NOVEMBER 2014 # 13

Upfront In Practice NextGen Profession Viagra And Vision: The Long Operate, But Don‘t Ablate, Benchmarking BRVO You Have a Great Idea. And The Short Of It and SMILE Now What?

12 34 – 36 40 – 42 46 – 49

Electrophysiology Hits the Clinic

Electrophysiological tests no longer need to be confined to the research lab. So could they soon be used for routine diagnoses? 18 – 25 Ecknauer+Schioch ASW Breathtaking So easytooperate!DirectAccess Beautiful cases. 1200cutsanteriorvitrectomy. trolled corticalclean-up.HFcapsulotomyfordifficult That’s 1.6 to3.2mm,fast,safeandtheACalwaysstable. Any nucleusfrom softtohardest, anyincisionfrom Strong www.oertli-catarhex3.com highest volumeinanyset-upatcontrolled costs. Lets you enjoy most advanced surgery from low to For You Built-in compressor. Justplugto90-230V. surgery. Fantastictoetipofflowcontrol. glaucomafunction, thefutureinterno ofcombined Truly portable, 5kg, fits ina pilot’s case.HFDSab Unique brings afriendlynoteinyourOR. Bright, easytoread display. Amarvelof design, without confusion.Programmable for20surgeons. easyPhaco ® . CortexMode TM forprecisely con- ® toanyfunction Ecknauer+Schioch ASW Breathtaking So easytooperate!DirectAccess Beautiful cases. 1200cutsanteriorvitrectomy. trolled corticalclean-up.HFcapsulotomyfordifficult That’s 1.6 to3.2mm,fast,safeandtheACalwaysstable. Any nucleusfrom softtohardest, anyincisionfrom Strong www.oertli-catarhex3.com highest volumeinanyset-upatcontrolled costs. Lets you enjoy most advanced surgery from low to For You Built-in compressor. Justplugto90-230V. . Fantastictoetipofflowcontrol. glaucomafunction, thefutureinterno ofcombined Truly portable, 5kg, fits ina pilot’s case.HFDSab Unique brings afriendlynoteinyourOR. Bright, easytoread display. Amarvelof design, without confusion.Programmable for20surgeons. easyPhaco ® . CortexMode TM forprecisely con- ® toanyfunction Month this Online 10:08 PM - 20 Oct 2014 10:08 PM-20Oct2014 5.#aao2014 Your aresident. for advice The Ophthalmologist @OphthoMag advice would you give aresident?What 10:06 PM-20Oct2014 #AAO2014 Pearls #2. ever. Bestadvice The Ophthalmologist @OphthoMag Top tipsfrom AAO 2014 Congress inChicago 2014 Academy ofOphthalmology Live updatesfrom theAmerican popular tweets… Here are some ofourmost got you tweeting thismonth? What on Twitter The Ophthalmologist See to to had whatthey sayathttp://youtu.be/M8fn5j2JL-4 innovation isdead. them tothemeeting, and, thinkthat whetherornotthey practiceandindustry,clinical andaskwhatattracted delegates andspeakersfrom thespheres ofresearch, itsfuture andhisplansfor and we interview the forum gives histhoughtson Kuldev Singh Meeting co-chair Futures Forum, London2014 The Ophthalmologist Live atOphthalmology Video:

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– @Ophthomag. Follow uson Twitter andjointhediscussion 10:05 PM-20Oct2014 Pearls.#aao2014 1. Pizza. The Ophthalmologist @OphthoMag Delegates share theirdream pizza 8:19 PM-21Oct2014 session thismorning. #AAO2014 #abitoffun League Ophthalmic Premier Agarwal’s Prof. Name theophthalmologists from Contents

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03 Online This Month Upfront

10 A Very Public Prepublication

07 Editorial 12 Viagra and Vision: the Long and The Road to Hell Is Paved with the Short of it Good Intentions By Mark Hillen Feature 13 Exogenous Testosterone Might Make Things Swell 18 Electrophysiology Hits the Clinic 08 Contributors As the devices become 13 This Month in Business smaller, cheaper and simpler, electrophysiological testing is no On The Cover 14 Gaze Deeper longer purely the domain of

NOVEMBER 2014 # 13 research institutes. Mark Latina

Upfront In Practice NextGen Profession Viagra and Vision: The SMILE: Operate, Benchmarking BRVO Your Journey From Invention Long and the Short of it But Don’t Ablate to Commercialization

10 23 – 31 33 – 40 43 – 47 The impact of electrophysiology on 16 Reading Scleral Signals discusses how these tests help Electrophysiology Hits the Clinic

Electrophysiological tests can aid in diagnosis, treatment and monitoring of visual disease 14 – 20 the holy trinity of diagnose, treat and monitor visual defects… in the ophthalmologist’s office. ISSUE 13 - NOVEMBER 2014

Editor - Mark Hillen [email protected]

Associate Editorial Director - Fedra Pavlou [email protected]

Associate Editor - Roisin McGuigan [email protected]

Associate Editor - Michael Schubert [email protected]

Senior Designer - Marc Bird [email protected]

Chief Executive Officer - Andy Davies [email protected]

Chief Operating Officer - Tracey Peers [email protected]

Publishing Director - Neil Hanley [email protected]

Audience Development Manager - Tracey Nicholls 30 [email protected]

Digital Content Manager - David Roberts [email protected]

Traffic and Administration Manager - In Practice Next Gen Claire Lally [email protected] 28 Satisfying the Demands of the 40 Benchmarking BRVO Post-LASIK Presbyope? We examine the last five years in Mac Operator Web/Print - Peter Bartley [email protected] Small-aperture intraocular lenses branch retinal vein occlusion – offer a new alternative to what have we learned, and where Social Media / Analytics - Stephen Mayers multifocal or accommodating might we go next? [email protected] IOLs for clear vision across near, intermediate and far distances. Published by Texere Publishing Limited, Booths Hall, 30 No More Drops for Surgery Profession Booths Park, Chelford Road, Knutsford, Cheshire, Patients in the Real World? WA16 8GS, UK Patient compliance with 46 You Have a Great Idea. Now What? postsurgical treatment regimens Nikki Hafezi gives a guide to after is often poor turning bright ideas into General enquiries: – can transzonular injection of commercial realities. www.texerepublishing.com [email protected] these drugs improve outcomes? +44 (0) 1565 752883 [email protected] 34 Operate, But Don‘t Ablate, and SMILE Sitting Down With Jesper Hjortdal shares his Distribution: experiences with SMILE, the 50 John Kanellopoulos talks about The Ophthalmologist distributes 17,934 printed copies and 7,295 electronic copies to a targeted refractive surgical technique corneal crosslinking, commercial European list of industry professionals. that uses only a femtosecond laser consultation and his demands for ISSN 2051-4093 and requires no flap creation. the best. OCULUS PARK 1® 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.

One Measurement – Three Results!

PARK 1® is a non-contact Pachymeter, Autorefractor and Keratometer. White-to-white, pupil size and pupil distance are measured automatically. All these features, in addition to the stylish design and touch screen display make the PARK 1® the best value for the money and a guarantee for an optimized workflow!

www.oculus.de

The Ophthalmologist PARK1 Produkt 210x266 e 10.14.indd 1 22.10.2014 19:27:43 OCULUS PARK 1® The Road to Hell Is Paved with Good Intentions Maurice Saatchi wants new legislation to free British doctors Editorial from fear of litigation in the pursuit of innovation. Others view it as a charlatan’s charter

here is a fantastic medical debate in the UK right now. In one corner, Maurice Saatchi, a man with no medical training but considerable clout in politics and media. In the other corner… most of the UK medical establishment. Saatchi’s Medical Innovation Bill (1) Tdivides them. The bill has a great narrative – you’d expect nothing less from the guru of advertising. Doctors learn to “do no harm” – fine, until you’re dealing with dying patients. Here, “fear of the law” stops doctors from trying “innovative” therapies to save those patients – or advance medical knowledge. Saatchi’s opinion (2) is that “All 165,000 cancer deaths in this country every year are wasted deaths because science advances not one centimetre as a result,” adding, “Nothing new is tried […] Scientific progress is being halted by the law and fear of negligence bills.” Should something be done? The UK’s Health Secretary, Jeremy Hunt, thinks so and supports the bill. Many doctors don’t. The Bolam test (3) is currently applied, and

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. states that a doctor is only negligent and compensation justified “if no responsible body of medical opinion would support References their treatment or if the treatment had no logical or rational 1. House of Lords and M.N. Saatchi, “Medical justification.” Has the status quo stifled innovation? Unlikely. The Innovation Bill (HL)”, Stationery Office NHS Litigation Authority states that such compensation claims (2014). bit.ly/medinnovbill are “vanishingly rare – 0.01 percent of such payments” (4). 2. M. Saatchi, “Lord Saatchi Bill: We must Might the bill help by codifying doctors’ stance and avoiding liberate doctors to innovate”, January 28th the need to interpret case law? If you innovate by “departing One Measurement – (2014). bit.ly/mstelegraph from the existing range of accepted treatments for a condition”, 3. Bolam v Friern Hospital Management you must consult “with appropriately qualified colleagues” and Committee (1957). bit.ly/bolamtest consider “all matters that appear to the doctor to be reasonably Three Results! 4. A. Prentice, “From The President: Medical necessary to be considered in order to reach a clinical judgment” Innovation Bill”, Bull. Royal Coll. Pathol., (1). Already holes are being picked, such as “What counts as an 167, 148–150 (2014). bit.ly/archieprentice appropriately qualified colleague?” (5). Perhaps future cases heard 5. I. Brassington, “Saatchi Bill – Update” BMJ in court will clarify this... Blogs, October 28th (2014). bmj.co/107fs1l Bills can be revised and loopholes closed. But I wonder how far science advances through anecdotal, ad hoc intervention? PARK 1® is a non-contact Pachymeter, Autorefractor and There’s no compulsion to publish or framework to pool those anecdotes to generate meaningful data. If you’re going to perform Keratometer. White-to-white, pupil size and pupil distance are an intervention that risks depriving someone of peace or comfort measured automatically. in the last days of their life, then the information gathered better count for something. I see no guarantees that it will. All these features, in addition to the stylish design and touch screen display make the PARK 1® the best value for the money and a guarantee for an optimized workflow! Mark Hillen Editor

www.oculus.de

The Ophthalmologist PARK1 Produkt 210x266 e 10.14.indd 1 22.10.2014 19:27:43 A NEW ERA HAS BEGUN, Contributors AND IT LOOKS AMAZING. Introducing TECNIS® IOL, the first and only presbyopia-correcting Extended Range of Vision IOL. Mark Latina Latina, an internationally renowned glaucoma specialist, is associate clinical professor of ophthalmology at Tufts University Medical School in Boston and currently a staff member at a number of eminent Massachusetts hospitals, as well as being in private practice. Latina invented Selective Laser (SLT) for the treatment of open angle glaucoma, has over 75 publications and chapters, and holds 10 patents. In his free time, Latina enjoys cooking, bicycling, kayaking and clamming. Read Mark‘s article on how electrophysiology is about to hit the clinic in a big way on page 18.

Günther Grabner Grabner studied medicine at the University of Vienna and went on to found Austria’s first bank in 1977. After spending time in California, he returned to Austria, where he is now director and full professor of the Salzburg Paracelsus Medical University Eye Clinic. He has edited several journals, published over 300 articles, and recently gave the Ridley Medical Lecture at the 2014 congress of ESCRS. His research interests include corneal and intraocular presbyopia and astigmatism. Günther introduces us to the IC-8 IOL on page 28.

Cathy Schanzer Medical director and chief surgeon at Southern Eye Associates in Memphis, Tennessee, Schanzer is mother to seven adopted children. She first traveled to Africa to participate in mission work in 1988 and in 2006 committed to establish and support the Serabu Eye Clinic in Sierra Leone with her husband, Tom Lewis. She now travels to the clinic twice a year to perform surgery. M. Stewart Galloway Galloway graduated from the University of Tennessee College of Medicine and is now at Cumberland Eye Care and Cookeville Eye Specialists in Tennessee. He has been volunteering with the World Cataract Foundation since 2001, making annual trips to Guerrero, Mexico, to perform surgery. He is married with two children and At last, your patients can enjoy increased spectacle independence with enjoys golfing, diving, and underwater photography. a true extended range of vision.1 • A full range of continuous, high-quality vision in all light conditions2 Read Cathy and Stewart’s summary of dropless cataract surgery on page 30. • Incidence of halo and glare comparable to a monofocal IOL1 • TECNIS® Symfony Toric IOL also available The world will never look the same. Nikki Hafezi For more information, contact your Abbott Medical Optics After earning a master’s degree at the Swiss Federal Institute of Technology, Hafezi sales representative. served as a development executive for a private hospital and a national public health agency. She later moved to Switzerland and, due to her expertise in intellectual property management, became managing director of GroupAdvance consulting 1. 166 Data on File_Extended Range of Vision IOL 3-Month Study Results (NZ). ® and CEO of EMAGine AG, a spin-off company from the University of Geneva 2. TECNIS Symfony DFU TECNIS® Symfony Extended Range of Vision Lenses are indicated for primary implantation for the visual correction of aphakia and preexisting corneal astigmatism in adult patients that develops CXL technology. She lives in Zug, Switzerland, with her husband and with and without presbyopia in whom a cataractous lens has been removed by extracapsular cataract extraction, and aphakia following refractive lensectomy in presbyopic adults, two daughters. Nikki’s guide to getting great ideas turned into reality starts on page 46. who desire useful vision over a continuous range of distances including far, intermediate and near, a reduction of residual refractive cylinder, and increased spectacle independence. These devices are intended to be placed in the capsular bag. For a complete listing of precautions, warnings, and adverse events, refer to the package insert. TECNIS and TECNIS SYMFONY are trademarks owned by or licensed to Abbott Laboratories, its subsidiaries or affiliates. ©2014 Abbott Medical Optics Inc., Santa Ana, CA 92705 www.AbbottMedicalOptics.com PP20140012 A NEW ERA HAS BEGUN, AND IT LOOKS AMAZING. Introducing TECNIS® IOL, the first and only presbyopia-correcting Extended Range of Vision IOL.

At last, your patients can enjoy increased spectacle independence with a true extended range of vision.1

• A full range of continuous, high-quality vision in all light conditions2 • Incidence of halo and glare comparable to a monofocal IOL1 • TECNIS® Symfony Toric IOL also available The world will never look the same. For more information, contact your Abbott Medical Optics sales representative.

1. 166 Data on File_Extended Range of Vision IOL 3-Month Study Results (NZ). 2. TECNIS® Symfony DFU TECNIS® Symfony Extended Range of Vision Lenses are indicated for primary implantation for the visual correction of aphakia and preexisting corneal astigmatism in adult patients with and without presbyopia in whom a cataractous lens has been removed by extracapsular cataract extraction, and aphakia following refractive lensectomy in presbyopic adults, who desire useful vision over a continuous range of distances including far, intermediate and near, a reduction of residual refractive cylinder, and increased spectacle independence. These devices are intended to be placed in the capsular bag. For a complete listing of precautions, warnings, and adverse events, refer to the package insert. TECNIS and TECNIS SYMFONY are trademarks owned by or licensed to Abbott Laboratories, its subsidiaries or affiliates. ©2014 Abbott Medical Optics Inc., Santa Ana, CA 92705 www.AbbottMedicalOptics.com PP20140012 10 Upfront

Upfront

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

We welcome suggestions on anything that’s impactful on ophthalmology;

please email aflibercept use resulted in a significantly [email protected] A Very Public greater improvement in mean change in best-corrected visual acuity (BCVA) Prepublication from baseline at 52 weeks (the study’s primary endpoint) compared with both Regeneron released preliminary bevacizumab and ranibizumab intravitreal data of the DRCR.net Protocol T injections. The share prices of both trial. The DRCR.net hasn‘t, Regeneron, and Bayer HealthCare (who and won’t for a while. have exclusive ex-US rights to aflibercept) rose on the news (Figure 2). It’s interesting to see the results of an In terms of safety, ocular and systemic independently-run Phase III clinical adverse event rates were similar across trial first reported in a press release (1) the three treatment arms of the study, by one of the companies whose drug was although the rates of Anti-Platelet involved, ahead of peer-review publication Trialists’ Collaboration (APTC)- – or even presentation at a congress. That’s defined arterial thromboembolic events exactly what’s happened in the case of the (non-fatal , non-fatal myocardial Diabetic Retinopathy Clinical Research infarction, and vascular death) in the trial Network (DRCR.net) Protocol T trial (2). were 2, 4 and 5 percent in the aflibercept, Three drugs were evaluated: aflibercept, bevacizumab and ranibizumab treatment bevacizumab and ranibizumab, in patients arms, respectively. According to the release, with diabetic macular edema (DME) there were also significantly more overall and visual acuity (VA) of between 20/32 cardiovascular events in the ranibizumab and 20/320 (Figure 1). Regeneron, who arm than the bevacizumab or aflibercept market aflibercept in the US, “felt they arms (p<0.01), including a greater number had a fiduciary duty to release limited of both cardiac and cerebrovascular events statements regarding the outcomes prior to in the ranibizumab group. the publication of the entire peer-reviewed It would appear that DRCR.net is data” (3). According to Regeneron’s release, “currently in the process of finalizing and Upfront 11

Figure 1. Trial design and topline results for the DRCR.net Protocol T study. APTC, Anti-Platelet Trialists’ Collaboration; A, aflibercept; B, bevacizumab; R, ranibizumab; VA, visual acuity; >> significantly greater than; < numerically fewer than.

Protocol T”, and point to ranibizumab’s uncertain,” and “Caution is warranted “well-characterized safety profile, with interpretation of the preliminary with more than 2.8 million patient- efficacy and safety results ahead of a full treatment years of exposure globally” presentation and final peer-reviewed (4). The US distributor, Genentech, put publication by the DRCR.net.” MH out a stronger statement: “We believe that the findings of a single trial at one References year must be viewed in context of the 1. Regeneron Pharmaceuticals Inc. Press release, totality of evidence establishing the “EYLEA® (aflibercept) Injection Demonstrates efficacy and safety profile of Lucentis. Significantly Greater Gains in Visual Acuity During the first year of the Protocol T than Both Bevacizumab and Ranibizumab in trial, patients in all study arms received NIH-Sponsored Diabetic Macular Edema Study”, Figure 2. Both Regeneron and Bayer’s share prices a similar number of injections and bit.ly/eyleadme. Accessed November 3rd, 2014. rose after the topline results from DRCR.net experienced no significant difference 2. J.A. Wells for DRCR.net, “The Diabetic Protocol T were released. in the percentage of serious adverse Retinopathy Clinical Research Network. Protocol events including hospitalizations, T. Comparative Effectiveness Study of Aflibercept, verifying the data prior to submission for death, or endpoints as represented by Bevacizumab and Ranibizumab for DME”, bit. publication” and they “intend to present the APTC (non-fatal stroke, non-fatal ly/protocolT. Accessed November 3rd, 2014. the final results at a future medical myocardial infarction, and vascular 3. American Society of Specialists, “Top- conference simultaneous to, or soon after, death) criteria” (5). They added that Line Data From DRCR.net Protocol T: publication” (1). Of note, “the DRCR. “these preliminary data include a new Regeneron Statement”, bit.ly/asrsregeneron. net will not be publicly discussing and not yet validated endpoint of ‘Any Accessed November 3rd, 2014. the results prior to publication” – Cardiovascular Event’ which contains a 4. Novartis AG. Press release, October 16, 2014, which is why it’s surprising that broad range of symptoms with unclear “Lucentis Efficacy and Safety in DME”, bit.ly/ Regeneron are (1). relationship to anti-VEGF drug use. novartisdme. Accessed November 3rd, 2014. Novartis, ranibizumab’s ex-US This endpoint indicates a potential 5. American Society of Retina Specialists “Top- distributor “is aware that the topline difference in cardiovascular events Line Data From DRCR.net Protocol T: results of the Diabetic Retinopathy among the three medicines. Whether Genentech Statement”, bit.ly/protocolTgenentech. Clinical Research Network (DRCR.net) this is a real or chance finding is Accessed November 3rd, 2014. 12 Upfront

Viagra and Vision: the Long and the Short of it

Are a significant number of users risking retinal damage?

In clinical trials of the erectile dysfunction drug Viagra, it has been observed that high doses can cause transient visual disturbances in otherwise healthy subjects, including blurred vision and photophobia. The active ingredient in Viagra, sildenafil, works by inhibiting phosphodiesterase 5 (PDE5), which in turn leads to vasodilation; however, it can also exert effects on PDE6, an enzyme with a key role in the phototransduction pathway, which could leave some users at risk of potential vision problems. Sildenafil could also potentially exert adverse effects on (heterozygous) carriers of a recessive allele that causes (RP). Researchers from Australia and New Zealand decided to investigate how PDE6 inhibition might affect individuals normal and carrier mice. vision is normal,” says first author Lisa who have preexisting susceptibilities to The initial results appear to confirm the Nivison-Smith, a researcher at the retinal damage; in this case, heterozygous researchers’ suspicions. The carrier mice University of New South Wales. “A carriers of genes for retinal dystrophy experienced longer and more severe visual better understanding of the effect of (1). In the study, mice with a nonsense disturbances than genetically normal this family of erectile dysfunction drugs mutation in a subunit of PDE6 were mice, exhibiting ocular changes for two could help scientists and clinicians plan used to create an animal homology weeks following the dose compared more successful strategies to account for for recessive RP. Mice carrying two of with the normal mice that returned factors such as a patient’s medication these mutations lose all photoreceptors almost entirely to a baseline state within and genetic makeup in diseases which by six weeks old, whereas carrier mice two days. Significantly, the carrier mice cause blindness.” have lower PDE6 activity, but retain also exhibited increased activity of The current work focuses only on normal retinal structure and function. cytochrome c, which can cause apoptosis photoreceptors, so further research is The mice were each given a single and is observed in retinal degeneration – needed to understand how sildenafil dose of sildenafil – the average dose implying that sildenafil may trigger cell affects the rest of the retina. RM administered was 29 mg/kg, which is the death in susceptible patients. equivalent of 20 times the recommended “These findings are highly significant Reference dosage for an average human adult. because about one in 50 people are 1. L. Nivison-Smith et al., “Sildenafil alters Electroretinograms, dissection and likely to be carriers of recessive genes retinal function in mouse carriers of retinitis immunohistochemistry were then used which cause retinal disease but are pigmentosa”, Exp. Eye Res., 128, 43–56 (2014). to quantify the effects of the drug on unlikely to know this, because their doi: 10.1016/j.exer.2014.08.014. Upfront 13

of the patients lacked any known risk This Month in Business factors for developing the CSCR– other than exogenous steroid Abbott and Zeiss join forces, use and the fact that they were Valeant and Allergan continue all male (see list). to battle Notably, the mean age at presentation (51 years) In an interesting move, Abbott and was a decade older than Carl Zeiss Meditec (CZM) have the average age of onset of announced a non-exclusive commercial CSCR, and testosterone collaboration in the USA. Along therapy had been initiated a with their own products, Abbott’s US mean duration of 14 months salesforce will now offer CZM’s cataract before presentation to the surgery products to their customers. vitreoretinal care centers. So CZM’s retail channels will continue to what’s the connection? Testosterone sell their own products through their is a vasoactive hormone, and in own channels in the USA. supraphysiological amounts, holds the The Valeant-Allergan takeover saga potential to increase choroidal bloodflow continues: Valeant and Bill Ackman and permeability – which may damage the have filed against Allergan in a Federal Exogenous retinal pigment epithelial layer, resulting court in California, accusing the in CSCR. So the lesson is this: if a male company of spreading misleading Testosterone patient presents with CSCR, the authors information in an attempt to block suggest “inquiring about testosterone the takeover; Allergan denies the Might Make therapy”, and in some cases “adjusting accusations and is still seeking to have or stopping therapy may be appropriate” the duo’s stake excluded from their Things Swell (1). MH December shareholder meeting. Meanwhile, Valeant sent a letter to Raised risk of central serous Reference Allergan’s board of directors confirming chorioretinopathy associated 1. E. Nudleman, S. Kiss, G.A. Williams, J.D. Wolfe, that “Valeant is prepared to improve with Androgel or Testopill “Central serous chorioretinopathy in its offer and provide value to your treatment patients receiving exogenous testosterone therapy”, shareholders of at least $200 a share” – Retina, 34, 2128-2132 (2014). doi: 10.1097/ which certainly beats the current offer Exogenous testosterone is used (in men) IAE.0000000000000198. on the table of $179 per share. to treat a whole host of conditions, from French company Nicox is continuing low endogenous testosterone production, its expansion strategy. Following the sarcopenia, depression to low libido and acquisition of ophthalmic company cognitive decline – and the indication list Risk factors for developing Doliage and of the anti-viral eye drop shows no sign of reducing. Unfortunately, CSCR (1). Carragelose, Nicox has now formed an popping Testopills or wearing an exclusive distribution agreement with Androgel patch seems to be associated • Male gender OptiMed in Australia and New Zealand. with an increased risk of central serous • Corticosteroid therapy <1 year We covered TxCell SA’s personalized chorioretinopathy (CSCR). before presentation Col-Treg cell therapy for the treatment Royal Oak, Michigan-based • Atypical concurrent of uveitis back in our June issue. The ophthalmologist, Eric Nudleman and psychosocial stress French company has now announced colleagues based both in Michigan and • Systemic infection that their treatment has demonstrated New York have presented a retrospective • Uncontrolled hypertension both safety and efficacy in a mouse case series of nine patients who • Exogenous steroid use. model study, and that a Phase I/II presented with CSCR to two tertiary clinical trial is scheduled to start in Q2 vitreoretinal care centers in the US. All 2015. RM 14 Upfront For Benefits Disadvantages Glaucoma • Can measure speed • Cannot show of filling of retinal peripapillary or deep vasculature retinal capillaries Tough on IOP. • Can show leakage from • Requires dye injection retinal blood vessels – risking potential Easy on . Gaze Deeper adverse events

OCT angiography offers high- OCT angiography • Can image all layers of • Requires additional resolution imaging of the deep retinal vasculature fixation time from retinal vasculature • No fluorescein-related patient side effects • Has limited depth of focus You might not think that one of • Can’t visualize leakage the most challenging aspects of eye imaging is obtaining a clear picture of The first preservative-free the blood vessels in the retina. After all, Adaptive optics • Can reduce distortion • Requires dedicated the retina is thin and nearly transparent, and improve image instruments and prostaglandin and yet – despite over half a century of resolution software retinal imaging – our most commonly • Can target layers • Requires a large individually number of images and (1 used method for doing so still has the patient to remain Effective IOP-lowering major limitations. motionless for longer (2 Fluorescein angiography (FA) is than other methods Low risk of hyperaemia today’s standard imaging method for examining retinal blood circulation. Table 1. The pros and cons of current retinal vasculature imaging methods. With it, ophthalmologists can easily see superficial blood vessels, but two out of the three major capillary networks in the retina remain largely a mystery; both a b c the radial peripapillary capillaries and the inner capillary network are poorly visualized with this method. The retinal capillaries that are seen in fluorescein angiograms are set against a backdrop of low-level fluorescence that’s often ascribed to the choroid, but may actually originate from the deeper capillary Figure 1. Imaging of the central macular region. a. fluorescein angiography; plexus. Why can’t these deeper layers of b. OCT angiography of the inner retinal vascular plexus; c. OCT angiography of the outer plexus. the retinal vasculature be seen clearly? The most likely reason for this is that Three ophthalmologists from Vitreous- infancy in terms of characterization retinal nerve fiber bundles scatter light, Retina-Macula Consultants of New York (Table 1). But the technique will evolve, leading to a diffuse glow instead of a compared OCT angiography with FA improve and should be increasingly sharply defined fluorescent image. imaging in the eyes of 12 study participants adopted. The study authors suggest that OCT angiography is a relatively new (1). Not surprisingly, they found that FA OCT angiography will help provide Abbreviated Prescribing Information TAFLOTAN® (tafluprost 0.0015% eye drops, solution, single-dose container).Presentation: Low-density polyethylene single-dose containers packed alternative to FA; it requires little in the failed to image the radial peripapillary better characterizations of the vascular in foil pouch. Each single-dose container has a fill volume of 0.3 ml and there are 10 containers in each foil pouch. The following pack sizes are available: 30 x 0.3 ml and 90 x 0.3 ml. One ml way of patient preparation and involves or deep capillary networks in any of the changes that occur over time in many of eye drops contains 15 micrograms of tafluprost. Indication: Reduction of elevated intraocular pressure in open angle glaucoma and in patients who would benefit from preservative-free eye drops or who are insufficiently responsive or intolerant or contra-indicated to first line therapy, as monotherapy or as adjunctive therapy to beta-blockers. Dosage and no dye injections – avoiding the rare, but twelve eyes. OCT angiography, however, common retinal diseases. MS Administration: The recommended dose is one drop of TAFLOTAN® in the conjunctival sac of the affected eye(s) once daily in the evening. Not recommended in children or adolescents (under

the age of 18). In renal or hepatic impairment use with caution. Contraindications: Hypersensitivity to tafluprost or to any of the excipients. Precautions: Before treatment is initiated, patients October 2014 real risk of dye-related adverse events. successfully imaged all layers of the should be informed of the possibility of eyelash growth, darkening of the skin and increased iris pigmentation. Some of these changes may be permanent, and may lead to differences in Reference appearance between the eyes when only one eye is treated. Caution is recommended when using tafluprost in aphakic patients, pseudophakic patients with torn posterior lens capsule or anterior The OCT part is the rapid scanning of retinal vasculature in all of the study chamber lenses, or in patients with known risk factors for cystoid macular oedema or iritis/uveitis. There is no experience in patients with severe asthma. Such patients should therefore be treated regions of retinal tissue; the angiography participants’ eyes (Figure 1). 1. R.F. Spaide, J.M. Klancnik Jr, M.J. Cooney, with caution. Interactions: Specific interaction studies with other medicinal products have not been performed with tafluprost. Pregnancy: Do not use in women of childbearing age/potential unless adequate contraceptive measures are in place. Driving: Tafluprost has no influence on the ability to drive. Undesirable Effects: The most frequently reported treatment-related adverse part is the algorithmic analysis of those OCT angiography isn’t likely to “Retinal vascular layers imaged by fluorescein event was ocular hyperaemia. It occurred in approximately 13% of the patients treated with preserved tafluprost and 4.1% of the patients treated with preservative-free tafluprost. Other side angiography and optical coherence tomography effects include: Common (1% to 10%): eye pruritus, eye irritation, eye pain, changes in eyelashes, dry eye, eyelash discolouration, foreign body sensation in eyes, erythema of eye lid, blurred images, identifying variations between replace FA imaging in the short term – vision, increased lacrimation, blepharal pigmentation, eye discharge, reduced visual acuity, photophobia, eyelid oedema and increased iris pigmentation and headache. Uncommon (0.1% to scans in measures of reflectivity, phase FA is a well-known, well-characterized angiography”, JAMA Ophthalmol. <1%): superficial punctate keratitis (SPK), asthenopia, conjunctival oedema, blepharitis, ocular discomfort, anterior chamber flare, conjunctival follicles, allergic conjunctivitis, anterior chamber cell, conjunctival pigmentation and abnormal sensation in eye, hypertrichosis of eyelid. Overdose: If overdose occurs, treatment should be symptomatic. Special Precautions for Storage: Store shift, or phase variance – which enables the method, and OCT angiography has a Epub ahead of print (2014). doi: 10.1001/ in a refrigerator (2°C - 8°C). After opening the foil pouch keep the single-dose containers in the original foil pouch, do not store above 25°C, discard an opened single-dose container with any jamaophthalmol.2014.3616. remaining solution immediately after use. MA Holder: Santen Oy, Niittyhaankatu 20, 33720 Tampere, Finland. Date of Preparation: 11/2012. construction of microvascular flow maps. number of limitations beyond its relative 1) Taflotan lowered IOP by 6.9 - 9.7 mmHg in masked, randomized studies 1-4. 1. Uusitalo H et al. Acta Ophthalmol 2010; 88: 12-19 2. Traverso C et al. J Ocul Pharmacol Ther 2010; 26: 97-104 3. Konstas AG et al. Comparison of 24-hour efficacy with Tafluprost compared with Latanoprost in patients with primary open-single glaucoma or ocular hypertension. Abstract 5104/A2458 4. Chabi A et al. Am J Ophthalmol 2012; 153: 1187-1196 2) Low risk of hyperaemia among prostaglandins: SPC texts of preservative-free Taflotan. For Glaucoma Tough on IOP. Easy on Eyes.

The first preservative-free prostaglandin Effective IOP-lowering (1 Low risk of hyperaemia (2

Abbreviated Prescribing Information TAFLOTAN® (tafluprost 0.0015% eye drops, solution, single-dose container).Presentation: Low-density polyethylene single-dose containers packed in foil pouch. Each single-dose container has a fill volume of 0.3 ml and there are 10 containers in each foil pouch. The following pack sizes are available: 30 x 0.3 ml and 90 x 0.3 ml. One ml of eye drops contains 15 micrograms of tafluprost. Indication: Reduction of elevated intraocular pressure in open angle glaucoma and ocular hypertension in patients who would benefit from preservative-free eye drops or who are insufficiently responsive or intolerant or contra-indicated to first line therapy, as monotherapy or as adjunctive therapy to beta-blockers. Dosage and Administration: The recommended dose is one drop of TAFLOTAN® in the conjunctival sac of the affected eye(s) once daily in the evening. Not recommended in children or adolescents (under

the age of 18). In renal or hepatic impairment use with caution. Contraindications: Hypersensitivity to tafluprost or to any of the excipients. Precautions: Before treatment is initiated, patients October 2014 should be informed of the possibility of eyelash growth, darkening of the eyelid skin and increased iris pigmentation. Some of these changes may be permanent, and may lead to differences in appearance between the eyes when only one eye is treated. Caution is recommended when using tafluprost in aphakic patients, pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema or iritis/uveitis. There is no experience in patients with severe asthma. Such patients should therefore be treated with caution. Interactions: Specific interaction studies with other medicinal products have not been performed with tafluprost. Pregnancy: Do not use in women of childbearing age/potential unless adequate contraceptive measures are in place. Driving: Tafluprost has no influence on the ability to drive. Undesirable Effects: The most frequently reported treatment-related adverse event was ocular hyperaemia. It occurred in approximately 13% of the patients treated with preserved tafluprost and 4.1% of the patients treated with preservative-free tafluprost. Other side effects include: Common (1% to 10%): eye pruritus, eye irritation, eye pain, changes in eyelashes, dry eye, eyelash discolouration, foreign body sensation in eyes, erythema of eye lid, blurred vision, increased lacrimation, blepharal pigmentation, eye discharge, reduced visual acuity, photophobia, eyelid oedema and increased iris pigmentation and headache. Uncommon (0.1% to <1%): superficial punctate keratitis (SPK), asthenopia, conjunctival oedema, blepharitis, ocular discomfort, anterior chamber flare, conjunctival follicles, allergic conjunctivitis, anterior chamber cell, conjunctival pigmentation and abnormal sensation in eye, hypertrichosis of eyelid. Overdose: If overdose occurs, treatment should be symptomatic. 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 foil pouch, do not store above 25°C, discard an opened single-dose container with any remaining solution immediately after use. MA Holder: Santen Oy, Niittyhaankatu 20, 33720 Tampere, Finland. Date of Preparation: 11/2012. 1) Taflotan lowered IOP by 6.9 - 9.7 mmHg in masked, randomized studies 1-4. 1. Uusitalo H et al. Acta Ophthalmol 2010; 88: 12-19 2. Traverso C et al. J Ocul Pharmacol Ther 2010; 26: 97-104 3. Konstas AG et al. Comparison of 24-hour efficacy with Tafluprost compared with Latanoprost in patients with primary open-single glaucoma or ocular hypertension. Abstract 5104/A2458 4. Chabi A et al. Am J Ophthalmol 2012; 153: 1187-1196 2) Low risk of hyperaemia among prostaglandins: SPC texts of preservative-free Taflotan. 16 Upfront Why Lumenis SLT?

perceive visual information. The infants in the study exhibited more brain activity in response to “fearful” eyes with visible sclera than to “non-fearful” eyes, and responded more to direct gazes than averted gazes. “This demonstrates that, like adults, infants are sensitive to eye expressions of fear,” says Tobias Grossmann, study co-author and director Precision Quality Leadership of the Early Social Development Group at the Max Planck Institute for Human Lumenis pioneered SLT technology Lumenis manufactures After thousands of lasers and Cognitive and Brain Sciences. “Their and leads the industry in research, its SLT systems in the USA, and millions of procedures, Lumenis brains clearly responded to social cues manufacturing, and service. The services them locally. We provide is the industry leader. Join us in conveyed through the eyes, indicating that even without conscious awareness, advanced design of our primary approved, qualified parts to our commitment to advancing human infants are able to detect subtle and secondary internal controls and support our systems in the field glaucoma treatment and raising social cues.” energy indicator ensures that every instead of relying on third-party the standard for patient care. Though infants respond sensitively to eye cues from birth, characteristics such laser pulse meets the exact power vendors. as eye orientation decline quickly in tolerance requirements. those later diagnosed with social deficits like autism. This study shows for the first time that responses such as fear and gaze detection occur subconsciously and that they are based on scleral signals only possible in human eyes. The existence of infants’ responses to eye cues, says sclera to determine where someone’s Grossmann, “likely provides a vital Reading Scleral focus lies. foundation for the development of social Our ability to read cues from the interactive skills.” MS Signals sclera is thought to facilitate many social and cooperative interactions, and References The way that babies process is known to be hardwired into the adult 1. M. Bindemann, C. Scheepers and A. M. Burton, information from eye . Until now, though, it has “Viewpoint and center of gravity affect eye Visit ophthalmic.lumenis.com to learn more. expressions adds another piece been unclear whether or not the ability movements to human faces”, J. Vis., 9, 1–16, to the social and emotional to read and process these cues exists in (2009). doi: 10.1167/9.2.7. development puzzle early development. 2. S. Baron-Cohen et al., “The ‘Reading the Mind To find out, researchers from the in the Eyes’ test revised version: a study with Eyes are important in social interactions. Max Planck Institute in Germany and normal adults, and adults with Asperger syndrome They’re the first and most influential the University of Virginia in the US or high-functioning autism”, J. Child Psychol. feature we look at in other people’s faces measured the brain responses of seven- Psychiat., 42, 241–251, (2001). (1), a critical component of reading month-old infants to a selection of 3. M. Ernest-Jones, D. Nettle, M. Bateson, others’ emotions (2), and instrumental in different eye expressions (4). The infants “Effects of eye images on everyday cooperative cooperative behavior (3). Human eyes, were shown images of wide and narrowed behavior: a field experiment”, Evol. Hum. Behav., in particular, are unique in that the sclera eyes with direct and averted gazes while 32, 172–178, (2011). is large and highly visible – and, because their brain activity was measured by 4. S. Jessen, T. Grossmann, “Unconscious of this, it plays a big part in social and electroencephalography. The images were discrimination of social cues from eye whites in emotional cues. Wide eyes, for instance, shown for only 50 milliseconds – far infants”, Proc. Natl. Acad. Sci. Epub ahead of indicate fear or surprise. We also use the less time than necessary to consciously print (2014).

PB-1154270_A Why Lumenis SLT?

Precision Quality Leadership

Lumenis pioneered SLT technology Lumenis manufactures After thousands of lasers and and leads the industry in research, its SLT systems in the USA, and millions of procedures, Lumenis manufacturing, and service. The services them locally. We provide is the industry leader. Join us in advanced design of our primary approved, qualified parts to our commitment to advancing and secondary internal controls and support our systems in the field glaucoma treatment and raising energy indicator ensures that every instead of relying on third-party the standard for patient care. laser pulse meets the exact power vendors. tolerance requirements.

Visit ophthalmic.lumenis.com to learn more.

PB-1154270_A

Feature 19

Electrophysiology Hits the Clinic

Current diagnostic methods for visual tests and imaging work are great, but can you obtain improved diagnoses with the addition of electrophysiological tests? For me, the answer is clear – after all, electrophysiology is no longer simply the domain of research institutes.

By Mark Latina

phthalmologists have a whole battery of tests At a Glance available to them to help diagnose vision • Electrophysiological testing, such as visually evoked disorders – both structural and functional (1). potentials (VEP) and (ERG), , slit lamp examinations, provide an objective analysis of the functionality of the , and optical coherence tomography neuro-visual pathway (OCT)O all provide images of the structures of the eye. • Fast, targeted testing, and easily interpretable results Examinations like Snellen visual acuity (VA), perimetry and now make it feasible to conduct these tests in the clinic Amsler grids all help us build up a picture of how well our • Along with clinical examinations, electrophysiological patients’ eyes function. Sometimes, relating the two is easy – testing can aid diagnosis of visual disease and help a cataract reduces VA as measured by Snellen, or the macular direct treatment plans degeneration that manifests first in a distorted Amsler • Electrophysiological testing can also provide insight on grid is detected by OCT. However, there are a number of the efficacy of therapy circumstances where relating the functional problem with a structural issue is hard or almost impossible. smaller and easier to operate with each new generation. Testing the neuro-visual pathway Visually evoked potential (VEP) testing involves patterned, flashing lights (stimuli) that elicit patterned depolarization of photoreceptors in the retina; the resulting electrical activity is measured at the visual cortex, thereby providing an objective measure of the function of the entire neurophysiologic system. VEPs can be measured directly with electrodes placed into the brain, but helpfully can also be measured externally with the placement of electrodes on the patient’s head over the region of the visual cortex. It’s not a new technique by any means – its first use was documented in the 1930s, and it has been used for many years for both the diagnosis and assessment of multiple sclerosis. The patient’s VEP response is evaluated for amplitude and latency – the amplitude, measured in microvolts (µv, see Illustration by Rachael Tremlett RachaelIllustration by Box 1), indicates the amount of electrical energy that reaches Figure 1. The human visual pathway. Light hits the retina, is converted to action the visual cortex, and this can vary depending on the number of potentials and the majority of nerve impulses transmitted to the lateral geniculate healthy retinal cells that are stimulated, and the visual system’s nucleus in the thalamus, synapse there, and are transmitted onwards towards the ability to discriminate between differently sized objects. The visual cortex. The visual cortex receives input from the eye on the opposite side of general principle is: the more difficulty a patient has seeing the skull; axons cross at the optic chiasm, just below the hypothalamus. the stimulus, the smaller the electrical response evoked and therefore, the smaller the amplitude measured (Box 2). Of course, vision involves the brain as well as the eye. Latency, measured in milliseconds (ms), indicates the Light hits the retina. Photoreceptors perform their function amount of time the electrical signal takes to travel from and generate action potentials – electrical signals – that are the retina to the visual cortex, and should exhibit minimal passed through bipolar cells on to the retinal ganglion cells variability between subjects. Latency can increase in cases (RGCs), whose axons bundle together forming the optic of optic neuritis or multiple sclerosis, as their pathology can nerve, passing that information onto the brain (see Figure 1). include demyelination of the optic nerve sheath. From there, most of that information is carried to the lateral Electroretinography (ERG) is performed in a similar geniculate nucleus (LGN) in the thalamus – in the opposite manner to VEP. Electrodes, until recently, were typically rested side of the skull, which means that around 50 percent from on the eye, and standardized patterns of light are displayed each optic nerves cross over at a single point – the optic on a screen in front of the patient. As with VEP, amplitude chiasm, situated at the base of the hypothalamus. The LGN and latency are measured in µv and ms, respectively, but the performs some processing of the information received, but ERG tells a different story. The ERG represents the combined its principal function is as a sensory relay; its neurons pass output of the action potentials produced by many of the the sensory information onwards to the visual cortex – the electrically active cell types within the retina. By varying the region responsible for the vast majority of processing and stimulus conditions (say, flash or pattern stimulus, the presence interpretation of the visual input received. or absence of a background light, or the colors shown), you can Electrophysiological tests allow us to assess the functional elicit a stronger response from some cell types than others. integrity of this neuro-visual pathway; however, the technique has For example, giving a dim flash visual stimulus on a dark- traditionally been the reserve of research facilities, as the necessary adapted eye will generate a response that’s primarily from instruments have historically been expensive, bulky and fragile. the rod photoreceptor system. If you perform a flash ERG But there’s a common trend with technology: devices get cheaper, on a light-adapted eye, the principal response comes from Feature 21

the cone system. A succession of sufficiently bright flashes a test that could be integrated into the daily routine of a will elicit ERGs containing an a-wave (the initial negative busy practice… deflection) followed by a b-wave (a positive deflection). The All of that has changed. Increasingly, clinical examinations photoreceptors produce the leading edge of the a-wave and of patients presenting to eyecare professionals are undergoing the remainder of the ERG wave is produced by a mixture ERG and having their VEPs assessed. Why? Because much of cells including photoreceptors, bipolar, amacrine, and like computer technology (calculations that took days for Müller cells or Müller glia. a punch-card fed mainframe the size of a building to The pattern ERG (PERG – see Boxes 3–5), evoked by perform can now be performed on your smartphone, an alternating checkerboard stimulus is used to detect smartwatch, or even a US$25 Raspberry Pi almost the amplitude and latency of the electrical signal as it “The instantly!) – a similar transformation has occurred passes through the RGCs. In practice, this means with VEP and ERG testing. that you can use a series of ERG tests to dissect out general The first step in bringing electrophysiological which cell types are causing vision dysfunction. testing to the clinic was the development of If a patient presents with an abnormal VEP, principle is: external sensors that could replace those PERG can be used to differentiate where applied directly to the eye but still obtain the abnormality arises – retinal or optic the more difficulty the data required. The electrodes applied nerve dysfunction. PERG can be to the eye capture very small electrical particularly helpful for the detection a patient has seeing signals – ranging from just 1.0 µv of early-stage-glaucoma changes, to 1000 µv. External electrodes before the onset of the stimulus, the smaller the measure more than 100 µv and defects. If a patient exhibits a pick up more neural noise, decreased PERG amplitude, electrical response evoked .” which is a problem. Signal it indicates that one of processing provides the cell types damaged in the solution. The glaucoma – RGCs – are present, but not healthy. background noise is usually random, so computerized signal Therefore, electrophysiological tests not only provide averaging can be used to remove the noise and leave the signal. information on where certain defects lie within in the neuro- By synchronizing the data acquisition to the timing of the visual visual pathway, but also what retinal cell types are dysfunctional. stimuli, you ensure that you isolate and process the right signal. Such information offers a useful, totally objective addition to To give you an example of what’s available now, I use a NOVA the ophthalmologist’s diagnostic armamentarium, helping to system (Diopsys, Pine Brook, NJ, USA) that uses disposable clarify results from other tests and assessments performed. sensors that are placed on the forehead for VEP testing and under the eye for ERG testing – both continuously collect electrical Big steps from research to the clinic circuit information. Clearly, these are far more comfortable for The value of VEP and ERG testing in ophthalmology has long the patient than electrodes placed on the eye, and the benefits been acknowledged, but their use has typically been restricted in terms of patient compliance are obvious. But do they work as to academic research institutions, as they weren’t simple to well as their predecessors? Extensive validation tests say so; data perform. In the past, ERG sensors had to be sterilized and collected via these external sensors is highly repeatable, and has then carefully placed directly on the eye so as not to injure the a very small standard deviation between subjects. The sensors patient. The sensor was irritating, something that the patient present no risk of injury, require no sterilization or disinfecting, had to tolerate for 45 to 50 minutes. After the test, specialized and the results tend to be more reproducible because they cause neuro-physiologists needed considerable amounts of time to patients less irritation than electrodes placed in direct contact decipher the resulting waveforms of electrical brain activity. with their eye. Although the resulting information was useful, it was hardly Better technology is one thing, but we also need VEP and 22 Feature

ERG protocols that are directly applicable to the everyday clinic – the second step. Here we can build protocols from empirical data generated over 30 years of testing. Case Study 1 For example, the earliest manifestation of glaucoma – in A 46-year-old male is currently taking Combigan (Allergan, terms of function – is a decline in low-contrast sensitivity, Irvine, CA, USA), has IOP in the range of 13.0–14.0 mmHg which is primarily a function of the neuro-visual pathway. and Snellen VA of 20/25. Heidelberg Retinal Tomography If you suspect a patient has degraded visual function that’s (HRT; Heidelberg Engineering, Heidelberg, Germany) consistent with early glaucomatous damage, you can now images show some optic disc cupping, creating clinical run a validated PERG protocol in minutes that can detect suspicion for a need to further reduce IOP. The patient’s that issue, helping you to confirm the diagnosis. In this case, visual field test results show many false positive responses, the International Society for Clinical Electrophysiology decreasing the treating physician’s confidence in the results. of Vision determined that the optimal PERG protocol for We performed a VEP on this patient for an objective measure this task is a pattern reversal stimulus, which is the preferred of visual function, and the results showed that the amplitudes means of measuring a patient’s ability to detect the edges in both low-and high-contrast amplitude and latency tests between black and white squares (1). The black and white were within normal limits. We were then able to assume that checkerboard pattern size can be adjusted and the data this patient has an intact pathway from the optic nerve to the suggests that the most effective is a 64 × 64 or 32 × 32 grid, as cortex. In spite of the patient’s inconsistent visual field testing, there are enough borders to elicit a response, while not being I felt confident that we could follow him without initiating any so small that patients with poor visual acuity have problems additional IOP-lowering therapies at this time. We scheduled seeing the individual squares. him to come back in a year for follow-up testing. The final big step is the ability to rapidly analyze the data that comes from VEP and PERG testing and present it in a straightforward way, so that the physician can quickly and easily interpret the results. No longer do you need to wait Case Study 2 days for neuro-physiologists to interpret and plot the data – A 75-year-old female was suspected to have glaucoma. Her VA the device will do this for you, automatically. was 20/40 in one eye and 20/20 in the other, with IOPs of 17.1 and 21.3 mmHg as measured by the Pascal tonometer (Ziemer Clinical applications Group AG, Port, Switzerland). Fundus imaging showed temporal Despite being most often characterized by ocular disc pallor and a slightly enlarged cup in the right eye; the left hypertension and gradual vision loss, glaucoma is best eye appeared healthy and her visual field test was suggestive of a described as a neurodegenerative disease that involves the defect in the superior-nasal quadrant. death of the neurons and axons of RGCs (2). Although we We performed Diopsys NOVA VEP and PERG tests to routinely use IOP to determine the severity of the disease assess the impact of cupping on the optic nerve. The VEP results and as a marker of nerve damage, the two aren’t always demonstrated that the nerve was healthy, with good functionality analogous. Many patients with glaucoma have unexplained from the optic nerve back to the cortex. However, the PERG visual defects or outlying scores on visual field examination testing failed to produce a good waveform. The amplitude was that can leave a physician with doubts over a diagnosis. robust (so the patient has a good number of RGCs present), but However, (as part of a comprehensive clinical examination) the latency of the PERG suggested that the RGCs were not VEP and PERG testing can provide additional information functioning properly, which may explain the visual field loss. that can help refine a diagnosis and better direct treatment The borderline morphology merited close follow-up, but we plans. Here, I offer some examples. elected not to prescribe additional treatment at this time. IOP at subsequent visits remained in the low teens and we resolved to repeat the tests and follow this patient over time. Box 1. How to interpret a VEP test A typical pattern-reversal VEP graph response will primarily consist of the N75 – P100 – N135 Complex. In normal patients, the first major negative peak occurs around 75 ms (N75). The first major positive peak occurs around 100ms (P100), and the second negative peak occurs around 135 ms (N135). Based on patient pathology, the waveform shape, amplitudes and latencies of these components change. Box 2. An abnormal VEP

Box 3. Contrast Sensitivity PERG Box 4. Concentric Stimulus Fields PERG Test Contrast sensitivity PERG testing uses reversing bar patterns at high and low Information gathered with concentric stimulus field testing affects the contrast. These tests are very reliable indicators of visual dysfunction that affect central, or paracentral area of the macula. This protocol, utilizing two the retina in a diffuse pattern like chronic open angle glaucoma and diabetic different degrees of stimulus, 24° and16° circles with contrast reversing retinopathy. As there is typically no specific topographic pattern of damage, the patterns is intended to aid in the diagnosis and care of diseases that information collected using this protocol may help in detecting the depth of the affect the retina in specific topographic patterns, like age-related macular macular dysfunction. It is equally applicable to children and adults. degeneration, cystoid macular edema, and toxic maculopothies. a

tests were normal. Nevertheless, she still complained vehemently of visual problems that were diffuse in nature. I performed a VEP, the results of which were totally abnormal. The detection of the electrical signal was nearly extinguished in both low- and high-contrast tests, and at various grating sizes, indicating that a significant neurologic abnormality was present. The PERG showed excellent magnitude, demonstrating healthy RGCs. We b forwarded this test to her neurologist, and with it they were able to move towards a diagnosis of a major neurological problem that was previously undetected. In this case, the patient did have raised IOP, making the case for glaucoma plausible. However, VEP testing allowed us to substantiate her subjective complaints and find the neurological, rather than ocular, origin.

Box 5. How to interpret a PERG a. A normal PERG response Case Study 5 b. An abnormal PERG response A 70-year-old male presented with VA of 20/20 in both eyes (OU) and IOP of 17 mmHg in the left eye and 15 mmHg in the right eye. His visual field testing showed field defects superonasally and diffuse effects in his left eye. HRT imaging showed disc cupping Case Study 3 in both eyes. We were unsure if this patient had stable IOPs and A 64-year-old female presented with VA of 20/20 and 20/25, but could be watched, or if he needed additional intervention, so we complained of blurred vision and vision loss. Her IOPs were 16 performed VEP and PERG tests. Both his amplitude and latency mmHg and 19 mmHg. The patient was not able to complete a were significantly lower and later, respectively, than normal in the Humphrey field test, so we tested her with frequency doubling VEP, confirming that the disc cupping and other visual effects technology perimetry (FDT). The FDT can generally pick detected were causing functional defects, which provided us with up earlier field changes; however, she did not do well on this a quantitative assessment of the degree of damage to the optic test either. Her optic nerves looked quite healthy with imaging nerve. The PERG also confirmed reduced voltage amplitudes and modalities, so we performed VEP. This too showed completely MagnitudeD values of less than 50 percent of the amplitude with a normal amplitude and latency. I chose not to perform PERG on poor waveform. This patient had far more advanced retinal damage this patient, as it is my suspicion that she is a poor test taker, and than we would have thought, which encouraged us to treat this does not have glaucoma nor does she need treatment. patient very aggressively with surgery, rather than simply watch and wait or advise that he takes additional topical medications.

Case Study 4 Case Study 6 A 59-year-old female presented with multiple complaints A 27-year-old male presented with VA of 20/20 and IOP of 14 regarding eye spasms, triple vision and headaches. She had a mmHg OU. HRT showed some disc cupping, so we proceeded history of ocular hypertension and substantial head trauma. Her with NOVA VEP testing to evaluate if the cupping was affecting IOP was 24 mmHg in her left eye and 29 mmHg in her right optic nerve function. The amplitude was within normal limits, eye, and her VA was 20/25 and 20/20 respectively. HRT imaging with some delay in latency at high-contrast OU. However, there showed optic nerves that appeared healthy, and her visual field was significantly decreased amplitude in the right eye indicating Feature 25

the potential for substantial damage. We then performed PERG Mark Latina, is currently an Associate Clinical Professor testing hoping to be able to clarify the location and severity of the of Ophthalmology at Tufts University Medical School and a pathology, and found that the patient had a basically extinguished Surgeon in Ophthalmology at Mass. Eye and Ear Infirmary, PERG signal. This is a very ominous sign of severe glaucomatous Boston, MA. damage, especially for such a young patient. We made the decision to treat this patient very aggressively, recommending surgery References rather than continue to change topical medications, to prevent 1. B. Skarf, et al., “Neuro-ophthalmologic examination: The visual sensory further deterioration of the optic nerve. system”,In Neuro-ophthalmology. Edited by Joel S. Glaser. Page 8. Lippincott Williamsand Wilkins, 1999. Tracking treatment success 2. M. Bach, et al., “ISCEV standard for clinical pattern electroretinography In most cases, the earliest signs we detect of glaucoma are (PERG): 2012 update”, Documenta Ophthalmologica, 126, 1–7 (2013). permanent atrophic changes to the optic nerve. However, DOI:10.1007/s10633-012-9353-y. recent studies have shown that damaged, but still viable, 3. W. Rokicki, M. Dorecka, W. Romaniuk, “Retinal ganglion cells death in RGCs precede the destruction of the optic nerve (3–5). glaucoma–mechanism and potential treatment. Part I”, Klin Oczna, 109, Multiple studies have found PERG and VEP testing capable 349–352, (2007). of discriminating between healthy and glaucomatous eyes, 4. V. Porciatti, L. M. Ventura, “Retinal ganglion cell functional plasticity and including detection of impairment of the innermost retinal optic neuropathy: a comprehensive model”, J. Neuroophthalmol., 32, layers in spite of normal optic disc morphology and visual 354–358(2012). doi: 10.1097/WNO.0b013e3182745600. field analysis (5–7). In fact, PERG in particular, has been 5. L. M. Ventura, et al., “The relationship between retinal ganglion cell function established to reveal glaucoma-related damage several years and retinal nerve fiber thickness in early glaucoma”, Invest. Ophthalmol. Vis. prior to visual detection of deterioration of the retinal nerve Sci., 47, 3904–3911 (2006). fiber layer via OCT imaging (8). 6. C. Pillai, et al., “Sensitivity and specificity of short-duration transient visual Some studies have already found that when initial RGC stress evoked potentials (SD-tVEP) in discriminating normal from glaucomatous is detected with PERG – and IOP is appropriately lowered – the eyes”, Invest. Ophthalmol. Vis. Sci., 54, 2847–2852 (2013). DOI: 10.1167/ dysfunction of the RGC cells can be reversed (9,10). Selective iovs.12-10097. laser trabeculoplasty (SLT) is my preferred first-line glaucoma 7. V. Parisi, et al., “Clinical ability of pattern electroretinograms and visual treatment, having proven to be as effective as medications (11) evokedpotentials in detecting visual dysfunction in ocular hypertension and without patient compliance issues, and we now use PERG to glaucoma”,Ophthalmology, 113, 216–228 (2006). measure disease stabilization or the need for further treatment 8. M. R. Banitt, et al., “Progressive loss of retinal ganglion cell function after SLT. precedesstructural loss by several years in glaucoma suspects”, Invest. To summarize, electrophysiology objectively measures the Ophthalmol. Vis.Sci., 54, 2346–2352 (2013). DOI:10.1167/iovs.12- function of the entire visual pathway, from the eyes to the visual 11026 cortex. VEP analyzes the entire system, while PERG can focus 9. L. M. Ventura, V. Porciatti, “Restoration of retinal ganglion cell function in on RGC function. Together, they can provide comprehensive early glaucoma after intraocular pressure reduction: a pilot study”, diagnostic information as well as better monitoring for treatment Ophthalmology, 112, 20–27, (2005). effect for a variety of subclinical disorders that affect vision. 10. M. Sehi, et al., “Reversal of retinal ganglion cell dysfunction after surgical Somewhat amazingly, we can now perform these tests in an reduction of intraocular pressure”, Ophthalmology, 12, 2329–2336, (2010). ophthalmologist’s office (rather than in an academic setting) DOI: http://dx.doi.org/10.1016/j.ophtha.2010.08.049 with a compact instrument that’s easy to use, non-invasive 11. M. Nagar et al., “A randomised, prospective study comparing selective laser and comfortable for the patient. It truly is impressive to see trabeculoplasty with latanoprost for the control of intraocular pressure in how advancements in technology have been able to open up ocularhypertension and open angle glaucoma”, Br. J. Ophthalmol., 89, the world of electrophysiology to a vastly greater number of 1413–1417 (2005). ophthalmologists – and patients. NEW ICARE HOME SELF-TONOMETER FOR EASY 24H IOP MONITORING BY OPHTHALMOLOGIST RECOMMENDATION In Practice

Surgical Procedures Diagnosis New Drugs

28-29 Satisfying the Demands of the Post-LASIK Presbyope Small-aperture IOLs offer a new alternative to multifocal or accommodating IOLs for clear vision across near, intermediate and far distances.

30-33 No More Drops for Patients in the Real World? Patient compliance with post-surgical treatment regimens after cataract surgery is often poor – can transzonular injections of these drugs improve outcomes?

34-36 Operate, But Don‘t Ablate, and SMILE Jesper Hjortdal shares his experiences with SMILE, the refractive surgical technique that uses only a femtosecond laser and requires no flap creation. 28 In Practice

Satisfying the Demands of the Post-LASIK Presbyope?

A small-aperture IOL could offer new hope for patients with cataract and presbyopia

By Günther Grabner

Modern laser vision correction has captured the attention of the world. Millions of people have benefited from the procedure, but with these stories of success comes a heightened expectation of post-surgical outcomes. Maintaining a Robert Ang standard of excellent vision at all distances Figure 1. The IC-8 small aperture IOL post-implantation. becomes complicated, though, once presbyopia becomes prevalent. And as We have Hermann von Helmholtz to the lens to respond to ciliary body ever-increasing numbers of patients who thank for our present understanding of contraction, theoretically coming closer had undergone LASIK previously are accommodation in the youthful, phakic to natural accommodation. Choosing now beginning to need cataract surgery, eye (1). At rest, the supporting equatorial these options for patients with cataracts they’re not going to be happy settling for zonules maintain tension on the crystalline and presbyopia means facing a range just good far vision while presbyopia robs lens, flattening its central curvature to of compromises, though, including them of their functional near vision. support distance focus. When the eye incomplete range of vision, loss of visual switches to near vision, the ciliary body quality due to induced glare and halo, constricts to release the zonular tension, and loss of binocular contrast. At a Glance allowing the anterior and posterior • As increasing numbers of LASIK surfaces of the lens to bow outward and Small aperture, but big advantages patients become both presbyopic and increase the converging power of the eye. But there is hope – a recently completed in need of cataract surgery, there is a This knowledge has paved the way for proof-of-concept study indicates that heightened demand and expectation the development of a wide variety of another option may be on the horizon. for a good range of vision after intraocular lenses (IOLs) – multifocal The IC-8 small-aperture IOL, (AcuFocus cataract surgery and accommodating – that attempt Inc., Irvine, CA, USA), is a new lens that • Some compromises are inevitable when to replace the eye’s natural loss of uses the same small-aperture principle multifocal or accommodating IOLs are ability to adjust between near and far as the KAMRA corneal inlay (also implanted in these patients vision. Multifocal lenses either direct by AcuFocus), which, in my opinion, • The IC-8 small-aperture IOL is a new light in different ways to support provides exceptional visual quality across lens that uses the same small-aperture vision at distinct distances, or have a broad range of distances. principle as the widely accepted different zones within concentric The vision correction method employed KAMRA corneal inlay rings for focusing at varying distances. by the KAMRA inlay has already gained • The lens is a oodg option for presbyopia Accommodating IOLs employ a widespread acceptance; when placed patients, providing reliable visual hinged connection between the optic in the non-dominant eye, it has proven quality across a range of distances. and supporting haptics that permits to be suitable for emmetropic and In Practice 29

post-LASIK presbyopes, as well as monofocal pseudophakic patients. The aggregate results for this state-of-the- art procedure yield a mean uncorrected near visual acuity improvement of 4 lines from J8 to J2, and a mean uncorrected distance visual acuity change from 20/16 to 20/20 (2) – though of course, patient selection and surgical technique have been refined over time. The mean depth of focus in inlay eyes, assessed using a minus lens test, is 2.75 + 0.45 D at 60 cm and 1.98 + 0.21 D at 40 cm (3). Most importantly, patients treated with the KAMRA small-aperture inlay report being satisfied with their vision 95 percent of the time, while only 8 percent of these patients report using reading glasses for any amount of time (4). The IC-8 IOL, which is also intended for monocular implantation into the non-dominant eye, uses the same Figure 2: Defocus curve of the IC-8 as compared with simulated monofocal IOL demonstrates the small-aperture principle as the inlay. It broad range of vision provided by the small aperture lens. works by blocking unfocused peripheral light rays with an embedded opaque nine of my patients; after one year, they University, Salzburg, Austria. annular mask while allowing paraxial achieved a mean near visual acuity of J1 and light rays through its central aperture. a mean of 20/20 for both intermediate and References The lens is a single-piece hydrophobic distance visual acuity (5). Importantly, even 1. H. Helmholtz, “Treatise on Physiological Optics”. acrylic lens, which contains a PVDF in low light conditions, the IOL with the Translated from the 3rd German ed. Southall polymer mask of 3.23 mm in total imbedded mask did not decrease binocular JPC, ed. New York: Dover Publications (1962). diameter, with a 1.36 mm aperture. This contrast sensitivity (6). Based on these 2. Data on File. AcuFocus, Inc. opaque mask is 5 microns thick and promising early results, the manufacturer 3. F. Carones, “Assessment of the KAMRA Inlay contains 3,200 microperforations. refined the IOL design and is now moving Using Video Keratography and Corneal OCT: 2 Year A small proof-of-concept study, using onto the next stage – initiating a post- Results”, presentation at the 2013 Congress of the an earlier silicone IOL model, showed market evaluation with the CE-marked ESCRS, Amsterdam, Netherlands, October 5–9, 2013. that monocular implantation of the IC-8 hydrophobic acrylic IOL. 4. M. Tomita, T. Kanamori, G.O. Waring, et al., small aperture IOL improved patients’ In my opinion, the small-aperture “Small-aperture corneal inlay implantation to range of vision after cataract extraction KAMRA corneal inlay has already treat presbyopia after laser in situ ”, (2). When the IOL is combined with shown to be an excellent option for J. Cataract Refract. Surg., 39, 898-905, (2013). -0.75 D of defocus, the result is an presbyopia patients, providing reliable doi:10.1016/j.jcrs.2013.01.034. equivalent add power of approximately visual quality across a range of distances. 5. G. Grabner, “Four decades of cataract surgery: 2.25 D. The defocus curve for the IC-8 Extending this principle to an IOL is personal visions for the future”, Ridley Medical clearly shows the improved range of an obvious next step and will bring the Lecture at the 2014 Congress of the ESCRS, vision that can be achieved (Figure 2). visual benefits of a small aperture to London, UK, September 13–17, 2014. As a result, patients experience a much presbyopic patients with cataracts. 6. S. Manzanera, J. Marin, P. Artal, “Contrast more natural visual acuity, rather than sensitivity with a small aperture IOL evaluated the sudden increases and decreases that Günther Grabner is a Professor of with an adaptive optics instrument”, poster at the occur with a bifocal or multifocal lens. Ophthalmology and Chairman of the 2014 Congress of the ESCRS, London, UK, I have implanted the IC-8 IOL into University Eye Clinic, Paracelsus Medical September 13-17, 2014. 30 In Practice

At a Glance • Although endophthalmitis is an uncommon complication of cataract surgery, its prevention is paramount • Convenience, cost and physical ability all decrease patient compliance with antibiotic drop regimen • Transzonular placement of antibiotics and steroids improves penetration and eliminates compliance issues • Advances in compounded formulations means that a single injection could suffice for most – and avoid eyedrops

Cataract surgery is one of the safest topical antibiotics. They can be applied No More Drops procedures in all of medicine and has before surgery to reduce the number of exceptionally high satisfaction rates. microbes on the ocular surface, during for Patients in the However, post-cataract surgery infection surgery to reduce the microbes reaching rates have been rising since 1994 (1), and the intraocular environment, and after Real World? the potentially serious consequences of surgery to eliminate any that may have endophthalmitis make its prevention reached the eye. While physicians can Ideally, all patients would of great importance. While discussions apply povidone iodine to the surgical adhere to antibiotic and steroid continue over the role of clear corneal area and add antibiotics to the irrigating eyedrop regimens, but they incisions and other factors (2), most solution during the perioperative period, don’t, and actually sometimes cases of sporadic postoperative infection the efficacy of protection is still largely they can’t. Transzonular are known to be a result of the patient’s dependent on patient compliance with a injection of these agents own periocular flora (3), and increased postoperative antibiotic eye drop regimen. after cataract surgery could infection risk from wound leakage. (4) There are two obvious drawbacks to overcome compliance woes. this approach. First, patient compliance The drawbacks of topical medications is dismal. It relies on patients purchasing By Cathy Schanzer and The most common prophylactic strategy their drops, which in some locations M. Stewart Galloway against endophthalmitis is the use of can be very costly, and remembering to In Practice 31

instill them properly. Even if they have the drops and intend to use them, they still may not be complying correctly with their doctor’s instructions. In fact, one study found that over 92 percent of cataract patients administer their eyedrops incorrectly (5). Some of the common reasons for this include: patient administration of multiple eyedrops in quick succession and leading to their dilution (therefore reducing effectiveness); patients forgetting which drop they’ve already taken (and making Figure 1. Cystoid macular edema (CME) incidence in patients (1,575 eyes) who underwent cataract their own decisions on how to compensate surgery who were treated with Tri-Moxi instead of topical medications, plus CME incidence rates in for this); patient failure to dose at regular specified sub-groups (9). ERM, epiretinal membrane; NSAID, non-steroidal anti-inflammaotry drug. intervals. And if a patient is already on glaucoma drops, this can only add to optimized solubility and viscosity for normally would. If you do bump a ciliary the confusion. ocular injection through small needles process and cause it to bleed, it is not The second major drawback to topical and cannulas (27- or 30-gauge) during the end of the world, you just raise the antibiotic drops is that endophthalmitis cataract surgery. The compounds have pressure in the eye for a few minutes to results from an infection that takes hold been formulated to be better retained stop the bleeding – much as you would in the vitreous. However, drops treat the in the vitreous than in the anterior put pressure on any wound. ocular surface, which means that drug chamber and so can be released gradually Some surgeons use Tri-Moxi on penetration and concentration within without risking toxicity to the corneal the majority of patients, but hesitate the vitreous varies. endothelium or altering the outflow of to perform the injection on patients the trabecular meshwork. with glaucoma. We feel that there A dropless alternative Putting the findings of others to the is no reason to exclude this patient Convincing evidence shows that test, Stewart administered Tri-Moxi, group – retina specialists have been antibiotics injected into the eye are not instead of topical medications, in 1,575 injecting triamcinolone into the only just as safe as topical antibiotics, but eyes of patients who underwent cataract posterior chamber for a long time, they’re more clinically- and cost-effective surgery (9). All of his patients were seen and have found it to be completely (6). Importantly, numerous studies have post-operatively on the same day, and safe below a 4 mg threshold. Tri- found that the rate of endophthalmitis is three to four weeks and six months post- Moxi was developed at 15 mg/5 ml; reduced to 0 percent when a prophylactic op. Not one of his patients developed most users inject 0.2 ml, delivering a antibiotic is injected intracamerally at the endophthalmitis and 98 percent 0.3 mg of triamcinolone dose into the end of a procedure (7,8). remained free from cystoid macular eye – well below that 4 mg threshold that Now the prospect of dropless edema and inflammation (Figure 1). might trigger a steroid response. There cataract surgery has leapt closer to has been talk about increasing the amount reality. Compounds have been developed Addressing steroid and injection concerns slightly to reduce the cases with rebound that can be administered in single Intuitively, you might worry about inflammation, but it has not been done dose injections (transzonularly), and potential injection-related problems, specifically to avoid any risk of steroid combine both the antibiotic and steroid like breaking zonules or having the response. Currently, our rate of rebound necessary following cataract surgery. vitreous run into the anterior chamber. inflammation lies at just 2.5 percent. Tri-Moxi (triamcinolone acetonide This has not been a concern based on and moxifloxacin hydrochloride) and our experience though – today it just No need to panic Tri-Moxi+Vanc (with vancomycin) feels like a standard part of the cataract Although patients are overwhelmingly (Imprimis Pharmaceuticals, San procedure. Patients with small pupils happy to get rid of the three to six weeks Diego, CA, USA) are patent-pending, can be a little more difficult because of drops, adequate patient education proprietary formulas that have you cannot guide the cannula as you is a necessity. When we first started 32 In Practice

“Knowing that all of your patients on such missions can go home after surgery having received all of their antibiotics and steroids should be a great comfort to any cataract surgeon.” In Practice 33

performing dropless cataract surgery, the Southern Eye Clinic in Serabu, References our patients went on to experience Sierra Leone in 2006. As with many 1. M. Taban, A. Behrens, R. L. Newcomb, et al., floaters or cloudy vision (a natural other missions, patients may walk for “Acute endophthalmitis following cataract occurrence given that an opaque days to reach a clinic to undergo cataract surgery: a systematic review of the literature”, Arch. liquid is injected into the eye) and surgery, and then the surgeons have no Ophthalmol., 123, 613–620, (2005). were calling us in a panic. We realized contact with them again after they leave. 2. M. Lundstrom G. Wejde, U. Stenevi, et al., that we needed to improve our patient It probably comes as no surprise to learn “Endophthalmitis after cataract surgery: a education preoperatively and we needed that there are many instances when nationwide prospective study evaluating to make sure that the post-operative treatment regimens are not properly incidence in relation to incision type and location”, nurse reminded them that they may followed in these regions. One example Ophthalmology, 114, 866–870, (2007). experience these things – and that Cathy saw was a cataract surgical center 3. M. G. Speaker, F.A. Milch, M.K. Shah, et al., it’s temporary. We have found that that was set up in Sierra Leone several “Role of external bacterial flora in the pathogenesis when patients weigh the benefits of years ago – the conditions weren’t of acute postoperative endophthalmitis”, dropless surgery with the downside of sufficiently sterile, and this resulted in Ophthalmology, 98, 639–49, (1991). the floaters, they universally prefer to about 200 people being blinded from 4. T. Wallin, J. Parker, Y. Jin, et al., “Cohort study of receive the injection. You need to explain endophthalmitis. In Serabu, Cathy 27 cases of endophthalmitis at a single institution”, to your patients that their vision will had a patient that had cataract surgery; J. Cataract Refract. Surg., 31, 735–741, (2005). be very poor on the day of surgery, but after going home, she returned weeks 5. J. A. An, O. Kasner, D. A. Sarnek, et al., by the next morning, most of that will later with advanced endophthalmitis. “Evaluation of eyedrop administration by have lifted – the ‘wow’ effect of cataract Cathy tried to wash out the anterior inexperienced patients after cataract surgery”, surgery is not lost with these patients. chamber, and do an anterior , J. Cataract Refract. Surg., online ahead of print. As great as the benefits of dropless but the tools to treat that kind of disease doi:10.1016/j.jcrs.2014.02.037. cataract surgery are in “regular” patients, just aren’t available out there. Knowing 6. S. Ndegwa, K. Cimon, M. Severn, “Intracameral they’re even greater in patients with that all of your patients on such missions antibiotics for the prevention of endophthalmitis certain disabilities. As Bradford, can go home after surgery having post-cataract surgery: review of clinical and UK-based ophthalmologist Rachel received all of their antibiotics and cost-effectiveness and guidelines”, Ottawa: Piling previously discussed in The steroids should be a great comfort to any Canadian Agency for Drugs and Technologies in Ophthalmologist, people with learning cataract surgeon. Health, http://bit.ly/1omx44L. Accessed September disabilities are 10 times more likely to Cathy and Stewart both feel that 15, 2014. have serious sight problems than the transzonular injections of steroids and 7. L. B. Arbisser, “Safety of intracameral general population (10) – and this is a antibiotics should be considered as moxifloxacin for prophylaxis of endophthalmitis group that is also highly likely to need standard for those cataract patients after cataract surgery”, J. Cataract Refract. assistance with administering their eye with physical or learning disabilities, Surg., 34, 1114–1120, (2008). doi: 10.1016/j. drops. Everything from poor motor or in deprived geographical regions. jcrs.2008.03.017. control to extreme phobia of eye drops With patient compliance being a 8. V. Galvis, A. Tello, M. A. Sanchez, et al., “Cohort can make compliance with a dosing global concern, however, they expect study of intracameral moxifloxacin in regimen extremely difficult for these the number of surgeons replacing postoperative endophthalmitis prophylaxis”, patients. Dropless cataract surgery has topical drops with injections will grow Ophthalmol. Eye Dis., 6, 104, (2014). doi: the potential to remove that worry from exponentially in the months and the 10.4137/OED.S13102. the ophthalmologist, the patient, and years to come. 9. M. S. Galloway, “Intravitreal placement of their carers. antibiotic/steroid as a substitute for post-operative Cathy Schanzer is the Medical Director drops following cataract surgery,” presentation On a mission and Chief Surgeon at Southern Eye at the American Society for Cataract and Understandably, compliance with eye Associates in Memphis, TN, USA. Refractive Surgeons Annual Meeting, Boston, drops is also of particular concern when M. Stewart Galloway is Medical Director MA, USA, April 25–29, 2014. providing foreign aid to underprivileged at Cumberland Eye Care and Cookeville 10. R. Pilling, “Serving Patients who have Learning communities. Stewart makes annual Eye Specialists in TN, USA. Disabilities,” The Ophthalmologist, http://bit. trips to southern Mexico with World ly/1wrcSzJ. Accessed September 16, 2014. Cataract Foundation, and Cathy started 34 In Practice

the lenticule is manually extracted, by administering two drops of topical Operate, But eliminating both the need for an excimer anesthesia and then by explaining the laser and the creation of a flap. An all-in- procedure to them – including the Don’t Ablate, one procedure like this offers a number lenticule incisions, its removal, and the of advantages over traditional LASIK; post-surgical eyedrop regimen – and and SMILE for instance, using only one laser means reassuring them that it will be painless. The that there is no need to move the patient patient is instructed to fixate a blinking More than three years of during surgery, while the absence of a flap target light, and to remain calm during the experience with this new kid reduces biomechanical impact by leaving operation of the laser. on the refractive surgery block the anterior corneal surface undisturbed. To start the procedure, we place the makes me think... this could be Most significantly, SMILE involves patient on the laser bed and patch the the future the manual removal of the lenticule left eye, as we always start with the right. from the corneal bed, which – when After putting in an eyelid speculum and By Jesper Hjortdal you compare it to the tissue ablation cleaning the right eye with saline and a method employed by the excimer laser – sponge to remove any debris from tears, we Small incision lenticule extraction allows us to reduce damage to tissue, and position the patient under the operating (SMILE) is a fairly recently developed avoid photoablation-related side effects. microscope and the laser and make sure form of refractive surgery that’s Despite these benefits, the procedure that they can see the fixation light. performed almost entirely with a has not yet become established as a As we apply suction, we ask the patient femtosecond. I would like to tell you standard surgical treatment – the cost to relax for the next 30 seconds so that about my own experiences with SMILE of the necessary equipment is high, and we can run the laser (Figure 1a, b). This and my thoughts about its place in the so far SMILE offers no better refractive usually goes smoothly, and once we future of laser . But first, outcomes than traditional methods. are finished, we can release the suction I‘d like to briefly explain how it works. I began performing SMILE three pressure and move the patient to the The femtosecond laser is used to cut a and a half years ago, after I went to observation position on the bed while refractive lenticule into the and India and met Rupal Shah – one of keeping them under the microscope. create a small incision, through which the only people performing SMILE Using a thin spatula, I perform the first at the time – and I thought that the dissection above the lenticule to be procedure looked very promising. We removed, perform the second dissection At a Glance introduced it into our own clinic by below the lenticule (Figure 1c), and • SMILE is a surgical technique, doing only a few of these femtosecond then remove it (Figure 1d). Finally, I put principally for the treatment of myopia, laser-only procedures at first, but after some antibiotic drops and diclofenac that uses only a femtosecond laser and about a year, we decided that they were into the eye, before repeating the entire does not require the creation of a flap both safe and promising – so SMILE procedure again on the left eye. • Benefits include faster treatment became our standard procedure. Once both extractions are done, the times, fewer side effects and avoidance Today, I am the head of a team that patient can sit up and relax; often, they of tissue ablation, which carries corneal includes four optometrists and three go out and wait for about 20 minutes biomechanical advantages corneal surgeons. The optometrists are while we perform the next operation. • Disadvantages include the cost of the responsible for all of our preoperative Then we take a look on a slit lamp, just laser and accessories – Zeiss is the only evaluation, while the surgeons carry out to see if there is any debris or fibrillar manufacturer – and the fact that the actual procedures. material on the surface – which, usually, SMILE (currently) provides no there isn’t. At that point, the patient improvements in refractive outcomes SMILE step-by-step can leave; we send them home with over traditional LASIK I will walk you through my standard antibiotics and weak steroids to use four • Further refinements and improvements approach to SMILE, which I believe is times a day. We see the patient again the to the technique are possible and will simple to perform and I find achieves day after surgery, check on corrective allow it to achieve its true potential - as consistent results. visual acuity, and explain what to watch the surgical procedure of choice for a wide Before beginning the procedure, we for during the recovery period. Our range of refractive disorders prepare the patient for surgery, first patients are usually seen by their local In Practice 35

“Some people have a b said that, while SMILE is definitely the future of laser eye surgery, the lasers aren’t quite good enough yet.” c d ophthalmologists after one week and then come back to us after three months so that we can do a sort of “quality check” – see if the patient is happy and what refraction they’ve ended up with. Ensuring only eligible candidates undergo the laser refractive surgery is always of the utmost importance. Currently, we use the same inclusion criteria for SMILE as for LASIK surgery: patients need to have a residual stromal bed of at least 250 µm, and we also perform a thorough preoperative Figure 1. SMILE procedure. a. Image obtained during femtosecond laser cutting of lenticule; posterior investigation to exclude patients side of lenticule has been cut and anterior cut is approximately 50 percent complete; b. Immediately with subclinical keratoconus. I think after completion of femtosecond laser cutting; c. Through a small peripheral incision, remaining tissue that, in a few years, we may be able to bridges are broken with a blunt spatula; d. Lenticule is removed through the peripheral incision. loosen the criteria a little, because the anterior corneal surface is more or there are still problems related to using force than you would like to, so I hope less undisturbed by this procedure, femtosecond lasers. One prominent that this will be addressed in future which I would assume makes the example is that you have to make two versions of the technology. In terms of cornea biomechanically stronger. For cuts, and you need to start with the deep further optimizing the quality of the the moment, though, we use the same cut – if you have any small bubbles that lenticule cut, I hope that a standardized, criteria for both surgeries. combine to form larger ones, you can smooth and easy dissection will be run the risk that your second cut could simpler to achieve than it is now. It isn’t Is the future of SMILE… be affected by these bubbles. But using common for pieces of the lenticule – for the future of laser surgery? the standard spot distance and energy instance, a little of the periphery – to Some people have said that, while settings on the VisuMax laser (Carl be left in the interface; that happens SMILE is definitely the future of Zeiss Meditec, Jena, Germany) we rarely only rarely even now. But I have reason laser eye surgery, the lasers aren’t quite have any problems with big bubble to believe that the actual cut quality, good enough yet. The technique itself formation in the lower cut – although though already good, will be made even appears to be what we’ve been waiting the actual dissection of the lenticule smoother in the future by developments for since the late 1990s, when the first can sometimes be a little difficult. You in femtosecond laser technology – and femtosecond lasers were developed – but occasionally have to use a little more I think many other laser companies 36 In Practice

FOR REFRACTIVE AND will be attempting to do this with any to develop similar products so that use of Improving and expanding SMILE number of new lasers and approaches. the SMILE technique can be expanded I think the future of SMILE lies in CATARACT SURGERY But I think that, at least when you - and competition might bring prices optimizing the femtosecond laser to get as experienced with the SMILE down! I think this could depend on perfect the actual lenticule cutting – technique as we are today, it is as safe as Zeiss licensing the patents, and also on whether this is done by smaller bubble the LASIK technique. We have found other companies’ ability to manufacture creation, faster shooting of the laser, that recovery might be a little slower, and sell lasers suitable for SMILE. or something else. There are various but the end result is as safe as LASIK options, and it is hard to say exactly how surgery. And when you treat high far in the future these developments will myopia with SMILE as opposed to with be or to what extent they will actually LASIK, in our experience the SMILE “It’s possible that improve the results of the procedure, but surgery can more precisely achieve the I’m optimistic. spherical equivalence that we want. in 10 years’ time, Also, the SMILE procedure right now is really only for myopia and myopic Cost and Competition almost everyone astigmatism. I think that there’s a need Reaching a new level in corneal tomography SMILE has the potential to be faster for the procedure to be developed into Patented Dual Scheimpflug system provides than other laser refractive techniques; will undergo a hyperopia treatment, which involves highly accurate pachymetry and ray-tracing, even there is no need to move the patient software that hasn’t been released yet. when the measurement is decentred. from a femtosecond laser to an excimer SMILE procedures, It’s relatively easy to program the laser laser as there is in LASIK. And when to treat hyperopia, but there can be The only true solution you have experience with the technique, technical issues related to cutting the Placido and Scheimpflug for highly accurate rather than pachymetry, elevation and curvature data – you can do two eyes in 20 minutes, donut-shaped lenticule that is needed in all eyes. which is pretty fast. There is a higher cost LASIK.” to treat the condition. Again, that has associated with it in comparison with something to do with how the bubbles Iris-based eye motion compensation LASIK, but I think that is something form and how well the periphery of the Have confidence in your follow-up measurements that every institution negotiates lenticule is cut. with realignment of maps in 3-D. individually. So let’s break down the It’s possible that in 10 years’ time, There are still challenges to be financial investment that you would almost everyone will undergo SMILE addressed before SMILE can become need to incorporate the technology. procedures, rather than LASIK. But a standard treatment in the clinic. The One platform, one solution. The actual list price of the VisuMax for applications like treating very low cost of purchasing a femtosecond laser, We simplify the daily workflow in your clinic laser is about €500,000, and then you myopia, traditional photorefractive software and accessories is very high at with an all-in-one solution, from refractive to cataract surgery. need to buy a separate software module keratectomy (PRK) has also been the moment, and because the refractive specifically for SMILE surgery. You also extremely successful. Large studies results show no clear-cut advantages need a single-use suction device for each have been published that show that over traditional methods, surgeons may patient, which is an additional cost – good results can be expected with this be hesitant to adopt an expensive new and I think the company charges a little type of surgery as well. technique like SMILE. I do think that more for the device if you want to use SMILE is also not used as a it has promise though, especially as it it for a SMILE procedure as opposed retreatment procedure. At the moment, offers a reduced risk of side effects from Only the GALILEI G4 unites Placido and Dual Scheimpflug patient’s eye. The new GALILEI G4, for first-class to a LASIK procedure. So I do think surgeons either open the SMILE tissue ablation or flap creation. technologies in one measurement. With the GALILEI G4, clinical results. the company tries to market SMILE cap with a femtosecond cut that In my opinion, SMILE is the future you get highly precise measurements for posterior and The GALILEI G4 is a modular platform, which can be as a sort of high-end procedure, and I resembles a LASIK flap and then use of refractive surgery, and I think we can anterior curvature, pachymetry, Total Corneal Power, Total upgraded according to your needs. think people are beginning to see it as an excimer laser for the retreatment, or expect to see more and more interest in the premium procedure of corneal laser they use our preferred method, which it in the future. Corneal Wavefront and the anterior segment of your Learn more on galilei.ziemergroup.com. refractive surgery. employs an excimer laser to perform a One of the problems with cost is that transepithelial PRK on a cornea that Jesper Hjortdal is Clinical Professor in the Carl Zeiss Meditec is currently the only has undergone SMILE. So there is Department of Ophthalmology at Aarhus company manufacturing a laser capable still a need for excimer laser procedures University, Aarhus, Denmark. of creating a refractive intrastromal as we continue to optimize the corneal lenticule; more companies need SMILE technique.

Get to know our new e-learning center: e-learning.ziemergroup.com

The_Ophthalmologist_nov2014_GALILEI_G4_Ad_210x266mm.indd 1 28.10.14 13:42 FOR REFRACTIVE AND CATARACT SURGERY

Reaching a new level in corneal tomography Patented Dual Scheimpflug system provides highly accurate pachymetry and ray-tracing, even when the measurement is decentred.

The only true solution Placido and Scheimpflug for highly accurate pachymetry, elevation and curvature data – in all eyes.

Iris-based eye motion compensation Have confidence in your follow-up measurements with realignment of maps in 3-D.

One platform, one solution. We simplify the daily workflow in your clinic with an all-in-one solution, from refractive to cataract surgery.

Only the GALILEI G4 unites Placido and Dual Scheimpflug patient’s eye. The new GALILEI G4, for first-class technologies in one measurement. With the GALILEI G4, clinical results. you get highly precise measurements for posterior and The GALILEI G4 is a modular platform, which can be anterior curvature, pachymetry, Total Corneal Power, Total upgraded according to your needs. Corneal Wavefront and the anterior segment of your Learn more on galilei.ziemergroup.com.

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The_Ophthalmologist_nov2014_GALILEI_G4_Ad_210x266mm.indd 1 28.10.14 13:42 Basic research Case report/ series 21% 11% Review Print 13%

Other 1% Clinical Letter Unavailable online 3% Clinical study Website4% trial 19% 31%

French 7 Japanese 7 Basic research 11% Other 8 Case report/ German 11 series 21% App https://theophthalmologist.com/app Full access is available through an existing personal subscription. Free full text 22% Review 13% e Ophthalmologist iPad edition is available for free Other on the Apple Newsstand upon Fullpayment/ text subscription 75% 1% and o ers a rich and Clinical Unavailable online 3% English 299 Letter engaging multimedia study Clinicalexperience in a stylish, 4% 31% trial purpose-built 19% app. e ability to read content o ine and download the past issue archive make it a must-have for frequent  yers. Free full text 22%

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upon Fullpayment/ text subscription 75% Basic research Case report/ series 21% 11% Review NextGen 13% Research advances BMJ 17.215 Other Experimental treatments Drug/device pipelines 1% Clinical Hepatology 12.003 Letter Unavailable online 3% Clinical study 4% trial 19% 31% Prog Retin Eye Res 9.439

French 7 Japanese 7 Development 6.208 Basic research 11% Other 8 Case report/ German 11 ’romb Haemost 6.094 series 21% J ’romb Haemost 6.081 Free full Cochrane text 22% Database Syst Rev 5.703 Review Noma H 24 13% Ophthalmology 5.563 Mimura T 23 Other upon Fullpayment/ text Int J Cardiol 5.509 Funatsu H 19 subscription 75% 1% Clinical Drugs 4.633 Letter Unavailable online 3% English 299 Clinical study Shimada K 4% 31% Semin ’romb Hemost 4.216 trial 19% Campochiaro PA 10 JAMA Ophthalmol 3.826 Rubio RG 8 Arch Ophthalmol 3.826 Yoshimura N 7

40–42 5 10 15 20 Tsujikawa A 7 Benchmarking BRVO What does analysis of the last five Free full years of literature on branch retinal Scott IU 7 vein occlusion tell 0us about the text 22% priorities of the field and the major Murakami T 7 contributors to it? Miyamoto K 7 Eguchi S 7 upon Fullpayment/ text subscription 75%

0 5 10 15 20 25 40 NextGen

Benchmarking BRVO Most frequent topics on PubMed

What does analysis of the Retinal Diseases last five years of literature on branch retinal vein Retinal Vein Occlusion occlusion tell us about the Macular Edema priorities of the field and the Visual Acuity major contributors to it? Injections By Mark Hillen Tomography, Optical Coherence Antibodies, Monoclonal Branch retinal vein occlusion (BRVO) Injections, Intraocular is a common retinal vascular disease of the elderly, with a typical age of onset Antibodies, Monoclonal, Humanized of around 60–70 years. The occlusion Prospective Studies is typically a thrombus, and a number of thrombolytic and fibrinolytic Angiogenesis Inhibitors approaches have been attempted to Prognosis Articles in MEDLINE are reverse BRVO in the acute setting, Aged, 80 and over indexed by Medical but these interventions have failed Subject Headings (MeSH) to show robust efficacy. Choroidal Retina topics, that describe the articles’ neovascularization and macular edema Intravitreal Injections main topics. Here are the top are common secondary complications, 25 MeSH terms over the Incidence lastfive years of the human for which argon laser, anti-VEGF agents, steroids and intravitreal Treatment Outcome BRVO literature steroids have all been commonly used Case-Control Studies treatment approaches. Fluorescein Angiography To provide insight into the past and predictions for the future of the Vascular Endothelial Growth Factor A field, a series of metrics were applied to the last five years of the published literature. We asked: 0 50 100 150 200 250 300 350

• What are the major topics for Publications (n) the field? • Which publications have the greatest impact? Publications • How is the knowledge per year available online? • Who are the most prolific authors? 2010 2011 2012 PubMed, was searched for branch 2013 retinal vein occlusion with results 75 75 limited to the last five years, in humans 73 (for a clinical focus). The data were 72 analyzed in Microsoft Excel 2013. Top 12 journals (by number of publications) Top 10 journals by Eigenfactor

Retina 33 Retina 33 PLoS One 0.78326 PLoS One 0.78326 Ophthalmology 24 Ophthalmology 24 BMJ 0.15344 BMJ 0.15344 Graefes Arch Clin Graefes Arch Clin Development 0.1238 Exp Ophthalmol 19 Exp Ophthalmol 19 Development 0.1238 Br J Ophthalmol 15 Br J Ophthalmol 15 Hepatology 0.1226 Hepatology 0.1226 Am J Ophthalmol 14 Am J Ophthalmol 14 Cochrane Database Syst RevCochrane 0.12189 Database Syst Rev 0.12189 Acta Ophthalmol 14 Acta Ophthalmol 14 Invest Ophthalmol Vis Sci Invest 0.08357 Ophthalmol Vis Sci 0.08357 Jpn J Ophthalmol 12 Jpn J Ophthalmol 12 Ophthalmology 0.06002 Ophthalmology 0.06002 Eur J Ophthalmol 11 Eur J Ophthalmol 11 J €romb Haemost 0.05267 J €romb Haemost 0.05267 Ophthalmologica 10 Ophthalmologica 10 Atherosclerosis 0.05032 Atherosclerosis 0.05032 Invest Ophthalmol Vis Sci Invest 10 Ophthalmol Vis Sci 10 Am J Ophthalmol 0.03945 Am J Ophthalmol 0.03945 Eye (Lond) 8 Eye (Lond) 8 €romb Haemost 0.0364€romb Haemost 0.0364 J Ocul Pharmacol €er 7J Ocul Pharmacol €er 7 Int J Cardiol 0.0336 Int J Cardiol 0.0336

0 5 10 150 20 5 25 10 30 15 35 20 25 30 35 0.0 0.1 0.2 0.30.0 0.4 0.1 0.5 0.2 0.6 0.3 0.7 0.40.8 0.5 0.6 0.7 0.8 Publications (n) Eigenfactor

Categorization Fee or free? Unavailable online 3% of articles Basic research 11% Unavailable online 3% Basic research 11%

Case report/ Free full Case report/ series 21% Free full text 22% series 21% text 22% Clinical Review Clinical study Review 13% study 31% 13% 31% Full text Clinical Full text upon payment/ OtherClinical trial 19% upon payment/subscription 75% Other 1% trialLetter 19% subscription 75% 1% Letter 4% 4% Articles are categorized according to PubMed criteria. Clinical study represents a clinical evaluation of a drug, device or technique that was not a clinical trials 42 In Practice

Language French 7 Japanese 7 Other 8 German 11

English 299

Top 12 authors Top journals by Impact Factor BMJ 17.215 Noma Noma H H24 24 BMJ 17.215 HepatologyHepatology 12.003 12.003 Mimura Mimura T T23 23 Prog Prog Retin Retin Eye Eye Res Res 9.439 9.439 Funatsu Funatsu H H19 19 Development Development 6.208 6.208 Shimada Shimada K K ’romb ’romb Haemost Haemost 6.094 6.094 Campochiaro Campochiaro PA PA 10 10 J ’romb J ’romb Haemost Haemost 6.081 6.081 Rubio Rubio RG RG 8 8 Cochrane Cochrane Database Database Syst Syst Rev Rev 5.703 5.703 Yoshimura N 7 Yoshimura N 7 Ophthalmology Ophthalmology 5.563 5.563 Tsujikawa A 7 Tsujikawa A 7 Int Int J Cardiol J Cardiol 5.509 5.509 ScottScott IU IU 7 7 Drugs Drugs 4.633 4.633 MurakamiMurakami T T7 7 Semin Semin ’romb ’romb Hemost Hemost 4.216 4.216 MiyamotoMiyamoto K K7 7 JAMAJAMA Ophthalmol Ophthalmol 3.826 3.826 EguchiEguchi S 7S 7 ArchArch Ophthalmol Ophthalmol 3.826 3.826

00 5 5 10 10 15 15 20 20 25 25 0 0 55 10 10 15 15 20 20 Publications (n) Publications (n) Manchester Shef eld Luebeck Birmingham UNITED KINGDOM GERMANY

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K Fewer injections. More locations.

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*The INTREPID 2-year results were presented at the 2013 EURETINA Congress in Hamburg, Germany. The targeted population includes wet AMD patients with lesion size ≤4 mm and macular volume >7.4 mm3 as measured by Stratus OCT™.

©2014 Oraya Therapeutics, Inc. All rights reserved. PMAF2014-215 The IRay is a CE-marked medical device. The IRay is not available for sale in the United States. For additional details, including safety and risk information, please see the Oraya website at www.orayainc.com. Oraya Therapy and I-Guide are trademarks and IRay is a registered trademark of Oraya Therapeutics, Inc. Stratus is a trademark of Carl Zeiss Meditec, Inc. www.orayainc.com Texere Publishing has expertise in science, technology and medicine publishing and marketing. Now you can tap into our expertise to meet your communication needs. We offer customized print, digital, audio and multimedia services that will enable you to engage with customers, colleagues/ employees, and the wider public. Use our skills to help you to achieve your business goals.

For more information contact Tracey Peers [email protected] Publishers of 01565 752883

Custom Publishing.indd 1 16/01/2014 15:29 Profession

Your career Your business Your life

Texere Publishing has expertise in science, technology and medicine publishing and marketing. Now you can tap into our expertise to meet your communication needs. We offer customized print, digital, audio and multimedia services that will enable you to engage with customers, colleagues/ employees, and the wider public. 46-49 Use our skills to help you to achieve your business goals. You Have a Great Idea. Now What? Nikki Hafezi gives a guide to turning For more information contact Tracey Peers bright ideas into commercial realities. [email protected] Publishers of 01565 752883

Custom Publishing.indd 1 16/01/2014 15:29 46 Profession

two criteria for a patent to be granted: facilitate a market counter-attack. For You Have a Great it must be (i) novel and (ii) useful or them, the more proprietary information inventive. Proving that your invention included the better! Of course, if the Idea. Now What? is novel is almost always the hardest invention is not properly covered by the obstacle when trying to obtain a patent patent in terms of specific claims, then How to translate a ‘light-bulb for a medical device or a pharmaceutical it can be hard to enforce, which is not moment’ into a commercially entity. Novelty is defined as being clear good either. viable reality. of any prior art before the actual filing In the medical devices field, most date of the patent application. What people consider IP the safest insurance By Nikki Hafezi do we mean by “prior art”? The term an inventor can have. But there are some includes (but is not limited to) any public companies that bring medical devices to Necessity is the mother of invention: presentation, scientific publication, market without any IP protection at all. a problem needs solving, someone poster, or any other form of public Such companies compensate with rapid has a good idea, an invention is born. information about the invention. Before speed of entry to the market, “podium In clinical medicine, ideas often arise going down the long and potentially power”, and (later) competitive prices to from the act of treating a patient; expensive path of patenting your maintain their market share. The latter someone considers how to improve a invention, you need to check for prior art often proves to be the challenging part; treatment modality’s speed, efficiency (or even potential patent infringement) it’s incredibly difficult to maintain a high or both – an invention is born. Notably, – and this no simple task. market share with no IP, because you make the more straightforward the idea, The first step is to search – extensively. it easy for competitors – they’ve seen what the more likely it is to be realized or There are publicly available online you’ve done, and there’s nothing stopping translated into practice. Here, I discuss databases (such as the European Patent them from copying you. the four important milestones along Office, http://www.epo.org/searching. your commercialization journey, and html, or Google Scholar, http://scholar. 2. Contracts: double-check your rights highlight what you need to consider to google.com/), but there are many other and obligations stand the best chance of success. search options, and sometimes it can be Shuji Nakamura was one of the three worthwhile paying for a search report to recipients of the 2014 Nobel Prize for 1. Patents: is your idea novel be performed by a national IP institute. Physics “for the invention of efficient and inventive? The art of drafting a patent application blue light-emitting diodes, which has Once you’ve had your idea or developed is a seemingly contradictory balance. enabled bright and energy-saving white your invention, you’ll likely want to On the one hand, you must include as light sources”. His discovery, which protect your intellectual property (IP) much of the area surrounding the patent made the blue LED possible, came with a patent. A patent represents as possible without infringing on any in the 1990s when he was working a limited monopoly. From an IP other IP or including prior art, but at the in his spare time, but his employer, perspective, an invention must satisfy same time be sparing or even vague with Nichia Corporation, took the rights to sensitive information to reduce the risk the discovery – as per the terms of his of a simple “invent-around.” It’s actually employment. They paid him a bonus of At a Glance this delicate balance that becomes ¥20,000 (€150) at the time – and may • Proving that your idea is novel and the major pitfall for many first-time have made over US$1.1 billion in profits inventive is key to obtaining a patent inventors, who usually want to include from the invention since then… • You need to understand your obligations everything in their application in the The lesson? You must seriously when negotiating contracts – and set hope of receiving a limited monopoly consider your employment contract your expectations accordingly on their idea or invention. However, before filing for patent. For inventors • Regulatory affairs: understand what what usually happens is that after 18 working in academic institutions regulatory bodies need from you is months from the filing date – which is both in the US and the EU, contracts central to gaining approval not usually enough time to develop and explicitly state that all IP generated is • Hard decisions: do you finance and bring a medical device to market – the fully owned by the university. However, develop yourself, or license or sell application is published and potential the inventor has the right to license the your innovation? competitors receive information to technology – the “right of first refusal”. Profession 47

If the university decides not to pursue that protects the company’s interests. IP rights for an invention, then the Specifically, the paragraph would state “Although you inventor is free to do so at his or her that the company would either own the own risk and expense. right to license – the right of first refusal think you’ve solved Industrial collaboration agreements – in the case of an academic collaboration that specifically refer to any IP or “work made for hire”, which states that a problem or made generated (in an exclusive field) for the the company is paying for the researcher’s duration of the collaboration must also services and owns anything that results something better, be considered carefully. from their work. Often, when industry provides funding These contract obligations are not you now have to for a researcher, the company has a necessarily a bad deal for the inventor. specific paragraph in their agreement Often, the academic institute has a prove it.” 48 Profession

Finance Pros Cons

Self-finance Fastest, limited obstacles Risk losing private to progress money. Required funds are always more than expected.

Fundraise: private Typically, “free money” or Long waiting periods foundations & in other words without (~1-2 years). governmental funding obligation to pay back. Risk of not being funded; time lost.

Prizes Typically, “free money”. Sometimes, the entity Domino effect: once will request a certain one entity grants a prize, percentage of shares of the likelihood increases future company. of receiving additional Sometimes, IP is prizes. not protected. In the case where the patent application is not yet published, it can be risky.

Venture Capital (VC) “Cash injection”. “Smart money”; typically, VCs want to know the company receives when the return on management and investment will be. business-related services If the invention is in addition to funds to at an early stage, the improve on its sales, likelihood of getting marketability and overall funds is relatively low. value.

Table 1. The pros and cons of funding options. technology transfer office that will fast the funds would be recuperated 3. Regulations: how to approve offset the costs of the patent drafting in a potential licensing agreement. your invention in Europe and and submission fees until a licensing In the case of industrial agreements, North America agreement is secured. These offices the inventor is almost always named Although you think you’ve solved a have a team of advisors that judge the on the patent application, and may problem or made something better, you technology’s market worth, meaning receive compensation in the form of a now have to prove it. Depending on the that the motivation for a technology consultancy – or in some cases a non- type of invention, this step may be the transfer office to approve the payment compete clause to deter “re-invention”. most time- and money-consuming. of these fees will be determined by how Profession 49

Europe As noted, the capital required to conduct • What companies already have In the case of a medical device in Europe, research for regulatory approval can be existing technology? Does the ultimately, the extent of the proof will substantial, so you may find yourself at an invention improve the company’s be dependent on the regulatory body all-important crossroads. There are several existing procedure/treatment? If responsible for issuing a CE mark. ways of raising funds but, fundamentally, not, would a competing company be If you can prove to the regulatory you must determine what is really feasible. interested in entering the market? bodies that your invention is similar to Table 1 offers funding options alongside • Can your invention be translated a device already on the market (with their advantages and disadvantages. into any other fields or applications? similar product specifications), then Why or why not? the threshold may be met. If there is nothing similar on the market for the Be a businessperson medical indication, then a scientific “Nothing slows The “crossroads” is always difficult file, with peer-reviewed publications, because it forces you into a new role. will be required. The more supporting down the progress of You must learn to separate the invention information submitted, the higher the from your own idea and start treating chances of a rapid decision in favor bringing a product it as a business idea/concept that needs of a CE mark. However, if you do not financing. From my personal experience, convince the regulatory body of the to market more than nothing slows down the progress of already proven safety and efficacy of the bringing a product to market more than treatment/device, then you will most the emotions and the emotions and attachment of the likely need to start conducting research inventor. Therefore, a pivotal question at to create a scientific file. Sometimes, attachment of the this stage is: are you ready for your new a full clinical trial will be needed, role of businessperson? which translates into many years and inventor. ” significant financial burden. In summary, when translating an idea into a possible commercial product, you North America If the finance and development must consider these four key aspects. My While the same basic principle holds route seems too daunting or simply guidance here is based on my personal true in North America, especially in the impossible, you are probably interested experience of working with and for US, the FDA can be more rigorous with in licensing (or selling) the invention. academic institutions in North American its requirements. In fact, the expectation Once again, there are a number of and Europe, primarily in the medical of long delays and large expenses related considerations that need to be taken device sector, so, as a caveat, I should say to the approval process leads some into account to maximize the earning that each invention should be treated ophthalmic companies to forgo the potential. For a medical device-related individually. All ideas/inventions have process altogether and not sell in the invention, you should consider: special circumstances, so it is important US. In particular for non-US start-up to adapt any guidance accordingly. companies, the amount of funding and • What exactly are you trying to As a final word, I cannot recommend know-how required to enter the US protect? And who do you want enough that it is important to include as can be too much to handle in the first to avoid knowing the secrets of your many experts in the respective field as 5–10 years of business. Unfortunately, invention? Why? possible to assist you through the initial though the FDA’s rigorous requirements • Who/what would benefit from your processes. You’ll save time (and money), can result in higher safety standards for invention? (For example, who: which will come in very handy to further its citizens, it can sometimes come at patient, distributor, user/surgeon, develop the invention and, hopefully, an expense: cutting-edge treatments or manufacturer; what: faster, safer, your start-up company. devices may be delayed or simply never easier, improved outcomes, cheaper, become available. smaller, lighter). Nikki Hafezi is the managing director • Would your invention help sell of GroupAdvance Consulting GmbH 4. Crossroads: finance/develop or existing procedures or machines/ and the CEO of EMAGine AG; both license/sell? devices? companies are based in Zug, Switzerland. Demanding the Best

Sitting Down With… John Kanellopoulos Clinical Professor of Ophthalmology, New York University Medical School, Partner at OMMA Eye Institute, and Founder and Scientific Manager of Laservision.gr Institute, Athens, Greece Sitting Down With 51

What was your route into ophthalmology? Some ophthalmologists are very It‘s funny, because I wanted to be an commercial. Do you think you have “I don’t want to be a orthopedic surgeon – I was a young avoided this? athlete, and in medical school I was very I consult for companies, which can bring salesman. I tell my interested in sports medicine. But I also commercial bias to my work. I try to liked research, and one of the researchers remain as objective as possible. Some patients the facts, and in the immunology lab where I worked people think my research funding comes was a Chinese corneal surgeon who had from industry gifts, but I mostly sponsor I will always advise left his country for political reasons. He myself; 50 percent of what my practice taught me to transplant rat and I nets goes back into research, which is a them according to taught him to drive. I think I got the lion’s huge monetary commitment for me. Now, share in that exchange! in my twentieth year of practice, I still what I think is best empathize with my patients. I don’t want What is a normal day like? to be a salesman. I want to give my patients for them.” I see patients four days per week, usually the facts, and I will always advise them 60–70 a day. Our process is meticulous; according to what I think is best for them. even if someone just comes for an eyeglass I’m fortunate to be able to practice in this always has significance. The three areas prescription, we still measure everything – way. I know that economic and quota I’m concentrating on, clinically and refraction, anterior segment tomography, pressures can take that away, so I consider academically, are corneal epithelium, OCT mapping of the epithelium and it a luxury. keratoconus diagnosis and CXL. cornea, and OCT imaging of the macula. We try to do that for every patient. What’s your management style? At what stage do you crosslink? I’m extremely demanding – I’m sure some For me it depends on the age of the patient Doesn’t that slow down your workflow? would say too demanding, but our patients and how seriously they take keratoconus. Yes, but it’s worth it. You’d be surprised drive our practice and we’re committed The younger they are, the keener I am how much we pick up. About 1 in 50 of our to excellent care. I don’t do all the day-to- to crosslink at first diagnosis – I would apparently “normal” patients will have a day management, but I’m very involved in recommend it to anybody under 20 years compelling eye irregularity. Sometimes it’s the hiring and assessment of associates. of age. For older patients, it depends on a disease we can address, and sometimes We also have eight optometrists – a real how serious the keratoconus is, how thin it needs to be taken into account if the testament to how ophthalmology and the cornea is (which tells me how much patient proceeds to other interventions optometry work together. I think the leeway I have for future thinning), and like cataract or refractive surgery. bottom line is that every aspect of our how rehabilitated the patient is; if they’re practice, academic or clinical, blends into functioning well with RGP lenses, I You practice in Greece, New York and also providing the best possible care. don’t know if I can reproduce their vision lecture at NYU. How?! with CXL. The New York practice is small; I consult What is exciting you in ophthalmology and take some of the complicated cases. right now? What advice would you give yourself ten At NYU, I work with the residents The direction corneal collagen crosslinking years ago? and try to involve them in some of (CXL) is taking. We’re really opening new I’ve thought about this a lot, as I’ve got our research projects – this is time- fields – for instance, predictable refractive many friends and respected colleagues consuming, but I enjoy helping young corrections with CXL alone is fascinating whose practices are completely different to doctors get their feet wet. Even if as a concept. I think, internationally, we’ve mine. It’s always compelling to look back they don’t follow an academic path, agreed that it works and has established at what you’ve done and ask, “What have knowing the nuts and bolts of research itself as a major player. The key questions I produced?” I think the academic research is important; it lets them read the for the future are: when should we treat I’ve done has made me a better clinician, literature in a much more educated way. and how early should we screen? That’s and I wouldn’t change it for anything. If To manage a practice on top of this, it’s where corneal epithelium imaging has Kanellopoulos Jr has the same drive as me, important to have good associates and a really come into play for us – I’d like he has no choice but to become proficient good manager. to see it in every patient, because it in these areas, because it’s made me happy. Coming soon...

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141028_Pre-marketing-Advert_V4_SAT-02-01-14-004_RZ.indd 1 28.10.14 17:38 The Ophthalmologist × Bayer HealthCare

Aflibercept and the Evolution of CRVO Management

Tackling visual impairment early, effectively and flexibly

Highlights from Bayer HealthCare’s Satellite Symposium ‘Aflibercept and the evolution of CRVO management,’ held on September 12, 2014, at the 14th EURETINA Congress, London, UK

This article has been produced on behalf of Bayer HealthCare and reports on a Bayer-funded and organized symposium. Prescribing information can be found on back cover 2 The Ophthalmologist × Bayer HealthCare The Ophthalmologist × Bayer HealthCare 3

diabetes mellitus and glaucoma. The angiogenesis and neovascularization (5). VEGF-A121 VEGF-A165 hPlGF2 VEGF-A121 VEGF-A165 A brief history Aflibercept: IC50 at 20 pM IC50 at 20 pM IC50 at 40 pM IC50 at 20 pM IC50 at 20 pM consequences of vision loss or impairment Notably, VEGF levels observed in CRVO (pM) (pM) (pM) (pM) (pM) are stark. In the US alone, $8 billion is cases are among the highest in all retinal Bevacizumab 854 1476 NB 630 1323 of CRVO and the lost in productivity each year as a result disorders (4), and ME is the most frequent leveraging of visual impairment and blindness (2), a cause of vision loss in those who have the Ranibizumab 675 1140 NB 576 845 treatment options figure to which CRVO contributes. This disease (5). efficacy and Aflibercept 15 16 2890 16 26 figure doesn’t even begin to account for the Historically, treatments for CRVO were devastating impact CRVO-induced vision unable to improve vision. The first available the window of Table 1. Aflibercept strongly inhibits VEGF and PIGF (both potent promoters of angiogenesis) in cell- loss has on patients’ quality of life, every day option, grid laser photocoagulation, was based assays (20). IC50 = 50 percent inhibitory concentration at 20 pM; NB = no detectable blocking under the assay conditions used. for the rest of their lives (3). Clearly, halting only ever intended to prevent complications opportunity PlGF, placental growth factor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor. disease progression as early, and for as in ischemic disease (8), and it’s unclear if long, as possible is our objective when radial optic neurotomy (RON) has any treating macular edema (ME) in patients benefit over and above natural history Andrew Lotery, Honorary Consultant with CRVO. (9). Grid laser photocoagulation is no Ophthalmologist at the University Hospital In order to understand current treatment longer recommended for the treatment of Southampton and Professor of Ophthalmology approaches, we need first to map the natural CRVO (10). More recently, the GENEVA at the University of Southampton. history of CRVO, which typically follows studies revealed that steroids do display this course: thromboembolism in the some efficacy in the treatment of ME in Bora Eldem, Hacettepe University Central retinal vein occlusion (CRVO) central retinal vein impairs retinal blood patients with retinal vein occlusion, but Hospital, Ankara, Turkey. is a global health concern. It’s estimated flow, resulting in increased intraluminal their use commonly resulted in increases to affect 2.5 million people worldwide; its pressure, forcing both fluid and blood in intraocular pressure and cataract Aflibercept is a fusion protein, designed age- and sex-standardized prevalence is products through the blood-retinal development (11). Latterly, anti-VEGF specifically to be a potent and durable 0.8 per 1,000 people (1). Prevalence is not barrier (4-6). Fluid accumulates in the agents have been shown to provide anti-VEGF and anti-placental growth thought to be affected by gender or ethnic retina (edema), and this reduces capillary significant vision improvements with a factor (PlGF) agent (Table 1). The background, but it’s known to increase perfusion, resulting in hypoxia and a rise good safety profile (11). Figure 1 shows Phase III COPERNICUS (16,17) significantly with advancing age – as do in levels of vascular endothelial growth the historical progress that’s been and GALILEO (18,19) clinical trials many of the systemic and ocular risk factors factor (VEGF) (7). This ultimately leads achieved to date in the treatment of (Figure 2) demonstrated that aflibercept Figure 2. Copernicus and Galileo study designs (16–19). for CRVO, like systemic hypertension, to a breakdown of the blood-retinal barrier, CRVO-induced ME. use rapidly improves both visual acuity AFL, aflibercept; F-U, follow-up; 2q4, 2mg every 4 weeks; q8, every 8 weeks; q12, every 12 weeks. (VA) and central retinal thickness (CRT) from baseline in patients with CRVO of both ischemic and non- ischemic origins, with a low incidence of adverse events. Like all anti-VEGF agents used   to treat the ME that’s caused by CRVO, getting the timing right and ‖ minimizing delays to commencing treatment are critical to achieving the  best possible outcomes for the patient.  Untreated CRVO results in progressive and irreversible vision loss, and early

aflibercept administration results in   better anatomical and visual outcomes: patients treated within two months of diagnosis have better outcomes with aflibercept than those whose treatment was delayed (18,19). Furthermore, Figure 3. Vision gains were largely maintained with less frequent than monthly dosing (16–19). patients switched from sham injections 2q4, 2 mg every 4 weeks; AFL, aflibercept; BCVA, best corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Figure 1. Timeline of advances in the management of CRVO-induced ME. to aflibercept do achieve VA gains, but Study; ‖ p<0.01; †p<0.001; ‡p<0.0001 vs. sham.

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1014-800 Supplement.indd 2-3 10/11/2014 11:50 4 The Ophthalmologist × Bayer HealthCare The Ophthalmologist × Bayer HealthCare 5

still improved mean best corrected visual acuity (BCVA) by over 17 letters within Beyond clinical 24 weeks (16–19), and most patients gained at least 15 letters within two trials: the months of diagnosis, with the mean gain   in BCVA after the first dose being more proactive treat- than two lines. Furthermore, patients that received initial treatment with and-extend   aflibercept maintained gains of at least 13 letters up to week 100 of treatment approach (21–23).

  But just how far out can you spread aflibercept injection and still see Figure 6. Specimen administration schedule for aflibercept therapy in patients with CRVO. The schedule functional improvements in vision? In should be determined by the treating physician based on patient response, and monitoring may be more both trials, patients received aflibercept frequent than the schedule of injections.*Discontinue treatment if there is no improvement in response after the first three injections. Figure 4. Aflibercept delivered rapid and durable improvements in CRT (22–23). as needed (pro re nata; PRN) from 2q4, 2 mg every 4 weeks; AFL, aflibercept; CRT, central retinal thickness. †p<0.001; ‡p<0.0001 vs. sham. week 24 onwards (Figure 2). Treatment trials. Why? In the real world, monitoring challenge is then to maintain those gains. was considered warranted only if Anat Loewenstein, Tel Aviv Medical Center occurred less than monthly and only a low In both COPERNICUS and GALILEO, pre-specified changes in CRT, fluid & Sackler Faculty of Medicine, University number of treatments were administered those receiving aflibercept had their dosing accumulation, edema or BCVA occurred of Tel Aviv, Israel. per year, allowing fluid to accumulate. based on visual and anatomic outcomes (18). The mean number of PRN injections The success of PRN treatment depends after week 24 of the trial. Furthermore, in GALILEO was 2.5 over this 6-month When treating ocular diseases, we want on monthly monitoring in the clinic. So a post-hoc analysis of COPERNICUS period, and the median time to the first to improve patients’ visual and anatomic I asked myself: might there be a better and GALILEO revealed that a majority PRN intravitreal aflibercept injection outcomes with the minimum amount of approach that maintains the benefits of patients required only three or fewer was 83 days (18). CRT showed similar burden. Anti-VEGF treatment is effective achieved in the first six months of monthly aflibercept injections in the second six patterns (Figure 4) – for example, at week for treating ME secondary to CRVO, but aflibercept therapy, but maximizes the months of the trials (25). 24 in the COPERNICUS study, CRT the burden can be treatment-associated intervals between doses, thereby reducing Aflibercept’s estimated long intravitreal was approximately three times greater adverse events or the hassle of frequent patient burden? half-life (26,27) and prolonged in the sham group compared with the clinic visits for intravitreal injections – Treat-and-extend regimens could suppression of VEGF (28) means that aflibercept-treated group (16,17). After both stressful and inconvenient. On the be the answer. The concept is simple: treatment intervals can be extended in this point, all patients received PRN other hand, drugs don’t work if patients initiate treatment with standard loading many patients to eight weeks or more aflibercept, and the CRT in the initially don’t receive them – regimen adherence doses of aflibercept, then slowly extend without compromising the VA gains sham-treated group managed to catch up is absolutely crucial for treatment success. the time between treatments until fluid achieved in the initial monthly dosing by week 52 (although this doesn’t reflect The question is therefore: how do we best recurs. This means that you understand period. A flexible treat-and-extend the VA gains). In GALILEO, sham- achieve the desired treatment outcomes what the patient’s maximum fluid-free posology for ME, secondary to CRVO, treated patients were switched to PRN while minimizing patient burden? interval is and you can adjust the dosing comprises an initial fixed monthly dosing aflibercept later – at week 52 – and also There’s also a big gap between what regimen accordingly. Of course, if the period to gain control of the disease; the showed rapid improvements in CRT works in a clinical trial and what happens fluid recurs, then it’s always an option to treatment intervals are then increased once treated with the active drug (18), in the real world – the AURA study gives treat more frequently in order to keep the based on visual and anatomic outcomes Figure 5. Visual outcomes during the 52 weeks of the GALILEO study. Mean change from baseline but even by week 76, they had not caught one such example (24). Investigators retina dry and maintain VA. Like fixed (Figure 6). BCVA by the status of retinal perfusion at baseline (18). up with the aflibercept group, again collected ‘real-life’ data on the clinical regimens, treat-and-extend is a proactive Results from the COPERNICUS and Perfused: fewer than 10 disc areas of non-perfusion. 2q4, 2 mg every 4 weeks; AFL, aflibercept; BCVA, best corrected visual acuity; underscoring the importance of timely management and resource utilization of approach, aiming to treat CRVO before GALILEO studies lead to the approved ETDRS, Early Treatment Diabetic Retinopathy Study. †p<0.0001 vs sham; ‡p<0.001 vs sham. intervention with aflibercept in patients 2,227 patients from eight countries who fluid accumulates; however, it is flexible, posology wording for the use of aflibercept with ME secondary to CRVO (23). had wet age-related macular degeneration allowing you to exercise your clinical for the treatment of ME secondary to they never equal those achieved by with aflibercept observed in the Furthermore, aflibercept treatment and were treated with ranibizumab. The judgment and identify the right treatment CRVO. They recommend that (21): patients who received aflibercept in the COPERNICUS and GALILEO trials significantly improves visual outcomes investigators found that real-life anti- interval for each of your patients. first place, underscoring the need for are largely maintained with a dosing relative to sham treatment, irrespective VEGF therapy use was associated with Most patients with CRVO attain • After the initial injection of early intervention (16,18). schedule less frequent than monthly of perfusion status at baseline (Figure 5) poorer than expected visual outcomes maximum VA gains after three or four aflibercept, treatment is given monthly Importantly, the vision gains regimens (Figure 3). Such a schedule (18). when compared with what was observed in monthly aflibercept injections; the – with the treatment interval being no

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1014-800 Supplement.indd 4-5 10/11/2014 11:50 6 The Ophthalmologist × Bayer HealthCare a b

shorter than one month. visual and anatomic outcomes should pioneered with aflibercept that has now (d). We did try to extend the treatment to • If no improvements in visual and be monitored and treatment should be been adopted for ranibizumab use in this six weeks (e), but we were unsuccessful (f ) anatomic outcomes are observed over resumed if these deteriorate. indication too (29). – it is likely that this patient has very high the course of the first three injections, • Usually, monitoring should be done In summary, the goals for treating levels of VEGF. The FA charts the response then continued treatment is not at the injection visits. During ME secondary to CRVO are clear; to treatment (g); through maintaining c d recommended. treatment interval extension through the challenge is how we achieve them. monthly treatment intervals over six • If improvements are seen, monthly to completion of therapy, the Maximum VA and anatomic outcomes, months, the patient had a VA of 20/40. treatment should continue until visual monitoring schedule should be as well as the prevention of irreversible The second case study comes from 2012, and anatomic outcomes are stable for determined by the treating physician vision loss, are achieved through and concerns a treatment-naïve patient three monthly assessments – based on the individual patient’s intensive treatment at the early stages with non-ischemic CRVO who presented thereafter, the need for continued response and may be more frequent of disease – the greatest visual gains to me two months after their initial vision treatment should be reconsidered. than the schedule of injections. occur within 12 weeks of starting loss. Their BCVA was 20/200, and FA and • If necessary, treatment may be treatment. A treat-and-extend regimen OCT imaging showed extensive ME. continued with gradually increasing Aflibercept has, therefore, a flexible using aflibercept, therefore, aims to At that time, the approved therapy was treatment intervals to maintain a posology, which allows a treat-and-extend prevent visual and anatomical decline by ranibizumab, so we started the patient e f stable visual and anatomic outcome. approach that is tailored to the individual providing therapy immediately prior to on monthly intravitreal injections of the If treatment has been discontinued, needs of the patient – an approach disease breakthrough. drug. OCT imaging taken four weeks after the third injection showed that the patient had a nice response, although his BCVA never improved beyond 20/40 – possibly because of an irregularity in Treat-and-extend his photoreceptor inner segment/ outer segment junction. After his fifth monthly in the clinic: case ranibizumab injection, we tried to extend the period between injections to six weeks. g study review This resulted in significant ME, and his chronic disease, and that each eye has its BCVA had degraded to 20/63. At this own individual recurrence-free interval. point in time, we were able to switch the This can be: patient to aflibercept. We initially used quite an aggressive • Difficult to predict based on imaging aflibercept regime – I used the maximum data prior to start of treatment recurrence free interval under ranibizumab • Quite stable over prolonged periods and added two weeks to that – in other of time Stephan Michels, City Hospital Triemli, Figure 7. Eleven-week recurrence-free interval with aflibercept (adapted to GALILEO) (18,23). words, he received the first injection of • Easily found by a “treat-and-extend” Zurich, Switzerland. At the week 24 primary endpoint, patients receiving intravitreal 2 mg aflibercept every four weeks had a aflibercept, and he returned to the clinic approach, and significantly greater mean change in BCVA than the sham-treated patients (18.0 vs 3.3 letters, respectively; six weeks later. His macula was dry, so we Typically we try to keep such patients on • Dependent on the anti-VEGF The COPERNICUS and GALILEO p<0.0001) (18). At week 76, patients in the intravitreal aflibercept 2q4 group reported a mean change from extended the treatment interval to eight this recurrence-free interval for six months drug used. studies show us that a significant gain baseline BCVA of 13.7 ETDRS letters, compared with sham-treated eyes, which gained 6.2 letters (23). weeks – successfully. We administered and then try to extend it again by two in VA of three lines in the first year of 2q4, 2 mg every 4 weeks; BCVA, best corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; PRN, pro re nata. the third aflibercept injection, then again weeks – if that doesn’t work, we keep the Because of these factors, fixed regimens aflibercept therapy is possible, and that the after eight weeks, then tried to push him patient for another six months on their – be it PRN, monthly or bimonthly dosing first injection is associated with the most employ. We have also learned not to delay treatment-naïve ischemic CRVO patient a little further by extending the interval original interval. Accordingly, six months – can’t fit the needs of all patients. If you extensive reduction in edema and increase treating our patients; extending PRN can who had been experiencing severe vision between the third and fourth injection to later, we tried to extend the treatment do employ an aflibercept treat-and-extend in VA (16,18). sometimes prove suboptimal (Figure 7). loss for two to three weeks (a). The patient’s ten weeks – but edema returned and his interval to nine weeks, but we started to regimen to treat ME in patients with However, treatment with six loading The following ischemic and non- VA was poor – 20/400, and the composite visual acuity worsened. We reduced his see some edema return, so it seems that CRVO, I have two tips I’d like to share. doses followed by variable-interval ischemic CRVO case studies show of the fluorescein angiography (FA) (b) treatment interval to eight weeks again, the patient’s maximum fluid-free interval First, the best tool to detect recurrence is treatment PRN isn’t necessarily the best the efficacy of aflibercept and how we showed large areas of non-perfusion. The which kept his retina edema-free. At the really is eight weeks. spectral domain OCT, and second, always approach in all patients because I believe developed appropriate treatment regimens ME was quite extensive (c), and we treated patient’s one-year follow up, eight weeks What you have to remember when remember that – just like wet AMD – that there are smarter, personalized for each patient. with monthly aflibercept – and we used a after the seventh aflibercept injection; treating ME in patients with CRVO function follows early anatomic changes… treat-and-extend strategies that we can The first case study (see Box) presents a laser on the peripheral, non-perfused areas his retina is dry and his BCVA is 20/32. is that, in most cases, you’re treating a so intervene at the earliest opportunity.

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1014-800 Supplement.indd 6-7 10/11/2014 11:51 References 16. D.M. Brown, J.S. Heier, W.L. Clark, et al., “Intravitreal aflibercept injection for macular edema 1. S. Rogers, R.L. McIntosh, N. Cheung, et al., “The prevalence of retinal vein occlusion: pooled data from secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study”, Am. J. population studies from the United States, Europe, Asia, and Australia”, Ophthalmology, 117, 313–319, Ophthalmol., 155, 429-437, (2013). doi:10.1016/j.ajo.2012.09.026. (2010). doi:10.1016/j.ophtha.2009.07.017. 17. D. Boyer, J. Heier, D.M. Brown, et al., “Vascular endothelial growth factor Trap-Eye for macular edema 2. D.B. Rein, P. Zhang, K.E. Wirth, et al., “The economic burden of major adult visual disorders in the secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study”, United States”, Arch. Ophthalmol., 124, 1754–1760, (2006). Ophthalmology, 119, 1024–1032, (2012). doi:10.1016/j.ophtha.2012.01.042. 3. V.A. Deramo, T.A. Cox, A.B. Syed, et al., “Vision-related quality of life in people with central retinal 18. J-F. Korobelnik, F.G. Holz, J. Roider, et al., “Intravitreal aflibercept injection for macular edema vein occlusion using the 25-item National Eye Institute Visual Function Questionnaire”, Arch. resulting from central retinal vein occlusion: one-year results of the Phase 3 GALILEO Study”, Ophthalmol., 121, 1297–1302, (2003). doi:10.1001/archopht.121.9.1297. Ophthalmology, 121, 202–208, (2014). doi:10.1016/j.ophtha.2013.08.012. 4. L.P. Aiello, R.L. Avery, P.G. Arrigg, et al., “Vascular endothelial growth factor in ocular fluid of patients 19. F.G. Holz, J. Roider, Y. Ogura, et al., “VEGF Trap-Eye for macular oedema secondary to central retinal with diabetic retinopathy and other retinal disorders”, N. Engl. J. Med., 331, 1480–1487, (1994). vein occlusion: 6-month results of the phase III GALILEO study”, Br. J. Ophthalmol., 97, 278-284, (2013). 5. T.Y. Wong, I.U. Scott, “Retinal vein occlusion”, N. Engl. J. Med., 363, 2135–2144, (2010). doi:10.1136/bjophthalmol-2012-301504. doi:10.1056/NEJMcp1003934. 20. N. Papadopoulos, J. Martin, Q. Ruan et al, “Binding and neutralization of vascular endothelial growth 6. N. Karia, “Retinal vein occlusion: pathophysiology and treatment options”, Clin. Ophthalmol., 4, factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab”, Angiogenesis, 15, 809-816, (2010). 171–185 (2012). doi: 10.1007/s10456-011-9249-6. 7. D. Kent, S.A. Vinores, P.A. Campochiaro, “Macular oedema: the role of soluble mediators”, Br. J. 21. Eylea® Summary of Product Characteristics (September 04, 2014). Bayer plc; Newbury, Berkshire, Ophthalmol., 84, 542-545, (2000). UK. 8. L. Laatikainen, E.M. Kohner, D. Khoury et al., “Panretinal photocoagulation in central retinal vein 22. J.S. Heier, W.L. Clark, D.S. Boyer, et al., “Intravitreal aflibercept injection for macular edema due to occlusion: a randomised controlled clinical study”, Br. J. Ophthalmol., 61, 741–753, (1977). central retinal vein occlusion: two-year results from the COPERNICUS study”, Ophthalmology, 121, 9. H.C. Hasselbach, F. Ruefer, N. Feltgen, et al., “Treatment of central retinal vein occlusion by radial 1414–1420 (2014). doi: 10.1016/j.ophtha.2014.01.027. optic neurotomy in 107 cases”, Graefes Arch. Clin. Exp. Ophthalmol., 245, 1145–1156, (2007). 23. Y. Ogura, J. Roider, J.F. Korobelnik, et al., “Intravitreal Aflibercept for Macular Edema Secondary to 10. CVOS group, “Evaluation of grid pattern photocoagulation for macular edema in central vein Central Retinal Vein Occlusion: 18-Month Results of the Phase 3 GALILEO Study”, Am. J. Ophthalmol. occlusion. The Central Vein Occlusion Study Group M report”, Ophthalmology, 102, 1425–1433, (1995). Epub ahead of print (2014). doi: 10.1016/j.ajo.2014.07.027. 11. J.A. Ford, N. Louis, P. Royle, et al., “Current treatments in diabetic macular oedema: systematic review 24. F.G. Holz, R. Tadayoni, S. Beatty, et al., “Multi-country real-life experience of anti-vascular and meta-analysis”, BMJ Open, 3, pii: e002269, (2013). doi:10.1136/bmjopen-2012-002269. endothelial growth factor therapy for wet age-related macular degeneration””, Br J Ophthalmol. Epub 12. SCORE group, “A randomized trial comparing the efficacy and safety of intravitreal triamcinolone ahead of print (2014). doi: 10.1136/bjophthalmol-2014-305327. with observation to treat vision loss associated with macular edema secondary to central retinal vein 25. K. Lorenz, “Intravitreal aflibercept in CRVO: Treatment interval exention based on visual and occlusion”, Arch. Ophthalmol., 127, 1101–1114, (2009). doi:10.1001/archophthalmol.2009.234. anatomic outcomes”. Poster presented at the 5th World Congress on Controversies in Ophthalmology 13. J.A. Haller, F. Bandello, R. Belfort Jr, et al., “Randomized, sham-controlled trial of dexamethasone (COPHy), Lisbon, Portugal; March 20–23, 2014. intravitreal implant in patients with macular edema due to retinal vein occlusion”, Ophthalmology, 117, 26. M.W. Stewart, P.J. Rosenfeld, “Predicted biological activity of intravitreal VEGF Trap”, Br. J. 1134–1146, (2010). doi:10.1016/j.ophtha.2010.03.032. Ophthalmol., 92, 667–668 (2008). doi: 10.1136/bjo.2007.134874. 14. D.M. Brown, P.A. Campochiaro, R.P. Singh, et al., “Ranibizumab for macular edema following central 27. M.W. Stewart, “What are the half-lives of ranibizumab and aflibercept (VEGF Trap-eye) in retinal vein occlusion: six-month primary end point results of a phase III study”, Ophthalmology, 117, human eyes? Calculations with a mathematical model”, Eye Reports. 1, e5 (2011). 1124–1133, (2010). doi:10.1016/j.ophtha.2010.02.022. 28. S. Fauser, V. Schwabecker, P.S. Muether, “Suppression of intraocular vascular endothelial growth factor 15. P.A. Campochiaro, D.M. Brown, C.C. Awh, et al., “Sustained benefits from ranibizumab for macular during aflibercept treatment of age-related macular degeneration”, Am. J. Ophthalmol., 158, 532–536 edema following central retinal vein occlusion: twelve-month outcomes of a phase III study”,Ophthalmology, (2014). doi: 10.1016/j.ajo.2014.05.025. 118, 2041-2049, (2011). doi:10.1016/j.ophtha.2011.02.038. 29. Lucentis® Summary of Product Characteristics (September 23, 2014). Novartis Pharmaceuticals UK.

Prescribing info inflammation e.g pain, photophobia or redness, which may be a clinical sign of hypersensitivity. Reports of systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events following intravitreal injection of VEGF inhibitors. Safety and efficacy of Eylea® 40 mg/ml solution for injection in a vial (aflibercept) Prescribing Information concurrent use in both eyes have not been systemically studied. Caution in patients with risk factors (Refer to full Summary of Product Characteristics (SmPC) before prescribing) for development of retinal pigment epithelial tears including large and/or high pigment epithelial Presentation: 1 ml solution for injection contains 40 mg aflibercept. Each vial contains 100 retinal detachment. Withhold treatment in patients: with rhegmatogenous retinal detachment or microlitres, equivalent to 4 mg aflibercept. Indication(s): Treatment of neovascular (wet) age-related stage 3 or 4 macular holes; with retinal break and do not resume treatment until the break is macular degeneration (AMD), macular oedema secondary to central retinal vein occlusion adequately repaired. Withhold treatment and do not resume before next scheduled treatment if (CRVO) and visual impairment due to diabetic macular oedema (DMO) in adults. Posology & there is: decrease in best-corrected visual acuity of ≥30 letters compared with the last assessment; method of administration: For intravitreal injection only. Must be administered according to central foveal subretinal haemorrhage, or haemorrhage ≥50%, of total lesion area. Do not treat in medical standards and applicable guidelines by a qualified physician experienced in administering the 28 days prior to or following performed or planned intraocular surgery. Eylea should not be intravitreal injections. Each vial should only be used for the treatment of a single eye. The vial used in pregnancy unless the potential benefit outweighs the potential risk to the foetus. Women of contains more than the recommended dose of 2 mg. The extractable volume of the vial (100 childbearing potential have to use effective contraception during treatment and for at least 3 microlitres) is not to be used in total. The excess volume should be expelled before injecting. Refer months after the last intravitreal injection. Populations with limited data: There is limited to SmPC for full details. Adults: The recommended dose is 2 mg aflibercept, equivalent to 50 experience of treatment with Eylea in patients with ischaemic, chronic CRVO. In patients microlitres. For wAMD treatment is initiated with one injection per month for three consecutive presenting with clinical signs of irreversible ischaemic visual function loss, the treatment is not doses, followed by one injection every two months. No requirement for monitoring between recommended. There is limited experience in DMO due to type I diabetes or in diabetic patients injections. After the first 12 months of treatment, treatment interval may be extended based on with an HbA1c over 12% or with proliferative diabetic retinopathy. Eylea has not been studied in visual and anatomic outcomes. In this case the schedule for monitoring may be more frequent than patients with active systemic infections, concurrent eye conditions such as retinal detachment or the schedule of injections. For CRVO, after the initial injection, treatment is given monthly at macular hole, or in diabetic patients with uncontrolled hypertension. This lack of information intervals not shorter than one month, and continues until visual and anatomic outcomes are stable should be considered when treating such patients. Interactions: No available data. Fertility, for three monthly assessments. Thereafter the need for continued treatment should be reconsidered. pregnancy & lactation: Not recommended during pregnancy unless potential benefit outweighs Treatment may be continued with gradually increasing treatment intervals to maintain a stable potential risk to the foetus. No data available in pregnant women. Studies in animals have shown visual and anatomic outcome. Continued treatment is not recommended if no improvement in embryo-foetal toxicity. Women of childbearing potential have to use effective contraception during visual and anatomic outcomes over the first three injections. If treatment is discontinued, monitor treatment and for at least 3 months after the last injection. Not recommended during breastfeeding. visual and anatomic outcomes and resume treatment if these deteriorate. Usually, monitoring Excretion in human milk: unknown. Male and female fertility impairment seen in animal studies should be done at the injection visits. During treatment interval extension until therapy completion, with high systemic exposure not expected after ocular administration with very low systemic the monitoring schedule should be determined by the treating physician based on the individual exposure. Effects on ability to drive and use machines: Possible temporary visual disturbances. patient’s response and may be more frequent than the schedule of injections. For DMO, initiate Patients should not drive or use machines if vision inadequate. Undesirable effects: Very common: treatment with one injection/month for 5 consecutive doses, followed by one injection every two conjunctival haemorrhage (phase III studies: increased incidence in patients receiving months. No requirement for monitoring between injections. After the first 12 months of treatment, anti-thrombotic agents), eye pain, visual acuity reduced. Common: retinal pigment epithelium tear, the treatment interval may be extended based on visual and anatomic outcomes. The schedule for detachment of the retinal pigment epithelium, retinal degeneration, vitreous haemorrhage, cataract monitoring should be determined by the treating physician. If visual and anatomic outcomes (nuclear or subcapsular), corneal abrasion or erosion, corneal oedema, increased intraocular pressure, indicate that the patient is not benefiting from continued treatment, treatment should be blurred vision, vitreous floaters, vitreous detachment, injection site pain, foreign body sensation in discontinued. Hepatic and/or renal impairment: No specific studies have been conducted. Available eyes, increased lacrimation, eyelid oedema, injection site haemorrhage, punctate keratitis, data do not suggest a need for a dose adjustment. Elderly population: No special considerations are conjunctival or ocular hyperaemia. Uncommon: Injection site irritation, abnormal sensation in eye, needed. Limited experience in those with DMO over 75years old. Paediatric population: No data eyelid irritation. Serious: cf. CI/W&P - in addition: endophthalmitis, cataract, transient increased available. Contra-indications: Hypersensitivity to active substance or any excipient; active or intraocular pressure, vitreous detachment, retinal detachment or tear, hypersensitivity (incl. allergic suspected ocular or periocular infection; active severe intraocular inflammation. Warnings & reactions), vitreous haemorrhage, cortical cataract, lenticular opacities, corneal epithelium defect/ precautions: As with other intravitreal therapies endophthalmitis has been reported. Aseptic erosion, vitritis, uveitis, iritis, iridocyclitis, anterior chamber flare, blindness. Consult the SmPC in injection technique essential. Patients must report any symptoms of endophthalmitis without delay. relation to other side effects. Overdose: Monitor intraocular pressure and treat if required. Increases in intraocular pressure have been seen within 60 minutes of intravitreal injection; special Incompatibilities: Do not mix with other medicinal products. Special Precautions for Storage: Store precaution is needed in patients with poorly controlled glaucoma (do not inject while the in a refrigerator (2°C to 8°C). Do not freeze. Unopened vials may be kept at room temperature intraocular pressure is ≥ 30 mmHg). Immediately after injection, monitor intraocular pressure and (below 25°C) for up to 24 hours before use. Legal Category: POM. Package Quantities & Basic perfusion of optic nerve head and manage appropriately. There is a potential for immunogenicity as NHS Costs: Single vial pack £816.00. MA Number(s): EU/1/12/797/002. Further information with other therapeutic proteins; patients should report any signs or symptoms of intraocular available from: Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire RG14 1JA, United Kingdom. Telephone: 01635 563000. Date of preparation: November 2014

Eylea® is a trademark of the Bayer Group 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 Bayer plc. Tel.: 01635 563500, Fax.: 01635 563703, Email: [email protected] This symposium was organized and funded by Bayer HealthCare Cited comment and opinion reflect the views of speakers and participants and do not necessarily reflect those of Bayer HealthCare. L.GB.10.2014.8606. Date of preparation: November 2014.

Eylea® (aflibercept solution for injection) is a registered trademark of the Bayer Group.

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