with sustained [email protected] Smart, Precise, Compact! Nina Duffissey, The Ophthalmologist, glaucoma surgery (SIGS) release anti-VEGF therapies, Texere Publishing Ltd, Haig House, Haig Road, offers multiple advantages over and makes the case for Knutsford, Cheshire, WA16 8DX, UK trabeculectomy. Soosan Jacob publishing all results, even those General enquiries www.texerepublishing.com overviews the technique, and that might be negative, to help [email protected] +44 (0) 1565 745 200 how to perform it. prevent duplications of research [email protected] work that might end New OCULUS Smartfield: Optimized for Distribution in disappointment… The Ophthalmologist (ISSN 2051-4093) monitoring functional impairment in glaucoma and The Ophthalmologist North America (ISSN 2398-9270), is published monthly by Texere Publishing Ltd and is distributed in the • Standard automated perimetry with a new feature: NextGen US by UKP Worldwide, 3390 Rand Road, South Plainfield, NJ 07080 PATH – Predictive function-structure display Periodicals postage paid at South Plainfield, NJ 36 Redefining the Eyedrop Sitting Down With POSTMASTER: Send US address changes to (Title), (Publisher) C/O 3390 Rand Road, • LCD-screen ensures reliable calibration Conventional treatment South Plainfield NJ 07080. for ocular surface tears has 50 Sean Ianchulev, Professor Single copy sales £15 (plus postage, cost available • on request [email protected]) Closed construction: no dark room required involved artificial tears, and of Ophthalmology at New Annual subscription for non-qualified recipients £110 cyclosporine and corticosteroid York Eye and Ear Infirmary Reprints & Permissions – [email protected] Visit the OCULUS booth 106 during WGC, Helsinki! The opinions presented within this publication are those of the authors drop regimens. Stephen Lane of Mount Sinai, New York, and do not reflect the opinions of The Ophthalmologist or its publishers, Texere Publishing. Authors are required to disclose any relevant financial discusses how new treatments and Founder of Eyenovia and arrangements, which are presented at the end of each article, where relevant. © 2017 Texere Publishing Limited. All rights reserved. are shaping the field of dry eye. Iantech Medical. Reproduction in whole or in parts is prohibited. www.oculus.de Follow us!

The Ophthalmologist Smartfield Perimeter 210x266 e 05.17.indd 1 22.05.2017 18:13:45 It's Time to make a Move

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The_Ophthalmologist_EU_FEMTO_LDV_Z8_Ad_201x266mm.indd 1 08.09.16 10:00 The Big News Is Big Data It's Time to Might the next Nobel Prize in Physiology or Medicine Editorial go to a coder, rather than a researcher or doctor? make a Move

n May, I attended the annual meetings of both ARVO and It has never been so simple to adapt new technology into your daily workflow. the Royal College of Ophthalmologists. And what was the big news at both? Big Data. The truly mobile FEMTO LDV Z8 finally enables you to use next generation IAs ever, many of the best conversations I’ve had on these femtosecond laser technology for your cataract and refractive surgeries. topics have been in hotel bars next to the congress venues... So what did I learn? Electronic medical records (EMRs) are the future. Well- www.femtoldv.com designed ones with lots of data are powerful – and will soon offer real-time information on the safety and efficacy of interventions in your institute and beyond. Of course, most of you dislike filling in the forms, clicking drop-down menus and radio buttons, spending more time typing than talking to patients. Fortunately, all of you people happily using Siri, Cortana and Google Now are making speech-to-text tech pretty awesome. Within 5–10 years, your EMRs could be filled in by the computer listening to the conversation with your patients, with any diagnostic scans being added in automatically. A quick check by the doc and it’s done. The automated algorithmic analysis of retinal image work is now well-known, and it is going to represent some amazingly helpful decision support and assist with the accurate triage of patients – separating the ‘worried well’ from those truly needing attention from ophthalmologists. Pearse Keane worries about the High Street: optometrists are all now adopting OCT. The amount of image data needing quality analysis will soon explode. It has to be dealt with somehow – and I think we have the answer. And AI approaches can do even more. I watched Cambridge University’s Peter Thomas present his group’s work on automated eye tracking, pupil and face analysis tech. It was so smart that it could map every muscle visible in the face and track each one’s every movement, so patients undergoing a short eye test need only be filmed to diagnose and assess any number of gaze, pupillary or facial nerve disorders. What’s most interesting to me is this: a future Nobel Prize in Physiology or Medicine could go to an artificial neural network researcher, whose contribution was entirely in silico – someone who has never seen the inside of a medical school, let alone interacted with a patient. And might that person and their team have done more than Lister, Fleming or even Hippocrates to transform medicine? Augencentrum Zytglogge, Dr. Baumann, Berne, Switzerland

Mark Hillen Editor

www.theophthalmologist.com The FEMTO LDV Z8 is CE marked and FDA cleared for the use in the United States. For other countries, availability may be restricted due to regulatory requirements; please contact Ziemer for details.

The_Ophthalmologist_EU_FEMTO_LDV_Z8_Ad_201x266mm.indd 1 08.09.16 10:00 10 Upfront

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

We welcome suggestions on anything that’s her institute (Lisa Hill and Ann Logan) Dropping and clinicians from Queens University, impactful on Belfast, UK (Mei Chen and Heping Xu), ophthalmology; the Needle the potential of CPPs to deliver drugs into please email edit@ the eye became evident. “Anti-VEGF theophthalmologist.com Topical anti-VEGF therapy therapies are well-established treatments may offer AMD patients an for AMD but there has been little research alternative to injections on their topical delivery,” says de Cogan. “The CPP formulation brings together “We hope to be able to provide a new the well-established field of CPPs and the method of treating patients with age-related unmet clinical need for improved delivery macular degeneration (AMD),” says Felicity methods for patients with AMD.” de Cogan of the University of Birmingham, CPPs (also known as protein UK, and lead author on a recently published transduction domains) act as chaperones, paper describing topical delivery of anti- facilitating the cellular uptake of complexed VEGF antibodies to the posterior segment proteins, but according to the authors, (1). And it looks like they may have found “The internalization mechanism has not one – with the help of cell-penetrating been fully elucidated.” In their study, peptides (CPPs). the team exploited simple charge-based Originally, de Cogan was researching the interactions to formulate anti-VEGF drug use of CPPs in microbiology, but through complexes decorated by the CPPs. After collaborations with neuroscientists at confirming that the peptides were nontoxic

a b

Figure 1. OCT images of fluorescent CPP in an eyedrop on the corneal surface the time of application (a) and within the anterior chamber by 6 minutes (b). Adapted from (1). CPPC, CPP complex. Upfront 11

to cultured ocular cells, they topically applied injection in a mouse model of choroidal eyedrop formulations. But what about complexes of CPPs and anti-VEGF drugs neovascularization (CNV), and found them the issue of poor patient adherence to (bevacizumab or ranibizumab) to rat and pig equally efficacious at reducing lesion size eyedrop regimens? “The regime won’t work eyes. Through OCT imaging and enzyme- (both p<0.001 versus negative controls of for everyone and some patients may find linked immunosorbent assay analysis of CPP-only, anti-VEGF-only and PBS eye a monthly injection preferable. The key ocular tissues, they demonstrated that CPPs drops). “The anti-VEGF therapeutic had to this technology is that it gives patients were able to enter the anterior chamber the same outcome on disease progression a choice and provides an alternative that (Figure 1) and reach the posterior segment. whether it was delivered topically by CPPs might have reduced side effects,” says de “We were surprised at how quickly CPPs or intravitreal injection,” says de Cogan. Cogan. The team hope to begin clinical could enter the eye after drop application; The topically-delivered anti-VEGFs were trials within a year of raising funding. RS they can be seen in high quantities in only found to reach physiologically-relevant six minutes,” says de Cogan, adding that a concentrations and clearance from the Reference key finding was the fact that CPPs could retina after 24 hours suggested the need 1. F de Cogan et al., “Topical delivery of carry a large therapeutic protein such as for a daily dosing regimen. anti-VEGF drugs to the ocular posterior anti-VEGF through to the back of the eye. According to de Cogan, CPPs are highly segment using cell-penetrating peptides”, Invest The team also compared anti-VEGFs effective antimicrobial agents, potentially Ophthalmol Vis Sci, 58, 2578–2590 (2017). delivered by CPPs with intravitreal negating the need for preservatives in PMID: 28494491.

baseline IOP 20–36 mmHg. (1), which stated that “VSY Business in Brief • England and Wales’ National Biotechnology BV and its exclusive Institute for Health and Care distribution partner Fritz Ruck Collaborations, acquisitions Excellence’s (NICE) has Ophthalmologische Systeme and a potential case of released a Final Appraisal GmbH were convicted by the court misleading information… Determination (FAD) in which to recall all their trifocal lenses on Ozurdex (dexamethasone 0.7mg the market and destroy all such • SightLife Surgical have teamed up intravitreal implant in applicator) lenses in their possession.” with Shigeru Kinoshita to bring is recommended as a “cost and • Representatives from VSY told The a new corneal therapy to market. clinically-effective treatment Ophthalmologist: (i) this is a ruling The treatment, which involves the option for people with sight- by the German Court of First injection of cultured human donor threatening posterior non- Instance; (ii) VSY have the right to endothelial cells into the anterior infectious posterior uveitis.” appeal the judgment in the Higher chamber, has shown promising • STAAR Surgical has announced District Court and if necessary, results in over 30 patients in Japan. that their EVO+ Visian the Federal Supreme Court in • Aerie Pharmaceuticals has implantable contact lens (ICL) has Germany – a process that may reported that their IOP-lowering received a CE mark. Containing take several years; (iii) this ruling combination therapy (netarsudil an aspheric extended depth of would only apply in Germany; and ophthalmic solution 0.02% focus (EDOF) optic, the ICL is (iv) VSY has asked the European [Rhopressa] and latanoprost; indicated for the correction or Patent Office to invalidate CZM’s Roclatan) has met the primary reduction of hyperopia and myopia Patent EP 2 377 493 B1, efficacy endpoint in their Phase between +3 D and -18 D. claiming that this trifocality III trial (Mercury 2). Over the • The District Court of Hamburg patent lacks novelty. 90-day study period, the once- has issued a preliminary injunction daily eyedrop showed statistically in favor of VSY Biotechnology Reference significant superiority over BV against Carl Zeiss Meditec 1. PR Newsire, “Patent Case of Carl Zeiss both latanoprost and Rhopressa AG (CZM) because of what Meditec AG and VSY Biotechnology B.V.” monotherapies for lowering IOP VSY describe as a “misleading (2017). Available at: http://bit.ly/VSYCourt. in patients with glaucoma and press release” published by Zeiss Accessed May 26, 2017.

www.theophthalmologist.com 12 Upfront

No More Playing Pirate?

Amblyopes might soon be able to ditch the patch for virtual reality therapy

Imagine receiving vision treatment just by watching your favorite television shows. Well, patients with amblyopia could soon be doing just that – with a virtual reality (VR) headset designed to rebalance visual input to both eyes. The idea is the brainchild of Dean Travers, a former professional skier who became interested in amblyopia after suffering post-concussion vision loss in one eye (20/20 to 20/80). Commenting on the mainstay treatment of patching he said, “Being a pirate isn’t cool for very long” (1), so he endeavored to develop something better, teaming up with fellow Harvard University students (Alex Wendland and Scott Xiao) to form start-up company Luminopia. “We were shocked that patching was still one of the best options to treat the condition, so we started looking into the research and came up with the idea of applying at Luminopia works by dynamically further validation studies and wants to VR,” says Xiao, co-founder and Chief rebalancing video input through a VR improve the device before potentially Scientific Officer. headset,” explains Iason Mantagos, launching the platform in Canada David Hunter of Boston Children’s also of Boston Children’s Hospital, and the US in the next few years. Says Hospital, Massachusetts, USA, is who is leading an ongoing clinical trial Hunter, “The idea that we might soon acting as Clinical Advisor to the team. evaluating the headset for binocular be able to tell kids that they don’t need “Nobody likes telling children they have stimulation treatment of amblyopia. In a patch or eyedrops, but will ‘have’ to to wear an eye patch all day, and for good the trial, patients wear a 3D headset and watch their favorite TV show or movie reason; patches are uncomfortable, and watch videos on a smartphone for one for an hour every day while wearing VR for kids with amblyopia, they actually hour per day. Split into two four week goggles is great news for doctors and cover up the eye that has better vision segments, patients enrolled in the eight parents alike.” And the kids can still making it harder to read and even play,” week trial were randomized to a ‘full’ play pirates – if they want. RS says Hunter. Similarly, he explains that treatment group who received the VR although eyedrops are another option therapy from the beginning, or a control Reference for treatment, they aren’t popular either group who watched regular videos for 1. Vector: Boston Children’s Hospital science and because of the side effects of pupil the first four weeks before crossing over clinical innovation blog, “Can virtual reality dilation and “foggy” vision. to the treatment for the remainder of headsets save vision in people with lazy eye?”, How does the VR system work? the trial. (2017). Available at: http://bit.ly/Luminopia. “The software designed by the team Next, the team plans to conduct Accessed May 22, 2017. Upfront 13

difference between IOPDCT and IOPGAT textbooks and guidelines.” Kniestedt Mind the Gap increases,” says Kniestedt. CCT was explains that a patient who has an IOP of

found to be negatively associated with 18 mmHg and an IOPDCT-GAT difference In patients with glaucoma discordant values (rs=-0.22, p<0.02). of 5 mmHg might have a higher glaucoma or thin corneas, don’t trust Concluding that GAT values are risk than a patient who has a GAT value GAT-corrected IOP significantly discordant with DCT of 20 mmHg but an IOPDCT-GAT difference values – instead look to measurements in eyes with thin corneas of 1 mmHg. “If we know the DCT-GAT the difference between and advanced glaucoma, the authors difference and, as such, the additional risk DCT and GAT advised: “[…] to not place reliance on GAT factor in any individual patient, then we can readings, and abandon any correction use the old GAT value perfectly well.” RS IOP measurements from Goldmann formula” (2). applanation tonometry (GAT) Commenting on the results, Kniestedt References assessments aren’t all that accurate; says, “The question is whether we really 1. CGV De Moraes et al., “Modalities of tonometry central corneal thickness (CCT) can need to know the accurate IOP, or if it is and their accuracy with respect to corneal thickness impact pressure readings, with IOPGAT sufficient to be aware of an additional risk and irregularities”, J Optom, 1 43–49 (2008). being underestimated on thin corneas factor such as IOPGAT-DCT difference. I PMC: 3972696. and overestimated on thick ones (1). would say that the second is sufficient; if 2. J Wachtl et al., “Correlation between dynamic But although several GAT correction we had a device to measure the real IOP – contour tonometry, uncorrected and corrected formulas exist, how accurate are they? and if the measurement was significantly Goldmann applanation tonometry, and stage of And how might those inaccuracies impact different from the ‘gold standard’ GAT glaucoma”, JAMA Ophthalmol, [Epub ahead of glaucoma care? – then we would need to re-write our print], (2017). PMID: 28494071. A Zurich-based team of researchers decided to investigate (2). “Over years working with dynamic contour tonometry (DCT) we realized that the well-known relationship between CCT and over- and underestimation of IOPGAT is not valid in all cases. The question came up of what results correction formulas provide as they calculate mainly with CCT parameters,” says corresponding author Christoph Kniestedt of Talacker Eye Center, Zurich, Switzerland. In their prospective, cross-sectional clinical trial, they measured IOP in 112 patients with glaucoma using Pascal DCT and GAT.

Comparing IOPDCT with conventional

(uncorrected) IOPGAT (IOPDCT-IOPGAT), they found a mean discordance of

3.3 mm Hg (p<0.001). Comparing IOPGAT that had been corrected by five separate formulas, the discordance between DCT and GAT ranged between 2.7 to 5.4 mmHg (all p<0.001). The group also identified a positive correlation between discordant IOP values and glaucoma severity (rs=0.33, p<0.001). “We have shown that glaucoma is in a more advanced stage when the

www.theophthalmologist.com 14 Upfront

Figure 1. CLARITY study design and key efficacy and safety outcomes. AFL, aflibercept; BCVA, best-corrected visual acuity; CI, confidence interval; mITT, modified intent-to-treat; PP, per-protocol, PRP, panretinal photocoagulation; R, randomization.

PDR (with and without macular edema) treated with PRP as standard-of-care CLARITY treated with PRP or ranibizumab for the past 40 years to demonstrate that 0.5 mg. After two years of follow-up, aflibercept could potentially be adopted Achieved the conclusion was that “treatment with as an alternative treatment option, in the ranibizumab resulted in visual acuity first year, in compliant PDR patients in the Can an anti-VEGF agent outdo that was noninferior to […] PRP” and future.” She also notes further avenues for PRP for the treatment of PDR? that “ranibizumab may be a reasonable investigation: “The three initial doses may treatment alternative, at least through represent over-treatment, and spreading a For nearly 40 years, the standard 2 years.” few doses evenly across the year may offer treatment for proliferative diabetic But what about aflibercept? a cost-effective alternative to PRP.” MH retinopathy (PDR) has been panretinal CLARITY (2) was a multicenter photocoagulation (PRP). It works Phase IIb non-inferiority trial that References (partly through reducing VEGF), but compared aflibercept 2 mg with PRP 1. JG Gross et al., “Panretinal at a cost: it risks permanent visual field over a one-year period. The study design Photocoagulation vs Intravitreous loss, DME exacerbation – and even and key results are illustrated in Figure Ranibizumab for Proliferative Diabetic with timely PRP treatment, 1 in 20 1, but the essence is this: patients with Retinopathy”, JAMA, 314, 2137–2146 eyes still go on to develop severe vision PDR, treated with aflibercept, displayed (2015). PMID: 26565927. loss. As retinal neovascularization is a superior visual acuity after one year 2. S Sivaprasad et al., “Clinical efficacy of central component of PDR, might the compared with those treated with PRP. intravitreal aflibercept versus panretinal mighty anti-VEGF agents that have The study’s chief investigator, Sobha photocoagulation for best corrected visual been so successful in treating other Sivaprasad, says: “This study is the first acuity in patients with proliferative diabetic retinal neovascular disease supplant to show superior visual outcomes with retinopathy at 52 weeks (CLARITY): a the venerable PRP? an anti-VEGF agent, when compared to multicentre, single-blinded, randomised, In 2015, the DRCR.net published the PRP, in PDR without baseline macular controlled, phase 2b, non-inferiority trial”, results of Protocol S (1), which compared edema. These are significant findings Lancet, Epub ahead of print (2017). PMID: the outcomes of patients with high-risk for an eye condition that has been 28494920. Creating success with a SMILE. ZEISS ReLEx SMILE Survival Scar

Characteristic retinal lesions provide clues on how Ebola virus enters the eye

What and why? Case-control prospective study examining whether any specific retinal signs can be attributed to past Ebola virus disease in survivors and whether the virus persists in the aqueous humor (1).

Who? Eighty-two Ebola virus disease survivors with post-Ebola syndrome who had previously reported ocular symptoms, and 105 unaffected and asymptomatic controls.

How? Ocular examinations, including widefield retina imaging (scanning laser ophthalmoscopy) and OCT analysis; paracentesis of the anterior chamber was performed on two patients with white cataract.

Findings? A novel retinal lesion was identified in 14.6 percent of Ebola virus disease survivors; the scarring followed the pattern of optic nerve axons (Figure 1). The aqueous humor sampled from two Ebola virus survivors with white cataract was negative for viral RNA.

Upshot? According to corresponding author Paul Steptoe (2), “The distribution of these retinal scars or lesions provides the first Convince observational evidence that the virus enters the eye via the optic yourself! nerve to reach the retina in a similar way to West Nile Virus. Luckily, they appear to spare the central part of the eye so vision is preserved.” He added, “Our study also provides preliminary evidence that in survivors with cataracts, aqueous fluid does not contain Ebola virus, therefore enabling access to surgery.” RS Minimally invasive refractive surgery. References 1. PJ Steptoe et al., “Novel retinal lesion in Ebola survivors, Sierra Leone”, Emerg A great smile can be a powerful asset, as everyone Infect Dis, (2017). DOI: 10.3201/eid2307.161608. knows. It can knock down barriers of doubt, draw people 2. University of Liverpool, “Ebola survivors have a ‘unique’ retinal scar”, (2017). in, create opportunities and set you up for success – Available at: http://bit.ly/EbolaScar. Accessed May 17, 2017. much like the minimally invasive treatment procedure SMILE. With over 750,000 treated eyes, over 1,000 SMILE surgeons worldwide and now with FDA approval in the US, it offers great prospects for success.

a b c University Liverpool. of

Figure 1. Composite SLO retinal images showing peripapillary or peripheral lesions, observed following the anatomic distribution of the ganglion cell axon (retinal nerve fiber layer). a. Example 1, right eye. b. Illustration of the ganglion cell axon anatomic distribution (courtesy of W.L.M. Alward). c. Example 2, right eye.

www.zeiss.com/smile 16  In My View

of a successful initial procedure is of Congenital utmost importance. In My Most of us were taught that we should Glaucoma: Are operate on pediatric glaucoma cases as early as possible – which means some procedures View We Operating are performed on children only a few days Prematurely? old. But operating on very young children In this opinion section, presents issues. Glaucoma diagnosis is not always clear at such an early age because it is experts from across the The instinct is to act early to very difficult to accurately measure IOP given world share a single save vision – but at what cost? the very narrow palpebral fissures present in strongly-held view or very young children. Opening such small key idea. By Nader Bayoumi, Assistant Professor of eyes almost invariably applies pressure to Ophthalmology at Alexandria Faculty of the globe, resulting in artefactually and Medicine, Alexandria University, Egypt artificially high IOP measurements. Submissions are welcome. Additionally, cloudy corneas in such young Articles should be short, patients are not always related to elevated focused, personal and IOP; many clear spontaneously with time. Further, a hasty decision to operate without passionate, and may waiting to perform further examinations deal with any aspect does not allow us to establish whether the of ophthalmology. disease is progressive in nature. And then They can be up to there are other issues related to the operative 600 words in length Glaucoma in children is a disaster waiting procedure itself; first, it’s technically difficult to happen. If undetected for too long (through a very narrow palpebral fissure) and and written in the or inadequately treated, the inevitable second, filtration surgery has a very high first person. fate is blindness. In children, treatment chance of failure because of the aggressive is almost always surgical and there are healing response in infants – the tendency Contact the team at edit@ many options, including angle surgery, to fibrose is inversely proportional to age. filtration surgery (or a combination of But... How long could and should you theophthalmologist.com the two), drainage device placement postpone surgery for glaucoma in young and cyclodestructive procedures. infants? In my practice, we recommend But inadequate treatment – just like two months. This is tempered by the no treatment – results in a relentless clinical scenario: two months would progression towards total vision loss. The not cause much optic cupping – or any visual deterioration is multifactorial and deterioration that cannot be reversed if can be attributed to corneal pathology the subsequent surgery was successful, (progressive enlargement, edema and plus corneal edema would not result in scarring), refractive error (myopic shift) any permanent scarring over this short and most importantly, optic nerve cupping period. Waiting also gives time for the attributed initially to posterior laminar palpebral fissure to grow, making IOP bowing (which is reversible) and later measurement more accurate (as well as neuronal damage (which is irreversible). diagnosis and evaluation) and surgery far Fortunately, timely successful surgery easier to perform. And if the cornea is results can reverse many of these changes. cloudy from a cause other than elevated The consensus is that the best chance is IOP, there is time for spontaneous the first chance, and that each subsequent clearing to occur. The final advantage procedure has progressively lower success of waiting is that the healing response rates. Hence, maximizing the chance gets less aggressive with time, improving In My View  17

chances of filtration surgery success. So wait for a 60-day delay that brings with changes induced by the disease. I strongly the surgeon’s dilemma is this: perform it a solid diagnosis, makes the procedure believe that the second option is the right a hasty, technically difficult operation technically easier to perform and has a one, and that’s why, in my practice, the with an extremely low chance of success, higher success rate, plus the eventual minimum age for operation on children with a potentially doubtful diagnosis… or reversal of almost all possible pathological with glaucoma is currently two months.

(thermal keratoplasty and conductive the Raindrop, Icolens and Flexivue – and Expectations keratoplasty, for example), but, because they the small aperture depth of focus Kamra are not widespread and have to some extent inlay, which has been approved in the US and Exit disappeared from the market because of and implanted in over 3,000 cases in the large amounts of regression, I will not last year (and more than 22,000 cases Strategies cover them here. since studies of it began) (5). All of these Similarly, decentered ablations in implants are highly biocompatible, and are In younger patients, focus presbyLASIK are no longer used. Central almost fully reversible; if the patient is not on the corneal plane for and peripheral presbyLASIK has been happy, take them out early, and the cornea correction of presbyopia published on extensively; if you want to get essentially reverts back to normal. into the details, Ioannis Pallikaris has done My advice in these cases? Manage patient By Günther Grabner, Chairman Emeritus, an excellent survey of these techniques expectations, always have an exit strategy University Eye Clinic Salzburg, Paracelsus (4). Central presbyLASIK is good for and remove corneal implants early if the Medical University, Salzburg, Austria near vision, but doesn’t perform well with patient isn’t happy. For younger patients distance vision and is a little difficult to without cataract who don’t want to risk correct. Peripheral presbyLASIK is good intraocular problems, corneal techniques for distance vision and has good safety, can offer better safety and are reversible – if but provides limited near vision. Patient you take out the inlay, it’s gone. There’s no satisfaction is generally high, but some risk of endophthalmitis, capsular rupture, patients can lose up to two lines of near refractive surprises as with IOLs, vitreous visual acuity. Spectacle independence loss, retinal detachment or secondary is better in hyperopes than in myopes, cataract, which means you lessen your No technique for correcting presbyopia and patient selection and management chances of an unhappy patient with side is perfect – a compromise always has to are crucial. However, it’s important to effects that are difficult to treat. This is why, be made. But I believe that solutions of remember that laser correction is a static in my view, the cornea is the way to go! the corneal plane are the best for younger modification of a dynamic process – so patients; there are many benefits and a as I said before, it’s always a compromise. The author reports no conflicts of interest few approaches you can take. If you have Moreover, there are few long-term studies relevant to the content of this article. a good laser available, it can be put to on the effect of epithelium remodeling over good use in the cornea – presbyLASIK time and the progression of presbyopia. References is well-established, and studies with Another option that I believe holds 1. R Cantú et al., J Refract Surg, 20, S711-3 long-term follow-up are available (1, 2). great promise are corneal inlays; indeed, (2004). PMID: 15521273. Newer techniques have also emerged; for the cornea is the best place to put a piece 2. JL Alió. Curr Opin Ophthalmol, 20, 264–271 example, laser blended vision, which has of plastic in the eye to treat presbyopia. (2009). PMID: 19537363. seen good success rates (3). PresbyLASIK Inlays have two primary advantages: they 3. DZ Reinstein et al., J Refract Surg, 25, 37–58 can simultaneously correct sphere and are tissue sparing and removable. But (2009). PMID: 19244952. astigmatism, is mostly reversible, and gives there are also the challenges of ensuring 4. PG Pallikaris, SI Panagopoulou. Curr Opin the option of extraocular correction – if that the optics are effective and that the Ophthalmol, 26, 265–273 (2015). PMID: the patient is not happy, you can always results are stable and predictable. A few 26058023. try a contact lens to avoid further laser options are now available, including 5. GO Waring IV, F Faria-Correia. Curr treatment. Other approaches do exist intracorneal microlens systems, such as Ophthalmol Rep, 2, 41–47 (2014).

www.theophthalmologist.com 18 Feature

THE CAPSULOTOMY:

FROM THERE TO WHERE? THE STORY UNFOLDS…

BY RICHARD PACKARD

www.theophthalmologist.com 20 Feature

he capsulotomy has a fascinating history – one tinged However, Kelman was performing anterior chamber phaco – with jealousy, rivalry, fashion, evolution, revolution and, to do that, you need to prolapse the nucleus into the anterior and even nationalistic pride – and it’s a story that’s chamber. Dick Kratz decided that he would like to perform phaco got a great deal more to tell. more in the posterior chamber, so he came up with the “can It started with the Frenchman, Jaques Daviel, who ushered opener” capsulotomy in the 1970s, which resulted in a ‘roundish’ inT the modern era of cataract surgery, abandoning couching opening (Box 9). (Box 1) for the first extracapsular cataract extraction (ECCE; Box 2). The British, for predominantly patriotic reasons, preferred couching (Box 3), but ECCE was always going to win out. Albrecht von Graefe improved it in 1850 with his eponymous knife (Box 4) and, extraordinarily, his technique lasted for over a century. That’s not to say that competing approaches weren’t developed along the way – Ignacio Barraquer devised the suction “THE BRITISH, FOR cup-based erisophake in 1917, which enabled rapid intracapsular extraction of the lens (Box 5), but its uptake was limited. So the PREDOMINANTLY von Graefe method persisted into the 1970s. The late 1950s and early 1960s saw lensectomy return to an PATRIOTIC REASONS, intracapsular approach, thanks to a combination of Joaquin Barraquer’s enzymatic zonulolysis approach and cryoextraction of PREFERRED the lens (Box 6). Around that time, Cornelius Binkhorst, one of the pioneers of lens implant surgery, realized that to make intraocular COUCHING, BUT lenses (IOLs) work, you needed to move away from fixation to vital tissues and use the capsule instead. And that’s why he developed his ECCE WAS ALWAYS two-loop iridocapsular lens – and he tried many different shapes of capsulotomy to get the best fixation (Box 7). We all know the story of GOING TO WIN OUT.” how Charles Kelman introduced phacoemulsification in 1967 – and Charlie devised a new way to make the capsulotomy, using a hooked cystitome: the Christmas tree (Box 8).

Box 1. Couching

Stabilize the eye with your thumb; introduce the needle perpendicularly into the eye, entering three millimeters behind the limbus. Gradually push forward with a rotating movement. Move the needle tip downwards to disrupt the lower zonule. Push the lens down into the vitreous with some slow sweeping movements. At least it is minimally invasive… Box 2. Daviel’s ECCE technique for opening the capsule and extracting the nucleus, first described in 1747

Daviel used a keratome and a pair of scissors to create a corneal flap, a cystitome to “circumsize” the capsular bag, a blunt spatula placed between the lens and iris to free the lens – and two fingers, gently pressed on the lower lid to express the nucleus. Feature 21

TIME FOR CCC The challenge has always been to make the CCC more precise in terms of size and centration, as this helps with IOL To begin with, the capsular opening was simply to give access centration, stability, effective IOL lens position, and being able to the cataract, but IOLs changed that. I remember being at to overlap the edge of the IOL with the capsule and “shrink- the AAO Annual Meeting in 1983 when there was a vigorous wrapping” the lens to lessen PCO. These are important factors, debate between the people who designed these lenses: Steve but acutely more so when multifocal and toric IOLs are used. Shearing, Bob Sinskey and Dick Kratz, as to whether or not the Then came the femtosecond laser. First used clinically lens should go into the capsular bag or the sulcus. The reason by Zoltán Nagy in 2008 (Box 12), it represented another for the debate? You really couldn’t guarantee that you’d be able fundamental change in how capsulotomies are made. For the to keep the IOL in the bag with the can-opener capsulotomy. first time, we could make a truly circular capsulotomy of a But of course, this all changed with the development of the pre-specified size in a pre-specified position – without the continuous curvilinear capsulorhexis (CCC), which is essentially variables of the manual technique. But it did come with some the current state of the art in (manual) cataract surgery (Box 10). caveats. You might need a second room for your laser, which The CCC meant that IOLs could be placed reliably and might interfere with your surgical flow. The device purchase securely in the capsular bag – although it did mean that certain and running costs are high, and as the recent EUREQUO procedures needed modification because of the containment registry publications have shown, there are very few scenarios by the capsular opening. And indeed they were. Several where patients have derived any benefit over manual cataract new phaco techniques were developed to overcome these surgery where the surgeon performs a CCC, rather than the difficulties: chip and flip, divide-and-conquer, nucleofractis laser performing a capsulotomy. Might there be other ways of and phaco chop and prechop. achieving the same consistency and accuracy? We know that one of the problems with leaving the posterior If you’re performing CCCs by hand, you might consider capsule in place (particularly in children) is that you get posterior Marie-José Tassignon’s CCC ring; once centered on the capsule, capsule opacification (PCO). Howard Gimbel gave us this you tear inside it. Others simply mark the cornea – or use the technique to do a posterior capsulotomy and then capture the high-tech equivalent, having it rendered on a head-up display IOL optic in it. Daniele Aron Rosa gave us the YAG laser back (like Alcon provides with Verion), which can be particularly in 1982, which wasn’t practicable for anterior capsulotomies (Box useful when you get a widely dilated pupil or a very large eye. 11) – but it reliably performs posterior capsulotomies, and is a However, on the horizon, there are number of new approaches standard procedure today for dealing with PCO. that make the capsulotomy more accurate and precise.

Box 3. The UK vs. Europe

Given “Brexit”, you might not be surprised to learn that the British medical establishment were very skeptical of Daviel’s new ECCE technique, when it was introduced. Percival Pott, a surgeon at St. Bartholomew’s Hospital, known for Pott’s disease (tuberculosis of the spine) and Pott’s fracture of the ankle, decided to publish in 1771 that, as far as he was concerned, cataract extraction was just a passing fashion, and he would continue to advocate couching the lens. Their European colleagues, of course, viewed things differently. Austrian surgeon, Joseph Beer, said, “Some of the English ophthalmologists rejected the extraction method in order to please Mr. Pott, others in order to stand out among the crowd. A third group did it out of national pride and out of hate of all things French. And a fourth group did it because they had bad results due to clumsiness.” 22 Feature

Box 4. Von Graefe sets the standard for more than a century

In 1850, Albrecht von Graefe refined the corneal flap procedure using his eponymous knife, and introduced a peripheral linear incision superior to the cornea; the shift in location from 6 o’clock to 12 o’clock further meant that the eyelid protected the wound, reducing infection and halving the failure rate from 10 to 5 percent.

Box 5. Ignacio Barraquer debuts the erisophake in 1917

Anesthesia, incision, application of the erisophake (a special cup and suction apparatus) then removal of both lens and instrument made for a very rapid procedure. Many surgeons visited Barraquer to learn the technique, but most continued to perform von Graefe’s method.

CAPSULOTOMY’S FUTURE fracture or tear). And thanks to how the laser works, it’s almost impossible not to get a free cap. CAPSULASER The preliminary results have been good, there’s been no pupil construction after laser use, no untoward anterior chamber The Capsulaser device (Excel-Lens; Box 13) is a small laser that activity postoperatively, and in a case series of 20 patients, is attached under the surgical microscope, and is connected to their corneas remained clear out to 18 months, with similar a small, shoebox-sized console. It’s a continuous laser, rather endothelial cell counts to patients that underwent normal than a pulsed laser, and it scans in a single circular pattern over cataract surgery. Also noteworthy is that these capsulotomies a period of one second to create the curvilinear capsulotomy have remained well centered and have not contracted at all opening. It requires the anterior capsule to be stained with – meaning that there’s been no subsequent change in IOL Trypan blue, which creates a chromatically selective target position. To date, another 400 eyes have been operated upon for the laser. The irradiation changes collagen IV to elastic and the CE mark trial has recently been completed. amorphous collagen, and this phase change results in not The device has also been used to perform posterior only a smooth edge but also a very elastic capsular rim (the capsulotomies in cadaver eyes, and what’s interesting here is capsulotomy can be extended from 5 to 12 mm without that it leaves the anterior hyaloid intact. Feature 23

“WHAT’S transition of water molecules that are trapped between the device and the capsular membrane – instantaneously creating INTERESTING a cleavage plane in the capsular membrane, making a strong (ABOUT capsulotomy. It is CE-marked and now available in Europe. CAPSULASER) IS APERTURECTC Mark Packer has been involved with ApertureCTC THAT IT LEAVES (International Biomedical Devices; Box 15) – another thermal device, which is currently under preclinical evaluation. It’s THE ANTERIOR similar to Zepto in many respects, but lacks the suction cup. It consists of a reusable handpiece and a disposable 1.2 HYALOID INTACT.” mm diameter tip that houses a circular 5.25 mm filament, which can be deployed once the tip is in situ. This is gently depressed on the capsule, a foot pedal is used to deliver a millisecond pulse of thermal energy, which melts the ZEPTO collagen and creates a perfectly round capsulotomy – and with it a smooth, strong and elastic capsular opening. The There are also now thermomechanical devices being developed manufacturers report that multiple filament dimensions are for anterior capsulotomy: you are probably aware of the Zepto available, ranging from 4–6 mm. device (Mynosys; Box 14). It consists of a soft, foldable clear suction cap that contains a nitinol capsulotomy ring that’s CAPSULOTOMY’S EVOLUTION inserted through a 2.2 mm clear corneal incision using a disposable handpiece. Once in the eye and aligned over the The role of the capsulotomy has changed with cataract visual axis, a push rod is retracted and the device unfolds into surgery over the last 270 years – from a crude opening to a circular shape, whereupon the surgeon can center the device give access to the nucleus for its removal, through various and apply suction. A pulse of electrical energy is delivered iterations of cystitomes and forceps to create different shapes in milliseconds to the nitinol ring, triggering a rapid phase of opening for IOL support, to CCC for those anterior and

Box 6. Joaquim Barraquer discovers alpha-chymotrpysin’s ability to dissolve zonules (1958)

This, combined with Tadeusz Krwawicz’s cryo probe (1961) – and its subsequent improvements by Percy Amoils (1965) – turned the tide back to intracapsular cataract extraction.

www.theophthalmologist.com 24 Feature

Box 7. Binkhorst’s experimentation

Cornelius Binkhorst (a) realized that good fixation away from vital tissues was critical, designed the iris-fixated four-loop lens (b) for use after intracapsular surgery. However, Binkhorst felt that if he a. b. could fixate a lens in the capsular bag it would remove the need for pupil involvement. This led to his two-loop iridocapsular IOL (c) – and he tried lots of different shapes of capsule opening to achieve best fixation (d).

c. d.

Box 8. Charlie Kelman’s Christmas Tree

Kelman introduces phacoemulsification in 1967 – and devises a new way to do capsulotomy with a hooked cystitome: the “Christmas tree.”

Box 9. Dick Kratz’s can- opener approach

Dick Kratz decided that posterior chamber phaco was safer than in the anterior chamber and devised the “can opener” capsulotomy and his iris plane phaco technique. One of the issues at the time was whether or not the IOL should go in the capsular bag or into the sulcus – you couldn’t guarantee that the can opener capsulotomy would keep the lens in the bag. Feature 25

Box 10. The origins of the CCC

Calvin Fercho from Fargo, North Dakota, started using a continuous tear capsulotomy in the late 1970s, and this was the predecessor of what became termed “continuous curvilinear capsulorhexis” (CCC), which was developed and taught by Howard Gimbel, Thomas Neuhann and Kimiya Shimizu in the mid-1980s. The CCC significantly reduced intraoperative complications, such as anterior capsular rim tear, and improved IOL centration and sequestration in the capsular bag. The arrival of Peter Utrata’s eponymous forceps in 1988 helped make CCC more controllable and easier to perform for many surgeons.

Box 11. The YAG laser

Daniele Aron Rosa tried her newly invented YAG laser for anterior capsulotomies back in 1982. The main drawback was that the surgery had to be carried out immediately – the soft lens matter “fluffed” up and IOP rose greatly after application of the laser.

www.theophthalmologist.com 26 Feature

Box 12. Zoltán Nagy performs the first capsulotomy with a femtosecond laser in 2008

But how does the femtosecond laser compare with manual capsulorhexis for accuracy? In one study, 100 percent of LenSx procedures achieved an accuracy of ±0.25 mm.

Only 10 percent of manual procedures achieved an accuracy of ±0.25 mm. No radial tears

. . . . .

D E ()

L () M ()

Z Nagy et al. “Initial clinical evaluation of an intraocular femtosecond laser in cataract surgery”, J Refract Surg, 25, 1053–1060 (2009). PMID: 20000286.

Box 13. The CapsuLaser device

(a) Present on the surgical microscope; (b) the console; (c) the process of laser capsulotomy; (d) the smooth edge of a. c. the disk; (e) Stronger capsulotomy than a manual CCC.

b. d. e. Feature 27

posterior capsules to contain the IOL. And now we have Richard Packard is a consultant ophthalmic surgeon and Director many devices from lasers to metallic thermal instruments to of Arnott Eye Associates in London, England, and was the senior automate the creation of perfectly round consistent central surgeon at the Prince Charles Eye Unit, King Edward VII Hospital capsulotomies – which should offer more effective lens in Windsor, and is credited as “almost single-handedly removing position predictability. phaco from the blacklist in the UK giving the procedure credibility Of course, IOLs have evolved with the capsulotomy, and a and validation.” He implanted the world’s first foldable soft lens in new generation of IOLs are being developed take advantage rabbits and has lectured and operated in 59 countries – often with of this; for example, the Oculentis FEMTIS IOL with its Charlie Kelman, and has chaired the ESCRS’ video competition small flaps – “rhexis clips” – that lock the lens inside the panel since 2000. He reports that he is a consultant and equity capsulotomy; or the Masket ND IOL (Morcher), which has holder in Excel-Lens, and consults for Core Surgical and Shire. a groove that fits inside the anterior capsulotomy. Could it be that the combination of these new, lower cost approaches to This feature is adapted from the presentation, “The capsulotomy capsulotomy – plus a new generation of IOLs that rely on the from there to where? The story unfolds…” given at the Cataract properties of capsulotomies made by these devices – will soon Surgery: Telling It Like It Is! annual meeting, held in Naples, consign manual CCCs to the history books too? FL in January 2017.

Box 14. The Zepto b. capsulotomy system

The disposable capsulotomy tip (a) consists of a foldable, soft, clear suction cup containing a nitinol ring that can enter through a 2.2 mm incision, and expands to create a 5.2 mm circular capsulotomy. The tip is delivered through a disposable handpiece, pictured in (b) above the a. b. device’s console.

Box 15. ApertureCTC a. Similar to Zepto, but without the suction ring, the disposable tip (a) is intended to be introduced through a 1.8 mm incision, and will come in sizes between 4.5 mm and 6.5 mm (in 0.5 mm increments), placed on to the capsule and activated to make the thermal capsulotomy. A b. render of the device’s console is shown in panel (b).

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www.be-confident-with-spectralis.com In Practice

Surgical Procedures Diagnosis New Drugs

30-33 Single Incision: Multiple Advantages Soosan Jacob shares how and why to perform stab incision glaucoma surgery (SIGS) in patients with open- angle glaucoma. 30 In Practice

Single Incision: Multiple Advantages

The what, how and why of stab incision glaucoma surgery (SIGS)

By Soosan Jacob

Though trabeculectomy can be effective in lowering IOP, it has a high failure rate and many patients suffer complications post-operatively. One of the main problems with trabeculectomy is that, when creating the flap, you’re creating a conjunctival wound that is going to heal by scarring – and scarring is one of the major reasons for failure. By making the conjunctival incision as flow, simplicity of the procedure and How do we get round these problems? small as possible by performing stab post-operative management, as well as (or small) incision glaucoma surgery economic advantages – it’s also faster (SIGS) – a procedure I introduced for to perform than trabeculectomy. I have At a Glance patients with open angle glaucoma been performing SIGS since 2013 • Although trabeculectomy is often (OAG) in 2013. and, in 2016, we at Dr. Agarwal’s Eye effective in lowering IOP, the The basic principle of SIGS is very Hospital and Eye Research Centre procedure comes with the risk of simple – it’s a single 2.8 mm keratome published results from a prospective conjunctival scarring, treatment incision straight through the conjunctiva interventional case series of 17 patients failure, and complications, such and sclera into the cornea and the (4), which are summarized in Box 1 as bleb failure, oversized bleb anterior chamber. This corneoscleral (SIGS Case Series). We are currently formation, bleb dysesthesia etc. tunnel is then compromised by at a much larger series. • For patients with OAG, one punching the inner corneal lip to One of the main advantages of SIGS, alternative is stab incision glaucoma create a controlled leak for aqueous reduced scarring, speaks for itself – surgery (SIGS), which creates drainage. Tunnel trabeculectomy has decreasing the amount of conjunctival an intentionally compromised been described previously as successful dissection means less scar formation. The corneoscleral tunnel through a single filtration surgery (1–3), and whilst small incision also preserves drainage stab or small incision SIGS uses the same concept, the scleral channels in the sub-conjunctival • Advantages of SIGS include less tunnel is created in one step as opposed tissue to a much larger extent than in fibrosis, posteriorly-directed flow, to tunnel trabeculectomy, which first trabeculectomy, meaning you are likely and a larger area of available creates a flap in the conjunctiva and also to get better subconjunctival drainage. virgin conjunctiva for future has a triplanar tunnel as opposed to the Complications are also minimized, surgeries biplanar nature in SIGS. because there is no flap. Of course, the • Here, I offer an overview on how risk of fibrosis is not abolished, and to perform SIGS, and explain why Why perform SIGS? mitomycin-C (MMC) can be given it could be a better primary surgery There are several key advantages to pre-operatively as a sub-conjunctival for patients with OAG and no performing SIGS: reduced risk of injection (0.1 ml of 0.005% or 0.01%) prior conjunctival dissection. fibrosis, posteriorly-directed aqueous or intra-operatively as a MMC-soaked In Practice 31

4 “With SIGS, there is no sideward flow because all flow is 1 directed posteriorly, 2 5 so the risk of oversized bleb formation and related complications

is reduced.” 6 sponge applied to the tunnel (0.01 or 0.02% for two minutes). Better aqueous drainage is another main advantage of SIGS over 3 trabeculectomy. The tri-planar flap created by trabeculectomy provides three directions of flow; both horizontal conjunctiva. SIGS leaves a large area as much in this location. directions as well as posteriorly. But of absolutely intact conjunctiva so it • 2.8 mm keratome entry. Position glaucoma surgeons only really want is easier to perform repeat procedures the tip of a 2.8 mm bevel-up posteriorly-directed flow as horizontal – crucial for patients with glaucoma. keratome 1.5 mm from the limbus flow to either side of the flap can lead You can start with a small incision in and begin to tunnel forwards. The to oversized and overhanging bleb the superior quadrant and, if that first keratome should just be visible formation and bleb dysesthesia. With surgery fails, you can then move to through the overlying sclera and SIGS, there is no sideward flow because other quadrants. conjunctiva (Image 3). Whilst the all flow is directed posteriorly, so the tunnel is being dissected, the eye risk of oversized bleb formation and How to perform SIGS position should be controlled by related complications is reduced. From holding the limbus with strong my experience, post-SIGS blebs are • After peribulbular anesthesia one-toothed forceps (Image 4). more diffuse posteriorly than those (and optional MMC) has been • Creating the corneoscleral tunnel. formed after trabeculectomy. applied, the first steps are to The scleral part of the tunnel SIGS also maximizes the amount achieve a mobile conjunctiva by should be short and shallow – of residual virgin conjunctiva. In loosening the speculum and to the ideal length of the entry conventional trabeculectomy, when push the conjunctiva downwards incision is 1.5 mm for the scleral a large area is dissected in the first using a two-handed sliding component and approximately 1 surgery, the available area of untouched technique (Images 1 and 2). A mm into the cornea (Images 5 conjunctiva for second surgeries superior site is preferable as the and 6). At the limbus, the blade becomes quite limited, increasing supero-nasal fornix is short and tip should be angled anteriorly the risk of failure caused by fibrosed the conjunctiva cannot be pushed to match the corneal curvature.

www.theophthalmologist.com 32 In Practice

can cause the anterior chamber to shallow. Instill viscoelastic into the anterior chamber through a paracentesis or through the SIGS tunnel entry. At this point phacoemulsification and IOL 7 12 implantation can be performed if the surgery is being combined with cataract removal; the SIGS tunnel will not leak as it is self-sealing because the ostium has not yet been created. Phacoemulsification should be performed with the main and side ports placed on either side 8 13 of the tunnel. • Creating the ostium. Slide a 1 mm Kelly Descemet’s 9 membrane punch in unretracted position and facing sideways along the tunnel and into the anterior chamber. Next, facing downwards, punch the internal lip of the corneal section and punch 14 vertically backwards; horizontal enlargement is not required. Once the limbus is reached, the tunnel can be examined by retracting the conjunctiva; the extreme edge of the final punch should be just seen deep within the tunnel (Images 9, 10 and 11). Irrigation over the tunnel can help with easy 10 15 visualization. • Peripheral iridectomy. Shallow the anterior chamber. Insert angled to the iris. Entry up to the non-toothed forceps and grasp shoulder of the blade should be the iris near its base just below made, avoiding both Descemet’s the ostium. Retraction of the membrane and the lens capsule conjunctiva with non-toothed (Image 7). Downwards pressure forceps by the assistant helps should be avoided while entering with visualization. Using curved 11 the anterior chamber. Vannas scissors, cut the iris near • Remove the blade in a smooth its base (Image 12). Push the backwards movement while iris back into anterior chamber, The blade can then be introduced holding the eye at the opposite ensuring that no iris is trapped 0.5–1 mm into clear cornea before limbus (Image 8); sideward in the tunnel (Image 13). As entering the anterior chamber movement of the blade can slice in trabeculectomy, a peripheral in a horizontal plane parallel tunnel sides and slow withdrawal iridectomy is not an absolute must, In Practice 33

solution (BSS) through side- SIGS Case Series port irrigation; there should be a free flow of fluid. If it is “ I have heard from difficult to visualize flow, hold • A total of 17 patients the conjunctival cut closed while many around the underwent SIGS with pre- irrigating and look for bleb operative subconjunctival formation. Additional punches world who are MMC. can be taken if the leak is • Mean reduction in IOP from inadequate. Suture the 2.8 mm performing SIGS pre-operative values was conjunctival cut with a running 38.81 ± 16.55 percent (p<0.000). 10-0 nylon suture and knot down in these complex • Mean number of topical with final loop – this twists the medications was reduced from edges of the conjunctival cut cases and are 1.35 pre-operatively to 0.59 post- making it leak proof (Images 14 operatively (p=0.025). and 15) – Tenon’s capsule should happy!” • Post-operatively, 64.70 percent not be included. Subconjunctival of patients achieved complete medications 0.5 ml garamycin (40 success, defined as an IOP mg/ml) and 0.5 ml dexamethasone world who are performing SIGS in these <18 mmHg with no (4 mg/ml) can be given into the complex cases and are happy! medications; 82.35 percent inferior fornix. Post-operative As with all surgeries, there is a learning maintained an IOP <18 mmHg management is similar to curve involved. But surgeons already with two medications. trabeculectomy. performing trabeculectomies will be • Intra-operative complications able to manage SIGS as well; it is also encountered were premature The results so far with SIGS have easy to convert SIGS to a conventional entry, trapdoor hinging of been very encouraging. Though the trabeculectomy if needed. We’ve had internal corneal lip, conjunctival procedure isn’t meant to completely many surgeons come to us from abroad buttonhole, very small replace trabeculectomies, it provides a just to learn this technique, as well as Descemet’s detachment and good primary surgical option for patients many who’ve seen the procedure online nonbasal peripheral iridectomy who might have been considered for a or at conferences, and it has been great (all n=1; all managed or no trabeculectomy, bringing advantages to hear how happy they are with the intervention taken). such as minimized scarring, posteriorly- results of the surgery. I hope that more • Six patients encountered post- directed flow, fewer post-operative ophthalmologists will be encouraged to operative complications of complications, as well as preserving adopt the approach with their patients. uncontrolled IOP, of which three conjunctiva for any additional future were managed medically and surgeries. It is also a quicker surgery to Soosan Jacob is a senior consultant three underwent repeat surgery. perform than trabeculectomy, which ophthalmologist at Dr. Agarwal’s Eye • No sight-threatening can increase efficiency in the clinic and Hospital and Eye Research Centre in complications were reported (4). provide economic advantages. Not every Chennai, India. patient is suitable for the procedure, however, and exclusions include prior References trabeculectomy, conjunctival scarring, 1. RA Schumer and SA Odrich, Am J angle-closure glaucoma and prior uveitis. Ophthalmol, 120, 528–530 (1995). PMID: however, it is preferred to be done But this isn’t always cut and dry: though 7573314. in all cases as it avoids iris tissue I personally wouldn’t consider SIGS for 2. JS Lai and DS Lam, J Glaucoma, 8, 188–192 blocking the ostium. a patient who already has conjunctival (1999). PMID: 10376259. • Checking the leak. Wash out scarring (for example, from retinal 3. Y Eslami et al. Int Ophthalmol, 32, 449–454 viscoelastic and assess leakage detachment surgery) because they won’t (2012). PMID: 22805881. through the SIGS tunnel harness the benefits of the procedure, 4. 4. S Jacob et al., J Ophthalmol, 2016, Article by irrigating balanced salt I have heard from many around the ID 2837562 (2016). PMID: 27144015.

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38–40 Redefining the Eyedrop Stephen Lane examines how the challenges of effectively delivering topical eye medication is being overcome. 36 NextGen

Redefining the Eyedrop

How we’re overcoming the challenges of effectively delivering topical eye medication

By Stephen Lane

Ocular surface disease (OSD) is with dedicated instruments. But new to activate a blink reflex that rapidly extremely common – and though it is treatment options have been slow to clears the drop from the surface within not always the primary complaint, it is emerge. Recently, lifitegrast (Xiidra, 15–30 seconds of instillation, through implicated in many cases that present to Shire Ophthalmics) was approved in spillover and drainage through the ophthalmic practices. Managing OSD the US to treat the signs and symptoms lacrimal system (2). It is estimated can be challenging because the signs and of dry eye. Lifitegrast is an integrin that only 1–7 percent of an eyedrop’s symptoms are variable and often poorly antagonist that binds to lymphocyte medication has a therapeutic effect on correlated, and the etiology is diverse. function-associated antigen 1 (LFA-1) the target tissue (3). Gels and ointments For many years, the mainstay of on T-cells to block the interaction of might have a longer dwell time on the OSD treatment has been topical LFA-1 with intercellular adhesion cornea, but because they create an uneven eyedrops, beginning with artificial molecule 1 (ICAM-1) – a cell surface refractive surface they also significantly tears and for more severe cases, topical protein that is overexpressed in patients distort vision, making their use during cyclosporine A or corticosteroids. In recent with dry eye disease. In so doing, it is waking hours limited. years, we have seen significant advances in believed to inhibit T-cell activation diagnostic technologies, with new point- and migration, and stop or reduce the of-service tests to measure tear osmolarity secretion of inflammatory cytokines. and inflammatory markers, and we can Clinical studies have shown that its now perform meibomian gland imaging onset of action is less than two weeks “Another challenge (1). However, addressing inflammation doesn’t necessarily solve the entire with eyedrops is that At a Glance spectrum of symptoms associated with • Ocular surface disease has OSD. The hunt for other adjunctive many compounds, traditionally been treated with therapies continues… artificial tears and topical including cyclosporine A or corticosteroids Challenges of topical therapy • Such topical medications comes One of the reasons that we have seen cyclosporine, are with the specters of poor treatment so few new agents for OSD is the compliance and tolerability issues, as pharmacological challenges associated poorly soluble.” well as difficulties with effectively with drops for the ocular surface. delivering medication to the ocular Certainly, the cornea is easily accessible, surface but designing a drop that stays in contact • In recent years, ocular surface with the cornea long enough to have an Another challenge with eyedrops disease and dry eye have become effect – while not causing discomfort, is that many compounds, including increasingly common complaints at toxicity, or visual disturbances in the cyclosporine, are poorly soluble. Current ophthalmic practices process – has been challenging. A formulations of topical cyclosporine get • New treatments and technologies standard eyedrop contains about 40– around this problem by suspending the are evolving to redefine the eyedrop. 50µL of fluid, which is sufficient volume drug in an oil-based emulsion, but the NextGen 37

patient has to shake the drops before use, and multiple excipients are needed to buffer the drug and maintain suspension, with each additional excipient having the potential to affect tolerability or efficacy. Finally, even if a new topical medication can overcome the hurdles of solubility and efficacy, we know that patient compliance with eyedrops is relatively Polyethylene glycol poor, even when they are prescribed an agent to treat a sight-threatening disease like glaucoma (4). In many cases, blurred Micronized loteprednol KPI-121 Nanoparticles vision, stinging, and other tolerability etabonate (D50 ~4 μm) issues contribute to poor adherence.

New approaches What if traditional eyedrops could be Figure 1. Smaller steroids: current micronized formulations of loteprednol etabonate (LE) get stuck replaced with a longer lasting form of in the mucus layer of the tear film; the drug particles aggregate – and they’re distributed poorly and drug delivery? Sustained release implants eliminated quickly, however polyethylene glycol (PEG)-coated LE nanoparticles easily penetrate the and reservoirs have certainly been an area mucus layer of the tear film, thereby enhancing drug delivery and retention on the ocular surface. of intense focus in vitreoretinal therapy, but these do not easily lend themselves the target endpoints (corneal staining and of dry eye symptoms (Cationorm), and to corneal applications. There is a ocular discomfort) (5). when cyclosporine A is embedded in the hydroxypropyl cellulose insert for sustained- Nanoparticle technology provides a oily core of the droplets (Ikervis) – although release treatment of dry eye (Lacrisert, promising avenue for delivery of established both products are currently only available in Bausch + Lomb) that has been available for drugs to the cornea and tissues beyond. certain European and Asian markets (8,9). many years. Certainly, some patients rely Research has shown that a mucoadhesive Kala Pharmaceuticals is developing on the lubrication that this insert provides nanoparticle drug delivery system mucus-penetrating nanoparticle for relief, but in my opinion it is a last-resort prolongs the precorneal residence time of technology (KPI-121) that delivers choice because the intermittent blur caused encapsulated cyclosporine A by adhering to loteprednol etabonate (an ester steroid) over by the sustained release of methylcellulose mucous membranes (6). OTX-101 (Seciera) approximately five days. Though topical has a significant impact on vision. Other is a novel nanomicellar formulation of corticosteroids have long been recognized delivery device approaches have also been cyclosporine A 0.09%, acquired from as a highly effective treatment for the trialed. An intracanalicular depot that Auven Therapeutics by Sun Pharma, ocular surface, clinicians have been wary slowly releases dexamethasone (Dextenza, who recently announced results from of their long-term use because of risks of Ocular Therapeutix) recently completed a a multicenter, randomized, double IOP spikes and cataract development. But Phase III pivotal trial (NCT02736175) masked, vehicle-controlled Phase III when loteprednol etabonate is formulated of its use for the control of postoperative confirmatory study. After 12 weeks of into tiny (200–400 nm) mucous- ocular inflammation and pain after cataract treatment, OTX-101 showed statistically penetrating particles (Figure 1), it can get surgery. As Dextenza met endpoints for significant improvements over the vehicle to target tissues very effectively without decrease in inflammation, I expect that control in Schirmer’s score and several causing unwanted side effects; Phase II the indication for its use will expand. key secondary endpoints (7). trials evaluating KPI-121 in 150 patients An iontophoresis device that delivered Similarly, Santen has a cationic with a clinical diagnosis of dry eye showed dexamethasone phosphate (EGP-437; nanoparticle water/oil micelle vehicle, significant improvements in conjunctival EyeGate Pharma) has showed statistically Novasorb, which contains a positively hyperemia and ocular discomfort at significant improvements in signs and charged surfactant and is electrostatically two weeks, with no difference in IOP symptoms of dry eye in response to a attracted to the negatively charged mucins between the drug and vehicle observed controlled adverse environment challenge on the surface of the eye, aiding retention. (10). Phase III trials of KPI-121 are now in a Phase II trial, but failed to achieve The vehicle is used alone for the treatment underway (NCT02813265).

www.theophthalmologist.com 38 NextGen

Varying the vehicle The ongoing need to redefine the eyedrop weekly treatment of experimentally induced dry For perhaps the first time, we are also OSD is a difficult and frustrating problem eye syndrome”, Nano Res, 8, 621–635 (2015). beginning to think of the eyedrop vehicle to treat, yet so very prevalent in our Available at: bit.ly/mucoadhesive. Accessed May itself – something that was of only minor practices. Despite the many challenges 18, 2017. interest in the past – as a delivery system. in developing new topical therapies, it 7. Sun Pharma, “Sun Pharma announces positive For instance, Imprimis Pharmaceuticals are is absolutely essential that we continue topline results of confirmatory Phase 3 clinical trial using a new technology in their LessDrops to evaluate new treatments that can for Seciera for treatment of dry eye”, (2017). formulation that allows combination of improve patient signs and symptoms. As Available at: http://bit.ly/Seciera. Accessed May multiple postoperative medications we continue to search and investigate new 17, 2017. into a compounded single drop; active compounds, I am encouraged that new 8. PY Robert et al., “Efficacy and safety of a cationic pharmaceutical ingredients that wouldn’t drug vehicle and drug delivery technologies emulsion in the treatment of moderate to severe dry ordinarily mix can be solubilized into a offer the promise of better efficacy, less eye disease: a randomized controlled study”, Eur J well-distributed particle suspension. More frequent dosing (and so less dependent on Ophthalmol, 26, 546–555 (2016). PMID: relevant to the treatment of OSD, a non- patient compliance), and better tolerability. 27515572. aqueous, preservative free drug delivery 9. IKERVIS 1 mg/mL eye drops, emulsion. system based on semifluorinated alkanes Stephen Lane is Clinical Professor of Summary of product characteristics. Available at: (EyeSol, Novaliq) has been shown to Ophthalmology at the University of bit.ly/ikervis. Accessed May 18, 2017. enhance the solubility, suspensibility and Minnesota and Medical Director of 10. Kala Pharmaceuticals, “Kala Pharmaceuticals stability of drugs such as cyclosporine A, Associated Eye Care in Stillwater, announces positive results from Phase 2 trial of and has a well-established ocular safety Minnesota, USA. KPI-121 in dry eye disease”, (2015). Available at: profile (11–15). From this technology stems http://bit.ly/KalaPharm. Accessed May 17, 2017. NovaTears, a multi-dose, preservative-free Financial Disclosures: Lane reports that 11. B Kirchhof et al., “Use of perfluorohexyloctane as a lubricating drop that has been commercially he is Chief Medical Officer of Alcon, and long-term internal tamponade agent in available in Europe since 2015. The low is a consultant for Novaliq GmbH, Shire complicated retinal detachment surgery”, Am J surface and interface tension from the Ophthalmics, Ocular Therapeutix, Ophthalmol, 133, 95–101 (2002). PMID: non-aqueous drop allows it to spread Bausch + Lomb, and Kala Pharmaceuticals. 11755844. quickly and uniformly over the entire 12. H Meinert and T Roy, “Semifluorinated alkanes –a ocular surface without relying on blinking References new class of compounds with outstanding properties for distribution; the drop volume is one- 1. CP Semba and TR Gadek, “Development of for use in ophthalmology”, Eur J Ophthalmol, 10, fourth that of a standard eyedrop at ~10 µL lifitegrast: a novel T-cell inhibitor for the 189–197 (2000). PMID: 11071025. which makes it less prone to spillover. In a treatment of dry eye disease”, Clin Ophthalmol, 13. P Steven et al., “Semifluorinated alkane eyedrops recent prospective, post-market multicenter 10, 1083–1094 (2016). PMID: 27354762. for treatment of dry eye disease –a prospective, study of the lubricating drop in patients 2. GA Peyman et al., “Perfluorocarbon liquids in multicenter noninterventional study”, J Ocul with evaporative dry eye disease (n=30), ophthalmology”, Surv Ophthalmol, 39, 375–395 Pharmacol Ther, 31, 498–503 (2015). PMID: significant improvements from baseline were (1995). PMID: 7604361. 26296040. observed at six weeks in four of five measures 3. D Ghate and HF Edelhauser, “Barriers to 14. RM Dutescu et al., “Semifluorinated alkanes as a assessed, including a 21 point decrease in glaucoma drug delivery”, J Glaucoma, 17, 147–156 liquid drug carrier system for topical ocular drug the Ocular Surface Disease Index score (2008). PMID: 18344762. delivery”, Eur J Pharm Biopharm, 88, 123–128 (13). NovaTears, with the addition of 4. AL Robin et al., “Adherence in glaucoma: objective (2014). PMID: 24844949. omega-3 fatty acids, is anticipated to be measurements of once-daily and adjunctive 15. GM Tosiet al., “F6H8 as an intraoperative tool approved in Europe by the end of 2017. The medication use”, Am J Ophthalmol, 144, 533–540 and F6H8/silicone oil as a postoperative company is also developing a cyclosporine (2007). PMID: 17686450. tamponade in inferior retinal detachment with A formulation in the EyeSol vehicle, 5. MA Patane et al., “Ocular iontophoresis of inferior PVR”, J Ophthalmol, 956831 (2014). CyclASol, and a recently completed Phase II EGP-437 (dexamethasone phosphate) in dry eye PMID: 24672710. trial in 207 patients with moderate to severe patients: results of a randomized clinical trial”, 16. Novaliq, “Novaliq announces positive topline dry eye showed significant improvements Clin Ophthalmol, 5, 633–643 (2011). PMID: results of Phase 2 clinical trial evaluating CyclASol in corneal staining compared with vehicle 21629568. in adults with moderate to severe dry eye disease”, (16); pivotal trials should be initiated 6. S Liu et al., “Phenylboronic acid modified (2017). Available at: http://bit.ly/CyclASol. by 2018. mucoadhesive nanoparticle drug carriers facilitate Accessed May 17, 2017. Upgrade your slit lamp with

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e Humanity in Science Award recognizes and rewards a scienti c project that has the potential to make the world a better place. Do you know of a project that is worthy of the prize? Nominations close on June 16th 2017

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R A I 42–45 Redefining POAG Primary open-angle glaucoma: one e Humanity in Science Award recognizes and rewards a scienti c disease or many? Louis Pasquale tackles the myths and misnomers project that has the potential to make the world a better place. plaguing the study of glaucoma.

Do you know of a project that is worthy of the prize? 46–49 Balancing the Cost of Success and Failure Ian Catchpole shares his story on working with sustained-release anti-VEGFs, and how publishing Nominations close on June 16th 2017 negative results can stop duplication of disappointments. humanityinscienceaward.com [email protected] @humanityaward humanityinscienceaward humanityinscience 42 Profession

Redefining POAG

Why it’s time to take the “P” out of POAG and consider the secondary causes behind the disease

By Louis Pasquale

How long have we been confused about primary open-angle glaucoma (POAG)? The answer is a really long time, and even the term glaucoma is a misnomer; its origin stems from the ancient Greek, glaukos, which likely referred to the dull sheen or “glaze” of blindness that arises to something. hemorrhages, which have been found to from a swollen cornea or cataract – both of I think it’s time to take a new approach present at a higher frequency in patients which can be caused by chronic intraocular and redefine POAG. My goal is to break with PC-OAG (2). pressure (IOP) elevation (1). it down into its different components and Genetically, we know that impaired Fast-forward to the present day and really understand what is going on. Over nitric oxide (NO) signaling plays an there’s a myriad of terminology related to many years of study, I have learned that important role in PC-OAG. Caveolin is POAG that doesn’t reflect the complicated it is likely to be several different diseases, a membrane protein that interacts directly etiology of the disease (see sidebar: “POAG and I believe the best approach is to identify with endothelial nitric oxide synthase Terminology through Time”). Even the the different subtypes and their unique risk (eNOS) to regulate NO production, and name “POAG” is bad because it fosters the factors. We have much to learn, but here is genomic variants in the CAV1/CAV2 suggestion that there is no secondary cause what we know so far... region associate with the PC-OAG subtype of the disease. But it needs to be secondary (3). This, together with research showing Replacing “P” with “PC” that IOP is elevated and outflow facility The first POAG subtype to treat as a reduced in eNOS knockout mice (4), means At a Glance separate entity is paracentral open-angle that we now know that NO signaling is very • Glaucoma specialists have been glaucoma (PC-OAG). The main feature important for the regulation of IOP – and confused by POAG for too long, and of this subtype is that disease attacks the it’s why we’re seeing potential new drugs on this may be because it is actually center of vision, causing early paracentral the horizon that target NO and associated multiple heterogeneous diseases visual field loss. When studied by OCT, pathways. Until these drugs make it into the • It’s time we redefined the disease, and many of these patients have triangular clinic, what are the options for patients with discuss the potential different subtypes defects in their pre-laminar optic nerve PC-OAG? A low target IOP is needed for and how best to manage them tissue – almost like a little man with a these patients (16 mmHg is too high) and • Patients with paracentral open- shovel dug out a trench in the superficial many may need even lower target IOPs in angle glaucoma should have low optic nerve head. Another feature of this the range of 10–12 mmHg. Additionally, target IOPs, and patients with subtype is that patients typically have observational research suggests that dietary African-derived open-angle lower IOPs than those observed in patients nitrates might favorably reduce the risk of glaucoma should be screened and with peripheral visual field loss. However, POAG (5), particularly for PC-OAG, and monitored alongside their children because many patients with PC-OAG may there’s certainly no harm in trying to get and family also have pressures in the normal-tension patients to eat more leafy green vegetables! • There remains much to learn, and glaucoma or high-tension glaucoma ranges we need to continue to find the (2), stratifying patients by IOP may not be Replacing “P” with “AD” different disease subtypes to better serving us well. Instead, we should perhaps The next POAG subtype is a very serve our patients consider other biomarkers, such as disc important entity and one we should be Profession 43

African descent had a reduced risk of disc hemorrhage compared with Caucasians (7). POAG “I think it’s time to This is intriguing because disc hemorrhages are a structural biomarker for disease Terminology take a new progression; yet, they occur less commonly in African Americans with open-angle through Time approach and glaucoma who are more likely to go blind from glaucoma than Caucasians with redefine POAG.” open-angle glaucoma. The reasons for this tendency are currently unclear, but these Pre-1970 terminology findings suggest that retinal hemodynamics • Chronic simple glaucoma recognizing more: African-derived open- might differ between these two populations, • Wide-angle glaucoma angle glaucoma (AD-OAG). We think of and we need to understand more so that we • Glaucoma simplex POAG as a disease of the elderly, and a can improve the care of our patients. common misconception is that it won’t be Post-1970 terminology found in people below the age of 40 years. Going backwards to move forwards • Normal tension glaucoma However, research performed in South As PC-OAG and AD-OAG subtypes • Low pressure glaucoma Florida has shown that at least one African- have unique themes, putting these patients • High tension glaucoma derived population is likely developing together in one basket with other patients • Open-angle glaucoma glaucoma a decade or two earlier than their with glaucoma means we’d be missing Caucasian counterparts (6). opportunities to learn more about each of Take for example a case of an African- them. To find new drug targets for POAG, American man with a positive family we need to entertain candidate mechanisms history of glaucoma (see box “A Case of AD- of the disease – of which there are many (see superior paracentral scotoma in the OAG”). Of note, this patient was only 32 sidebar: “Candidate Disease Mechanisms right eye, and superior nasal step years old, his IOPs weren’t particularly high for POAG”). The best way to identify these and nasal step in the left eye. (18–24 mmHg), central corneal thickness might be through a reverse engineering (CCT) measures were low, and there was cycle of discovery (Figure 1a). You may be thinking “this sounds just no evidence of a secondary glaucoma upon The following case helps demonstrate the like the PC-OAG subtype,” but I would examination. So what do we do differently concept of reverse engineering: like to draw attention to her GYN history for this type of patient? We get them and and mention that estrogen is a big driver their family on our radar – they’re all high- • At 47 years of age, a female patient of NO synthase 3 activity. It also has a role risk patients who need intervention, even was identified as a glaucoma in glaucoma-related traits, as indicated their children. Research into the genetics of suspect because of cupping. by several studies: retinal ganglion cells AD-OAG is spearheaded by Joan O’Brien, • Her OB/GYN history, which express estrogen receptors (8), and optic Mike Hauser and others. Constance Okeke many of us ophthalmologists nerve structure and retinal sensitivity on is championing the effort to educate all tend to ignore, was remarkable. visual field tests both vary as a function of patients about the importance of a positive She experienced pre-eclampsia the menstrual cycle (9, 10); IOP decreases family history of glaucoma, with emphasis at 30 years of age, and underwent during pregnancy despite the fact that on counseling young AD-OAG patients a hysterectomy and bilateral CCT increases in the third trimester (11); that their siblings and even their children oophorectomy at the age of 53. and a post-hoc analysis of a randomized should be under ophthalmic surveillance. • At 61 years of age, the patient controlled trial (RCT) has shown that post- But we can do more – we need to noticed she’d lost the superior part menopausal estrogen hormone therapy was deepen our understanding of AD-OAG of her visual field in her right eye. associated with lower IOP (12). But what because there are pathophysiological IOP was 21 mmHg in both eyes about POAG? Several studies indicate an differences between African-Americans and examination showed excavation increased risk of the disease in women and Caucasians. For instance, a well- of the neuroretinal rims in both eyes, with a reduced estrogen exposure during executed study examined over 10,000 disc but worse in the right eye. their lifetime (13–19). Estrogen has also photographs and showed that people of • Visual field assessments showed been shown to preserve visual function

www.theophthalmologist.com 44 Profession

Generate hypotheses and erform population-based perform clinic-based studies to confirm initial Candidate studies study results Disease to test them EVEE ENGINEEING Mechanisms CYCLE DICVEY IN AG for POAG atient question Construct animal models Doctor, why do I have to validate novel disease AG and how can we stop it targets for AG

• Endothelial cell dysfunction Devise CTs that answer the patient’s question and help with impaired NO signaling them retain their sight • Estrogen deficiency • Mitochondrial dysfunction • Neuroinflammation . esearch shows that opulation based studies • Insulin resistance estrogen levels impact suggest estrogen exposure • Oxidative stress glaucoma-related traits is related to AG • Ocular connective tissue disorder EVEE ENGINEEING CYCLE DICVEY IN ED-AG Estrogen exhibits atient presents with neuroprotection and structure in a rat model of open-angle premature menopause in experimental model and C-AG of glaucoma glaucoma (20). So when looking at the reverse cycle of engineering, this patient Next steps devise CTs that answer the patient’s question and might actually have estrogen-deficient help them retain their sight POAG (ED-OAG) because of her GYN history (Figure 1b), and the next steps would be to figure out how to leverage this Figure 1. Reverse engineering cycle of discovery in (a) POAG and (b) ED-OAG. information to design RCTs that answer ED-OAG, estrogen-deficient open-angle glaucoma; PC-OAG, paracentral open-angle glaucoma; the question of how we can help this patient POAG, primary open-angle glaucoma; RCT, randomized controlled trial. safely improve the local estrogen levels in her eyes and retain her sight. Of course, we exfoliation. Physiological cupping should use, and eye rubbing could be informative. are far from being able to achieve that goal also be treated with caution because many Performing a diurnal curve to look for at the current time. genetic markers for a large cup-to-disc IOP spikes and neuroimaging might also ratio are also markers for POAG (21), and reveal why some patients are deteriorating Some parting thoughts these patients should be monitored for the at a rapid rate. Clinically, there is much to think about development of glaucoma. In the future, with POAG, and we need to see the we’ll hopefully know the full complement Let’s help our patients… bigger picture. POAG may be associated of genes dictating optic nerve cup and I’ve defined subtypes of POAG that I with increased IOP, but the majority of shape, and be able to use this information believe exist. They each have different patients with the disease do not have IOPs to predict which patients might get POAG. features, different genetic markers that exceeding 35 mmHg. Caution should also be merited in cases of point to specific biochemical pathways So when confronted with a patient with rapid visual field progression because this in their disease – different etiologies that “POAG” who has very high pressures, is rare in patients with POAG – if you’re dictate how best they should be managed. you should be considering other causes of seeing this, seek alternative causes for To achieve a precision medicine approach elevated IOP such as steroid exposure or rapid progression. Asking about steroid to treatment, we need to perform more Profession 45

research to find all the different subtypes, and we need to accept that some patients may have overlapping features of several A Case of AD-OAG different subtypes of the disease. Let’s help our patients by taking the “P” out of Background Eye exam POAG. I said that it has to be secondary • Male, 32 years old • Vision: 20/600 sc OD; 20/20 sc OS to something – in fact, it is secondary to • Last eye exam was eight years • IOP: 24 mmHg OD; 18 mmHg OS many things. ago; routine eye exam revealed • CCT: 512 µm OD; 522 µm OS loss of vision in right eye • Slit lamp examination Louis Pasquale is Director of the Glaucoma • Patient knew OD vision was unremarkable Service and Telemedicine at Massachusetts “weak,” but it hadn’t been • Gonioscopy: Gr III open 360° OU Eye and Ear Infirmary, Harvard Medical affecting his daily activities with 1+PTM School, Boston, USA. Financial disclosures: Paid Consultant for Bausch + Lomb and Eyenovia. Travel support from The Glaucoma Foundations in New York and San Francisco.

References 1. N Mantzioros., Available at: http://bit.ly/ HistoryGlaucoma. Accessed February 7, 2017. 2. SC Park et al., Ophthalmol, 118, 1782–1789 (2011). PMID: 21665283. 3. SJ Loomis et al., Ophthalmol, 121, 508–516 (2014). PMID: 24572674. 4. Y Lei et al., Invest Ophthalmol Vis Sci, 56, 4891–4898 (2015). PMID: 26225628. 5. JH Kang et al., JAMA Ophthalmol, 134, 294–303 (2016). PMID: 26767881. 6. CL Bokman et al., PLoS One, 30, e115942 (2014). PMID: 25549331. 7. A Skaat et al., Ophthalmol, 123, 1476–1483 (2016). PMID: 27117781. 8. C Munaut et al., Br J Ophthalmol, 85, 877–882 (2001). PMID: 11423466. 9. ME Akar et al., Acta Ophthalmol Scand, 82, 741–745 (2004). PMID: 15606474. 10. I Yucel et al., Can J Ophthalmol, 40, 51–57 (2005). PMID: 15825530. 11. K Green et al., Ophthalmic Res, 20, 353–357 (1988). PMID: 3237393. 12. TS Vajaranant et al., Am J Ophthalmology, 165, 115–124 (2016). PMID: 26940165. 13. YE Wang et al., Ophthalmology, 123, 729–736 16. TS Vajaranant et al., Menopause, 21, 391–398 19. KS Na et al., PLoS One, 11, e106473 (2014). (2016). PMID: 26948305. (2014). PMID: 24061049. PMID: 25210892. 14. LR Pasquale and JH Kang. Eye, 25, 633–641 17. LR Pasquale et al., J Glaucoma, 16, 598–605 20. K Prokai-Tatrai et al., Molecular Pharmaceutics, 5, (2011). PMID: 21336255. (2007). PMID: 18091177. 3253–3261 (2013). PMID: 23841874. 15. CA Hulsman et al., Am J Epidemiol, 15, 138–144 18. PA Newman-Casey et al., JAMA Ophthalmol, 21. BJ Fan et al., Invest Ophthalmol Vis Sci, 28, (2001). PMID: 11447046. 132, 298–303 (2014). PMID: 24481323. 1788–1792 (2011). PMID: 21398277.

www.theophthalmologist.com 46 Profession

Balancing the Cost of Success and Failure

Publishing negative results might not flatter – but it does matter

By Ian Catchpole

Late on in my career at GSK, my colleagues and I published a paper (1). It could have been groundbreaking. In some ways it was. We were seeking a better

way to treat wet AMD – one that would understand what kind of problems were At a Glance obviate much of the burden of monthly out there in ophthalmology: scientifically, • Collectively, companies and research clinic visits for intravitreal injections of clinically, and everything else that we institutions have invested millions anti-VEGF therapy that we see today. might need to deal with when building trying to develop intravitreally Despite solving many problems along the an ophthalmic franchise. It was apparent administered, extended-release anti- way, ultimately, the project failed – but we even then (ranibizumab had been approved VEGF agents for the treatment of should all learn from its failure. Let me in the US less than a year before for the retinal neovascular disease that can tell you my story. treatment of wet AMD) that the large act for as long as 6 months number of clinic visits and intravitreal • GSK, in collaboration with Discovering ophthalmology anti-VEGF injections – one a month, OctoPlus N.V., developed a novel It started back in 2007, when I first worked going forward for as long as the drug potent anti VEGF molecule and in the field of ophthalmology. GSK’s head continued to work – was going to be the hydrogel microparticle combination of research at the time was Tachi Yamada, big issue, in addition to the hefty cost of that almost fitted the bill – and and he was interested in the gene therapy the drugs themselves. was close to a clinical trial. Had area. He knew one of the biggest names it worked, it would have been a in that field – Jim Wilson at University of Combining drug with delivery platform paradigm changer. Pennsylvania – and he enabled GSK to Around that time, GSK acquired a • One of the issues that led to the access some of the Wilson group’s novel company called Domantis that worked project’s termination was caused by adeno-associated virus (AAV) vectors. We on domain antibodies and antibody fundamental and poorly understood started working with Jim’s group and also fragments. As part of that, we acquired aspects of primate accommodation, a number of researchers from the UCL certain relatively small anti-VEGF which led to microparticle migration Institute of Ophthalmology in London molecules – certainly smaller than into the anterior chamber looking at gene therapy approaches to ranibizumab. Here was an opportunity to • The issues highlighted in this research ocular disease. The opportunities were play with drug delivery – i.e. to pack a lot are relevant for others pursuing great – here was an organ where you could of drug in to a sustained release vehicle and the use of particulate injectables for actually see the effects of what you were build a long-acting injectable anti-VEGF. intravitreal ocular delivery, some of doing! We also started re-profiling existing So we presented that idea to the GSK whom are not easily able to afford GSK assets and considering ophthalmic equivalent of Dragon’s Den – an internal the key experiments in the primate applications for them – this was a therapy poster presentation and competition eye needed to de-risk likely similar area that had great promise! I started going session called the Goldfish Awards. issues in man to the ARVO meetings to start trying to We didn’t win – but what we presented Profession 47

Figure 1. PolyActive hydrogel microparticles. Figure 2. Proposed structure of the dual domain antibody in complex with two VEGF molecules. Adapted from (1). Adapted from (2). generated enough interest within the newly antibodies (ADA) responses post-dose at formed GSK Ophthalmology group that high frequency which blocked detection they thought it that was a good idea to “The big challenge of the released anti-VEGF, and it made pick it up. We had started reviewing drug it challenging to interpret the results. delivery options, and came across a Dutch was rebuilding the Nevertheless, we gathered together enough company called Octoplus N.V. (now part data to demonstrate that substantial levels of the Dr. Reddy’s franchise) who had an molecule to make it of active anti-VEGF molecule were present aqueous hydrogel drug delivery platform in the rabbit vitreous at six months post- (Figure 1) that not only managed to keep a more potent dose and to justify progressing to the the proteins active for a long time, but non-human primate (NHP) model. The also released them with pretty much first VEGF inhibitor.” cynomologous monkey is far closer than order kinetics – i.e. with minimal ‘burst’ rabbits to humans in terms of ocular release – over a long period. They hadn’t anatomy and function – it also seemed really performed any studies in the eye, so concentrations up to >200 mg/mL (a huge likely that the closer similarity to human we moved forward together. amount) to enable the release of sufficient would help reduce the negative impact and Even then, there were stumbling blocks. quantities to be effective for at least 6 frequency of ADA responses; enabling Our original candidate molecule just wasn’t months. But we did it. simpler detection and interpretation of the potent enough – so the big challenge was pharmacokinetics of the released molecule. rebuilding the molecule to make it a more Progressing through the preclinical steps It turned out that these successful and potent VEGF inhibitor. What we ended The next step was preclinical in vivo very expensive experiments both validated up making (Figure 2) was at least as potent experiments. We did our first studies many aspects of the approach but also as the most potent anti-VEGF available in rabbits, as it is the model of choice ended the project… on the market today, aflibercept (2). We for studies of ocular delivery. The use of We’d found that in vitro, we could then had to work to find and evaluate a rabbit eyes are not without issue; though release effective doses of anti-VEGF polymer that could keep the protein intact the intravitreal volume is relatively large molecule from the microparticle/ hydrogel, in the distinctly “wet” environment of the at 1.3 ml, it is still smaller than man PolyActive, platform over a 12-month eye and release therapeutic levels of it over (4.5 ml), but with a huge lens, so you need period, and in vivo, this translated to at a 6–12 month period. That was no easy to make sure that injection avoids the lens least six months’ worth of effective levels task: the principal technical challenge was – and then there were issues with immune of anti-VEGF released in both the rabbit to load enough protein material from the responses. Our antibody fragment was a and NHP experiments. We used the antibody fragment into the microparticle humanized protein: the rabbit’s immune NHP laser choroidal neovascularization itself – you needed to get liquid protein system kicked in and generated anti-drug (CNV) model (the pre-clinical model of

www.theophthalmologist.com 48 Profession

wet AMD used to validate ranibizumab prior to the clinic) to test how successfully our therapy managed to suppress the production of laser-induced leaky new blood vessels: we’d dose the eyes, wait 4–6 months, and challenge the eye with the laser – and found that we still got good protection even 6 months out. In that respect, moving forwards to a clinical trial looked promising. But there were three major challenges that prevented us from doing so – and these represent crucial lessons for any other research group that’s trying similar intravitreal particle-based drug delivery systems. It’s not always 100 percent success and steps forward into the clinic.

“It’s not always 100 percent success and steps forwards into the clinic.”

Three big challenges The first hurdle was ocular inflammation: 6–9 months, based on experiments where surprised by the latter observation – we we were seeing it in the NHP eyes as similar PolyActive implants had been hadn’t seen anything like that in our well as the rabbits. Although both protein placed subcutaneously in the rat – but when rabbit studies, and it seemed to be driven and microparticles were prepared at high we looked at the PolyActive material in the by the primate (and presumably human) quality and were shown to have extremely NHP eye, it was still there at 6 months, 9 eye’s process of lens accommodation- low levels of endotoxin, they were still months… and it was only really 12 months disaccommodation (3). It seems that research-grade materials, i.e., not prepared after implantation before we started to ciliary muscle-driven lens movement at GMP grade purity. So it might have see any major en masse reduction and causes fluid to flow between the vitreous been possible to reduce the degree of degradation. That meant it would be very and anterior chamber, and the particles inflammation by improving the quality difficult to re-dose – the accumulation of get disturbed and caught up in it. And so, of what we were administering, unless material in the eye would start to become despite some great technical achievements the inflammation was solely driven by the a problem after only a few doses. But the along the way – developing a potent particulate nature. But these weren’t the third and biggest problem was related to anti-VEGF antibody fragment, and being only challenges. The second issue was a the microparticles themselves. They would able to concentrate, load and deliver this lack of degradation of the polymer at the travel from the vitreous into the anterior biologic over a long period with a novel same rate as the release of the molecule. chamber. These three issues combined lead drug delivery vehicle – we fell at this The polymer was predicted to last for to termination of the project. We were quite last hurdle. Profession 49

learn of and from our experience – and not feel the need to cover old ground. The big questions I’m left with are: how can others build from the positive aspects of our findings and address the remaining issues? Can those working on particulates really take heed of the full message and switch funding and research activities to concentrate on generating similar data to ours with temperature sensitive solidifying erodible gels? If others with a negative data story are reluctant to share knowledge with the field perhaps they should reconsider and think of what other medical research could have been done with the money others spend repeating their mistakes? The answer to that latter question is the true cost of failure.

Ian Catchpole is a GSK Fellow, Cell & Gene Therapy, and is based in their Stevenage campus in Hertfordshire, England.

References 1. 1. P Adamson et al., “Single ocular injection of a sustained-release anti-VEGF delivers 6 months pharmacokinetics and efficacy in a primate laser CNV model”, J Control Release, 244, 1–13 (2016). PMID: 27810558. Being open negatively influence their share price. 2. 2. A Walker et al., “Novel Interaction Why am I talking about our work, Also, how many biotech companies and Mechanism of a Domain Antibody-based both the successes and its ultimate academic groups are receiving funding Inhibitor of Human Vascular Endothelial failure? I strongly believe that negative from research councils or companies to Growth Factor with Greater Potency than results, especially those that have such fund costly studies – only to repeat our Ranibizumab and Bevacizumab and a strong bearing on the future of a findings? A huge combined investment Improved Capacity over Aflibercept”, J Biol field should be published (4). Anyone has likely already been made with this Chem, 291, 5500–5511 (2016). PMID: evaluating a similar drug-delivery type of approach by GSK together with 26728464. method needs to be aware of our work other pharma and biotech companies. 3. 3. MA Croft et al., “Mechanism of – GSK was not alone in working on Although our project didn’t work out, accommodation: new findings and the this approach. There are still biotech there were positive aspects from our implications for presbyopia”, IOVS, 56 (2015) companies developing particle-based study. We clearly demonstrated that ARVO E-Abstract 3568. Available at: drug delivery approaches for intravitreal hydrogel systems can keep anti-VEGF biy.ly/macroft. injection who have not performed NHP protein molecules stable and active, and 4. 4. K Park, “Ocular microparticle studies and are either unaware of our can enable them to be released for over formulations for 6-month delivery of findings or are reluctant to accept the 6 months in the eye at effective doses to anti-VEGF”, J Control Release, 244, 136 full consequences of them, as it might treat wet AMD. I hope that others will (2016). PMID: 27964806.

www.theophthalmologist.com The Impatient Innovator

Sitting Down With... Sean Ianchulev, Professor of Ophthalmology at New York Eye and Ear Infirmary of Mount Sinai; Founder and CEO, Eyenovia; and Founder and Chairman of the Board, Iantech Medical. Sitting Down With  51

You’re a true innovator – where does changed only incrementally since the eminence. There are so many ideas out that stem from? 70s – from the time of Fyodorov’s IOL there – I get approached every week I come from an academic background, fundamental models. There have been by a colleague or resident who have but I’m very impatient and find many permutations and improvements had a light bulb go off. But an idea the academic approach to product in preoperative formulae since then, is just the beginning – it needs to be development too slow, which is partly but intra-operative aberrometry was matured into a solution, the solution why I work closely with industry. based on a categorically different developed into a product and ultimately Such collaborative approaches are paradigm – in-theater measurement into a business which can scale and increasingly necessary, because product of aphakic autorefraction. And now touch many patients, and that takes a development is now so complex. If you aberrometry has been used to improve village, or as the Transcend team say, want to get even a simple device into care for more than half a million it takes a tribe! I think we need to get patients today, you need to partner patients, and counting – the method more efficient and smarter about how we with people from many disciplines: is almost ubiquitous. Similarly, practice medicine. My team published engineering, medicinal chemistry, when I joined Eugene de Juan and a study in Ophthalmology 18 months quality, manufacturing, and venture Transcend Medical to develop the ago, where we analyzed a database of capital. It’s no longer as easy as coming CyPass Micro-Stent nine years ago, 20,000 office-based cataract surgeries, up with a Sinskey hook and trying people couldn’t see the point – they and found it to be pretty safe – not a it on patients! For example, even were happy with their trabeculectomies single case of endophthalmitis. This something as safe and non-invasive as and tubes. But today, microstents have gave some people heartburn, but it intraoperative aberrometry took more revolutionized glaucoma treatment, and has tremendous implications: avoiding than 10 years and millions of dollars MIGS is the fastest growing category the OR frees up OR space for other of development to get to patients. On in ophthalmology. You simply don’t procedures, and aligns cataract surgery the pharmaceutical side even more know where innovation will take you, with refractive surgery in terms of how so – when I was at Genentech and led and building market models is often so it’s done. It reduces resource use and the clinical development of Lucentis, treacherous – it is necessary, but often improves efficiency – leaving the OR it needed more than a decade and gives investors a false sense of security rooms for the more major procedures hundreds of millions of dollars to get as they are trained in excel spreadsheets which need it. it into the clinic. Product development and data analytics. From my experience, and commercialization are non-trivial all the technologies I have been involved What advice would you give to parts of the science and innovation in exceeded estimates by a factor of at aspiring innovators? process, which is like launching a least 10. On the venture side, I have Follow your passion and trust yourself. mission in space – thoughtful, well- seen the flip side of the coin as well – Doctors are not always the greatest planned and disciplined development when beautiful and intricate forecasting businessmen, but being able to wear are required, and this costs real money. models come to naught. So, I trust my a clinician’s hat when judging new clinical gut and try to ask one simple technologies – to really understand their Which of your innovations do you question – how can I make patients’ clinical utility – is tremendously helpful. consider to be the most disruptive? and physicians’ lives better? What is But you can’t know from the outset Intraoperative aberrometry is a good the clinical utility? And then disruption which ideas will result in paradigm example. When I came up with the idea, and adoption seem to follow. shifts; you have to persevere – and for I tried it on my patients using a simple that you need passion. auto-refractor during cataract surgery in What’s the biggest challenge in 2003. It was so powerful and predictive ophthalmology today? An extended version of this interview is that even 20 patients were enough to get First, we need more bright, available online at: top.txp.to/issues/0617/802 a signal. Getting clinical information entrepreneurial ophthalmologists to early in the process was critical – we get involved and step out of the clinical Sean Ianchulev reports the following published the original series in JCRS. practice treadmill. Ophthalmology has relevant disclosures: Founder and Chairman Little did I realize this would break genericized itself both technologically of Iantech, Inc; Founder and CEO of down a 50 year-old paradigm of and practice-wise; it is all about volume Eyenovia, Inc; Advisor to Alcon-Novartis; pre-operative biometry, which had and less about differentiation and and a partner of PME Ventures.

www.theophthalmologist.com Product Name: TAPTIQOM® 15 micrograms/ml + 5 mg/ml eye drops, solution in single-dose container. Composition: One drop (about 30 µl) contains about 0.45 micrograms of taflupost and 0.15 mg of timolol. One single-dose container (0.3 ml) of eye drops contains 4.5 micrograms of taflupost and 1.5 mg of timolol. Please refer to the Summary of Product Characteristics (SmPC) for a full list of excipients. Indication: Reduction of intraocular pressure in adult patients with open angle glaucoma or ocular hypertension who are insufficientlyresponsive to topical monotherapy with beta-blockers or prostaglandin analogues and require a combination therapy, and who would benefitfrom preservative free eye drops. Posology and method of administration: Recommended dose is one drop in the conjunctival sac of the affected eye(s) once daily. Not to exceed one drop per day in the affected eye. Not recommended in children or adolescents (under the age of 18). In renal or hepatic impairment use with caution. To reduce systemic absorption, patients should be advised to use nasolacrimal occlusion or close the eyelids for 2 minutes after instillation. Excess solution should be wiped away to reduce the risk of darkening of eyelid skin. If more than one ophthalmic product is used, fiveminutes should separate their administration. Contact lenses should be removed before instillation. Contraindications: Hypersensitivity to the active substances or to any of the excipients. Reactive airway disease including bronchial asthma, or a history of bronchial asthma, severe chronic obstructive pulmonary disease. Sinus bradycardia, sick sinus syndrome, including sino-atrial block, second or third degree atrioventricular block not controlled with THE NEXT STEP pace-maker. Overt cardiac failure, cardiogenic shock. Warnings and precautions: Before initiating treatment, patients should be informed of the possibility of eyelash growth, darkening of the eyelid skin and increased iris pigmentation related to taflupost. These changes may be FOR POWERFUL permanent, and lead to differences in appearance between the eyes if only one eye is treated. Similar cardiovascular, pulmonary and other adverse reactions as seen with systemic beta-adrenergic blocking agents may occur. The incidence of systemic adverse reactions after topical IOP LOWERING ophthalmic administration is lower than with systemic administration. Caution should be exercised when prescribing TAPTIQOM® to patients with cardiac or severe peripheral vascular disorders eg Raynaud’s disease or syndrome. Use with caution in patients with mild/moderate 1 COPD and in patients subject to spontaneous hypoglycaemia or labile • Up to 40% vs baseline diabetes. Beta-blockers may mask signs of hyperthyroidism and block systemic beta-agonist effects such as those of adrenaline. Anaesthetists should be informed when a patient is receiving timolol. Patients with a • Low level of history of severe anaphylactic reaction may be more reactive to repeated 2 challenge with such allergens and be unresponsive to the usual doses hyperaemia (7%) of adrenaline used to treat anaphylactic reactions. The known effects of systemic beta blockers may be potentiated when TAPTIQOM ® is given 2 concomitantly. The use of two topical beta-blockers is not recommended. • One drop once daily Patients with corneal disease should be treated with caution as ophthalmic beta-blockers may induce dry eyes. When timolol is used to reduce elevated intraocular pressure in angle-closure glaucoma, always use a miotic. Caution is recommended when using taflupost in aphakic patients, pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, and in patients with known risk factors for cystoid macular oedema or iritis/uveitis. Please see the SmPC for further information. Interactions with other medicinal products: Potential for hypotension / marked bradycardia when administered with oral calcium channel blockers, beta-adrenergic blockers, anti-arrhythmics, digitalis glycosides, parasympathomimetics and guanethedine. Please refer to the SmPC. Pregnancy: Do not use in women of childbearing age/potential unless adequate contraceptive measures are in place. Breast-feeding: It is not recommended to breast-feed if treatment with TAPTIQOM® is required. Driving and using machines: If transient blurred vision occurs on instillation, the patient should not drive or use machines until clear vision returns. Undesirable effects: Conjunctival/ocular hyperaemia occurred in approximately 7% of patients participating in clinical studies with TAPTIQOM®. Other common side effects include: eye pruritus, eye pain, change of eyelashes (increased length, thickness and number of lashes), eyelash discolouration, eye irritation, foreign body sensation, blurred vision, photophobia. Adverse reactions that have been seen with either of the active substances (taflupost or timolol) and may potentially occur also with TAPTIQOM® include: increased iris pigmentation, anterior chamber cells/flae, iritis/uveitis, deepening of eyelid sulcus, hypertrichosis of eyelid, exacerbation of asthma, dyspnea, allergy, angioedema, urticaria, anaphylaxis, hypoglycaemia, syncope, ptosis, bradycardia, chest pain, palpitations, oedema, cardiac arrest, heart block, AV block, cardiac failure. Please also see the SmPC. Overdose: Treatment should be symptomatic and supportive. Special precautions for storage: Store in a refrigerator (2°C - 8°C). After opening the foil pouch keep the single-dose containers in the original pouch and do not store above 25°C. Discard open single- dose containers with any remaining solution immediately after use. Package quantities and price: 30 x 0.3ml single-dose containers £14.50. Marketing authorisation holder: Santen Oy, Niittyhaankatu 20, 33720 Tampere, Finland. Marketing authorisation number: PA 0879/003/001. Date of authorisation: 28/11/2014. Legal Category: POM. Prescribing information job code: STN 0418 TAP 00001a Date of prescribing information: 14/04/2016.

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Santen UK Limited (Email: [email protected] or telephone: 0345 075 4863).

TAPTIQOM is a registered trademark of Santen Pharmaceuticals Co., Ltd. References: 1.Holló G et al. Fixed-Dose Combination of Tafluprost and Timolol in the Treatment of Open-Angle Glaucoma and Ocular Hypertension: Comparison with Other Fixed-Combination Products. Adv Ther. 2014; 31: 932-944 2.Taptiqom SPC, last changed October 2014

Job code: STN 0918 TAP 00038 Date of preparation: September 2016