EVOLUTION OF PORTABLE VISUAL FIELD TESTS P. 16 • MANAGING THE ANOPHTHALMIC PATIENT P. 26 Review of Ophthalmology Vol. XXV, Patients Problems Premium-IOL 2019 • Managing • Options for the Non-phaco Candidate Artifi • Cataract Surgery in ERM No. 4 • April ANGLE CLOSURE: GONIOSCOPY OR OCT? P. 60 • BE PREPARED FOR PEDIATRIC RETINA PATIENTS P. 66 RESEARCHERS DELVE INTO ORBITAL CANCERS P. 70 • WILLS EYE RESIDENT CASE P. 71

AprilApril 201920019

reviewofophthalmology.comreviewwofophthalmology.ccom TS PATIEN WELCOM ALL E!

Techniques and technology that let you help more cataract patients.

• How to Deal with Premium-IOL Problems P. 30 • Peel Back the Veil on ERM Management P. 40 • MSICS and miLoop for Non-phaco Candidates P. 54

cial Irises ALSO INSIDE:

• The Continuing Role of Lasers in PDR P. 44 • The Artifi cial Iris in Practice P. 48

001_rp0419_fc.indd 1 3/22/19 3:17 PM +3.25 D

RP0419_J & J Vision.indd 1 3/19/19 11:05 AM REVIEW NEWS Volume XXV • No. 4 • April 2019 Correlations Found Between Glaucoma and Pregnancies

It’s well-established that the incidence coma group and the no-glaucoma between the age of 16 to 20 years or and prevalence of glaucoma is group in both the number of deliv- 21 to 23 years was associated with a affected by gender, but the reasons eries the women had undergone and two-fold increased risk of open-an- for this remain unclear. Noting that the subject’s age at the time of the gle glaucoma, compared to a refer- some previous studies have found fi rst delivery. ence group of subjects aged 24 to 26 a correlation between having given (p<0.05). birth and glaucoma, researchers in The authors conclude that these South Korea set out to pursue this fi ndings suggest that changes taking further. place in the body during pregnancy A study published in the Janu- may affect the development of glau- ary 2019 issue of The Journal of coma. Glaucoma used a population-based, Without further data, any explana- cross-sectional analysis of data tion for these effects is theoretical, from the Korean National Health but the authors hypothesize a num- and Nutrition Examination Survey, ber of possible explanations for their conducted in 2010 and 2011, to in- fi ndings. These include: high estro- vestigate any association between gen levels during pregnancy; tran- pregnancy, delivery and the preva- sient events during labor, including lence of open-angle glaucoma in systemic hypotension and decreased 1,798 postmenopausal South Korean ocular perfusion because of massive women. Demographic information, • When the analysis was adjusted bleeding, inducing glaucoma-like comorbidities and health-related be- to account for age, hypertension changes in the optic nerve; increased haviors were included in the analysis. and intraocular pressure, the low- oxytocin levels during labor inducing Excluded from the database were est increased risk for open-angle capillary constriction and decreasing subjects with evidence of retinal glaucoma was associated with two aqueous outfl ow; stress during labor detachment or age-related macu- deliveries; women with one delivery causing the release of epinephrine lar degeneration; pseudophakic and had a greater risk of open-angle glau- and norepinephrine, increasing IOP; aphakic subjects; anyone who did not coma than those with two deliveries and valsalva maneuvers during labor undergo an ophthalmic evaluation; (p=0.023). Those with three or more producing intermittent increases in and anyone with a history of intraoc- deliveries also had a greater risk of IOP. ular surgery. (The authors note that open-angle glaucoma than those While all of these changes are one limitation of their study was the with two deliveries (p=0.027). short-lived, raising the question small number of women in the sur- • Giving birth for the fi rst time of whether they could have such a vey who had no pregnancies, making it impossible to draw any conclusions Farewell ... and Welcome regarding subjects in that situation.) This issue marks a changing of the guard in our Retinal Insider department. After 20 years Several correlations between of expertly co-editing the column alongside Carl Regillo, MD, Emmett Cunningham, MD, num ber of pregnancies and glauco- PhD, is stepping down. Review and its readers thank Dr. Cunningham for his fi ne work. In ma were found: his place comes Yoshihiro Yonekawa, MD, an expert clinician and surgeon currently at Mas- • There was a signifi cant differ- sachusetts Eye and Ear Infi rmary, but soon to be at Wills Eye Hospital. We’d like to take this ence between the open-angle glau- opportunity to welcome Dr. Yonekawa to the magazine.

April 2019 | reviewofophthalmology.com | 3

003_rp0419_news.indd 3 3/22/19 11:56 AM ® REVIEW REVIEW News E DITORIAL STAFF News

Editor in Chief signifi cant impact, the authors note two Phase III trials, MERCURY 1 Walter C. Bethke that the risk of glaucoma increases (NCT 02558400) and MERCURY (610) 492-1024 with more pregnancies/births. The 2 (NCT 02674854). The company [email protected] primary exception to that is that the reports that Rocklatan achieved the risk didn’t increase between the fi rst primary 90-day effi cacy endpoint, as Senior Editor and second births; the authors hy- well as positive 12-month safety and Christopher Kent pothesize that this might refl ect the effi cacy results, showing statistically (814) 861-5559 optic nerve’s ability to recover from signifi cant intraocular pressure re- [email protected] small insults below a certain thresh- duction vs. either latanoprost or net- old. Only when the challenging con- arsudil alone at each time point. Associate Editor ditions recur three or more times For its part, Bausch + Lomb an- Alexandra Skinner would the physiologic insult cause nounced the FDA approval of a (610) 492-1025 the likelihood of later glaucoma to treatment for postoperative infl am- [email protected] increase further. mation and pain following ocular “This population-based study surgery: corticosteroid Lotemax SM. Chief Medical Editor showed an association between B+L says that Lotemax SM uses sub- Mark H. Blecher, MD pregnancy and risk of open-angle micron technology to deliver fast Art Director glaucoma,” notes Peter A. Netland, drug dissolution in tears and improve Jared Araujo MD, PhD, Vernah Scott Moyston drug exposure into the aqueous, and (610) 492-1032 Professor and Chair at the University that it provides two times greater [email protected] of Virginia in Charlottesville. “The penetration to the aqueous humor physiologic changes that take place compared to Lotemax Gel (lotepred- Senior Graphic Designer during pregnancy are complex and nol etabonate ophthalmic gel) 0.5%. Matt Egger numerous. The possibility of a hor- The drug has the lowest preser- (610) 492-1029 mone effect on the risk of glaucoma vative percentage in a loteprednol [email protected] is interesting and merits further in- etabonate formulation, and has a pH vestigation.” close to that of human tears, B+L Graphic Designer adds. Ashley Schmouder In one randomized study, at po- (610) 492-101048 stop day eight, the new drug cleared [email protected] New Drugs anterior chamber cells in 29 percent of patients vs. 9 percent of patients International coordinator, Japan Approved by who were administered only vehicle, Mitz Kaminuma and 73 percent of the Lotemax SM [email protected] patients reported being clear of pain FDA vs. 48 percent of vehicle patients. Business Offi ces 11 Campus Boulevard, Suite 100 Two companies, Aerie Pharmaceu- Newtown Square, PA 19073 ticals and Bausch + Lomb, received (610) 492-1000 Food and Drug Adminstration ap- Court Moves Fax: (610) 492-1039 provals in recent months. Aerie’s glaucoma drug Rocklatan Against Drug Subscription inquiries: (netarsudil and latanoprost oph- United States — (877) 529-1746 thalmic solution) 0.02%/0.005% has Outside U.S. — (845) 267-3065 been approved by the U.S. Food and Compounder E-mail: Drug Administration for the treat- The federal court in the Northern [email protected] ment of open-angle glaucoma and District of Texas has ordered JMA Website: www.reviewofophthalmology.com ocular hypertension. It’s the fi rst q.d. Partners, doing business as Guardian fi xed-dose combination of a prosta- Pharmacy Services in Dallas, to stop glandin analog and a Rho kinase in- producing compounded drug prod- hibitor. The approval was supported by (Continued on page 8)

4 | Review of Ophthalmology | April 2019

0003_rp0419_news.indd03_rp0419_news.indd 4 33/22/19/22/19 11:5611:56 AMAM DID YOU KNOW? KEELER has slit lamps!

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REVIEW Board

BUSINESS OFFICES 11 CAMPUS BOULEVARD, SUITE 100 NEWTOWN SQUARE, PA 19073 ONTRIBUTORS SUBSCRIPTION INQUIRIES (877) 529-1746 C (USA ONLY); OUTSIDE USA, CALL (847) 763-9630 CHIEF MEDICAL EDITOR PEDIATRIC PATIENT Mark H. Blecher, MD Wendy Huang, MD BUSINESS STAFF CONTACT LENSES PLASTIC POINTERS PUBLISHER JAMES HENNE Penny Asbell, MD Ann P. Murchison, MD, MPH (610) 492-1017 [email protected] CORNEA / ANTERIOR SEGMENT REFRACTIVE SURGERY REGIONAL SALES MANAGER Thomas John, MD Arturo S. Chayet, MD MICHELE BARRETT (610) 492-1014 [email protected] GLAUCOMA MANAGEMENT RETINAL INSIDER Peter Netland, MD, PHD Carl Regillo, MD, FACS REGIONAL SALES MANAGER Kuldev Singh, MD Emmett T. Cunningham Jr., MD, PHD, MPH MICHAEL HOSTER (610) 492-1028 [email protected] MASTERS OF SURGERY TECHNOLOGY UPDATE Taliva D. Martin, MD Steven T. Charles, MD CLASSIFIED ADVERTISING Sara J. Haug, MD, PhD Michael Colvard, MD (888)-498-1460 MEDICARE Q & A WILLS RESIDENT CASE SERIES VICE PRESIDENT OF OPERATIONS Paul M. Larson, MBA Jason Flamendorf, MD. CASEY FOSTER (610) 492-1007 [email protected]

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REVIEW OF OPHTHALMOLOGY (ISSN 1081-0226; USPS No. 0012-345) is published monthly, 12 times per year by Jobson Medical Informa- tion. 440 Ninth Avenue, 14th Floor, New York, N.Y. 10001. Periodicals postage paid at New York, NY and additional mailing offi ces. Postmaster: Send address changes to Review of Ophthalmology, PO Box 71, Congers, NY 10929-0071. Subscription Prices: US One Year $63.00, US Two Year $112.00, Canada One Year $99.00, Canada Two Year $181.00, Int’l One Year $158.00, Int’l Two Year $274.00. For subscription information call (877) 529-1746 (USA only); outside USA, call (845-267-3065. Or email us at [email protected]. Canada Post: Publications Mail Agreement #40612608. Canada Returns to be sent to Bleuchip International, P.O. Box 25542, London, ON N6C 6B2.

6 | Review of Ophthalmology | April 2019

0003_rp0419_news.indd03_rp0419_news.indd 6 33/22/19/22/19 11:5711:57 AMAM NOW APPROVED. COMING SOON.

BIG TIME INNOVATION1 THE FIRST AND ONLY OPHTHALMIC STEROID INSERT DEXTENZA is an advancement in steroid treatment

• Resorbable, so no need for removal2 • Designed to deliver a tapered dose1 • Insert can be removed via saline irrigation • Contains fluorescein for visualization2 or manual expression, if necessary2 • No additional components or • Physicians rated DEXTENZA as easy assembly required2 to insert3*

VISIT BOOTH 1737 AT ASCRS

INDICATION Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections DEXTENZA is a corticosteroid indicated for the of the eye (including herpes simplex). treatment of ocular pain following ophthalmic surgery. Fungus invasion must be considered in any persistent IMPORTANT SAFETY INFORMATION corneal ulceration where a steroid has been used or is in CONTRAINDICATIONS use. Fungal culture should be taken when appropriate. Use of steroids after cataract surgery may delay DEXTENZA is contraindicated in patients with healing and increase the incidence of bleb formation active corneal, conjunctival or canalicular infections, including epithelial herpes simplex keratitis (dendritic ADVERSE REACTIONS keratitis), vaccinia, varicella; mycobacterial infections; The most common ocular adverse reactions that fungal diseases of the eye, and dacryocystitis. occurred in patients treated with DEXTENZA were: WARNINGS AND PRECAUTIONS anterior chamber inflammation including iritis and iridocyclitis (9%); intraocular pressure increased (5%); Prolonged use of corticosteroids may result in glaucoma visual acuity reduced (2%); eye pain (1%); cystoid with damage to the optic nerve, defects in visual macular edema (1%); corneal edema (1%); and acuity and fields of vision. Steroids should be used conjunctival hyperemia (1%). with caution in the presence of glaucoma. Intraocular pressure should be monitored during treatment. The most common non-ocular adverse reaction that occurred in patients treated with DEXTENZA was Corticosteroids may suppress the host response headache (1%). and thus increase the hazard for secondary ocular infections. In acute purulent conditions, steroids may Please see brief summary of full Prescribing mask infection and enhance existing infection. Information on adjacent page.

*73.6% of physicians in Study 1 and 76.4% in Study 2 rated DEXTENZA as easy to insert.

References: 1. Sawhney AS et al, inventors; Incept LLC, assignee. US patent 8,409,606 B2. April 2, 2013. 2. DEXTENZA [package insert]. Bedford, MA: Ocular Therapeutix, Inc; 2018. 3. Walters T et al. J Clin Exp Ophthalmol. 2016;7(4):1-11. © 2019 Ocular Therapeutix, Inc. All rights reserved. DEXTENZA is a registered trademark of Ocular Therapeutix, Inc. PP-US-DX-0071 02/2019

RP0319_Ocular Thera.indd 1 2/13/19 10:08 AM DEXTENZA was studied in three randomized, vehicle-controlled studies (n = 351). The mean age of the population was 68 years REVIEW (range 43 to 87 years), 62% were female, News and 85% were white. Forty-six percent had brown iris color and 31% had blue iris color. The most common ocular adverse (Continued from p. 6) BRIEF SUMMARY: Please see the reactions that occurred in patients treated DEXTENZA Package Insert for full with DEXTENZA were: anterior chamber prescribing information for DEXTENZA inflammation including iritis and iridocyclitis ucts that are intended to be sterile until the company (11/2018) (9%); intraocular pressure increased (5%); shows it has complied with the Federal Food, Drug, and 1 INDICATIONS AND USAGE visual acuity reduced (2%); eye pain (1%); cystoid macular edema (1%); corneal edema Cosmetic Act and other requirements. DEXTENZA® (dexamethasone ophthalmic (1%); and conjunctival hyperemia (1%). insert) is a corticosteroid indicated for the According to an announcement of the decision by the treatment of ocular pain following ophthalmic The most common non-ocular adverse surgery (1). reaction that occurred in patients treated with DEXTENZA was headache (1%). FDA, the agency inspected Guardian in 2016 and, as 4 CONTRAINDICATIONS 8 USE IN SPECIFIC POPULATIONS a result, issued the pharmacy a warning letter for un- DEXTENZA is contraindicated in patients with active corneal, conjunctival or canalicular 8.1 Pregnancy sanitary conditions, among other FD&C Act violations. infections, including epithelial herpes simplex Risk Summary keratitis (dendritic keratitis), vaccinia, Then, in 2017, the FDA received adverse event reports varicella; mycobacterial infections; fungal There are no adequate or well-controlled regarding at least 43 patients who received ocular injec- diseases of the eye, and dacryocystitis. studies with DEXTENZA in pregnant women to inform a drug-associated risk for major tions of a drug compounded by Guardian containing 5 WARNINGS AND PRECAUTIONS birth defects and miscarriage. In animal 5.1 Intraocular Pressure Increase reproduction studies, administration of triamcinolone and moxifl oxacin during cataract surgery. topical ocular dexamethasone to pregnant Prolonged use of corticosteroids may result mice and rabbits during organogenesis The patients reportedly suffered symptoms that includ- in glaucoma with damage to the optic nerve, produced embryofetal lethality, cleft palate defects in visual acuity and fields of vision. and multiple visceral malformations ed decreased vision, poor night vision, loss of color vision Steroids should be used with caution in the [see Animal Data]. presence of glaucoma. Intraocular pressure and reductions in best-corrected vision. Upon investi- should be monitored during the course of Data the treatment. Animal Data gation, the FDA says it found a high percentage of an 5.2 Bacterial Infection Topical ocular administration of 0.15% excipient, poloxamer 407, and the presence of potential Corticosteroids may suppress the host dexamethasone (0.75 mg/kg/day) on process-degradation products in the compounded drug. response and thus increase the hazard gestational days 10 to 13 produced for secondary ocular infections. In acute embryofetal lethality and a high incidence The current consent decree requires Guardian to stop purulent conditions, steroids may mask of cleft palate in a mouse study. A daily infection and enhance existing infection dose of 0.75 mg/kg/day in the mouse is sterile operations until it takes corrective action such [see Contraindications (4)]. approximately 5 times the entire dose of dexamethasone in the DEXTENZA product, as hiring a qualifi ed independent expert to inspect its 5.3 Viral Infections on a mg/m2 basis. In a rabbit study, topical ocular administration of 0.1% operation, establishes a comprehensive quality control Use of ocular steroids may prolong the dexamethasone throughout organogenesis course and may exacerbate the severity of (0.36 mg /day, on gestational day 6 followed program and receives authorization from the FDA to many viral infections of the eye (including by 0.24 mg/day on gestational days 7-18) herpes simplex) [see Contraindications (4)]. produced intestinal anomalies, intestinal resume operating. 5.4 Fungal Infections aplasia, gastroschisis and hypoplastic kidneys. A daily dose of 0.24 mg/day is Fungus invasion must be considered in any approximately 6 times the entire dose of persistent corneal ulceration where a steroid dexamethasone in the DEXTENZA product, has been used or is in use. Fungal culture on a mg/m2 basis. should be taken when appropriate [see Contraindications (4)]. 8.2 Lactation Companies Hope 5.5 Delayed Healing Systemically administered corticosteroids appear in human milk and could suppress The use of steroids after cataract surgery growth and interfere with endogenous may delay healing and increase the corticosteroid production; however the Success is in the Genes incidence of bleb formation. systemic concentration of dexamethasone 6 ADVERSE REACTIONS following administration of DEXTENZA is low [see Clinical Pharmacology (12.3)]. There The following serious adverse reactions are is no information regarding the presence of In a mini feeding frenzy of sorts, spurred by the poten- described elsewhere in the labeling: DEXTENZA in human milk, the effects of the drug on the breastfed infant or the effects tial of gene therapy, Roche agreed to purchase Luxtur- • Intraocular Pressure Increase [see of the drug on milk production to inform risk Warnings and Precautions (5.1)] of DEXTENZA to an infant during lactation. na-maker Spark Therapeutics in February for approxi- • Bacterial Infection [see Warnings and The developmental and health benefits of mately $4.3 billion, and in March Biogen announced Precautions (5.2)] breastfeeding should be considered along with the mother’s clinical need for DEXTENZA that it’s buying gene-therapy maker Nightstar for about • Viral Infection [see Warnings and and any potential adverse effects on the Precautions (5.3)] breastfed child from DEXTENZA. $877 million. • Fungal Infection [see Warnings and 8.4 Pediatric Use Precautions (5.4)] According to an offi cial statement by Roche, in addi- Safety and effectiveness in pediatric patients • Delayed Healing [see Warnings and have not been established. tion to the already approved Luxturna, a one-time gene Precautions (5.5)] 8.5 Geriatric Use therapy for biallelic RPE65 mutation-associated retinal 6.1 Clinical Trials Experience No overall differences in safety or dystrophy, Spark Therapeutics’ lead clinical asset is SPK- Because clinical trials are conducted effectiveness have been observed between under widely varying conditions, adverse elderly and younger patients. 8011, a novel gene therapy for the treatment of haemo- reaction rates observed in the clinical trials of a drug cannot be directly compared to 17 PATIENT COUNSELING INFORMATION philia A, which is expected to start a Phase III clinical rates in the clinical trials of another drug Advise patients to consult their surgeon if and may not reflect the rates observed pain, redness, or itching develops. trial in 2019. in practice. Adverse reactions associated with ophthalmic steroids include elevated Nightstar’s lead candidate is the adeno-associated vi- intraocular pressure, which may be associated with optic nerve damage, ral vector-based therapy NSR-REP1, a gene therapy for visual acuity and field defects, posterior subcapsular cataract formation; delayed the treatment of choroideremia, a rare, X-linked genetic wound healing; secondary ocular infection MANUFACTURED FOR: retinal disorder that currently has no treatment. NSR- from pathogens including herpes simplex, Ocular Therapeutix, Inc. and perforation of the globe where there REP1 is currently in a Phase III trial. The company has is thinning of the cornea or sclera [see Bedford, MA 01730 USA Warnings and Precautions (5)]. PP-US-DX-0072 other potential treatments in the works as well, including gene therapies targeting X-linked retinitis pigmentosa and Stargardt’s disease.

8 | Review of Ophthalmology | April 2019

0003_rp0419_news.indd03_rp0419_news.indd 8 33/22/19/22/19 11:5711:57 AMAM Monthly MACKOOL ONLINE CME CME SERIES | SURGICAL VIDEOS

MackoolOnlineCME.com MONTHLY Video Series We are excited to continue into our fourth year of Mackool Online CME. With the generous support of several ophthalmic companies, I am honored to have our To view CME video viewers join me in the operating room as I demonstrate go to: the technology and techniques that I have found to be www.MackoolOnlineCME.com most valuable, and that I hope are helpful to many of my colleagues. We continue to edit the videos only to either change camera perspective or to reduce down time – allowing you to observe every step of the procedure. Richard J. Mackool, MD Episode 40: As before, one new surgical video will be released monthly, “A Systematic Approach and physicians may earn CME credits or just observe the case. New viewers are able to obtain additional CME credit by reviewing previous videos that are to a Diffi cult Eye” located in our archives. Surgical Video by: Richard J. Mackool, MD I thank the many surgeons who have told us that they have found our CME program to be interesting and instructive; I appreciate your comments, suggestions and questions. Thanks again for joining us on Mackool Online CME.

Video Overview: CME Accredited Surgical Training Videos Now When the goal is to implant a toric IOL in an eye with Available Online: www.MackoolOnlineCME.com recurring bouts of uveitis, poster synechiae, an extremely Richard Mackool, MD, a world renowned anterior segment ophthalmic shallow chamber and a previous microsurgeon, has assembled a web-based video collection of surgical iridectomy, a step-by-step cases that encompass both routine and challenging cases, demonstrating both approach is required. Here I familiar and potentially unfamiliar surgical techniques using a variety demonstrate my approach of instrumentation and settings. including a pars plana vitrectomy to fi rst deepen the This educational activity aims to present a series of Dr. Mackool’s surgical videos, anterior chamber. carefully selected to address the specifi c learning objectives of this activity, with the goal of making surgical training available as needed online for surgeons motivated to improve or expand their surgical repertoire. Learning Objective: After completion of this educational activity, participants should be able to: • incorporate techniques for deepening the anterior chamber and enlarging a miotic pupil in a post-uveitis eye with posterior synechiae, circumferential pupillary membrane and shallow chamber into their practice

Satisfactory Completion - Learners must pass a post-test and complete an evaluation form to receive a certifi cate of completion. You must listen to/view the entire video as partial credit is not available. If you are seeking continuing education credit for a specialty not listed below, it is your responsibility to contact your licensing/certifi cation board to determine course eligibility for your licensing/certifi cation requirement.

Physicians - In support of improving patient care, this activity has been planned and implemented by Amedco LLC and Postgraduate Healthcare Education. Amedco LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team

JOINTLY ACCREDITED PROVIDERTM Credit Designation Statement - Amedco designates this enduring material activity for a maximum of .25 AMA PRA Category 1 INTERPROFESSIONAL CONTINUING EDUCATION CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Additionally Supported by: Endorsed by: Jointly provided by: Supported by an unrestricted independent In Kind Support: Review of Ophthalmology® medical educational grant from: Glaukos MST Sony Healthcare Video and Web Production by: & Alcon Crestpoint Management Solutions JR Snowdon, Inc Carl Zeiss Meditec Less stress, pure success ...in your O.R. day1

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References: 1. Omeros survey data on file. 2. Silverstein SM, Rana V, Stephens R, Segars L, Pankratz J, Shivani R, et al. Effect of phenylephrine 1.0%-ketorolac 0.3% injection on tamsulosin-associated intraoperative floppy-iris syndrome. J Cataract Refract Surg. 2018;44(9):1103-1108. 3. Rosenberg ED, Nattis AS, Alevi D, et al. Visual outcomes, efficacy, and surgical complications associated with intracameral phenylephrine 1.0%/ketorolac 0.3% administered during cataract surgery. Clin Ophthalmol. 2018;12:21-28. 4. Bucci FA Jr, Michalek B, Fluet AT. Comparison of the frequency of use of a pupil expansion device with and without an intracameral phenylephrine and ketorolac injection 1%/0.3% at the time of routine cataract surgery. Clin Ophthalmol. 2017;11:1039-1043. 5. Visco D. Effect of phenylephrine/ketorolac on iris fixation ring use and surgical times in patients at risk of intraoperative miosis. Clin Ophthalmol. 2018;12:301-305. 6. Walter K, Delwadia N. Miosis prevention in femtosecond cataract surgery using a continuous infusion of phenylephrine and ketorolac. Presented at: 2018 American Society of Cataract and Refractive Surgery (ASCRS) and American Society of Ophthalmic Administrators (ASOA) Annual Meeting; April 13-17, 2018; Washington, DC. 7. Matossian C. Clinical outcomes of phenylephrine/ketorolac vs. epinephrine in cataract surgery in a real-world setting. Presented at: American Society of Cataract and Refractive Surgery (ASCRS) and American Society of Ophthalmic Administrators (ASOA) Annual Meeting; April 13-17, 2018; Washington, DC. 8. Al-Hashimi S, Donaldson K, Davidson R, et al. Medical and surgical management of the small pupil during cataract surgery. J Cataract Refract Surg. 2018;44:1032-1041. 9. Gayton JL. E-poster presented at: 15th International Congress on Vision Science and Eye; 2017 Aug 10-11; London, UK. 10. Katsev DA, Katsev CC, Pinnow J, Lockhart CM. Intracameral ketorolac concentration at the beginning and end of cataract surgery following preoperative topical ketorolac administration. Clin Ophthalmol. 2017;11:1897-1901. 11. Waterbury LD. Alternative drug delivery for patients undergoing cataract surgery as demonstrated in a canine model. J Ocul Pharmacol Ther. 2018;34:154-160. 12. Visco D. et al. Study to evaluate patient outcomes following cataract surgery when using OMIDRIA with postoperative topical NSAID administration versus a standard regimen of postoperative topical NSAIDs and steroids. Presented at: 28th Annual Meeting of the American College of Eye Surgeons (ACES), the American Board of Eye Surgery (ABES), and the Society for Excellence in Eyecare (SEE), Caribbean Eye Meeting; February 1-5, 2019; Cancún, Mexico. 13. OMIDRIA [package insert]. Seattle, WA: Omeros Corporation; 2017.

RP0419_Omeros.indd 1 3/11/19 11:51 AM Visit us at ASCRS Booth 1327

OMIDRIA® (phenylephrine and ketorolac intraocular solution) 1% / 0.3% is added to ophthalmic irrigating solution used during cataract surgery or intraocular lens replacement and is indicated for maintaining pupil size by preventing intraoperative miosis and reducing postoperative ocular pain.

The data are compelling and consistent—OMIDRIA makes cataract surgery better for you and your patients Published and presented clinical studies and manuscripts in press and/or in preparation report that in post-launch (i.e., not included in current labeling), prospective and retrospective, double-masked and open-label, cohort and case-controlled, single- and multi-center analyses, the use of OMIDRIA, compared to the surgeons’ standard of care, statistically significantly:

• Prevents Intraoperative Floppy Iris Syndrome (IFIS)2 • Reduces complication rates (epinephrine comparator)3 • Decreases use of pupil-expanding devices (epinephrine comparator)3-8 • Reduces surgical times (epinephrine comparator)3,5,7,8 • Prevents miosis during femtosecond laser-assisted surgery (epinephrine comparator)6,9 • Improves uncorrected visual acuity on day after surgery (epinephrine comparator)3 • Delivers NSAID to the anterior chamber and related structures better than routine preoperative topical drug administration, resulting in effectively complete postoperative inhibition of COX-1 and COX-210,11 • Reduces the incidence of rebound iritis, postoperative pain/photophobia, and cystoid macular edema (CME) in patients without preoperative vitreomacular traction (VMT), when used with a postoperative topical NSAID (compared to postoperative topical NSAID + corticosteroid without OMIDRIA)12 OMIDRIA inhibits prostaglandin release, reducing intraoperative inflammation, to prevent miosis and reduce postoperative pain13 OMIDRIA is separately reimbursed under Medicare Part B and by many Medicare Advantage and commercial payers.* Contact your OMIDRIA representative today or visit omidria.com to learn more.

*Based on currently available information and subject to change without notice. Individual plan coverage, policies, and procedures may vary and should be confirmed. Omeros does not guarantee coverage or payment.

IMPORTANT SAFETY INFORMATION OMIDRIA must be added to irrigating solution prior to intraocular use. OMIDRIA is contraindicated in patients with a known hypersensitivity to any of its ingredients. Systemic exposure of phenylephrine may cause elevations in blood pressure. Use OMIDRIA with caution in individuals who have previously exhibited sensitivities to acetylsalicylic acid, phenylacetic acid derivatives, and other nonsteroidal anti-inflammatory drugs (NSAIDs), or have a past medical history of asthma. The most commonly reported adverse reactions at ≥2% are eye irritation, posterior capsule opacification, increased intraocular pressure, and anterior chamber inflammation. Please see the Full Prescribing Information for OMIDRIA at www.omidria.com/prescribinginformation. You are encouraged to report Suspected Adverse Reactions to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

OMIDRIA® and the OMIDRIA logo® are registered trademarks of Omeros Corporation. © Omeros Corporation 2019, all rights reserved. 2019-007

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RO0119_Focus Labs.indd 1 1/10/19 11:42 AM April 2019 • Volume XXV No. 4 | reviewofophthalmology.com Cover Focus 30 | Premium IOLs: Dealing with Postop Problems Christopher Kent, Senior Editor Problems can still arise with advanced IOLs. Here’s help.

40 | Peel Back the Veil on ERM Management Michelle Stephenson, Contributing Editor Experts weigh in on diagnosis, as well as the timing of the ERM procedure.

54 | MSICS and miLoop for Non-phaco Candidates Alexandra Skinner, Associate Editor What to do when the gold standard, phaco, isn’t an option. Features

44 | The Continuing Role of Lasers in PDR Kristine Brennan, Contributing Editor Though anti-VEGF is effective, experts say it still may be best to start with PRP in some patients.

48 | The Artificial Iris in Practice Christopher Kent, Senior Editor The first approved iris prosthesis is helping many patients—although it has limitations.

April 2019 | reviewofophthalmology.com | 13

013_rp0419_toc.indd 13 3/22/19 4:52 PM Departments

3 | Review News 16

16 | Technology Update The Evolution of Portable Visual Field Tests Innovation is making it easier to test visual function at home using portable and/or virtual reality tech.

26 | Plastic Pointers Managing the Anophthalmic Socket How to treat the anophthalmic patient when he presents with problems related to his implant.

60 | Glaucoma Management Diagnosing Angle Closure: Gonioscopy vs. OCT Both approaches offer advantages, but gonioscopy remains the gold standard. 60 66 | Retinal Insider Be Prepared for Pediatric Patients Pediatric retina patients’ ocular anatomy can pose unique challenges.

69 | Classifieds

69 | Ad Index

70 | Research Review Researchers Delve into Orbital Lymphoma 66

71 | Wills Eye Resident Case Series

14 | Review of Ophthalmology | April 2019

013_rp0419_toc.indd 14 3/22/19 4:52 PM TRANSFORMING MIGS IN MORE WAYS THAN ONE.

Optimized Outflow: Two multi-directional stents designed to restore natural outflow Clinically Proven: Significant IOP reduction across a wide range of clinical studies1,2 Procedural Elegance: Predictability and precision to meet the needs of your practice Proven Safety: Safety profile similar to cataract surgery alone1

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INDICATION FOR USE. The iStent inject ® Trabecular Micro-Bypass System Model G2-M-IS is indicated for use in conjunction with cataract surgery for the reduction of intraocular pressure (IOP) in adult patients with mild to moderate primary open-angle glaucoma. CONTRAINDICATIONS. The iStent inject is contraindicated in eyes with angle-closure glaucoma, traumatic, malignant, uveitic, or neovascular glaucoma, discernible congenital anomalies of the anterior chamber (AC) angle, retrobulbar tumor, thyroid eye disease, or Sturge-Weber Syndrome or any other type of condition that may cause elevated episcleral venous pressure. WARNINGS. Gonioscopy should be performed prior to surgery to exclude congenital anomalies of the angle, PAS, rubeosis, or conditions that would prohibit adequate visualization of the angle that could lead to improper placement of the stent and pose a hazard. MRI INFORMATION. The iStent inject is MR-Conditional, i.e., the device is safe for use in a specified MR environment under specified conditions; please see Directions for Use (DFU) label for details. PRECAUTIONS. The surgeon should monitor the patient postoperatively for proper maintenance of IOP. The safety and effectiveness of the iStent inject have not been established as an alternative to the primary treatment of glaucoma with medications, in children, in eyes with significant prior trauma, abnormal anterior segment, chronic inflammation, prior glaucoma surgery (except SLT performed > 90 days preoperative), glaucoma associated with vascular disorders, pseudoexfoliative, pigmentary or other secondary open-angle glaucomas, pseudophakic eyes, phakic eyes without concomitant cataract surgery or with complicated cataract surgery, eyes with medicated IOP > 24 mmHg or unmedicated IOP < 21 mmHg or > 36 mmHg, or for implantation of more or less than two stents. ADVERSE EVENTS. Common postoperative adverse events reported in the randomized pivotal trial included stent obstruction (6.2%), intraocular inflammation (5.7% for iStent inject vs. 4.2% for cataract surgery only), secondary surgical intervention (5.4% vs. 5.0%) and BCVA loss * 2 lines * 3 months (2.6% vs. 4.2%). CAUTION: Federal law restricts this device to sale by, or on the order of, a physician. Please see DFU for a complete list of contraindications, warnings, precautions, and adverse events. REFERENCES: 1. iStent inject ® Trabecular Micro-Bypass System: Directions for Use, Part #45-0176. 2. Hengerer FH. Personal experience with second-generation trabecular micro-bypass stents in combination with cataract surgery in patients with glaucoma: 3-year follow-up. ASCRS 2018 Presentation. © 2018 Glaukos Corporation. Glaukos and iStent inject are registered trademarks of Glaukos Corporation. PM-US-0026

RP0419_Glaukos.indd 1 3/26/19 6:02 PM Technology Update

REVIEW Edited by Michael Colvard, MD, and Steven Charles, MD

The Evolution of Portable Visual Field Testing Innovative technology is making it easier to check visual function at home using portable and virtual methods. Robert Chang, MD, Palo Alto, Calif.

he idea of testing visual fi elds out- office setting and is typically ad- convenience to fi ll in the gaps. Tside the offi ce isn’t new. However, ministered by a perimetrist to help The additional data would be use- novel technology is making it easier patients maintain focus. Unfortu- ful in two main situations: to check visual function more reliably nately, this gold-standard medical • for reassure that a glaucoma sus- at home. Ideally, this would facili- test, which is highly subjective, can’t pect is still normal; and tate monitoring of presumed stable be repeated as often as physicians • to assess whether a glaucoma pa- or controlled glaucoma patients or would like. There are problems with tient is progressing. suspects, to reduce the overall num- patient attention, fatigue, compre- Of course, office examination ber of offi ce visits per year. Innova- hension, boredom, etc., and typical- would likely still be needed for con- tive solutions have shifted from in- ly, patients only perform one or two fi rmatory testing and treatment rec- ternet and desktop-based testing to fi elds per year in the offi ce (or even ommendations, but a faster, easier more portable and virtual methods fewer if lost to follow-up). Thus it self-administered test outside the that help to reduce fixation losses, would be nice to have a way for pa- offi ce could be used as a screening improve engagement and possibly tients to test themselves at their own method to help determine when pa-

help reshape the para- GLNCE Optical tients need to return to the digm of repeatable visual specialist. field testing—especially Many glaucoma patients in low-resource settings. routinely see the doctor on Here’s a look at the cur- a schedule, every three, six rent state of “at-home” or 12 months, depending visual fi eld testing. on the level of risk or stage of disease. At-home testing The Benefi ts affords the possibility of re- mote monitoring and en- While visual fi elds re- abling tele-glaucoma care. main the gold standard for monitoring visual A Potential function, the perimetry Disadvantage? machine is a large, care- fully calibrated bowl Melbourne Rapid Fields is an iPad app that uses a moving fi xation Visual fields alone, that’s mostly used in an target to test up to 30 degrees of fi eld. whether done in-office or

16 | Review of Ophthalmology | April 2019 This article has no commercial sponsorship.

016_rp0419_tech.indd 16 3/22/19 3:32 PM INVELTYS The ƼVWXERHSRP] corticosteroid FDA approved for &-(XVIEXQIRX of post-operative inflammation and pain following ocular surgery

Powered by AMPPLIFY™ Drug Delivery Technology

Indication -2:)08=7 PSXITVIHRSPIXEFSREXISTLXLEPQMGWYWTIRWMSR  MWMRHMGEXIHJSVXLIXVIEXQIRXSJTSWXSTIVEXMZIMRƽEQQEXMSRERH pain following ocular surgery. Important Safety Information INVELTYS is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures. Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and ƼIPHWSJZMWMSR-JXLMWTVSHYGXMWYWIHJSVHE]WSVPSRKIV-34WLSYPHFIQSRMXSVIH Use of corticosteroids may result in posterior subcapsular cataract formation. Use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. The initial prescription and VIRI[EPSJXLIQIHMGEXMSRSVHIVWLSYPHFIQEHIF]ETL]WMGMERSRP]EJXIVI\EQMREXMSRSJXLITEXMIRX[MXLXLIEMHSJQEKRMƼGEXMSR WYGLEWWPMXPEQTFMSQMGVSWGST]ERH[LIVIETTVSTVMEXIƽYSVIWGIMRWXEMRMRK Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions, steroids may mask infection or enhance existing infection. Use of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. In clinical trials, the most common adverse drug reactions were eye TEMR  ERHTSWXIVMSVGETWYPEVSTEGMƼGEXMSR  8LIWIVIEGXMSRW may have been the consequence of the surgical procedure. Please see Brief Summary of Prescribing Information for INVELTYS on the next page. (loteprednol etabonate ophthalmic suspension) 1%

US-INV-1800111

RP0319_Kala.indd 1 2/11/19 9:41 AM INVELTYSTM (loteprednol etabonate ophthalmic suspension) 1%, ADVERSE REACTIONS for topical ophthalmic use Adverse reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION infrequent optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, delayed wound healing INDICATIONS AND USAGE and secondary ocular infection from pathogens including herpes INVELTYS is a corticosteroid indicated for the treatment of simplex, and perforation of the globe where there is thinning of the post-operative inflammation and pain following ocular surgery. cornea or sclera.

CONTRAINDICATIONS Clinical Trial Experience—Because clinical trials are conducted INVELTYS is contraindicated in most viral diseases of the cornea and under widely varying conditions, adverse reaction rates observed conjunctiva including epithelial herpes simplex keratitis (dendritic in the clinical trials of a drug cannot be directly compared to rates keratitis), vaccinia, and varicella, and also in mycobacterial infection in the clinical trials of another drug and may not reflect the rates of the eye and fungal diseases of ocular structures. observed in practice. The most common adverse drug reactions in the clinical trials with INVELTYS were eye pain and posterior capsular WARNINGS AND PRECAUTIONS opacification, both reported in 1% of patients. These reactions may Intraocular Pressure (IOP) Increase—Prolonged use of corticosteroids have been the consequence of the surgical procedure. may result in glaucoma with damage to the optic nerve, as well as defects in visual acuity and fields of vision. Steroids should be used USE IN SPECIFIC POPULATIONS with caution in the presence of glaucoma. If this product is used for Pregnancy—Risk Summary: INVELTYS is not absorbed systemically 10 days or longer, intraocular pressure should be monitored. following topical ophthalmic administration and maternal use is not expected to result in fetal exposure to the drug. Cataracts—Use of corticosteroids may result in posterior subcapsular cataract formation. Lactation—Risk Summary: INVELTYS is not absorbed systemically by the mother following topical ophthalmic administration, and Delayed Healing—Use of steroids after cataract surgery may delay breastfeeding is not expected to result in exposure of the child healing and increase the incidence of bleb formation. In those to INVELTYS. diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. The Pediatric Use—Safety and effectiveness in pediatric patients have initial prescription and renewal of the medication order should be not been established. made by a physician only after examination of the patient with the aid of magnification such as slit lamp biomicroscopy and, where Geriatric Use—No overall differences in safety and effectiveness appropriate, fluorescein staining. have been observed between elderly and younger patients.

Bacterial Infections—Prolonged use of corticosteroids may suppress NONCLINICAL TOXICOLOGY the host response and thus increase the hazard of secondary ocular Carcinogenesis, Mutagenesis, Impairment of Fertility— infections. In acute purulent conditions of the eye, steroids may Long-term animal studies have not been conducted to evaluate mask infection or enhance existing infection. the carcinogenic potential of loteprednol etabonate. Loteprednol etabonate was not genotoxic in vitro in the Ames test, the mouse Viral Infections—Use of corticosteroid medication in the treatment lymphoma thymidine kinase (tk) assay, or in a chromosome of patients with a history of herpes simplex requires great aberration test in human lymphocytes, or in vivo in the single dose caution. Use of ocular steroids may prolong the course and mouse micronucleus assay. may exacerbate the severity of many viral infections of the eye (including herpes simplex). For a copy of the Full Prescribing Information, please visit www.INVELTYS.com. Fungal Infections—Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid Manufactured for: application. Fungus invasion must be considered in any persistent Kala Pharmaceuticals, Inc. Waltham, MA 02453 corneal ulceration where a steroid has been used or is in use. Marks designated by TM and ® are owned by Fungal cultures should be taken when appropriate. Kala Pharmaceuticals, Inc. Patented. See www.kalarx.com/patents Contact Lens Wear—The preservative in INVELTYS may be © 2018 Kala Pharmaceuticals, Inc. All rights reserved. absorbed by soft contact lenses. Contact lenses should be removed US-INV-1800055 December 2018 prior to instillation of INVELTYS and may be reinserted 15 minutes following administration.

RRP0319_KalaP0319_Kala PI.inddPI.indd 1 22/11/19/11/19 9:429:42 AMAM at home, normally don’t lecting a high volume of provide enough clinical lower-resolution data. Ag- data to manage glau- gregating more data over coma patients, despite a longer period of time serving as a clinical end may actually be more pre- point. Specialists also Micro Medical Devices dictive than the smaller review glaucoma risk amount of higher-quality factors, optic nerve data that’s acquired only appearance, intraocu- during annual or semi- lar pressure, structural annual offi ce visits. macular and nerve fi- ber layer imaging, and Portable Tests a complete eye exam. If portable visual field Portable visual fields data were relied upon continue to evolve with to make the diagno- the advent of tablets, sis of progression, the smartphones and virtual diagnosis might come reality headsets. Some of too late, as glaucoma is the most notable tests, irreversible and identi- both past and present, in- fication of progression clude the following: prior to fi eld loss is opti- • Moorfields Motion mal. With that in mind, Displacement Test. One it’s imperative to con- of the early portable visual tinue to examine a glau- fi eld tests was the Moor- coma patient at regular- fields Motion Displace- ly scheduled offi ce visit ment Test. Developed on intervals. Furthermore, a laptop PC, the MDT sometimes too much was designed for speed additional data results and patient ease of use. in noise, creates addi- In the test, patients saw tional work interpreting A limitation of using portable devices to perform VF testing is the inability 32 white lines on a gray test results, and may to control fi xation and the distance from the eye to the screen. Virtual background while fixat- even be more costly, if reality headsets may solve those issues through adjustable fi xation using ing in the center. When gaze tracking. there’s overtesting. any of the lines moved or “wiggled,” the patient Artifi cial base, one can imagine that with more would click a button. The two-min- Intelligence data, the algorithms could optimize ute test could be completed without comparison of patients with similar glasses and even when a cataract was Researchers are exploring how to severity, or their own baseline, with present. While the MDT is no lon- apply artifi cial intelligence algorithms better predictive analytics. Addition- ger available, it represented the early to all sorts of ophthalmic test results, ally, when some risk factors change, push to move away from an office- with most of the recent excitement self-directed, out-of-the-offi ce test- based perimeter and onto existing centering on deep learning. Multiple ing allows for additional, concentrat- computer screens, a test that could publications have analyzed automa- ed repeat testing at that time point be administered both online and of- tion of visual fi eld interpretation for to make a more informed decision fline. (Other similar computerized the detection of glaucoma.1-4 about the timing or risk/benefi t ratio perimetric strategies include rarebit While physicians currently plot VF of a given therapeutic intervention. perimetry, Peristat and campimetry.) glaucoma progression analysis using Finally, even if a lower-resolution, • Melbourne Rapid Fields Test. a visual function index for event- simple, portable test isn’t as accurate Dr. George Kong created Visual Field based and trend-based progression as a high-resolution, in-office gold Easy (https://itunes.apple.com/us/ analysis relative to a normative data- standard, there’s still value in col- app/visualfi elds-easy/id495389227), a

April 2019 | reviewofophthalmology.com | 19

016_rp0419_tech.indd 19 3/22/19 3:32 PM Technology

REVIEW Update

BioFormatix sive environment can improve user engagement. VR headsets can take advantage of smartphones and eas- ily test individual eyes without one needing to be patched. There are multiple inexpensive, lightweight, mobile VR applica- tions and software platforms that are either available or in develop- ment, such as Vivid Vision (https:// www.seevividly.com), BioFormatix’s VirtualEye Perimeter (http://bio- formatix.com/perimetry.html), MicroMedical Devices’ PalmScan VF2000 (https://micromedinc.com/ our-devices/palmscan-vf2000-visual- fi eld-perimeter/) and Elisar’s eCloud Perimeter (https://www.elisar.com/). These applications can be used with a variety of input “clickers.” With virtual reality, no matter where the patient looks, the stimulus can be shown relative to One early VR study by Athens’ fi xation at that moment. Gyroscopes can account for head movement, and the immersive Stylianos Tsapakis and co-workers environment can improve user engagement. found a high correlation between the reliability of VF testing using a VR free iPad app, now known as the Mel- strongly with HFA across four visits testing system they developed and bourne Rapid Fields test. The MRF over six months.6 the Humphrey test.8 The central 24 takes advantage of a moving fi xation In terms of speed, MRF was simi- degrees of visual fi eld were tested in target in order to effectively increase lar to SITA-fast and was signifi cantly 20 eyes of 10 patients using VR glass- the tablet surface area to test up to faster than SITA-standard (MRF 4.6 es, a smartphone with a 6-inch dis- 30 degrees of fi eld. Several published ±0.1 minutes vs. SITA-fast 4.3 ±0.2 play and software that implemented a studies have validated the device as minutes vs. SITA-standard 6.2 ±0.1 fast-threshold 3-dB step staircase al- a screening tool similar to a tangent minutes, p<0.001).6 MRF proved to gorithm. The results were compared perimeter.5-7 be very repeatable, with intraclass to those using the Humphrey perim- MRF denoted a further shift to- correlation coeffi cients (with a value eter test on the same group of pa- ward portability of VF tests, thanks to of 1 being a perfect correlation) for tients, which resulted in a correlation the advent of iPads making software baseline and the six-month visit be- coeffi cient of r=0.808 (p<0.0001).8 more portable. It’s easy to use, inex- ing 0.98, compared to 0.95 and 0.93 The next level of improvement pensive and can be used anywhere, for SITA-fast and SITA-standard, re- over virtual reality visual field which is a big advantage in remote spectively.6 testing would be to eliminate the locations. Over time, threshold test- • Virtual Reality Peripheral Vi- subjective aspect of clicking to in- ing strategy, stimulus size and screen sion Testing. One of the major limi- dicate when a visual stimulus is contrast have been standardized tations of using portable devices to seen. Could there be a way to de- across tablets. perform VF testing is the inability tect a patient’s response to a given A recent study by Australia’s to control fixation and the distance stimulus via the brain, without any Selwyn Prea, BOptom, Mphil, and from the eye to the screen. Virtual input? This is the goal of nGoggle, colleagues included 60 patients; it reality headsets solve those issues a portable brain-computer interface was conducted to compare the re- through adjustable fi xation using gaze (like an electroencephalograph) that peatability of the MRF vs. the Hum- tracking. With VR, no matter where detects visual function through re- phrey Field Analyzer SITA-standard the patient looks, the stimulus can corded electrical responses directly and fast programs. The investigators be shown relative to fi xation at that from the visual cortex. found that MRF had good test-retest moment. Gyroscopes can account repeatability and that it correlated for head movement, and the immer- (Continued on page 53)

20 | Review of Ophthalmology | April 2019

016_rp0419_tech.indd 20 3/22/19 3:33 PM Advertorial sponsored by Bausch + Lomb

The Role for Vyzulta® in the Management of Open-angle Glaucoma and Ocular Hypertension

Constance Okeke, MD, MSCE

Glaucoma is a heterogenous group of diseases that damage the optic Prostaglandin Analogs nerve affecting an estimated 70 million people worldwide, including Prostaglandin analogs (PGAs)—the most widely prescribed IOP- 2 million in the US.1 As there are no treatment modalities available for lowering agents—act mainly by increasing aqueous outflow through the a damaged optic nerve and no means by which to regenerate tissue or uveoscleral pathway.9,10 A key benefit of the PGA class is that drops can restore vision that has been lost, we continue to rely on protecting the be administered once daily, which is particularly valuable in the treatment optic nerve from the stress of elevated intraocular pressure (IOP).1,2 As of chronic conditions with low rates of medication adherence, such the single treatable risk factor for glaucoma progression,2-7 elevated as glaucoma.11 The PGAs are generally considered the most effective IOP remains the target of all current medical, surgical, or laser class of IOP-lowering agents,12-17 able to reduce IOP by 25% to 33% treatments. from baseline with single-agent therapy.18 They are also typically well IOP is necessary to give the eye its shape; excessive pressure, tolerated; ocular side effects when they occur are commonly mild and however, represents an imbalance in aqueous production and its tolerated.18 For many of us in clinical practice, the relationship between outflow and poses a risk to the optic nerve. Aqueous humor originates in IOP-lowering medication tolerability and adherence is clearly evident. the ciliary body and exits the anterior chamber via two main pathways— the unconventional or uveoscleral pathway, and the conventional or Latanoprostene Bunod trabecular pathway.8 What is novel about Vyzulta® (latanoprostene bunod ophthalmic The trabecular pathway—comprised of the trabecular meshwork solution) 0.024%, a nitric oxide (NO)-releasing prostaglandin F2 (TM), Schlemm’s canal, and adjacent tissue—is the route through which analog for the reduction of IOP in patients with OAG or ocular a majority of fluid is thought to leave the eye. It is IOP-responsive, ie, able hypertension, is its dual mechanism of action.19,20 Latanoprostene to increase or decrease outflow in order to maintain healthy intraocular bunod is metabolized into two moieties—latanoprost acid, which acts aqueous fluid levels and pressure.1 Notably, the trabecular pathway has on the uveoscleral pathway, as is typical of a PGA, and butanediol been shown to be a primary site of outflow obstruction in eyes affected mononitrate, which releases gaseous NO (Figure 1).20 Both moieties by primary open-angle glaucoma (POAG).1,8 are responsible for the molecule’s pharmacological activities.20 NO is a

INDICATION VYZULTA® (latanoprostene bunod ophthalmic solution), 0.024% is a prostaglandin F2 analog indicated for the reduction of intraocular pressure in patients with open-angle glaucoma or ocular hypertension. IMPORTANT SAFETY INFORMATION • Increased pigmentation of the iris and periorbital tissue (eyelid) can occur. Iris pigmentation is likely to be permanent • Gradual changes to eyelashes, including increased length, increased thickness, and number of eyelashes, may occur. These changes are usually reversible upon treatment discontinuation • Use with caution in patients with a history of intraocular inflammation (iritis/uveitis). VYZULTA should generally not be used in patients with active intraocular inflammation • Macular edema, including cystoid macular edema, has been reported during treatment with prostaglandin analogs. Use with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema • There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products that were inadvertently contaminated by patients • Contact lenses should be removed prior to the administration of VYZULTA and may be reinserted 15 minutes after administration • Most common ocular adverse reactions with incidence *2% are conjunctival hyperemia (6%), eye irritation (4%), eye pain (3%), and instillation site pain (2%)

Please see Brief Summary of Full Prescribing Information for Vyzulta® on the last page of this advertisement. 1

RRP0419_BLP0419_BL VyzultaVyzulta 1.indd1.indd 1 33/22/19/22/19 9:549:54 AMAM VYZULTA® (latanoprostene bunod ophthalmic solution), 0.024%

Butanediol mononitrate

Latanoprost acid 1,4-Butanediol Nitric oxide (prostaglandin analog)

EXTRACELLULAR MATRIX REMODELING CELL RELAXATION

UVEOSCLERAL TRABECULAR MESHWO RK / OUTFLOW SCHLEMM’S CA NAL OUTFLOW

UNCONVE AL PATHWAY NTI N O TIO NA N L E PA V T N H O W C A Y

REDUCED IOP FIGURE 1 One molecule, two pathways: Vyzulta® (latanoprostene bunod ophthalmic solution 0.024%) is a nitric oxide-releasing prostaglandin F2 analog that increases both trabecular and uveoscleral outflow.

particularly exciting aspect of Vyzulta,® as it acts to relax the fibers of the at night was noninferior to that with timolol 0.5% dosed twice daily. In TM along the trabecular pathway, opening a second aqueous humor APOLLO (N = 420), IOP reduction with Vyzulta dosed once daily at escape route for lowering IOP (Figure 1).20 night was superior to timolol 0.5% dosed twice daily (Table 1).16,17 The release of NO by Vyzulta is important, as evidence suggests In VOYAGER, a phase 2, 29-day dose-ranging comparison that abnormal NO formation or signaling may play a role in IOP study of subjects with OAG or ocular hypertension, Vyzulta led to a dysregulation in glaucoma.20 NO is synthesized by nitric oxide 9.0 mm Hg (34.6%) mean diurnal IOP decrease from baseline vs. synthase (NOS) in endothelial cells at various sites in the body, 7.77 mm Hg (29.8%) decrease with latanoprost 0.005% (P = 0.005).25 inducing vasodilation, gastric emptying, and other generally dilatory A post-hoc analysis revealed that 42% of patients treated with Vyzulta or relaxation-inducing functions.21,22 In normal eyes, endogenous NO achieved at least 2 mm Hg greater IOP reduction vs. mean diurnal production in Schlemm’s canal plays a role in regulating IOP.20 NO IOP reduction with latanoprost 0.005% (7.8 mm Hg).26 In a study is a gas and cannot be directly measured due to a half-life of mere evaluating increasing concentrations of latanoprost in patients with OAG seconds;21,22 however, reduced aqueous humor concentrations of NO or ocular hypertension, no greater IOP-lowering effect was shown with markers (eg, cGMP, NADPH, and total nitrite levels) in glaucomatous concentrations higher than the clinical dose of 0.005%.27 The additional eyes supports the hypothesis that impaired NO production contributes IOP lowering of Vyzulta observed in the VOYAGER study is believed to be to imbalanced aqueous dynamics and increased IOP.21-23 attributable to the activity of NO.25 NO performs its actions via the complex cGMP/protein kinase G signaling cascade, resulting in multiple downstream events including Sustained IOP reduction was observed among patients rho kinase inhibition and, ultimately, TM relaxation.20,24 Further research treated with Vyzulta for 52 weeks in the JUPITER study.28 should investigate what long-term impact NO-releasing molecules such as latanoprostene bunod have on the TM in glaucomatous eyes. It was also noteworthy that Vyzulta clinical trials showed meaningful IOP reduction among patients with high and low baseline IOP. The Clinical Trials phase 3 open-label JUPITER trial conducted in Japan followed In clinical studies of up to 12 months’ duration in patients with OAG OAG patients (including those with normal-tension glaucoma) being or ocular hypertension, the IOP-lowering effect of Vyzulta once- treated with Vyzulta for at least 12 months (N = 130).28 Mean baseline daily was up to 9.1 mm Hg from baseline.16,17,19 The two pivotal phase 3 IOP was 19.6 mm Hg in study eyes, and 75% of patients had IOP clinical trials—APOLLO and LUNAR—evaluated the noninferiority of between 15 and 21 mm Hg.28 Mean IOP reductions from baseline Vyzulta vs. timolol 0.5% in patients with OAG or ocular hypertension. among Vyzulta-treated eyes were 22% at week 4 (to 15.3 mm Hg), In LUNAR (N = 420), IOP reduction with Vyzulta dosed once daily and 26.3% at week 52.28 These findings suggest that Vyzulta may

Please see Important Safety Information on first page of this advertisement. Please see Brief Summary of Full Prescribing Information for Vyzulta® on the last page of this advertisement. 2

RRP0419_BLP0419_BL Vyzulta2.inddVyzulta2.indd 1 33/20/19/20/19 10:0410:04 AMAM TABLE I Change from baseline in mean IOP in APOLLO and LUNAR study Week 2 Week 6 Month 3

8 am 12 pm 4 pm 8 am 12 pm 4 pm 8 am 12 pm 4 pm APOLLO

LBN mean CFB (mm Hg) –9.0 –8.5 –7.7 –9.1 –7.9 –9.0 –8.7 –7.9

Timolol mean CFB (mm Hg) –7.8 –7.2 –6.6 –8.0 –7.4 –6.7 –7.9 –7.4 –6.6

Treatment di@ erence –1.21 –1.37 –1.11 –1.03 –1.24 –1.26 –1.02 –1.27 –1.33

P value <0.001 <0.001 <0.001 <0.002 <0.001 <0.001 <0.002 <0.001 <0.001 LUNAR

LBN mean CFB (mm Hg) –8.3 –8.1 –7.5 –8.8 –8.5 –7.8 –8.8 –8.6 –7.9

Timolol mean CFB (mm Hg) –7.9 –7.3 –6.9 –7.9 –7.7 –6.8 –7.9 –7.4 –6.6

Treatment di@ erence –0.44 –0.76 –0.69 –0.92 –0.84 –0.98 –0.88 –1.29 –1.34

P value 0.216 0.022 0.025 0.005 0.007 0.003 0.006 <0.001 <0.001

be effective in patients with lower baseline IOP, which is typically Third, patients with normal-tension glaucoma or those with low harder to treat. Durable IOP reduction over 1 year on Vyzulta® is also baseline IOP are good candidates for treatment with Vyzulta, as encouraging. documented in a long-term clinical trial.28 In patients with low baseline Importantly, in addition to robust efficacy, Vyzulta has an acceptable IOP, Vyzulta might be implemented as first-line monotherapy, as safety profile.16,17,28 In the LUNAR and APOLLO studies, the switchover monotherapy, if not achieving target IOP, or as an adjunct to most common ocular adverse events observed were conjunctival medical or surgical therapy. hyperemia (6%), eye irritation (4%), eye pain (3%), and instillation site Fourth, glaucoma patients in adult early stage comprise a group with pain (2%); the rate of study discontinuation due to an ocular adverse the potential to benefit from treatment with Vyzulta because Vyzulta event was 0.6%.19 In the JUPITER trial over 52 weeks, 1 patient of 130 is the first NO-releasing PGA with action at the TM.1,8 Sustained (0.8%) dropped out of the study due to an ocular adverse event, which IOP reduction was observed among patients treated with Vyzulta for was related to a cataract and considered unrelated to treatment.28 52 weeks in the JUPITER study.28 That said, I consider Vyzulta whenever IOP-lowering is needed—even if it is just a few points— Vyzulta in Clinical Practice irrespective of disease stage. In my view, Vyzulta warrants utmost consideration for IOP-lowering treatment in the following four clinical scenarios or patient types. First, Talking about Novel Treatments Vyzulta could be a good first-line agent for a wide range of patients I find that patients are quite receptive to hearing about a novel with OAG or ocular hypertension across a range of starting IOPs. medication that could possibly help them; and many appreciate that my For example, a treatment-naive patient who presents with IOP with practice is up to date on the most current therapeutic offerings. When 30 mm Hg or higher could be treated with Vyzulta first line and counseling patients, I explain that Vyzulta has a dual mechanism of monitored for effect. action. I mention the results of the VOYAGER study in which Vyzulta Second, established patients who are not responding to was more effective at lowering IOP than latanoprost;25 so it might current treatment with another IOP-lowering agent, such as help to lower IOP in them. And I let them know that it is indicated for timolol or latanoprost, may benefit from Vyzulta in an effort to treatment of glaucoma, dosed once a day, and has an acceptable safety achieve a lower IOP over the short and long term. As discussed profile.16, 17, 19, 28 above, in clinical trials, once-daily Vyzulta was superior to Vyzulta is remarkable not only because it was shown to be effective twice-daily timolol at month 316,17 and superior to latanoprost.25 in clinical trials, is dosed once daily, and is novel in its mechanism of Vyzulta has the potential to reduce IOP while maintaining the action, but also because it may impact outflow through the TM.24 More benefits of monotherapy. It’s important to remember that any increment will be learned as basic and clinical research continues on the topic; in of IOP lowering is clinically meaningful. Research has shown that for the meantime, it is important to get an effective, novel medication like every 1 mm Hg IOP reduction, risk for disease progression is reduced Vyzulta into the hands of our patients. by 10% to 19%.2,3, 29

Please see Important Safety Information on first page of this advertisement. Please see Brief Summary of Full Prescribing Information for Vyzulta® on the last page of this advertisement. 3

RRP0419_BLVyzulta3.inddP0419_BLVyzulta3.indd 1 33/20/19/20/19 10:0610:06 AMAM 16. Weinreb RN, Scassellati Sforzolini B, Vittitow J, et al. Latanoprostene Constance Okeke, MD, MSCE, is a board bunod 0.024% versus timolol maleate 0.5% in subjects with open-angle certified ophthalmologist who has practiced glaucoma or ocular hypertension: The APOLLO study. Ophthalmology. ophthalmology since 2001. She has a specialty 2016;123(5):965-73. 17. Medeiros FA, Martin KR, Peace J, et al. Comparison of latanoprostene in glaucoma and cataract surgery and currently bunod 0.024% and timolol maleate 0.5% in open-angle glaucoma or ocular sees patients in private practice at Virginia Eye hypertension: the LUNAR study. Am J Ophthalmol. 2016;168:250-9. Consultants in Norfolk, VA. She is a Fellow of 18. Prum BE Jr, Rosenberg LF, Gedde SJ, et al. Primary Open-Angle Glaucoma Preferred Practice Pattern® Guidelines. Ophthalmology. 2016;123(1):41-111. the American Academy of Ophthalmology 19. VYZULTA Prescribing Information. June 2018. Bausch + Lomb, Inc. Bridgewater, NJ. and a member of the American Glaucoma 20. Cavet ME, DeCory HH. The role of nitric oxide in the intraocular pressure Society and the Association for Research lowering efficacy of latanoprostene bunod: review of nonclinical studies.J Ocul Vision and Ophthalmology. Dr. Okeke Pharmacol Ther. 2018;34:52-60. is a paid consultant to Bausch + Lomb. 21. Galassi F, Renieri G, Sodi A, et al. Nitric oxide proxies and ocular perfusion pressure in primary open angle glaucoma. Br J Ophthalmol. 2004;88:757-60. 22. Nathanson JA, McKee M. Alterations of ocular nitric oxide synthase in human glaucoma. Invest Ophthalmol Vis Sci. 1995;36:1774-84. REFERENCES 23. Doganay S, Evereklioglu C, Turkoz Y, et al. Decreased nitric oxide production in primary open-angle glaucoma. Eur J Ophthalmol. 2002;12:44-8. 1. Goel M, Picciani RG, Lee RK, et al. Aqueous humor dynamics: a review. Open Ophthalmol J. 2010;4:52-9. 24. Fogagnolo P, Rossetti L. Medical treatment of glaucoma: present and future. Expert Opinion on Investigational Drugs. 2011;20:947-59. 2. Garway-Heath DF, Crabb DP, Bunce C, et al. Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial. Lancet. 25. Weinreb RN, Ong T, Scassellati Sforzolini B, et al; VOYAGER study group. A 2015;385(9975):1295-304. randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the 3. Leske MC, Heijl A, Hussein M, et al; Early Manifest Glaucoma Trial Group. VOYAGER study. Br J Ophthalmol. 2015;99(6):738-45. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol. 2003;121(1):48-56. 26. Data on File. Bausch & Lomb Incorporated. 4. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension 27. Eveleth D, Starita C, Tressler C. A 4-week, dose-ranging study comparing Treatment Study: a randomized trial determines that topical ocular hypotensive the efficacy, safety and tolerability of latanoprost 75, 100 and 125 mg/mL medication delays or prevents the onset of primary open-angle glaucoma. Arch to latanoprost 50 mg/mL (Xalatan) in the treatment of primary open-angle Ophthalmol. 2002;120(6):701-13. glaucoma and ocular hypertension. BMC Ophthalmol. 2012;12:9. 5. Heijl A, Leske C, Bengtsson B, et al. Reduction of intraocular pressure and 28. Kawase K, Vittitow JL, Weinreb RN, Araie M; JUPITER Study Group. Long-term glaucoma progression: Results from the Early Manifest Glaucoma Trial. Arch safety and efficacy of latanoprostene bunod 0.024% in Japanese subjects with Ophthalmol. 2002;120(10):1268-79. open-angle glaucoma or ocular hypertension: The JUPITER Study. Adv Ther. 2016;33(9):1612-27. 6. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field 29. Heijl, A. Glaucoma treatment: by the highest level of evidence. The Lancet. deterioration. Am J Ophthalmol. 2000;130(4):429-40. 2015;385(9975):1264-66. 7. Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am VYZULTA and the V design are registered trademarks of Bausch & Lomb J Ophthalmol. 1998;126(4):487-97. Incorporated or its affiliates. ©2019 Bausch & Lomb Incorporated. 8. Braunger BM, Fuchshofer R, Tamm ER. The aqueous humor outflow pathways in All rights reserved. VYZ.0066.USA.19 glaucoma: A unifying concept of disease mechanisms and causative treatment. Eur J Pharm Biopharm. 2015;95(Pt B):173-81. 9. Schachtschabel U, Lindsey JD, Weinreb RN. The mechanism of action of prostaglandins in uveoscleral outflow. Curr Opin Ophthalmol. 2000;11:112-5. 10. Symphony National. Total Glaucoma Market. July 2016-June 2017. 11. Okeke CO, Quigley HA, Jampel HD, et al. Adherence with topical glaucoma medication monitored electronically the Travatan Dosing Aid study. Ophthalmology. 2009;116:191-9. 12. Alm A, Stjernschantz J. Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning. A comparison with timolol. Scandinavian Latanoprost Study Group. Ophthalmology. 1995;102(12):1743-52. 13. Camras CB. Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma: a six-month masked, multicenter trial in the United States. The United States Latanoprost Study Group. Ophthalmology. 1996;103(1):138-47. 14. Higginbotham EJ, Schuman JS, Goldberg I, et al; Bimatoprost Study Groups 1 and 2. One-year, randomized study comparing bimatoprost and timolol in glaucoma and ocular hypertension. Arch Ophthalmol. 2002;120(10):1286-93. 15. Netland PA, Landry T, Sullivan EK, et al; Travoprost Study Group. Travoprost compared with latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension. Am J Ophthalmol. 2001;132(4):472-84.

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RP0419_BL Vyzulta4.indd 1 3/20/19 10:08 AM BRIEF SUMMARY OF PRESCRIBING INFORMATION Doses ≥ 20 μg/kg/day (23 times the clinical dose) produced 100% embryofetal lethality. Structural abnormalities observed in rabbit fetuses included anomalies of the great This Brief Summary does not include all the information needed to use VYZULTA vessels and aortic arch vessels, domed head, sternebral and vertebral skeletal anomalies, safely and effectively. See full Prescribing Information for VYZULTA. limb hyperextension and malrotation, abdominal distension and edema. Latanoprostene ™ VYZULTA (latanoprostene bunod ophthalmic solution), 0.024%, for topical bunod was not teratogenic in the rat when administered IV at 150 mcg/kg/day (87 times ophthalmic use. the clinical dose) [see Data]. Initial U.S. Approval: 2017 The background risk of major birth defects and miscarriage for the indicated population 1 INDICATIONS AND USAGE is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies. VYZULTA™ (latanoprostene bunod ophthalmic solution) 0.024% is indicated for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Data 4 CONTRAINDICATIONS Animal Data None Embryofetal studies were conducted in pregnant rabbits administered latanoprostene bunod daily by intravenous injection on gestation days 7 through 19, to target the period 5 WARNINGS AND PRECAUTIONS of organogenesis. The doses administered ranged from 0.24 to 80 mcg/kg/day. Abortion 5.1 Pigmentation occurred at doses ≥ 0.24 mcg/kg/day latanoprostene bunod (0.28 times the clinical VYZULTA™ (latanoprostene bunod ophthalmic solution), 0.024% may cause changes to dose, on a body surface area basis, assuming 100% absorption). Embryofetal lethality pigmented tissues. The most frequently reported changes with prostaglandin analogs (resorption) was increased in latanoprostene bunod treatment groups, as evidenced have been increased pigmentation of the iris and periorbital tissue (eyelid). by increases in early resorptions at doses ≥ 0.24 mcg/kg/day and late resorptions at doses ≥ 6 mcg/kg/day (approximately 7 times the clinical dose). No fetuses survived Pigmentation is expected to increase as long as latanoprostene bunod ophthalmic in any rabbit pregnancy at doses of 20 mcg/kg/day (23 times the clinical dose) or greater. solution is administered. The pigmentation change is due to increased melanin content Latanoprostene bunod produced structural abnormalities at doses ≥ 0.24 mcg/kg/day in the melanocytes rather than to an increase in the number of melanocytes. After (0.28 times the clinical dose). Malformations included anomalies of sternum, coarctation discontinuation of VYZULTA, pigmentation of the iris is likely to be permanent, while of the aorta with pulmonary trunk dilation, retroesophageal subclavian artery with pigmentation of the periorbital tissue and eyelash changes are likely to be reversible in absent brachiocephalic artery, domed head, forepaw hyperextension and hindlimb most patients. Patients who receive prostaglandin analogs, including VYZULTA, should be malrotation, abdominal distention/edema, and missing/fused caudal vertebrae. informed of the possibility of increased pigmentation, including permanent changes. The long-term effects of increased pigmentation are not known. An embryofetal study was conducted in pregnant rats administered latanoprostene bunod daily by intravenous injection on gestation days 7 through 17, to target the Iris color change may not be noticeable for several months to years. Typically, the period of organogenesis. The doses administered ranged from 150 to 1500 mcg/kg/day. brown pigmentation around the pupil spreads concentrically towards the periphery of Maternal toxicity was produced at 1500 mcg/kg/day (870 times the clinical dose, on the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor a body surface area basis, assuming 100% absorption), as evidenced by reduced freckles of the iris appear to be affected by treatment. While treatment with VYZULTA™ maternal weight gain. Embryofetal lethality (resorption and fetal death) and structural (latanoprostene bunod ophthalmic solution), 0.024% can be continued in patients who anomalies were produced at doses ≥ 300 mcg/kg/day (174 times the clinical dose). develop noticeably increased iris pigmentation, these patients should be examined Malformations included anomalies of the sternum, domed head, forepaw hyperextension regularly [see Patient Counseling Information (17) in full Prescribing Information]. and hindlimb malrotation, vertebral anomalies and delayed ossification of distal limb 5.2 Eyelash Changes bones. A no observed adverse effect level (NOAEL) was established at 150 mcg/kg/day (87 times the clinical dose) in this study. VYZULTA may gradually change eyelashes and vellus hair in the treated eye. These changes include increased length, thickness, and the number of lashes or hairs. Eyelash 8.2 Lactation changes are usually reversible upon discontinuation of treatment. Risk Summary 5.3 Intraocular Inflammation There are no data on the presence of VYZULTA in human milk, the effects on the VYZULTA should be used with caution in patients with a history of intraocular breastfed infant, or the effects on milk production. The developmental and health inflammation (iritis/uveitis) and should generally not be used in patients with active benefits of breastfeeding should be considered, along with the mother’s clinical need intraocular inflammation as it may exacerbate this condition. for VYZULTA, and any potential adverse effects on the breastfed infant from VYZULTA. 5.4 Macular Edema 8.4 Pediatric Use Macular edema, including cystoid macular edema, has been reported during treatment Use in pediatric patients aged 16 years and younger is not recommended because of potential with prostaglandin analogs. VYZULTA should be used with caution in aphakic patients, in safety concerns related to increased pigmentation following long-term chronic use. pseudophakic patients with a torn posterior lens capsule, or in patients with known risk 8.5 Geriatric Use factors for macular edema. No overall clinical differences in safety or effectiveness have been observed between 5.5 Bacterial Keratitis elderly and other adult patients. There have been reports of bacterial keratitis associated with the use of multiple-dose 13 NONCLINICAL TOXICOLOGY containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility disruption of the ocular epithelial surface. Latanoprostene bunod was not mutagenic in bacteria and did not induce micronuclei 5.6 Use with Contact Lens formation in the in vivo rat bone marrow micronucleus assay. Chromosomal aberrations were observed in vitro with human lymphocytes in the absence of metabolic activation. Contact lenses should be removed prior to the administration of VYZULTA because this product contains benzalkonium chloride. Lenses may be reinserted 15 minutes after Latanoprostene bunod has not been tested for carcinogenic activity in long-term animal administration. studies. Latanoprost acid is a main metabolite of latanoprostene bunod. Exposure of rats and mice to latanoprost acid, resulting from oral dosing with latanoprost in lifetime 6 ADVERSE REACTIONS rodent bioassays, was not carcinogenic. The following adverse reactions are described in the Warnings and Precautions section: Fertility studies have not been conducted with latanoprostene bunod. The potential to pigmentation (5.1), eyelash changes (5.2), intraocular inflammation (5.3), macular impact fertility can be partially characterized by exposure to latanoprost acid, a common edema (5.4), bacterial keratitis (5.5), use with contact lens (5.6). metabolite of both latanoprostene bunod and latanoprost. Latanoprost acid has not been 6.1 Clinical Trials Experience found to have any effect on male or female fertility in animal studies. Because clinical trials are conducted under widely varying conditions, adverse reaction 13.2 Animal Toxicology and/or Pharmacology rates observed in the clinical trials of a drug cannot be directly compared to rates in the A 9-month toxicology study administered topical ocular doses of latanoprostene bunod clinical trials of another drug and may not reflect the rates observed in practice. to one eye of cynomolgus monkeys: control (vehicle only), one drop of 0.024% bid, one VYZULTA was evaluated in 811 patients in 2 controlled clinical trials of up to 12 months drop of 0.04% bid and two drops of 0.04% per dose, bid. The systemic exposures are duration. The most common ocular adverse reactions observed in patients treated equivalent to 4.2-fold, 7.9-fold, and 13.5-fold the clinical dose, respectively, on a body with latanoprostene bunod were: conjunctival hyperemia (6%), eye irritation (4%), eye surface area basis (assuming 100% absorption). Microscopic evaluation of the lungs pain (3%), and instillation site pain (2%). Approximately 0.6% of patients discontinued after 9 months observed pleural/subpleural chronic fibrosis/inflammation in the 0.04% therapy due to ocular adverse reactions including ocular hyperemia, conjunctival dose male groups, with increasing incidence and severity compared to controls. Lung irritation, eye irritation, eye pain, conjunctival edema, vision blurred, punctate keratitis toxicity was not observed at the 0.024% dose. and foreign body sensation. Distributed by: 8 USE IN SPECIFIC POPULATIONS Bausch + Lomb, a division of 8.1 Pregnancy Valeant Pharmaceuticals North America LLC Risk Summary Bridgewater, NJ 08807 USA There are no available human data for the use of VYZULTA during pregnancy to inform U.S. Patent Numbers: 6,211,233; 7,273,946; 7,629,345; 7,910,767; 8,058,467. any drug associated risks. VYZULTA is a trademark of Bausch & Lomb Incorporated or its affiliates. Latanoprostene bunod has caused miscarriages, abortion, and fetal harm in rabbits. Latanoprostene bunod was shown to be abortifacient and teratogenic when administered © Bausch & Lomb Incorporated intravenously (IV) to pregnant rabbits at exposures ≥ 0.28 times the clinical dose. Based on 9464800 11/2017 VYZ.0055.USA.16 Issued: 11/2017

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RRP0419_BLP0419_BL Vyzulta5.inddVyzulta5.indd 1 33/20/19/20/19 10:1010:10 AMAM Plastic Pointers

REVIEW Edited by Anna P. Murchison, MD, MPH

Managing the Anophthalmic Socket How to treat the anophthalmic patient when he presents with problems related to his implant. Anna P. Murchison, MD, MPH, Philadelphia, and Carlo R. Bernardino, MD, FACS, Salinas, Calif.

nophthalmia, from the Greek, dermis-fat grafts. The implants come Patient Evaluation A meaning “absence of eye,” is un- in a range of shapes and degree of in- common as a congenital condition. tegration with the overlying prosthetic. When a patient with anophthalmia Congenital anophthalmia, sometimes Recent surveys note porous materials and an implant presents, there are a used interchangeably with microph- as the most commonly used for im- few basic questions the general oph- thalmia, can be due to chromosomal, plants.1,2 thalmologist should ask after a general environmental or monogenic ophthalmic and surgical history: factors. More commonly, anoph- • Does the patient have pain thalmia is acquired, most often with the prosthetic in? due to a blinding trauma or a • Does the prosthesis fall out? blind painful eye. In this article, • Is there discharge or bleeding we’ll help you understand how to from the socket? evaluate and manage anophthal- • How old is the current pros- mic sockets to allow patients to thetic and when was the last time Figure 1. Anophthalmia, left. The left eye socket has a achieve the best functional and it was polished? deep superior sulcus with lower lid retraction and lash cosmetic outcomes possible. position abnormalities, compared to the unaffected right • Does the patient have poly- eye. carbonate glasses to protect the The Surgical History seeing eye? • Is the patient happy with the Whether the anophthalmia was con- All anophthalmic sockets undergo cosmesis and movement of the pros- genital or acquired, when a patient changes, including orbital fat atrophy thetic? undergoes implant surgery, it’s with and changes in the orbital circulation.3 When evaluating the anophthalmic the following goals in mind: treat the These changes and the placement of socket it’s important to note the gen- underlying condition; replace the or- an orbital implant can lead to a variety eral appearance and symmetry com- bital volume; maximize motility; and of complications and management dif- pared to the contralateral side. With provide the most comfortable and aes- fi culties. the prosthetic in place the patient thetically symmetric appearance pos- For these reasons, it is important should be evaluated for enophthalmos sible. Today, most implants are solid that the general ophthalmologist be or prosthetic malposition. The lower (polymethyl methacrylate or silicone), able to adequately evaluate and treat eyelid should be evaluated for laxity. porous (hydroxyapatite and high- simple problems of the anophthalmic Lash position and lid margin position density polyethylene) or autogenous socket. should be noted, as entropion can indi-

26 | Review of Ophthalmology | April 2019 This article has no commercial sponsorship.

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REVIEW Pointers

cate socket contracture. The superior this is usually the last management op- sulcus should be checked for deepen- tion. Instead, the primary treatment is ing and symmetry with the opposite prosthetic polishing and topical cro- side (Figure 1). The upper eyelid posi- molyn sodium or topical steroids. tion should be examined for ptosis, and Other conditions that may cause dis- levator function should be evaluated. charge are poor prosthetic fi t, implant Evaluate the movement of the pros- extrusion, pyogenic granuloma in the thetic compared to the seeing eye. socket, excessively deep fornices, con- Poor movement can be due to for- junctival infection or nasolacrimal duct nix abnormalities, enophthalmos or obstruction. poor prosthetic depth. Address any • Enophthalmos. This is caused socket or prosthetic abnormality, and by either the prosthetic’s position or a if the patient is still unhappy with the deep superior sulcus, and can be pres- motility, there are surgical prosthetic- ent initially or develop over time due implant coupling methods that may to implant size, implant shifting and/ improve motility for the patient (Fig- or change or atrophy of the orbital tis- ures 2A to 2C). sues. It can be addressed by surgically Remove the prosthetic and evalu- Figure 2. Anophthalmia, right. In addition to augmenting the orbital volume. A va- ate it. If the prosthetic is thick it may the asymmetry in primary gaze with a deep riety of surgical techniques can be ap- be placing pressure on the lower lid sulcus of the right upper lid, the patient has plied, including subperiosteal implants and could be camoufl aging low orbital very poor motility of the prosthesis. The or secondary orbital implants. (A volume. Also, note whether the pros- underlying motility should also be comprehensive discussion of implants thetic is smooth and clean. Evaluate evaluated with the prosthesis removed and and surgical techniques is beyond the the prosthetic should be examined. the socket for infl ammation, excessive scope of this general review.) mucous, giant papillary conjunctivitis After surgery, if any superior sulcus under the upper eyelid and pyogenic lary conjunctivitis. This infl ammatory deformity remains, there are surgical granulomas. Take note of the forniceal reaction is diagnosed by visualizing pa- and fi ller options to improve the ap- depth, and whether the superior for- pillae of 1 mm or greater on the supe- pearance. However, for the patient nix is excessively deep or the fornices rior tarsal conjunctiva. The conjunctiva interested in a non-surgical fi x, placing aren’t well defi ned. Examine the tissue becomes edematous and excessive dis- a +2 D sphere or higher over the af- over the implant for thinning, fi stula charge can be seen. Since the patho- fected side will magnify the eye socket or defects. Lastly, on palpation of the genesis is thought to be a combination and make the enophthalmos less no- socket, note the presence or absence of immunologic response to the pros- ticeable. Caution should be used in in- of an implant and its position. thetic/deposits and mechanical trauma creasing the thickness of the prosthetic Of course the patient should wear from the prosthetic itself, though the to compensate for this volume loss, as protective glasses and have careful ex- process isn’t fully understood, one over time the lower lid will become ams of the seeing eye, with the fre- might think the optimal treatment is more lax and the prosthetic will sink quency of exams determined by the removal of the prosthetic, as in con- inferiorly. patient’s age, history and the health of tact lens-related GPC. However, since • Lower eyelid laxity. Lower lid the eye. socket contraction can occur without laxity, with or without lid margin mal- the prosthetic or a conformer in place, position, can be partially due to the Treatments weight of the prosthetic and can lead to other changes, Following are the more including ptosis of the up- common complaints of the per lid. This is addressed anophthalmic patient, and by having the prosthetic re- how to manage them. made, followed by surgery • Discharge. This is a with horizontal lid shorten- common complaint, and ing. If there’s any forniceal there can be a range of un- Figure 3. Anophthalmia with implant exposures. Figure A shows shortening or other fi ndings, derlying causes for it. A com- exposure of a smooth, acrylic implant. Figure B shows an exposed, they would also need to be mon etiology is giant papil- porous implant leading to mucoid discharge. addressed.

28 | Review of Ophthalmology | April 2019

026_rp0419_plastics.indd 28 3/22/19 5:02 PM • Socket contracture. This can The History of Anophthalmos Management accompany lid malposition and has myriad causes. There’s no single surgi- The fi rst enucleations were possibly performed by the Chinese as early as 2,600 BC. cal technique to address socket con- However, the fi rst report by Johannes Lange7 was not until 1555, and the fi rst description 8 tracture and management should be of the procedure appeared in 1583, by George Bartisch. In the 1800’s the procedure made individualized and address lid position dramatic advances, including extraocular muscle disinsertion, as well as the introduction of controlled anesthesia, leading to great improvements and increased use of the procedure.9 abnormalities at the same time. Evisceration seems to have fi rst been performed unintentionally by James Beer in 1817 • Orbital implant exposure or after an expulsive choroidal hemorrhage; in 1874 J.F. Noyes completed the fi rst planned extrusion. Thankfully, this is an un- evisceration. There were several modifi cations of the procedure, later discarded, until common patient presentation, with Alfred Graefe and P.H. Mules’ more modern version in 1884.2 average incidences of 5.6 percent (ex- The fi rst ocular prosthetics, of painted metal, were described in 1579, and glass prosthet- posure) and 1.3 percent (extrusion) ics from Vienna were also starting to be made. Since then, many other materials and with porous implants (Figures 3A and shapes have been tried, such as ivory, rubber, wool and cartilage. In recent history, the 3B).4 When this occurs, the time since advent of inert plastics has given us the implants we use today. —AM and CB surgery and size of the defect can im- pact the management. Surgery is often trochlear irritation and possible recur- specialty management to avoid orbital required, and involves a simple closure rent tumors.6 Amputation neuromas, and facial asymmetry. or a patch graft. an exuberant overgrowth of neurons The anophthalmic socket has a • Upper eyelid ptosis. This is com- and connective tissue at the transected unique set of problems and requires a mon in the anophthalmic socket. This nerve, are uncommon but can result in different clinical and surgical approach can be a true ptosis or a pseudoptosis pain, particularly with eye movement. than a socket with a globe. The man- due to poor support from the prosthet- Periorbital pathologies, such as sinus agement of these patients should be ic or poor orbital volume and implant diseases or central nervous system tu- carried out with close communication location. As is well known, any orbital mors can also cause referred socket between the ophthalmologist and ocu- surgery, such as volume augmenta- pain and should be considered. If the larist to achieve optimal comfort and tion, should precede eyelid correction. etiology isn’t found on examination or cosmesis for patients. Once any socket problems have been improved with medical therapy, imag- corrected, the ptosis can be addressed. ing may be warranted. Dr. Murchison is the director of the If the ptosis is mild the ocularist can Psychogenic factors, such as drug- Wills Eye Emergency Department and build up the prosthetic superiorly to seeking behavior, can also lead to pain, a member of the Oculoplastic and Or- support the upper eyelid. However, but these are diagnoses of exclusion. bital Surgery Service at Wills Eye Hos- since this increases the weight of the Chronic pain syndromes, which can pital. Dr. Bernardino is an oculoplas- prosthetic it can begin a cycle of prob- overlap with psychogenic factors, can tic surgeon at Vantage Eye Center in lems in the future by inducing lower also complicate the evaluation and are Salinas. The authors report no fi nan- eyelid laxity, which then leads to a diagnosed in conjunction with other cial interest in any product discussed. deeper superior sulcus and the need specialists after ruling out orbital/pros- 1. Su GW, Yen MT. Current trends in managing the anophthalmic for a larger prosthetic in a perpetuating thetic etiologies. In these cases, pa- socket after primary enucleation and evisceration. Ophthalmic cycle. If the ptosis is to be addressed tients nearly always need referral to an Plast Reconstr Surg 2004;20:4:274-280. 2. Viswanathan P, Sagoo MS, Olver JM. UK national survey surgically, the ophthalmologist should ocularist for assessment and prosthetic of enucleation, evisceration and orbital implant trends. Br J keep in mind that levator strength may modifi cation and/or polishing. If the Ophthalmol 2007;91:5:616-9. 5 3. Smith TJ et al. Primary and secondary implants in the be underestimated. etiology isn’t clear and persists after anophthalmic orbit: Preoperative and postoperative computed prosthetic polishing and lubrication, tomographic appearance. Ophthalmology 1991;98:1:106-10. 4. Wladis EJ, et al. Orbital implants in enucleation surgery: A Other Considerations the patient may need a CT scan to aid report by the AAO. Ophthalmology 2018;125:2:311-317. in diagnosis. 5. Nunnery WR, Cepela M. Levator function in the evaluation and management of blepharoptosis. Ophthalmol Clin North Am Orbital pain in the anophthalmic It’s worth mentioning that pediatric 1991;4:1-16. socket can be difficult to diagnose, anophthalmia can be even more dif- 6. Jordan DR, Klapper SR. Enucleation, evisceration, secondary orbital implantation. In: Black E, Nesi F, Gladstone G, Levine since the etiology can range from pros- ficult to manage, especially because M, Calvano C, eds. Smith and Nesi’s Ophthalmic Plastic and thetic irritation or migration/extrusion the orbit of a child is not fully devel- Reconstructive Surgery, 3rd Ed. New York: Springer, 2012. 7. Beard CH. Enucleation. In: Ophthalmic Surgery. Philadelphia: P. of the implant to neurologic causes. oped until after age 5. As the soft tissue Blakiston’s Son & Co., 1910:457-477. One should also rule out lacrimal in- and orbit can require expansion, these 8. Luce CM. A short history of enucleation. Int Ophthalmol Clin 1970;10:681-7. sufficiency, inflammation (scleritis, often challenging cases may require 9. Fox SA. Enucleation and Allied Procedure. In Ophthalmic Plastic sympathetic ophthalmia and GPC), multiple surgeries and sometimes sub- Surgery, 4th Ed. New York: Grune & Stratton Inc. 1970:475-501.

April 2019 | reviewofopthalmology.com | 29

0026_rp0419_plastics.indd26_rp0419_plastics.indd 2299 33/22/19/22/19 5:035:03 PMPM Cataract Patients REVIEW Cover Focus Premium IOLs: Dealing With Postop Problems

Christopher Kent, Senior Editor

Advanced- s intraocular lenses have be- clude objective or subjective prob- come more technologically lems related to the ocular surface, technology IOLs Aadvanced, the issues surround- including dry eye; residual refractive ing patient selection, lens implanta- error; IOL-related concerns, such as have far fewer tion and patient management have problems with night vision or quality- become more complex. At the same of-vision issues; blurred vision as a postop issues time, the technology used to select the result of posterior capsular opacifi ca- best lens for a given patient has im- tion; or simply unmet expectations. than in the past, proved dramatically, and doctors’ un- Essentially, our patients are our cus- derstanding of how to choose appro- tomers, and good customer service but problems can priate candidates and manage them underlies everything. Leaving clinical still arise. Here’s before and after surgery has become issues unresolved will lead to dissat- far more sophisticated than it was isfaction.” help. when premium lenses fi rst appeared. Here, surgeons offer insights re- R. Bruce Wallace III, MD, FACS, garding how to manage problems that founder and medical director of Wal- may arise, along with a few pearls for lace Eye Associates in Alexandria, preoperative patient management Louisiana, and clinical professor of that can help to minimize these post- ophthalmology at Louisiana State operative issues. University and Tulane Schools of Medicine in New Orleans, notes that Refractive Surprises success with these lenses has become easier. “The lenses are better now,” he Although an imperfect lens power says. “We still have a few postopera- calculation is always a possibility when tive issues, but not nearly the number a postoperative refractive surprise oc- we had in the past.” curs, such issues are becoming less Nevertheless, problems can still common. (For more on how to avoid occur. “When it comes to advanced miscalculating the lens power, see technology IOLs, several possible “IOL Power Formulas: 10 Questions postoperative concerns can lead to a Answered” in the January 2018 issue dissatisfi ed patient,” notes Elizabeth of Review.) Other issues such as cor- Yeu, MD, a partner at Virginia Eye neal problems and toric lens rotation Consultants in Norfolk, and an assis- also need to be considered. tant professor at the Eastern Virginia “Postoperative ocular surface issues Medical School. “Potential issues in- can lead to visual diffi culties, discom-

30 | Review of Ophthalmology | April 2019 This article has no commercial sponsorship.

0030_rp0419_f1.indd30_rp0419_f1.indd 3030 33/22/19/22/19 12:0412:04 PMPM fort and an unhappy patient, and the Elizabeth Yeu,MD practices at The Morris Eye Group in number one cause of ocular surface Encinitas, California, says it’s remark- issues is dry-eye disease,” notes Dr. able how good refractive outcomes Yeu. “Preoperative dry eye can lead to have become, with both monofocal a refractive surprise, with undercor- and presbyopia-correcting lenses. rected or overcorrected astigmatism “However, every once in a while some- or an altered spherical equivalent out- one will fall outside the normal range, come—but postoperative exacerba- with long or short axial lengths, or tion of dry-eye symptoms can also be steep or fl at corneas,” he notes. “It can problematic. be a little more diffi cult to achieve a “Dry eye isn’t as straightforward as A refractive surprise can result from subtle perfect outcome with these patients, corneal problems missed before the we used to believe,” she continues. “If surgery—or that occurred after the surgery so postoperatively, refractive surprises you look at a study like the one con- because of the use of postoperative drops. sometimes still need to be addressed. ducted by Pria Gupta, MD and Chris Above: A Salzmann’s nodule at 10 o’clock. “There are several ways to address Starr, MD,1 about three-quarters of them,” he says. “Even very low re- patients coming in for cataract surgery dropper or because of the toxicities of sidual astigmatism can effect near, in- have at least mild to moderate dry eye, the medications, it goes from subclini- termediate and distance vision, and it’s but only a small number of them have cal EBMD to a very clinically relevant important to address this in patients actually been diagnosed with dry-eye EBMD. It may not be that the clini- who receive a premium lens, which disease. It’s a diagnosis that’s easy to cian missed the problem—the EBMD requires an excellent optical system. miss in many patients. Many of our may simply become a much bigger If the patient has a small amount of older patients may not feel dry, per se, issue as the surface decompensates mixed astigmatism, but has a spherical or they may not have the classic symp- postoperatively. equivalent of plano, I might address tom of irritation. They may only have “Because this is a possibility, when- this with manual limbal relaxing inci- a fl uctuating vision issue, if the disease ever you have an unhappy patient re- sions. Performing LASIK or PRK is is mild preoperatively. But postopera- lated to a refractive ‘miss’ leading to a reasonable option for patients who tively, a subclinical or asymptomatic a sub-par visual outcome, you have have a higher level of compound or case of dry eye may become clinically to look for a few things,” she contin- mixed astigmatism. symptomatic. The reasons are not ues. “A carefully performed refrac- “Patients with higher levels of re- completely straightforward, but use tion is going to be very important, but sidual spherical errors might require a of medications relating to the cataract that has to be accompanied by a very lens exchange, or in rare cases a piggy- surgery is a common etiology.” careful ocular surface examination, back IOL,” he continues. “However, it Adding to the complexity of the both before and after staining. Prior would have to be a big refractive miss problem, a refractive surprise can also to any drop instillation, you should re- for me to do a lens exchange. Again, be the result of other subtle corneal peat whatever diagnostic images were with the new equipment and formulas problems that were missed before the obtained preoperatively, to compare we’re using today, needing a lens ex- surgery—or that have occurred fol- them and see if there’s an interval dif- change is uncommon, even in patients lowing surgery because of the post- ference that could be the source of with previous refractive surgery.” operative drops. These can include the surprise outcome. If the problem Dr. Yeu agrees. “If the refractive er- subtle epithelial basement membrane appears to be caused by a poor ocular ror is small, say, on the order of 1.25 D dystrophy, nodular degeneration or a surface, aggressive treatment to nor- or less, and it’s just mixed astigmatism pterygium that wasn’t addressed pre- malize the surface will be necessary as because the spherical equivalent is rel- operatively. “Some patients coming an initial step, prior to moving forward atively close to emetropia, performing in for cataract surgery have very mini- with any other intervention. Lastly, astigmatic keratotomy or one or more mal epithelial basement membrane a macular OCT should be a part of limbal relaxing incisions could be the dystrophy that may only involve the the evaluation for patients with sub- answer,” she says. “However, if it’s a superior 10 percent of the peripheral optimal postoperative vision and for larger refractive error, or the spheri- cornea,” says Dr. Yeu. “If you lift up refractive misses.” cal equivalent is signifi cantly off, then the lid, it’s actually relatively com- you’ll have to think about whether the mon to fi nd this. But postoperatively, Residual Refractive Error patient is a candidate for a laser appli- whether because the patient caused cation like LASIK or PRK, or whether corneal trauma with the tip of the eye Arrdalan Eddie Aminlari, MD, who the patient would be better served by

April 2019 | reviewofophthalmology.com | 31

030_rp0419_f1.indd 31 3/22/19 12:04 PM Cover Cataract Patients

REVIEW Focus

Prevalence of Dry Eye in Cataract Patients Dissatisfaction with MF IOLs

60 100 n=136 patients 80 40 54.4

60 %

40 20 23.5 levels of dry eye 20 11 8.1 3

% of patients with different 0 0 Level 0 Level 1 Level 2 Level 3 Level 4 PCO Dry Eye ITF Dry Eye Severity Score Ametropia Unexplained Addressing dry eye in premium lens patients, both preoperatively and postoperatively, is crucial, surgeons say. Studies suggest that three- quarters of patients coming in for cataract surgery have at least mild to moderate dry eye, but only a small number of them have actually been diagnosed.1 Above, left: One study found that 25.9 percent of cataract patients had previously received a diagnosis of dry-eye disease, but 80.9 percent had an ITF dry eye level of 2 (indicating moderate dry eye) or higher, based on the presence of signs and symptoms.3 Right: At the same time, a signifi cant number of multifocal lens patients attribute dissatisfaction with their lenses to symptoms of dry eye.4

doing an IOL exchange. Ultimately, postoperative rotation occur. “The recting lens, I’ll choose the lowest add especially if it’s a quality-of-vision con- LENSAR system incorporates Intelli- possible, and I’d consider a mid- to cern, the patient may need an IOL Axis, which creates a capsular mark al- low-add multifocal or an extended- exchange. However, resorting to a lens lowing the placement of the lens with depth-of-focus IOL. exchange isn’t that common anymore, a much higher degree of certainty,” he “If we’re proceeding with one of because our current advanced tech- explains. “Postoperatively, if you fi nd these patients I’ll start by treating the nology lenses produce a better over- a residual astigmatic error on refrac- nondominant eye,” she continues. all quality of vision, with fewer of the tion, it’s easy to identify the location “Then, if the patient has a signifi cant night-vision dysphotopsia concerns of the toric markers in relation to the problem during the postoperative that patients may complain about.” capsular mark. period, we can stop and decide how Of course, when the implanted lens “In that situation, if I do see rota- to move forward. One option is to is toric and the patient’s astigmatism tion, I don’t wait very long to go in and balance the nondominant eye with isn’t effectively resolved, postop rota- rotate the lens,” he adds. “I usually go a monofocal for distance in the domi- tion is an obvious potential culprit. Dr. in within the fi rst few weeks.” nant eye. That gives the patient a kind Aminlari says that he’s found two strat- of customized vision, where they’re egies that help to prevent postop toric Managing Dysphotopsias able to maintain ‘social reading.’ That lens rotation. “At the time of surgery, means that although they won’t be I leave the intraocular pressure a little When implanting a presbyopia-cor- able to sit and read a book or work on lower than I would normally leave it,” recting IOL, dysphotopsias such as the computer for more than 10 or 15 he says. “I can check by palpation to glare and haloes are a common post- minutes without spectacles to support make sure the eye isn’t overinfl ated, as operative complaint. Dr. Yeu points their near vision, they can at least look there’s a tendency for the lens to rotate out that most patients who are likely at their phone or read a restaurant in this situation. It’s also important to be bothered by postoperative dys- menu without having to search for to remove all viscoelastic, including photopsias can be identified before reading glasses. Meanwhile, this ar- underneath the lens, because retained surgery. “When I talk to the patient rangement will mitigate their night viscoelastic can also cause a lens to preoperatively, I look to see if the pa- vision problems. This approach has rotate after surgery. These strategies tient has a high level of concern or a lot allowed me to avoid doing an IOL ex- come into play with toric multifocals of fear tied to night-vision-related is- change in a number of patients.” and extended-depth-of-focus torics sues,” she says. “Of course, this might Dr. Yeu says this same strategy can as well.” be an concern for someone who does work when a patient seems like a good Dr. Aminlari adds that he uses the commercial driving at night or works candidate for bilateral implantation LENSAR femtosecond system, which the graveyard shift. If that individual of a presbyopia-correcting IOL, but has a feature that helps him should is determined to try a presbyopia-cor- ends up unhappy with the dyspho-

32 | Review of Ophthalmology | April 2019

0030_rp0419_f1.indd30_rp0419_f1.indd 3232 33/22/19/22/19 12:0512:05 PMPM David F. Chang, MD topsias. “If a patient like this comes back four to six months later and the situation hasn’t gotten better, but the patient doesn’t want to lose the free- dom of independence from specta- cles, I’ll offer them the same option,” she says. “Doing an IOL exchange in the dominant eye, swapping out the presbyopia-correcting lens with a monofocal for distance, often saves us from having to do a bilateral IOL ex- change. Patients are often happy with that compromise.”

Postoperative Pain

Dr. Yeu notes that patient dissatis- An IOL that’s signifi cantly tilted can cause a refractive problem and lead to a shift in faction is frequently associated with refractive astigmatism—especially when it’s a multifocal or extended-depth-of-focus IOL. postoperative pain. “It’s important for us to do everything we can around encounter a visually signifi cant decen- hard to tell, if you can’t see the haptic the time of surgery to prevent pain,” tered presbyopia-correcting IOL, it behind the iris. Sometimes it’s impor- she says. “That’s why it’s important to defi nitely needs to be addressed,” says tant to examine the lens while it’s still consider using preoperative and peri- Dr. Yeu. “If the patient has already in the eye; rotate it into the anterior operative NSAIDs. Intraoperatively, had a YAG capsulotomy, that makes chamber and look at the haptics to see of course, we try to disturb as little for a much more challenging scenario, if there’s any abnormality there.” of the corneal epithelium as possible, and trying to center the IOL may not beyond what’s necessary to perform be a great option. But if the capsule is Managing a Tilted IOL intraocular surgery. intact, you can consider reopening the “Sometimes postoperative pain is bag and then trying to center the IOL. Dr. Yeu notes that an IOL that’s sig- tied to dry eye or ocular surface dis- “You have to fi gure out whether the nifi cantly tilted can defi nitely cause a ease that’s gone from being relatively IOL is decentered because there’s refractive problem—especially when asymptomatic to being uncomfort- something wrong with the zonules, it’s a multifocal or extended-depth- able,” she adds. “Then you have to go leading to uneven distribution of forc- of-focus IOL—and lead to refractive down the pathway of doing the ocular es on the bag, or whether the IOL just astigmatism shifts. “Work by Mitch surface examination and deciding how needs to be repositioned inside the Weikert and Doug Koch has dem- to manage whatever you fi nd.” bag,” she continues. “Sometime you’re onstrated that it’s not uncommon for Dr. Aminlari notes that most of in the operating room and you try to IOLs to tilt evenly across the horizon- the pain he’s seen postoperatively has center the IOL and you realize that it tal axis, inducing mild against-the-rule been in connection with dry eye. “I’ve keeps creeping in one direction. The astigmatism.2 More significant IOL never seen serious postoperative pain, fi rst thing you should be thinking of as tilting can occur with decentration of presumably because the medications the surgeon is that there’s some level the IOL, capsular contraction, inad- we use control the infl ammation in the of zonular laxity in that one quadrant. vertently malpositioned haptics (for eye and help to prevent that,” he says. In such a patient, placing a capsular example, one in the capsular bag and “However, dry eye sometimes causes tension ring to provide equatorial bal- one in the sulcus), or poor coverage of a burning sensation and blurred vision ance of support throughout will allow the optic edge by the anterior capsule. intermittently, which is another reason you to center the IOL much more For that reason, it’s important for us to to look for postoperative dry eye and readily.” be as accurate as possible when mak- address it promptly.” Dr. Wallace suggests checking the ing the capsulorhexis or capsulotomy, haptics with the lens still inside the which is why I use either a femtosec- Managing a Decentered IOL eye. “If a lens doesn’t seem to center ond laser or the Zepto capsulotomy properly, there may be a haptic that’s system when I’m using an advanced- “In the uncommon instance that I not working properly,” he notes. “It’s technology IOL. Those technologies

April 2019 | reviewofophthalmology.com | 33

030_rp0419_f1.indd 33 3/22/19 12:05 PM Cover Cataract Patients

REVIEW Focus

by LASIK. Other ocu- lar problems such as a thin cornea could also make a patient less-than-ideal as a Mitchell P. Weikert. MD Weikert. P. Mitchell candidate for LASIK. You have to do a thor- ough evaluation of the eye, beyond just the refractive error, to fi g- ure out whether the patient would benefi t from LASIK. “One of the good Above, left: Residual mixed astigmatism, undercorrected. In this situation surgical options include adding a things about a piggy- limbal relaxing incision or opening femtosecond laser LRIs. If staying within the same meridian as an existing back lens compared LRI, you can lengthen the existing LRI or place an additional LRI central to the existing one. Above, right: to LASIK,” adds Dr. Residual mixed astigmatism, overcorrected. If there’s a gaping LRI, you can suture it and then place a thera- Wallace, “is that if it peutic bandage soft contact lens. If you’re dealing with a “fl ipped axis” toric IOL, you can add an LRI in the doesn’t work prop- opposite axis. However, quality of vision may be compromised. erly—if there’s a degradation of visual allow me to create a standardized, the sulcus. It came in low and minus acuity—changing the lens is better perfectly round, well-centered cap- powers, so you could use it in those than doing a second LASIK procedure sulotomy every time. That allows for patients who had a myopic or small which would sacrifice more corneal very circumferential and equal cover- hyperopic error. tissue. That means you have an option age of the optic edge.” “Now our options are a bit more if you later have another surprise with Dr. Aminlari notes that when pa- limited,” she continues. “The Bausch that eye.” tients present with lens tilt—which he + Lomb silicone IOL is a three-piece says is very uncommon—they often with a square edge, but it only goes Postop Treatment: Timing Counts need a lens exchange. “Some surgeons to zero diopters, so it can’t be used might want to attempt scleral fi xation in patients with a myopic error. Then Because the eye can take weeks or of the lens,” he says. “It’s possible that there’s the AR40, which is a round- months to calm down following sur- the zonules holding the capsular bag edged hydrophobic acrylic three- gery—and because some postopera- in place are broken, and if so, there’s piece IOL; that lens is available into tive problems will resolve on their nothing we can do to fix them. In the minus powers. However, there are own, given time—surgeons agree that those situations, probably the safest concerns that if you use the same ma- holding off trying to address postoper- approach is to remove the lens from terial for both IOLs you might end up ative complaints (with the exception of the eye and come up with a better so- causing interlenticular opacifi cation. a toric IOL malrotation) is important. lution, such as putting a new lens into I haven’t seen that happen as long as “If I suspect the patient just needs the ciliary sulcus.” one of the IOLs is in the sulcus and time to adjust to the lenses, I often the other IOL is in the bag. However, won’t do much in terms of interven- The Piggyback Option because none of our lens options are tion until some time has passed,” says ideal, I don’t use the secondary piggy- Dr. Aminlari. “Instead, I pay atten- Dr. Yeu says she rarely considers back option very often.” tion to the patient’s complaints, try implanting a piggyback lens because Dr. Wallace says he has occasion- to be as supportive as I can, and be- the lens options are limited. “We used ally resorted to implanting a piggy- come their advocate. This is similar to have access to the STAAR silicone back lens to resolve a postoperative to patients who’ve just started wear- three-piece IOL,” she points out. problem. “Some of these patients are ing progressive-lens spectacles. They “That was great because it was an an- not good candidates for LASIK,” he may complain in the beginning, but teriorly round-edged, three-piece lens points out. “These are not 20-year- eventually they get used to them. Over made of silicone, a little bit larger than old myopes. They have issues like time, patients start to neuroadapt to a standard IOL; it could easily go into dry eye that might be made worse the multifocal or extended-depth-of-

34 | Review of Ophthalmology | April 2019

030_rp0419_f1.indd 34 3/22/19 12:05 PM DISCOVER LOTEMAX® SM: SUBMICRON STRONG

Join your peers for a webinar presentation introducing the exciting new advancements of LOTEMAX® SM, the newest loteprednol etabonate formulation from Bausch + Lomb

REGISTER FOR ONE OF THE FOLLOWING WEBINAR SESSIONS:

MARGUERITE MCDONALD, MD MITCHELL JACKSON, MD Tuesday, April 9th• 6:00 PM ET | 3:00 PM PT Wednesday, April 24th• 8:00 PM ET | 5:00 PM PT

AUDREY TALLEY ROSTOV, MD RAJESH RAJPAL, MD Thursday, April 25th• 9:00 PM ET | 6:00 PM PT Wednesday, May 15th• 6:00 PM ET | 3:00 PM PT

Dates and speakers are subject to change or substitution.

THIS LIVE WEBINAR PRESENTATION WILL COVER: • OVERCOMING CHALLENGES of ocular drug delivery • NEW SM TECHNOLOGY™ in LOTEMAX® SM • LOTEMAX® SM FORMULATION features designed • THE PROVEN EFFICACY AND SAFETY of LOTEMAX® SM with the patient in mind

This promotional webinar is sponsored by Bausch + Lomb. No CME/CE or food will be provided for this program. Only physicians and healthcare professionals involved in providing patient care or product recommendations may attend this educational program.

REGISTER NOW AT www.reviewofophthalmology.com/LotemaxSMWebinar2019

INDICATION IMPORTANT SAFETY INFORMATION (CON'T) LOTEMAX® SM (loteprednol etabonate ophthalmic gel) 0.38% • Prolonged use of corticosteroids may suppress the host is a corticosteroid indicated for the treatment of post-operative response and thus increase the hazard of secondary ocular infl ammation and pain following ocular surgery. infections. In acute purulent conditions, steroids may mask infection or enhance existing infections. IMPORTANT SAFETY INFORMATION • Employment of a corticosteroid medication in the treatment of • LOTEMAX® SM, as with other ophthalmic corticosteroids, patients with a history of herpes simplex requires great caution. is contraindicated in most viral diseases of the cornea and Use of ocular steroids may prolong the course and may conjunctiva including epithelial herpes simplex keratitis exacerbate the severity of many viral infections of the eye (dendritic keratitis), vaccinia, and varicella, and also in (including herpes simplex). mycobacterial infection of the eye and fungal diseases of • Fungal infections of the cornea are particularly prone to develop ocular structures. coincidentally with long-term local steroid application. Fungus • Prolonged use of corticosteroids may result in glaucoma with invasion must be considered in any persistent corneal ulceration damage to the optic nerve, defects in visual acuity and fi elds of where a steroid has been used or is in use. Fungal cultures should vision. If LOTEMAX® SM is used for 10 days or longer, IOP should be taken when appropriate. be monitored. • Contact lenses should not be worn when the eyes are infl amed. • Use of corticosteroids may result in posterior subcapsular • There were no treatment-emergent adverse drug reactions that cataract formation. occurred in more than 1% of subjects in the three times daily • The use of steroids after cataract surgery may delay healing and group compared to vehicle. increase the incidence of bleb formation. In those with diseases causing thinning of the cornea or sclera, perforations have You are encouraged to report negative side eff ects of been known to occur with the use of topical steroids. The initial prescription drugs to the FDA. Visit www.fda.gov.medwatch prescription and renewal of the medication order should be made or call 1-800-FDA-1088. by a physician only after examination of the patient with the aid Please see Brief Summary of full Prescribing Information on of magnifi cation such as slit lamp biomicroscopy and, where adjacent page. appropriate, fl uorescein staining.

®/TM are trademarks of Bausch & Lomb Incorporated or its affi liates. © 2019 Bausch & Lomb Incorporated. All rights reserved. Printed in USA. LSM.0056.USA.19

RP0419_BL Lotemax house.indd 1 3/19/19 11:00 AM

BRIEF SUMMARY OF PRESCRIBING INFORMATION produced malformations when administered orally to pregnant rabbits at doses 4.2 times the recommended human ophthalmic dose (RHOD) and to This Brief Summary does not include all the information needed to use pregnant rats at doses 106 times the RHOD. In pregnant rats receiving oral LOTEMAX® SM safely and effectively. See full prescribing information ® doses of loteprednol etabonate during the period equivalent to the last for LOTEMAX SM. trimester of pregnancy through lactation in humans, survival of offspring was ® reduced at doses 10.6 times the RHOD. Maternal toxicity was observed in LOTEMAX SM (loteprednol etabonate ophthalmic gel) 0.38% rats at doses 1066 times the RHOD, and a maternal no observed adverse For topical ophthalmic use effect level (NOAEL) was established at 106 times the RHOD. The Initial U.S. Approval: 1998 background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general INDICATIONS AND USAGE ® population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20%, LOTEMAX SM is a corticosteroid indicated for the treatment of post- of clinically recognized pregnancies. Data: Animal Data. Embryofetal studies operative inflammation and pain following ocular surgery. were conducted in pregnant rabbits administered loteprednol etabonate by DOSAGE AND ADMINISTRATION oral gavage on gestation days 6 to 18, to target the period of organogenesis. Invert closed bottle and shake once to fill tip before instilling drops. Apply one Loteprednol etabonate produced fetal malformations at 0.1 mg/kg (4.2 times drop of LOTEMAX® SM into the conjunctival sac of the affected eye three the recommended human ophthalmic dose (RHOD) based on body surface times daily beginning the day after surgery and continuing throughout the first area, assuming 100% absorption). Spina bifida (including meningocele) was 2 weeks of the post-operative period. observed at 0.1 mg/kg, and exencephaly and craniofacial malformations were observed at 0.4 mg/kg (17 times the RHOD). At 3 mg/kg (128 times the CONTRAINDICATIONS ® RHOD), loteprednol etabonate was associated with increased incidences of LOTEMAX SM, as with other ophthalmic corticosteroids, is contraindicated abnormal left common carotid artery, limb flexures, umbilical hernia, scoliosis, in most viral diseases of the cornea and conjunctiva including epithelial and delayed ossification. Abortion and embryofetal lethality (resorption) herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, in occurred at 6 mg/kg (256 times the RHOD). A NOAEL for developmental mycobacterial infection of the eye and fungal diseases of ocular structures. toxicity was not established in this study. The NOAEL for maternal toxicity in WARNINGS AND PRECAUTIONS rabbits was 3 mg/kg/day. Embryofetal studies were conducted in pregnant Intraocular Pressure (IOP) Increase: Prolonged use of corticosteroids may rats administered loteprednol etabonate by oral gavage on gestation days 6 result in glaucoma with damage to the optic nerve, defects in visual acuity to 15, to target the period of organogenesis. Loteprednol etabonate produced and fields of vision. Steroids should be used with caution in the presence of fetal malformations, including absent innominate artery at 5 mg/kg (106 times glaucoma. If this product is used for 10 days or longer, intraocular pressure the RHOD); and cleft palate, agnathia, cardiovascular defects, umbilical should be monitored. hernia, decreased fetal body weight and decreased skeletal ossification at 50 Cataracts: Use of corticosteroids may result in posterior subcapsular mg/kg (1066 times the RHOD). Embryofetal lethality (resorption) was cataract formation. observed at 100 mg/kg (2133 times the RHOD). The NOAEL for Delayed Healing: The use of steroids after cataract surgery may delay developmental toxicity in rats was 0.5 mg/kg (10.6 times the RHOD). healing and increase the incidence of bleb formation. In those diseases Loteprednol etabonate was maternally toxic (reduced body weight gain) at 50 causing thinning of the cornea or sclera, perforations have been known to mg/kg/day. The NOAEL for maternal toxicity was 5 mg/kg. A peri-/postnatal occur with the use of topical steroids. The initial prescription and renewal of study was conducted in rats administered loteprednol etabonate by oral the medication order should be made by a physician only after examination gavage from gestation day 15 (start of fetal period) to postnatal day 21 (the of the patient with the aid of magnification such as slit lamp biomicroscopy end of lactation period). At 0.5 mg/kg (10.6 times the clinical dose), reduced and, where appropriate, fluorescein staining. survival was observed in live-ERUQRIIVSULQJ'RVHV•PJNJ WLPHVWKH Bacterial Infections: Prolonged use of corticosteroids may suppress the RHOD) FDXVHGXPELOLFDOKHUQLDLQFRPSOHWHJDVWURLQWHVWLQDOWUDFW'RVHV• host response and thus increase the hazard of secondary ocular infections. mg/kg (1066 times the RHOD) produced maternal toxicity (reduced body In acute purulent conditions of the eye, steroids may mask infection or weight gain, death), decreased number of live-born offspring, decreased birth enhance existing infection. weight, and delays in postnatal development. A developmental NOAEL was Viral infections: Employment of a corticosteroid medication in the treatment not established in this study. The NOAEL for maternal toxicity was 5 mg/kg. of patients with a history of herpes simplex requires great caution. Use of Lactation: There are no data on the presence of loteprednol etabonate in ocular steroids may prolong the course and may exacerbate the severity of human milk, the effects on the breastfed infant, or the effects on milk many viral infections of the eye (including herpes simplex). production. The developmental and health benefits of breastfeeding should Fungal Infections: Fungal infections of the cornea are particularly prone to EHFRQVLGHUHGDORQJZLWKWKHPRWKHU¶VFOLQLFDOQHHGIRU/27(0$;® SM and ® develop coincidentally with long-term local steroid application. Fungus any potential adverse effects on the breastfed infant from LOTEMAX SM. invasion must be considered in any persistent corneal ulceration where a Pediatric Use: Safety and effectiveness of LOTEMAX® SM in pediatric steroid has been used or is in use. Fungal cultures should be taken when patients have not been established. appropriate. Geriatric Use: No overall differences in safety and effectiveness have been Contact Lens Wear: Contact lenses should not be worn when the eyes are observed between elderly and younger patients. inflamed. NONCLINICAL TOXICOLOGY ADVERSE REACTIONS Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal Because clinical trials are conducted under widely varying conditions, studies have not been conducted to evaluate the carcinogenic potential of adverse reaction rates observed in the clinical trials of a drug cannot be loteprednol etabonate. Loteprednol etabonate was not genotoxic in vitro in directly compared to rates in the clinical trials of another drug and may not the Ames test, the mouse lymphoma tk assay, or in the chromosomal reflect the rates observed in practice. Adverse reactions associated with aberration test in human lymphocytes, or in vivo in the mouse micronucleus ophthalmic steroids include elevated intraocular pressure, which may be assay. Treatment of male and female rats with 25 mg/kg/day of loteprednol associated with infrequent optic nerve damage, visual acuity and field etabonate (533 times the RHOD based on body surface area, assuming defects, posterior subcapsular cataract formation, delayed wound healing 100% absorption) prior to and during mating caused preimplantation loss and and secondary ocular infection from pathogens including herpes simplex, and decreased the number of live fetuses/live births. The NOAEL for fertility in perforation of the globe where there is thinning of the cornea or sclera. There rats was 5 mg/kg/day (106 times the RHOD). were no treatment-emergent adverse drug reactions that occurred in more than 1% of subjects in the three times daily group compared to vehicle. LOTEMAX is a trademark of Bausch & Lomb Incorporated or its affiliates. © 2019 Bausch & Lomb Incorporated USE IN SPECIAL POPULATIONS Bausch + Lomb, a division of Valeant Pharmaceuticals North America LLC Pregnancy: Risk Summary: There are no adequate and well controlled Bridgewater, NJ 08807 USA studies with loteprednol etabonate in pregnant women. Loteprednol etabonate produced teratogenicity at clinically relevant doses in the rabbit LSM.0091.USA.19 and rat when administered orally during pregnancy. Loteprednol etabonate Based on 9669600-9669700 Revised: 02/2019

RRP0419_BLP0419_BL LotemaxLotemax PIPI house.inddhouse.indd 1 33/19/19/19/19 10:5710:57 AMAM Cover Cataract Patients

REVIEW Focus

focus lenses, and in the long run they when I see them at the early postop- problem. But the patient couldn’t get benefi t from them. erative follow-up. In that situation, I clear vision, and we couldn’t refract “In terms of treating residual astig- give them a small sub-Tenon’s aliquot him. matism, it’s important to wait until of a steroid, take them off of all other “We were puzzled, because there you’re getting measurements that are medications and do everything pos- was no obvious explanation,” he con- consistent,” he continues. “I typically sible to optimize the corneal surface. tinues. “All of his retinal fi ndings were do a refraction at four weeks; at that The steroid will help them for the normal. He had a little posterior cap- time we check to make sure there’s no next two to four weeks. Meanwhile, sular opacity, but it was very early; we residual astigmatism. If there is, and I’ll have them lubricate aggressively didn’t want to do a YAG laser, hoping the patient has visual complaints, I’ll with a preservative-free artifi cial tear. it might work, because it would make often start aggressive dry-eye therapy Once the eye looks better, I may use it much harder to exchange the lens if and have the patient return one to two punctal plugs and have the patient we needed to do that. We treated ag- months later. If the astigmatism is con- take omega-3 supplements.” gressively with lubrication, to no avail. sistent, then I’ll perform topography Even though it hadn’t been 12 weeks and check the refraction myself. At since the surgery, we fi nally decided to that time I’ll make the decision about explant the lens. However, the patient whether to do an LRI, LASIK or a lens “If you ignore then came in so that we could redo all exchange. the measurements, and he announced “If it’s because of toric lens rota- complaints, even that his vision was suddenly fi ne. We tion, the sooner you correct it, the bet- if you don’t think remeasured to see for ourselves, and ter,” says Dr. Yeu. “Some technologies, sure enough, all the problems had such as the iTrace from Tracey Tech- they’re well-founded, gone away. nologies, can measure the internal you’ll end up with an “The lesson we learned was to stick aberrations and determine what the to our protocol,” Dr. Crotty concludes. best position of the toric IOL should unhappy patient.” “Things really do change over time. be. There’s also a free application at —R. Bruce Wallace, MD That’s why we don’t like to do anything astigmatismfi x.com that can help you with a patient until about 12 weeks correct the problem. If you use that, after surgery. This patient is now per- it’s very important to know exactly fectly happy and doing well, and we what the position of the toric lens is didn’t have to do a thing. But it took a at present; then that information has Dr. Aminlari agrees. “Often, I fi nd little handholding and patience on the to be coupled with a very careful, ac- that the problem is more of a postop- part of both doctor and patient to get curate manifest refraction, either done erative dry eye issue,” he says. “That’s through two months of poor vision.” by you or by an expert refractionist. why I want to give patients time to get Accurate data will be essential for de- off of their postoperative medications Postoperative Pearls termining exactly how much the lens and use some aggressive artifi cial tears implant should be rotated in order to before I make any of those decisions.” These strategies can help manage minimize the patient’s postoperative Robert T. Crotty, OD, clinical direc- premium patients who present with refractive error.” tor at Wallace Eye Associates, says that postoperative concerns: As long as the problem isn’t tied to his experience has confi rmed the idea • Don’t ignore postoperative a toric lens rotating inside the eye, Dr. that it’s crucial to wait several months complaints, even if you feel they’re Yeu says it’s important to wait to ad- before trying to compensate for an unjustified. “This has to be under- dress the problem until the patient is imperfect result. “Recently, Dr. Wal- stood by the entire team, not just the fi nished with the postoperative drops. lace put toric multifocals in both eyes doctor,” Dr. Wallace points out. “That “If the patient is on generics, I will ei- of a patient,” he says. “The fi rst eye includes the technicians and every- ther switch over to a less-frequent dos- was great; everything went as planned one taking care of the patient. Patients ing regimen, or initiate preservative- and the patient was very happy. Then want to feel that you care. If you ignore free medications,” she says. “Some we did the second eye and ended up complaints, even if you don’t think patients just have a really tough time with a little residual astigmatism, and they’re well-founded, you’ll end up with preservatives. It’s not common, in a different direction than we would with an unhappy patient. At the least, but I’ve seen patients whose ocular have expected. The lens was correct- have the patient return for remeasur- surface looks like it’s taken a beating ly aligned; there wasn’t any rotation ing and don’t charge for the visit. This

April 2019 | reviewofophthalmology.com | 37

0030_rp0419_f1.indd30_rp0419_f1.indd 3737 33/22/19/22/19 12:0512:05 PMPM Cover Cataract Patients

REVIEW Focus

Preoperative Pearls for Preventing Postop Problems Everyone agrees that the best cure for postoperative prob- expect your vision to be perfect. No lens out there is perfect, and lems with premium lenses is preventing them in the fi rst place. they need to know that up front.” Surgeons suggest employing these preoperative strategies to • Make sure patient expectations are realistic. “Most minimize the likelihood of postop trouble: patients have certain expectations that are not reasonable,” • Examine the cornea carefully and address any problems notes Arrdalan Eddie Aminlari, MD, who practices at The Morris before considering implanting a premium lens. “When we’re Eye Group in Encinitas, California. “That’s why it’s so important doing preoperative measurements, one of the things we’re looking to talk to the patient about what to expect postoperatively. I fi nd for is higher-order aberrations, including from the cornea,” says that I spend more time having that discussion with premium lens Robert T. Crotty, OD, clinical director at Wallace Eye Associates. patients than I do explaining glaucoma to my glaucoma patients. “We look for Fuchs’ dystrophy, anterior basement membrane In fact, they have more concerns than my glaucoma patients.” dystrophy and other irregularities. Occasionally, we’ve had Experts also emphasize the importance of covering the pos- patients with nodular degeneration; in that situation we have a sible need for reading glasses postop and the risk of night vision corneal specialist do a superfi cial keratectomy and let that heal for problems. They add that this includes working with doctors in a few months. If the cornea looks better at that point, that patient your referral network, to ensure that they don’t set unrealistic may be a candidate for a multifocal—or more likely an extended- expectations that you will then need to dial down. You can also depth-of-focus lens. Corneal irregularities need to be looked at ask referring doctors to give you a heads-up if an incoming patient very carefully before you talk about premium lenses.” may have characteristics (such as a Type-A personality) that might • Try giving these patients a preoperative personality type prove to be problematic. questionnaire. “We show the patient a bar graph where one end • Make sure the ocular surface is pristine before taking is ‘perfectionist’ and the other end is ‘very easy-going,’ ” explains biometry measurements. “You won’t get accurate biometry if the Dr. Crotty. “We ask the patient to put an X on the line showing patient has dry eye,” says R. Bruce Wallace III, MD, FACS, founder where he or she falls on that spectrum. If I see the X by perfec- and medical director of Wallace Eye Associates in Alexandria, Loui- tionist, I want to talk more to that patient. There’s nothing wrong siana. “You have to address the dry eye in order to get the right with being a perfectionist, but we want the patient to know that numbers for the IOL calculation.” it may be diffi cult to tolerate haloes when driving at night if you (continued on facing page)

is basic stuff, but it helps to keep the potential problems such as macular pterygium, so we have to clean up the patient happy.” edema or signifi cant dry eye. Those ocular surface before we attempt to fi x Dr. Aminlari agrees, noting that it’s things can be treated, potentially im- the astigmatic error.” important to make sure patients know proving patients’ vision, but the ma- • Check for postoperative dry you’re on their side. “Most postopera- jority of patients will have complaints eye. Dr. Aminlari says dry eye is a tive complaints are fi xable, so listening related to high expectations. It’s im- signifi cant factor in his patient popu- to our patients and being an advocate portant to reassure the patient, and lation (partly because he’s located in for them is the most important aspect make them understand that neuroad- California, where it’s usually dry and of postoperative care, in my opinion,” aptation to these lenses can take up to sunny). “Many patients need to be he says. “Certainly don’t write off pa- six months.” treated preoperatively for dry eye, but tient complaints. We may do a perfect • Don’t correct astigmatism I also see it postoperatively,” he says. surgery, but the postoperative period based on topography alone, or be- “Many of the medications we give may not be perfect for the patient.” fore the ocular surface is pristine. these patients postoperatively have • Separate problems that you “We should not be correcting a re- preservatives and can cause dry eye. can address from those that are sidual refractive error based on what So aggressive treatment of dry eye, likely to resolve with time. Dr. we see topographically, especially if both pre- and post-cataract surgery, Aminlari points out that making this there’s a discrepancy between the will be helpful in clearing the surface distinction gets easier with experience. magnitude and meridian of residual of the eye to allow optimal vision. You “That’s why it’s important to talk to astigmatism on topography versus have to remember that the fi rst refrac- patients and understand where they’re what you fi nd using your IOLMaster tive surface of the eye is the tear fi lm, coming from,” he says. “Then, do a or Lenstar,” says Dr. Yeu. “The topog- so to get the best visual function, you very thorough check to make sure that raphy data may also be altered by a have to optimize it.” you’re ruling out the more signifi cant Salzmann’s nodular degeneration or • Make sure your staff is edu-

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0030_rp0419_f1.indd30_rp0419_f1.indd 3838 33/22/19/22/19 5:105:10 PMPM Preoperative Pearls (continued)

• Give every premium patient a macular OCT. “There’s problems are not entirely gone—so you don’t want to tell the enough hidden maculopathy out there that any given patient might patient that they won’t have any of these issues—but they are not be a good candidate for a multifocal implant, but without that less common than with other multifocals.” OCT you won’t know until you’ve operated,” says Dr. Wallace. Dr. Crotty explains that surgeons in his practice shoot for plano “Then you fi nd out that the corrected vision isn’t as good as it to -0.25 D in the dominant eye, and then maybe -0.5 D in the non- should be. A macular OCT will reveal any problem before you dominant eye, to try to improve near vision with extended-depth- proceed.” of-focus lenses. “Those patients have to understand that they’ll • Give patients plenty of preoperative warning about have a little more trouble reading small print or medicine bottles, dysphotopsias. “Virtually all of the multifocals and extended- and when trying to read in dim light,” he says. “If they understand depth-of-focus lenses, to some degree, cause dysphotopsia,” says that on the front end, they’ll do better with that type of lens.” Dr. Aminlari. “Often, in twilight, patients will complain of glare and • Think twice before putting a multifocal in a patient who haloes. With the Symfony lens, for example, they describe a ‘spi- has glaucoma. “I know that some physicians are comfortable derwebbing’ of images. In my experience, patients educated on putting a multifocal in a patient with mild glaucoma, but glaucoma the potential for this have fewer complaints postoperatively. I hear is a progressive disease,” Dr. Aminlari points out. “In 10 years it patients say, ‘It’s not nearly as bad as you made it sound like it could be signifi cantly worse, so someone getting a multifocal now could be.’ And of course I reassure patients that this phenomenon may be in trouble if they develop progressive glaucoma later on. will tend to improve over time.” Also, in the subset of patients with pseudoexfoliation, there’s a • Consider implanting an extended-depth-of-focus lens higher risk of lens instability and potential decentration over time.” instead of a multifocal. Dr. Crotty says that extended-depth-of- • If implanting a multifocal or toric lens in a high myope, focus lenses like the Symfony have some benefi ts relative to other consider using a capsular tension ring. “High myopes with high multifocals. “Some younger patients who work on a computer all axial length have a little more capsular instability,” Dr. Aminlari day need more arm’s-length vision with these lenses,” he says. points out. “For that reason, if we’re putting a multifocal or toric “Even truck drivers may get a little bit better night vision, because lens in those patients, we use a capsular tension ring to provide the haloes and glare issues are noticeably less with extended- more stability for the lens.” depth-of-focus lenses than with a standard multifocal. Those —CK

cated about the lenses you’re us- Things are Getting Better ing these lenses,” he adds. “No one ing. “When we start offering an ad- wants to go back to surgery and take vanced-technology lens, we bring in Implanting premium lenses can a lens out. But it’s important to realize the company representative to speak seem daunting to surgeons who aren’t that the problems that might require a to our staff,” says Dr. Aminlari. “The already doing so, in no small part be- premium lens explantation are pretty rep tells us about some of the experi- cause of the potential for ending up uncommon these days.” ences other physicians have had with with unhappy patients who have paid the lens. Having the staff know about extra money out-of-pocket. However, Drs. Aminlari, Wallace and Crotty these issues enables them to reassure Dr. Wallace hopes that most surgeons have no relevant fi nancial ties to any patients who have complaints after aren’t put off, because postoperative product discussed. Dr. Yeu is a con- surgery. They can also report to me issues following premium lens im- sultant for Carl Zeiss Meditec and what the patient is saying. plantation have become less and less Bausch + Lomb. “This is especially helpful because frequent. 1. Gupta PK, Drinkwater OJ, VanDusen KW, Brissette AR, Starr CE. sometimes patients are more open “I think a lot of surgeons are afraid Prevalence of ocular surface dysfunction in patients presenting with a technician than they are with to use multifocals because patient ex- for cataract surgery evaluation. J Cataract Refract Surg 2018;44:9:1090-1096. the physician,” he notes. “The patient pectations are so much higher when 2. Wang L, Guimaraes de Souza R, Weikert MP, Koch DD. may not want the doctor to think of you have to pay extra money for what Evaluation of crystalline lens and intraocular lens tilt using a swept-source optical coherence tomography biometer. J Cataract him as a complainer, so he may not you’re getting,” he says. “That’s true, Refract Surg 2019;45:1:35-40. tell the doctor things that he will tell but it’s a problem that can be ad- 3. Trattler W, Donnenfeld E, Majmudar P, et al. Incidence of concomitant cataract and dry eye: A prospective health the technician. That’s another reason dressed. assessment of cataract patients’ ocular surface. IOVS it’s good to have my technician be very “Unfortunately, surgeons hear hor- 2010;51:5411. 4. Woodward MA, Randleman JB, Stulting RD. Dissatisfaction up-to-date with the technology I’m ror stories about certain patients and after multifocal intraocular lens implantation. J Cataract Refract using.” that makes them nervous about offer- Surg 2009;35:6:992-7.

April 2019 | reviewofophthalmology.com | 39

0030_rp0419_f1.indd30_rp0419_f1.indd 3939 33/22/19/22/19 12:0512:05 PMPM Cataract Patients REVIEW Cover Focus Peel Back the Veil on ERM Management

Michelle Stephenson, Contributing Editor

Experts weigh rimary epiretinal membrane times be missed preoperatively,” he is common, with a preva- says. “You don’t want to dilate a pa- in on diagnosis, Plence of 4 to 18.5 percent, tient two weeks postoperatively and and it commonly occurs together see an epiretinal membrane. You re- as well as the with cataracts.1 In patients with ally want to know that ahead of time, both conditions, surgeons say, set- and I think a good macular OCT is timing of the ERM ting realistic expectations and de- the best way to do that.” ciding which procedure to perform procedure. fi rst can improve outcomes and pa- Single or Combined Procedure? tient satisfaction. When a cataract patient presents Role of OCT with an epiretinal membrane, sur- geons will need to decide whether to According to Vance Thompson, perform a combined surgery or per- MD, who is in practice in Sioux form the cataract surgery first and Falls, SD, it’s important to perform address the epiretinal membrane at a optical coherence tomography on ev- later time. “Even if I think it’s best to ery routine cataract surgery patient. perform cataract surgery fi rst, I will “This is mainly because we’re trying usually work with a retinal specialist, to avoid any disappointing visual sur- especially if it’s a pretty signifi cant prise. We also do a full dilated retinal epiretinal membrane,” says Thomas evaluation and examine the macula Oetting, MD, clinical professor of very closely. Sometimes, we have a ophthalmology and visual sciences patient who has an epiretinal mem- at the University of Iowa. “The ret- brane that can be seen on OCT, but ina specialist will talk to the patient is not seen on physical exam. Or, you about the process and the potential may see something subretinal that for addressing the epiretinal mem- you don’t see on your exam,” he says. brane after cataract surgery. Every Nick Mamalis, MD, professor of now and then, the retina specialist ophthalmology at the University will surprise me by saying that he or of Utah’s John Moran Eye Center, she wants the patient to undergo a agrees. “Sometimes, especially with combined procedure.” moderately dense cataracts, we just If the decision is made to do the don’t get a great view, and a very sub- cataract surgery as the fi rst, stand- tle epiretinal membrane can some- alone procedure, the surgeon will

40 | Review of Ophthalmology | April 2019 This article has no commercial sponsorship.

0040_rp0419_f2.indd40_rp0419_f2.indd 4040 33/22/19/22/19 12:1412:14 PMPM H. Michael Lambert, MD need to take the presence warrant surgery.” of an epiretinal mem- Dr. Thompson says brane into consideration. that he never performs “I always ask myself what a combined procedure, I can do for this patient, , and he leaves it up to the either if they need a vit- retina specialist to decide rectomy in the future or which procedure should if they already have de- be performed fi rst. “Most creased contrast sensitiv- retina specialists say it’s ity,” says Dr. Oetting. “So, tough to predict how visu- there are issues regarding ally significant a mild or IOL choice and the pa- sometimes even moder- tients’ propensity to ex- ate epiretinal membrane perience cystoid macular can be and to truly make a edema, because these pa- balanced decision. Many tients are at high risk of The Moran Eye Center’s Nick Mamalis, MD, says that if a patient has a times, they suggest taking developing the condition minor cataract but signifi cant ERM, the retina specialist should perform out a visually significant after surgery. We can try the membrane peel and vitrectomy before the cataract surgery is done. cataract first, so that we to prevent cystoid macu- can quantify how much lar edema using prophylaxis. I always Often, with combined proce- the epiretinal membrane is affect- make a big deal about showing pa- dures, retina specialists like to put ing the patient’s vision. However, an tients the OCT so that they know their ports in first when the eye is epiretinal membrane is not an emer- what it looks like before cataract sur- completely pressurized. “In these gency. Time doesn’t typically affect gery. No matter how much you talk cases, we’ll have them put in their the success of surgery. It can be help- about it, patients are always slightly ports for the vitrectomy, and then ful to have a patient make an edu- suspicious that the cataract surgery put in the irrigation line and keep cated decision based on his or her caused the epiretinal membrane. the pressure fairly low,” Dr. Mamalis vision post-cataract surgery. You just This is one of the main reasons to explains. “Then, I’ll go ahead and don’t want a visual surprise. Patient get an OCT on all routine cataract just do my regular phacoemulsifi ca- expectations are so high with cataract surgery patients.” tion. The only difference is that I put surgery. If you don’t tell them ahead Dr. Mamalis says the decision be- a single 10-0 nylon radial suture in of time that they have an epiretinal tween standalone and combined pro- the cataract wound. Even if it’s a 2.4- membrane and that their vision may cedures depends on how signifi cant mm wound, I’ll still put a suture in not be as good as they were hoping, the epiretinal membrane is. “If it’s there so that there’s no chance of the then they think the surgery caused a dense epiretinal membrane and wound opening during the vitrec- it. And that’s the last thing we want,” there’s a lot of distortion of the reti- tomy. The retina specialist will then he says. na, or if there’s any sign of traction on proceed with the vitrectomy and the Recently, a study was conducted to the retina, then the decision would membrane peel.” assess cataract surgery outcomes in be different than if you were looking If a patient has an insignifi cant cat- patients with epiretinal membranes.1 at a small epiretinal membrane with aract and a very signifi cant epireti- The study was a retrospective clini- minimal distortion, no obvious trac- nal membrane, Dr. Mamalis has the cal database study that included 812 tion and no obvious edema,” he says. retina specialist perform the mem- eyes with primary epiretinal mem- “In the setting of a small epiretinal brane peel with the vitrectomy fi rst. brane and 159,184 reference eyes. membrane, I think it’s all right to “Retina specialists are very good at Compared to the reference eyes, do the cataract surgery fi rst. Then, counseling patients and telling them eyes with epiretinal membrane had if the epiretinal membrane worsens, that one of the side effects of a vit- higher rates of cystoid macular ede- a procedure can be done later. If rectomy is that the cataract will get ma and less postoperative improve- there’s a relatively dense epiretinal worse,” he says. “That can happen ment in visual acuity. membrane and it’s causing traction relatively quickly, and, in these cas- In this study, epiretinal membrane and a lot of distortion, you can per- es, retina specialists will send the eyes assessed four to 12 weeks post- form a combined procedure with a patient back to me for the cataract operatively gained 0.27 logMAR (ap- retina colleague.” surgery when it gets bad enough to proximately three Snellen lines), with

April 2019 | reviewofophthalmology.com | 41

040_rp0419_f2.indd 41 3/22/19 12:14 PM Cover Cataract Patients

REVIEW Focus

200 of 448 (44.6 percent) improving indication to multifocal IOLs, but Outcomes and Expectations by 0.30 logMAR or more (≥3 Snellen not to toric IOLs. “Because you’re lines) and 32 of 448 (7.1 percent) most likely going to do a vitrectomy, Dr. Oetting notes that patients worsening by 0.30 logMAR or more. I would not implant a silicone lens,” with an epiretinal membrane who Reference eyes gained a mean of he says. “Besides those exceptions, I undergo cataract surgery generally 0.44 logMAR (approximately four think the IOL discussion is relatively have a good outcome, but says it’s Snellen lines), with 48,583 of 77,408 simple. The cataract surgery itself important for patients to have re- (62.8 percent) improving by 0.30 log- is relatively straightforward. There’s alistic expectations. “Often, there’s MAR or more and 2,125 of 77,408 really not that much different about some decline in vision that’s related (2.7 percent) worsening by 0.30 log- it. I sometimes will put in a slightly to the retina and some decline in MAR or more. Although all eyes with larger lens, like an Alcon MA50, be- vision that’s related to the cataract, preoperative VA of 20/40 or less im- cause it’s easier to do a vitrectomy and you’re only addressing the cata- proved, only reference eyes with a with a bigger lens. However, I usually ract part,” he says. “Cystoid macular preoperative VA better than 20/40 just use a single-piece acrylic lens.” edema is a real issue, so you have to showed improvement. Cystoid mac- warn patients about that, and you ular edema developed in 57 of 663 Postoperative Considerations have to treat for that. That can be ERM eyes (8.6 percent) and 1,731 a limiting factor for a while, but it of 125,435 reference eyes (1.38 per- Postoperatively, it’s important to typically lasts only for the fi rst two or cent). Epiretinal membrane surgery avoid cystoid macular edema. Dr. three months. Patients can usually was performed in 43 of 663 epiretinal Oetting recommends using the separate the symptoms of the epireti- membrane eyes (6.5 percent). prednisone a little longer. “Instead nal membrane from the symptoms Additionally, an Australian study of doing my usual taper of q.i.d. for of the cataract. I explain these dif- found that combined cataract and a week, then t.i.d. for a week, then ferences before surgery, so they can epiretinal membrane vitrectomy is b.i.d., then q.d. with prednisone ac- recognize that the distortion and the just as effective as consecutive op- etate, I might go 6, 4, 3, 2, 1,” he says. metamorphopsia that comes from erations for improving visual acuity, “I usually give patients a week to heal the epiretinal membrane is not going while reducing the risk of exposing a postoperatively before starting an to get much better with the cataract patient to two separate surgical pro- NSAID. I typically use Acular (ke- surgery, but the glare and the gener- cedures.2 torolac tromethamine, Allergan) and alized blur will improve with cataract This retrospective study included Pred Forte (prednisolone acetate surgery. This helps patients to not be 209 eyes: 62 had cataract surgery pri- ophthalmic suspension, Allergan), disappointed with their outcome.” or to epiretinal membrane peel, 105 as they are inexpensive. We usually Dr. Thompson agrees. “Whenever had combined epiretinal membrane place intracameral moxifl oxacin, so you mention a retinal issue, patients peel and cataract surgery, and 28 we do not routinely use a topical an- get very concerned, because they’ve had cataract surgery after epiretinal tibiotic. I use the NSAID for about heard of things like macular degener- membrane peel. Patients who had a month, and then I assess the pa- ation. It is worth taking time to help cataract surgery before epiretinal tient. If any cystoid macular edema alleviate their fears and set realistic membrane, versus combined surgery, is present, then I will continue it for expectations,” he says. “It’s important had improvements in visual acuity at longer.” to make sure that they’re psychologi- three months (-0.10 vs -0.08) and Dr. Oetting sees patients a year cally handling the explanation well, 12 months post-follow-up (-0.18 vs after cataract surgery to assess the and that their expectations are set for -0.22), with no signifi cant difference epiretinal membrane. “We want to surgery to maximize the chance for between the groups. There was also see how the epiretinal membrane their success.” no difference between the groups is doing and assess whether it has with regard to the proportion of eyes gotten to the point where a retina Dr. Thompson, Dr. Mamalis and that had perioperative or postopera- surgeon might want to do a mem- Dr. Oetting report no fi nancial inter- tive complications. brane peel,” he says. “If there is some est in the specifi c products discussed. functional decline that appears to be 1. Hardin JS, Gauldin DW, Soliman MK, Chu CJ, Yang YC, Sallam IOL Choice related to the epiretinal membrane AB. Cataract surgery outcomes in eyes with primary epiretinal following the cataract surgery, I think membrane. JAMA Ophthalmol. 2018;136:2:148-154. 2. Ng FJ, Allen P, Vote BJ. Combined epiretinal membrane and According to Dr. Oetting, an it warrants having a retina specialist cataract surgery: Visual outcomes. Australian Medical Student epiretinal membrane is a contra- look at the patient.” Journal. April 15, 2018. http://www.amsj.org/archives/6366

42 | Review of Ophthalmology | April 2019

0040_rp0419_f2.indd40_rp0419_f2.indd 4242 33/22/19/22/19 12:1612:16 PMPM COMING 2019 Open your eyes to what’s on the horizon in dry eye.

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RP0119_Sight Sciences.indd 1 12/27/18 3:16 PM Laser for PDR REVIEW Feature The Continuing Role Of Lasers in PDR

Kristine Brennan, Contributing Editor

Though anti- nti-VEGF injections have two choices, and here are the pluses revolutionized the treatment and minuses of both. Given your VEGF is effective, Aof neovascular AMD and di- health and stability, what would you abetic eye disease. Prior to their prefer to do?’ By and large, Pro- experts say it still FDA approval—and in the case of tocol S from the DRCR.net [Dia- bevacizumab, off-label use—pan- betic Retinopathy Clinical Research may be best to retinal photocoagulation was the Network] demonstrated that visual standard of care for diabetic reti- acuity is about the same with both,” start with PRP in nopathy. Laser treatment, however, he says. has drawbacks, including loss of pe- DRCR.net Protocol S compared some patients. ripheral vision and night vision over visual-acuity outcomes in high-risk a course of repeated treatments. PDR patients who received ranibi- Furthermore, although successful zumab injections and laser treat- laser treatment helps prevent sig- ment.2 Patients were randomly nifi cant vision loss, it may not yield assigned to PRP or to six intravit- improved visual acuity to the same real ranibizumab injections, ad- degree that anti-VEGF therapy ministered every four weeks, and can.1 Here, retina specialists explain then PRN at follow-up. The study why retinal laser treatments are still showed noninferiority of visual out- vital for managing PDR, even as the comes with ranibizumab therapy hunt for less burdensome, more ef- in comparison to PRP. “The visual fective therapies continues. fi elds are generally better and fuller in patients who receive anti-VEGF Choosing One or Both therapy, so those patients have bet- ter peripheral vision. But overall, “I think it’s best handled as a con- VA-wise, outcomes are about the versation between physician and same,” says Dr. Stewart. patient,” says Michael W. Stewart, The patients who got ranibizum- MD, professor and chair of ophthal- ab in Protocol S, however, showed mology at the Mayo Clinic Florida less progression of their PDR than in Jacksonville, in reference to the did those who underwent PRP, and task of helping PDR patients choose more regression of central macular whether to try anti-VEGF, laser or thickness. They also didn’t require a combination of both modalities. vitrectomy as often as the patients “You can start by saying, ‘Here are treated with laser.

44 | Review of Ophthalmology | April 2019 This article has no commercial sponsorship.

0044_rp0419_f3.indd44_rp0419_f3.indd 4444 33/22/19/22/19 12:4012:40 PMPM A prospective, interventional case of which therapy ophthalmologists however. “I want to be clear that series was conducted in 17 patients and patients choose. “PRP is still an I’m not against anti-VEGF; in fact, I (20 eyes) with high-risk PDR, who essential therapy for patients with often combine the two treatments,” were treated with intravitreal beva- PDR,” he says. “It’s impossible to he stresses. “In cases where patients cizumab (2.5 mg) followed by PRP guess who is going to be adherent present with vitreous hemorrhage, when the peripheral vitreous be- with regular visits. By five years, I will often start with anti-VEGF came clear, or two weeks after in- only 66 percent of patients in Pro- until the hemorrhage has cleared jection.3 Although this was a small tocol S followed up, and that was a enough to permit laser treatment. study (20 eyes of 17 patients) with a clinical trial, where there is gener- Also, patients with center-involving mean follow-up of 7.5 months, the ally much closer attention paid to diabetic macular edema need anti- Snellen visual-acuity testing and fl u- these patients.” VEGF therapy. In both of those sce- orescein angiography suggested that narios, I’ll try to add PRP as soon combined intravitreal bevacizumab as it’s feasible to do so; and I make and PRP was an effective treatment it very clear to the patient that the option. “I think [the physician injection is only a temporizing mea- At 52 weeks, the Clinical Effi cacy sure. In cases of PDR with high-risk of Intravitreal Aflibercept Versus and patient] can agree characteristics and no vitreous hem- Panretinal Photocoagulation for in certain cases that orrhage or macular edema, I will Best Corrected Visual Acuity in go immediately to PRP. But I think Patients with Proliferative Diabet- anti-VEGF would be every practice also needs to imple- ic Retinopathy (CLARITY) study ment a tracking system for these demonstrated that patients treated a better choice, after patients, with calls and letters if they with intravitreal afl ibercept had bet- taking into account miss appointments,” he says. ter outcomes than patients who re- “We know that PRP has a more ceived PRP at one year.4 concerns such as permanent effect on regression of treatment burden, cost neovascular disease, which has been What Does it All Mean? well documented in long-term fol- and the possibility of low-up studies,” Dr. Hsu continues. What do such findings suggest non-compliance.” “However, the long-term effects of for the future of ophthalmic laser anti-VEGF therapy on controlling treatments for PDR? “I think it’s — Michael W. neovascularization are somewhat patient-dependent, but I personally unclear. The DRCR network fi ve- think the fallback is always laser,” Stewart, MD year Protocol S results indicated says Dr. Stewart. “The physician and that most patients still needed, on the patient would need to reach an average, three injections even in agreement in any individual case. Dr. Hsu and colleagues have pub- year fi ve, suggesting that anti-VEGF So I think they can agree in certain lished two studies: one looking at monotherapy will require ongoing cases that anti-VEGF would be a factors that increase the risk of loss treatment in the long run to main- better choice, after taking into ac- to follow-up in PDR patients5 and tain its effi cacy,” he says. count concerns such as treatment the other comparing outcomes of The lack of a predictable endpoint burden, cost and the possibility of PDR in patients lost to follow-up for anti-VEGF monotherapy for noncompliance.” who had PRP and anti-VEGF ther- PDR lends credence to the continu- Jason Hsu, MD, co-director of apy.6 ing role of laser treatment, where retina research at Wills Eye Hos- “Given the outcome results we feasible. “I worry that if a patient pital, associate professor of clinical saw in our second study, I would with PDR is lost to follow-up for ophthalmology at Thomas Jeffer- be devastated if even one patient an extended period of time, he may son University Hospital and in prac- of mine who had anti-VEGF mono- suffer irreversible vision loss if no tice at Mid Atlantic Retina in the therapy was lost to follow-up and PRP has been done,” notes Dr. Hsu. Philadelphia area, is in agreement went blind, when that could have “Even the most reliable-appearing about the continuing importance been prevented with PRP,” he patient has unforeseen events, such of lasers—in no small part because says. Dr. Hsu emphasizes that anti- as loss of a job, loss of health insur- noncompliance is a risk regardless VEGF therapy is important, too, ance or an extended illness, since

April 2019 | reviewofophthalmology.com | 45

0044_rp0419_f3.indd44_rp0419_f3.indd 4545 33/22/19/22/19 12:4112:41 PMPM 044_rp0419_f3.indd 46

All images: Jason Hsu, MD 46 characteristics.” in allPDRpatientswithhigh-risk is togetPRPinassoonpossible tients. Asaresult,mygeneralgoal these arebydefinitionsickerpa- right eye, causingsomeretinal striaeinthemacula. diabetic retinopathy. Severe fibrovascular proliferation canbeseenalongtheinferotemporal arcade ofthe Figure 1.Fundusphotoofa51-year-old diabeticwithnopriortreatment whopresented withproliferative photocoagulation, leaving preretinal fibrosis. Visual acuityis20/40. Figure 2.Oneyear later, theactiveneovascular componenthas regressed afterpanretinal REVIEW |

Feature Review ofOphthalmology

Laser forPDR | April2019 alarmed memostwasthatwhen patients atlong-termrisk.“What on anti-VEGFtherapyaloneputs ings convincedhimthatreliance Dr. Hsusaysthathisstudyfi nd- erative retinopathythatthenleadsto back, youdon’t getarunawayprolif- “In casethepatientdoesn’t come disease incasesofnoncompliance. that laseroffersbettercontrolof turned backonagain, once theVEGFdriveis unable toreturn—then they getsickandthey’re come back,orbecause and theycannolonger insurance haschanged to comeback,ortheir they’ve justdecidednot ment—perhaps because es afollow-upappoint- reason thatpatientmiss- tions, andthenforsome vitreal anti-VEGFinjec- a roadofrepeatintra- you takeapatientdown laser treatmentisthatif a bigfactorinfavorof people arenowcitingas eration. Onethingthat an importantconsid- he says.“To me that’s permanent visionloss,” follow-ups accurately.” is goingtoreturnfor study he says.“Whileour after thetreatment,” ever—immediately for ayearormore—if quarter didnotreturn found thatmorethana anti-VEGF orPRP, we who receivedeither we lookedatpatients allow ustopredictwho that thesefactorsdonot residence, therealityis come fromZIPcodeof age adjustedgrossin- based onregionalaver- race, andlowerincome American orHispanic younger age,African- to follow-up,including eral riskfactorsforloss Dr. Stewartagrees 5 identifiedsev- 3/22/19 12:41 PM there are some patients who’ll de- doesn’t have robust evidence to back months? Six years? The longer we’re velop severe proliferative disease it up at this time, either. “Micropulse able to have a sustained anti-VEGF and permanent vision loss as a re- is a great treatment,” he says, “but it’s effect, then the less potential disad- sult,” he says. “But if laser therapy only been used on small numbers of vantage it would have over laser pho- were already in place, that wouldn’t people, and there aren’t any really tocoagulation in the long run, but we be the case. Some people think that good randomized controlled trials. just don’t have such an agent available such a reactivation of the VEGF drive The data doesn’t really support the yet.” is a rebound, and that it may be even treatment. In fact, it probably has no The quest for a better therapy may more exuberant than it was initially.” great advantage over standard laser in go beyond longer-acting anti-VEGF Dr. Hsu found that anti-VEGF-only terms of visual outcomes.” drugs, according to Dr. Stewart. patients he followed fared worse than “Somewhere along the way, we’re go- those who’d been treated with laser.6 ing to have the ability to reverse dia- “Our second study showed that PDR betic retinopathy,” he says. “The anti- patients who had only received anti- “What alarmed me VEGF agents will do that to some VEGF injections prior to being lost degree, in that they’ll reverse what we to follow-up had worse outcomes,” most was that when see as hemorrhages and exudates and he says. “Despite visual acuity being we looked at patients things like that, but they don’t really fairly similar just before being lost to change the underlying perfusion sta- follow-up, the anti-VEGF group had who received either tus as much as we’d like. Somewhere poorer visual acuity upon return and anti-VEGF or PRP, we along the way, we’re going to get a at the fi nal visit, even after a period drug that’s going to help us reverse of retreatment. This may have been found that more than a nonperfusion, and that’s what’s going driven by worsening of the PDR, as to result in a true reversal of retinopa- we saw a signifi cantly higher rate of quarter did not return thy. We don’t know what form that traction retinal detachment in the for a year or more—if will take, and we don’t know what the anti-VEGF group upon return and at biological target would be. But it will the fi nal visit, with a third of the eyes ever—immediately after be a very attractive treatment option developing this complication, ver- the treatment.” when we have it.” sus only about 2 percent in the PRP group. In addition, surgery to repair — Jason Hsu, MD Dr. Stewart receives institutional the TRD was performed in 20 per- research support from Allergan and cent of eyes in the anti-VEGF group; Regeneron; consults for Alkahest; and while no eyes in the PRP group re- is on the advisory board for Bayer. quired TRD repair, suggesting the With regard to pharmaceutical Dr. Hsu receives grant support from severity was much greater in the anti- therapies for PDR, the hunt is still on, Genentech/Roche. VEGF group.” says Dr. Stewart. Durability would be 1. Stewart MW. Treatment of diabetic retinopathy: Recent an important characteristic of future advances and unresolved challenges. World J Diabetes 2016;7:16:333-41. The Search Continues treatments, since compliance is sub- 2. Writing Committee for the DRCR Network, Gross JG, ject to the fallibility of human nature Glassman AR, Jampol LM, et al. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: Dr. Stewart says that other laser and the vicissitudes of life. “Real life is A randomized clinical trial. JAMA. 2015:314:2137-2146. 3. Yang C-S, Hung K-C, Huang y-M. Intravitreal bevacizumab modalities have been tried in com- always more complicated than a pro- (Avastin) and panretinal photocoagulation in the treatment of bination with anti-VEGF injections, spective research trial,” he says, “and high-risk proliferative diabetic retinopathy. J Ocul Pharmacol Ther 2013;29:6:550–555. but they haven’t compared favorably in proliferative disease, what we’re 4. Sivaprasad S, Prevost TA, Vasconcelos JC, et al. Clinical effi cacy of intravitreal afl ibercept versus panretinal to PRP. “People have pursued periph- worried about is the compliance issue. photocoagulation for best corrected visual acuity in patients eral photocoagulation as an adjunct to There’s the very real risk of runaway with proliferative diabetic retinopathy at 52 weeks (CLARITY): A multicentre, single-blinded, randomised, controlled, phase anti-VEGF therapy for the treatment proliferative disease. 2b, non-inferiority trial. Lancet 2017; 389:10085:2193-2203. 5. Obeid A, Gao X, Ali FS, Talcott KE, Aderman CM, Hyman L, of macular edema, as a way of down- “It’s possible that better future Ho AC, Hsu J. Loss to follow-up in patients with proliferative regulating VEGF,” he says. “Thus far, treatments would be able to be put diabetic retinopathy after panretinal photocoagulation or intravitreal anti-VEGF injections. Ophthalmol 2018;125:1386. it’s been disappointingly unsuccessful. into the eye at less-frequent intervals, 6. Obeid A, Su D, Patel SN, Uhr JH, Borkar D, Gao X, Fineman MS, Regillo CD, Maguire JI, Garg SJ, Hsu J. Outcomes of Theoretically, it makes great sense, but we really don’t know how to best eyes lost to follow-up with proliferative diabetic retinopathy but practically it’s just never worked.” define a ‘longer-acting’ treatment,” that received panretinal photocoagulation versus intravitreal anti-vascular endothelial growth factor. Ophthalmol He says that micropulse laser therapy Dr. Stewart adds. “Would it be six 2019;126:3:407-13.

April 2019 | reviewofophthalmology.com | 47

0044_rp0419_f3.indd44_rp0419_f3.indd 4747 33/22/19/22/19 12:4112:41 PMPM Artificial Iris REVIEW Feature The Artifi cial Iris In Practice

Christopher Kent, Senior Editor

The fi rst approved lthough customized intraocular appearance by eliminating visible iris replacements for a damaged defects. The prosthesis is custom-de- iris prosthesis Airis have been available for signed to mimic the appearance of some time outside the United States, the patient’s other (undamaged) iris, is helping many it’s only recently that the CustomFlex based on photographs approved by Artifi cialIris, created by HumanOp- the patient and surgeon. The pupil patients—although tics in Germany, became the first opening has an undulated edge re- stand-alone prosthetic iris to receive sembling that of a natural iris. it has limitations. approval from the U.S. Food and When implanting the device, the Drug Administration. To date, there’s outside diameter is cut to the appro- still no billing code allowing fi nancial priate size for the patient’s eye using reimbursement for implanting the de- a trephine. The CustomFlex can be vice, but surgeons are nevertheless inserted into the ciliary sulcus using a pleased to have something to offer sclerocorneal approach, or via “open patients who need an iris prosthesis. sky” during penetrating keratoplasty. Here, surgeons who have implanted (The company notes that the device the device share some of their experi- can also be implanted in the capsular ence and advice. bag.) It comes in two formats: with or without fi ber. The former design al- Characteristics of the Device lows suturing of the device, if needed; the latter design does not. The CustomFlex ArtificialIris is a The FDA approval followed a non- fl exible, biocompatible silicone device randomized clinical trial involving 389 indicated for use in adults or children patients. More than 70 percent of sub- with congenital aniridia and/or iris jects receiving the implant reported a defects. It has a black, opaque back signifi cant decrease in light sensitivity surface that completely absorbs light, and glare, and significant improve- only allowing light to pass through ments in health-related quality of life. the fi xed, central 3.35-mm aperture. Furthermore, 94 percent reported Compared to vision with a damaged satisfaction with the outcome. Com- or missing iris, this improves contrast plication rates were low; they included sensitivity, reduces glare and light dislocation, strands of device fi ber in sensitivity and eliminates transillumi- the eye, increased IOP, iritis and the nation defects. The Customflex can need for additional surgery to reposi- also improve an individual’s cosmetic tion, remove or replace the device.

48 | Review of Ophthalmology | April 2019 This article has no commercial sponsorship.

0048_rp0419_f4.indd48_rp0419_f4.indd 4848 33/22/19/22/19 12:1812:18 PMPM Kevin M. Miller, MD The Patient Experience

“These can be some of the most gratifying cases an ophthalmologist may encounter,” says Michael E. Sny- der, MD, who practices at the Cin- cinnati Eye Institute and is volunteer assistant professor at the University of Cincinnati School of Medicine. “Pa- tients who get the custom, fl exible ar- tifi cial iris often refer to the experience as being ‘life-changing.’ As one might expect, many folks with iris damage or deformities have suffered with light sensitivity, glare, halos, arcs and mon- ocular shadow images. In the over- whelming majority of patients, most or all of the patient’s photic symptoms are relieved after device placement. How people feel about the restoration of a more normal appearance to their An example of an excellent outcome. Top images: This patient suffered a blunt injury to her left eye following phakic intraocular lens implantation; the iris and the implantable contact eyes can also be quite dramatic. lens were expelled, leaving her aniridic with a cataract. She then underwent cataract “As ophthalmologists, we often extraction with intraocular lens implantation and passive fi xation of a dark brown custom don’t appreciate the degree to which artifi cial iris in the ciliary sulcus. Bottom images: Three months later the color match is patients feel like their vision is washed excellent and the iris is perfectly centered. out because of the iris defects,” he continues. “This is especially true in suffered trauma, leaving them with a cornea may be hazy; abnormal corneal pseudophakes. As it turns out, any boatload of other issues,” he says. “By blood vessels may have grown in; and light that enters the eye around the and large, these are sick eyes. Their severe dry eye, epitheliopathy, nys- periphery of the IOL margin is defo- cornea is often decompensating; many tagmus or early cataracts may also be cused. This affects vision much like have glaucoma as a side effect of the present. Aniridic capsules are thin and the experience of being in a movie trauma; they may have double vision, easy to tear, and these patients often theater when someone opens the door a retinal detachment or silicone oil in have glaucoma. So even the nontrau- to the theater, letting light in from the the eye. An iris defect is just one of matized eyes have lots of comorbidity. outdoors. Even though the projector their problems. For example, I had a “Because of that, when we do sur- is still focused on the screen with the patient whose eye was gutted when gery on these eyes, we try to fix as same number of lumens of light, the a bungee cord snapped and the hook many of these problems as we can,” viewing experience is diminished by on the end ripped through his eye and he explains. “We might be doing a cor- the defocused excess light.” lids. Another patient had his globe neal transplant, lens exchange, cata- Kevin M. Miller, MD, Kolokotrones ruptured by fl ying glass from a broken ract removal or a host of other things. Chair in Ophthalmology at the David bottle. In my experience, 95 percent The recovery may be long and dif- Geffen School of Medicine, UCLA, of the cases needing an iris are like fi cult, not because of the artifi cial iris, was an investigator during the FDA that.” but because of all the other problems. clinical trial of the artifi cial iris. Many What about patients whose eyes Once a corneal transplant is healed, of the patients he now treats that re- haven’t suffered trauma? “It’s a rare the patient may have double vision, ceive an artificial iris have suffered patient in my practice who is born so we have to fi x that. Once we fi x the serious ocular damage, and he notes with some or all of the iris missing, double vision the patient might have that it’s not always easy to determine although we do see a few,” says Dr. a blepharoptosis and we might have how these patients feel about receiv- Miller. “But even those patients have to fi x that. Some of these problems go ing an artifi cial iris, because they have additional comorbidities. A congenital on for years and years. As a result, the so many other ocular problems. “Pa- anaridic, born without an iris, may patient’s feelings about the artificial tients with iris defects typically have have a limbal stem cell defi ciency; the iris are hard to capture because they

April 2019 | reviewofophthalmology.com | 49

048_rp0419_f4.indd 49 3/22/19 12:18 PM 048_rp0419_f4.indd 50 to theirisinrighteye islessthanideal. and custom-paintedblueartificial iris. The irisisinferiorlydecentered andthecolormatch penetrating keratoplasty andscleral suture fixation ofaposteriorchamber intraocular lens andnoiris.Bottomimages:scarred cornea The patient’s appearance three monthsafter thatresulted inexpulsion ofhisirisandlens. injury lefthimaphakicwithabadly The injury An example ofanimperfectoutcome. Top images: This patientsuffered aruptured globe

50 Kevin M. Miller, MD ance ofmostpatients’eyes.” and itimprovesthecosmeticappear- the lightandglaresensitivityproblem, not,” hesays.“Theartifi cial irissolves had theartificial irisputin?Defi “Does anybodyeveryregrethaving unhappy withtheartifi cial irisitself. notes thatpatientsarerarely, ifever, go throughsomuch.” native iristissue.Arealistic expecta- appearance canvaryabitmore than ditions,” Dr. Snyderexplains.“The the deviceindifferentlightingcon- variations incolorandluminosityof of thefelloweye,therecanbesubtle made tomatchanindexphototaken diffi cult thanitmaysound. sense, gettingaperfectmatchismore to theothereye’s irismakesperfect the appearanceofartificialiris The ChallengeofIrisMatching Despite thesecaveats,Dr. Miller “While thedevicesarecustom- Although thepremiseofmatching REVIEW |

Feature Review ofOphthalmology

Artificial Iris | April2019 nitely nitely addressing, suchasscarring froma because oftheotherproblems we’re First, theymayhavecosmetic issues for manypatients,tworeasons. not perfect.Infact,it’s farfromperfect says Dr. Miller. “However, it’s usually the cosmeticappearanceofeye,” down, mostpatientsarepleasedwith cialIris isroughly4mm.” with anindwellingCustomFlexArtifi ingly, theapparentpupilsizeinaneye magnifi the pupilasseenthroughcornea’s entrance pupil,ortheappearanceof as pupilsizeisactuallytheof we ophthalmologistsusuallythinkof observed fromoutsidetheeye.“What (3.55 mm)isdifferentfromthesize actual diameteroftheartifi lighting.” tail partydistance’innormalroom to, thefelloweyeatwhatIcall‘cock- look eitherthesameas,orverysimilar tion isthatthecustomiriswilltypically “I’d say that after the eye has settled “I’dsaythataftertheeyehassettled Dr. Snyderalsopointsoutthatthe cation,” heexplains.“Accord- cial pupil pupil cial - one thing, you have to show that you one thing,youhavetoshow that you a numberofcriteria,”henotes. “For let youimplanttheseunless meet artifi the otherissueseyepresents. sometimes it’s verydiffi cult becauseof Series injectorandunfoldit.But just injectitusinganAMOSilver plant,” hesays.“Sometimesyoucan “In somecasesit’s veryeasytoim- depending onthepatient’s situation. planting theartifi cial irisvarieswidely How HardIsIttoImplant? and brightnessisverychallenging.” for allofthis,butmatchingthecolor course, wedoourbesttocompensate than whenyouholditinyourhand.Of it looksmuchlighterinsidetheeye focuses alotoflightontotheiris,so artifi is alteredalittlewhenyouplacean rors. Lastbutnotleast,thebrightness printing processintroducescolorer- image onpapertosendit,andthe camera. Thenwehavetoprintthe spectral sensitivityofthefi lm ordigital color saturationintheimageand lighting whenthephotoistaken, perfect colormatching,includingthe along thewaythatcouldresultinim- But youcanimagineallofthesteps based onthephotographtheyreceive. where artistspainttheprostheticiris graphs ofthefelloweyetoGermany, the irisisn’t perfect.We sendphoto- process bywhichthecompanypaints artifi efforts,” hecontinues.“Althoughthe the othereye,despiteeveryone’s best can leadtoanimperfectmatchwith how goodtheartificial irislooks. too goodaboutyoureye,regardlessof you’ve beenthrough,youmaynotfeel infl brown iris,butyoureyeischronically or aptosis.Ifyouhaveniceartifi corneal transplant,amisalignedeye “The companythat’s distributingthe Dr. Millersaysthediffi culty of im- “Second, therearemanyfactorsthat amed becauseofallthesurgeries cial iris,VEOOphthalmics,won’t cialirisinsideaneye.Thecornea cial irisesarehand-painted,the cial cial 3/22/19 12:18 PM SERVICE SOLUTIONS

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RP0419_Lombart.indd 1 3/21/19 11:04 AM Feature Artificial Iris REVIEW

have considerable experience doing Michael E. Snyder, MD result, the pupil is often a little bit off- complex ophthalmic maneuvers inside center. When suturing it in an open- the eye. You have to have experience globe configuration, which is what with lens exchange and related pro- we do most of the time, it’s very hard cedures. That makes sense, because to center the device. You don’t really these eyes are often very complex, know how the iris is going to sit rela- messed-up eyes, and it takes a surgeon tive to the center of the cornea until with a broad skill set to be able to deal the eye is closed up and pressurized. with all of the other issues that may ac- By that point, if it’s not perfectly cen- company implanting an iris. The com- tered, there’s too much trauma associ- pany doesn’t want to have surgeons ated with reopening the eye to start with limited experience attempting to over again, so we generally don’t. implant these devices and making the “How obvious any decentration is eye worse than it was to start with.” depends partly on the color of the iris,” Dr. Snyder says there defi nitely is Dr. Miller adds. “If it’s a light blue or a learning curve to implantation. “As green iris, it can be very obvious when with surgery in any complex eye, some it’s not perfectly centered. If it’s a dark cases are harder than others,” he notes. brown iris, nobody can tell.” “VEO Ophthalmics, the distributor Dr. Snyder notes that patients need of the CustomFlex, has developed a to understand that the prosthesis won’t rather robust training program; sev- address other visual issues. “Eyes that eral investigators from the initial study benefit from an iris prostheses also serve as mentors to new implanters. tend to have other comorbid patholo- Surgeons who are experienced and gies,” he points out. “Visual limitations Even when the color match is excellent facile in complex cases such as scleral- are more commonly set by these other and the artifi cial iris is well-centered, the sutured PCIOLs, or cases involving changing size of the natural iris in the other factors.” vitreous management in the anterior eye can cause the eyes to be an imperfect Dr. Miller agrees. “We have to put segment or management of zonulopa- match in bright or dim lighting conditions. this in the context of all of the other thy, will fi nd their skill sets will serve problems these patients present with,” them well as they acquire experience fect, both in terms of appearance and he says. “If the patient has a macula- working with iris prosthesis patients.” in terms of resolving visual diffi culties. off retinal detachment and a dense The manufacturer notes that the “As with any procedure, setting pa- cataract and a cornea scar, we’re going CustomFlex should not be implanted tient expectations is important,” says to do our best to fi x all of this. How- in patients who are pregnant, or have Dr. Snyder. “It’s worth mentioning ever, the patient will still have issues an active ocular infection or uncon- that the fellow eye’s pupil size will be postoperatively because of all of these trolled inflammation; any untreated changing with ambient light while the other problems, and there will prob- medical issues that are potentially custom iris aperture stays constant. As ably be additional surgeries in the pa- vision-threatening; rubeosis of the a result, in bright sunlight the fellow tient’s future. We have to make sure iris; proliferative diabetic retinopathy; eye may have a smaller pupil than the the patient understands this. Don’t Stargardt’s retinopathy; or any disor- pseudopupil of the custom iris, while oversell the fi nal result.” der that might cause the eye to be in a very dim room, the fellow-eye • Don’t be shy about deciding abnormal in size, shape or function. pupil may appear larger.” to learn the procedure. “If you oc- Iris color may also be a giveaway in casionally treat patients with trauma- Strategies for Success some cases. “The match [between the tized or missing irides, this should be eyes] should be close, but the colors part of your armamentarium,” says Surgeons offer these suggestions will be off a little bit,” notes Dr. Miller. Dr. Miller. “There is a learning curve, to increase the likelihood of ending “As a result, in about half of these eyes but you have to take the fi rst step at up with a good outcome and a happy you can’t tell that the patient has an some point. Most of the procedures patient: artifi cial iris, but in others, you can tell. we do have a prescribed certifi cation • Don’t overpromise the result. “Also,” he continues, “it’s hard to protocol that you have to go through, Patients need to be forewarned that perfectly position the iris inside the and expanding your skill set is an im- the outcome could be less than per- eye when suturing it in place. As a portant part of being a surgeon.

52 | Review of Ophthalmology | April 2019

048_rp0419_f4.indd 52 3/22/19 12:19 PM Technology

REVIEW Update

“However,” he adds, “if you only encounter a trauma- (Continued from page 20) tized or missing iris once a year, it probably makes more sense to refer that patient to another surgeon. You need In a study involving the nGoggle, researchers (some of to do a lot of these surgeries to become good at it, and you whom have a fi nancial interest in nGoggle Inc.) sought won’t become good at it doing one patient every year.” to objectively assess visual function loss in 62 eyes of 33 • Be prepared to implant the iris for free. “If you’re glaucoma patients. Each subject underwent VF testing going to get into this, you’re going to be doing it for free for using the nGoggle and a standard automated perimetry a while,” Dr. Miller points out. “There’s no billing code for test over the course of three months. The nGoggle was this right now, so patients pay for the iris, but the surgeon able to distinguish between healthy eyes and those with does the surgery for free.” glaucomatous neuropathy.9 Researchers measured values • If a cataract patient needs an artifi cial iris, don’t such as receiver operating characteristic curves sum- do the cataract surgery fi rst and then refer the pa- marizing diagnostic accuracy, intraclass correlation coef- tient for the other procedure. “I’ve had patients re- fi cients and coeffi cients of variation for assessing repeat- ferred to me this way, with the best of intentions,” says Dr. ability. The ROC curve area for the nGoggle mfSSVEP Miller. “It may be a simple case, like congenital anaridia was 0.924 (95% CI: 0.863-0.964), which was larger than with a cataract. The other doctor says, ‘I’ll take out your SAP MD (AUC=0.813; 95% CI: 0.716-0.896), SAP MS cataract and it will make you better.’ Actually, it makes (AUC=0.797; 95% CI: 0.687-0.880; p=0.030) and SAP them a lot worse. Their glare sensitivity usually gets much PSD (AUC=0.768; 95% CI: 0.657-0.858; p=0.012).9 worse after the cataract comes out, because now light hits As the nascent field of portable visual field testing the edge of the IOL implant and the capsule that’s opaci- continues to develop, we’re reminded of how much fi ed around the implant. technological advancements play a role in enabling new “These patients should have the iris implanted at the diagnostics, that don’t need to be restricted to the medi- same time the cataract surgery is done,” he explains. “Be- cal offi ce. These new enhancements may make visual sides leaving the patient with worse vision, separating the fi eld exams more interesting, faster and more reliable. surgeries results in a much greater cost to the patient. If we Moving forward, generating more functional visual data do both surgeries at once, we can bill for the cataract sur- will be useful for quantifying rates of progression more gery and put in the artifi cial iris for free. If the only reason accurately to match with optimally timed interventions. for the trip to the OR is to implant the iris, the patient may Automated algorithms will continue to improve as we be looking at a huge bill for both the iris and the trip to the enter the era of big data, driven by Internet-connected OR. That OR cost would have been covered by insurance portable devices. if both surgeries had been done at the same time.” Robert Chang, MD, is an ophthalmologist at Byers Eye At Last, an Option Institute at Stanford Eye Institute.

As mentioned earlier, the CustomFlex is now being dis- 1. Kucur S, Holló G, Sznitman R. A deep learning approach to automatic detection of early glaucoma from visual fi elds. PLoS One 2018;13:11:e0206081. doi: 10.1371/journal.pone.0206081. tributed through VEO Ophthalmics. It takes four to eight eCollection 2018. weeks for the custom iris to be delivered after receipt of 2. Ting DSW, Pasquale LR, Peng L, Campbell JP, Lee AY, Raman R, Tan GSW, Schmetterer L, the order and the approved photographs. Keane PA, Wong TY. Artifi cial intelligence and deep learning in ophthalmology. Br J Ophthalmol 2019;103:167-175. “I’m glad we finally have an approved artificial iris,” 3. Li F, Wang Z, Qu G, Song D, Yuan Y, Xu Y, Gao K, Luo G, Xiao Z, Lam DSC, Zhong H, Qiao Y, says Dr. Miller. “Only a few patients will need the iris, Zhang X. Automatic differentiation of glaucoma visual fi eld from non-glaucoma visual fi led using fortunately, but it’s nice to fi nally have something we can deepconvolutional neural network. BMC Med Imaging 2018;18:1:35. 4. Asaoka R, Murata H, Iwase A, Araie M. Detecting preperimetric glaucoma with standard offer when patients have a messed-up eye. Artifi cial pupil automated perimetry using a deep learning cassifi er. Ophthalmology 2016;123:1974-80. contact lenses are hard and uncomfortable to wear, and 5. Johnson CA, Thapa S, George Kong YX, Robin AL. Performance of an iPad application to detect they don’t really solve all of the problems that come with moderate and advanced visual fi eld loss in Nepal. Am J Ophthalmol 2017;182:147-154. 6. Prea SM, Kong YXG, Mehta A, He M, Crowston JG, Gupta V, Martin KR, Vingrys AJ. a disrupted or missing iris. The only other alternatives are Six-month longitudinal comparison of a portable tablet perimeter with the Humphrey Field tinted glasses and patching the eye. Now we have an op- Analyzer. Am J Ophthalmol 2018;190:9-16. tion that didn’t exist before.” 7. Vingrys AJ, Healey JK, Liew S, Saharinen V, Tran M, Wu W, Kong GY. Validation of a tablet as a tangent perimeter. Transl Vis Sci Technol 2016;5:4:3. eCollection 2016 Jul. For more information about obtaining the device, visit 8. Tsapakis S, Papaconstantinou D, Diagourtas A, Droutsas K, Andreanos K, Moschos MM, Brouzas veo-ophthalmics.com. D. Visual fi eld examination method using virtual reality glasses compared with the Humphrey perimeter. Clin Ophthalmol 2017;11:1431-1443 9. Nakanishi M, Wang YT, Jung TP, Zao JK, Chien YY, Diniz-Filho A, Daga FB, Lin YP, Wang Y, Medeiros Dr. Snyder is a consultant for HumanOptics. Dr. Miller FA. Detecting glaucoma with a portable brain-computer interface for objective assessment of has no relevant fi nancial interests. visual function loss. JAMA Ophthalmol 2017;135:6:550-557.

April 2019 | reviewofophthalmology.com | 53

0048_rp0419_f4.indd48_rp0419_f4.indd 5353 33/22/19/22/19 3:303:30 PMPM Cataract Patients REVIEW Cover Focus MSICS and miLoop for Non-phaco Candidates

Alexandra Skinner, Associate Editor

What to do when hacoemulsification has be- cataract, the procedure can cause come the status quo for stress to the endothelium. Nick Ma- the gold standard, Psurgeons performing cata- malis, MD, a professor of ophthal- ract removal in the United States. mology at John Moran Eye Center, phaco, isn’t an However, even this gold-standard University of Utah notes, “If you technique has its drawbacks. Some have someone with an endothelial option. patients cannot safely undergo a dystrophy, you want to remove the phaco procedure due to underlying lens nucleus with as little energy as endothelial issues or mature cata- possible.” racts. Also, for many locations in the On a similar note, even if a patient developing world, phaco is not an has no existing corneal issues, if he economical option. While phaco may has a very hard cataract, he’ll have to be the current surgical approach of undergo extended phacoemulsifi ca- choice, techniques like sutureless tion to break it up, which can still manual small incision cataract sur- pose problems. Hunter T. Newsom, gery and devices like the miLoop can MD, medical director of Newsom play a role in cataract removal for Eye and lifetime visiting professor at non-phaco candidates in the United the University of Iowa says, “When States and in the developing world. you have a cataract that’s extremely Here, experts share their tips and hard and dense, you have to use a techniques for cataract surgery in large amount of phaco, and that’s patients who can’t, or shouldn’t, un- going to cause a more significant dergo phaco. amount of energy to be put inside the eye, which is going to damage The Non-phaco Candidate the corneal endothelium.” Patients in the developing world Several factors can make a patient frequently present with advanced a better candidate for a procedure cataracts. “Oftentimes in the devel- other than phaco. These include hav- oping world you have patients with ing a weak corneal endothelium or a relatively hard, dense, leathery dense cataract, or living in the de- nucleus, which requires a lot of ul- veloping world with limited access to trasound energy to remove,” says health-care resources. Dr. Mamalis. On a recent trip to Since phacoemulsifi cation delivers South Sudan, Alan Crandall MD, ultrasonic energy as it breaks up the the John A. Moran Presidential Pro-

54 | Review of Ophthalmology | April 2019 This article has no commercial sponsorship.

0054_rp0419_f5.indd54_rp0419_f5.indd 5454 33/22/19/22/19 12:3412:34 PMPM Hunter T. Newsom, MD fessor, senior vice chair and som expands on this idea, director of glaucoma and citing added costs associ- cataract at the Moran Eye ated with the disposable Center, says, “All we saw instruments and acces- were dense, white, some- sories. “Single-use is the times black cataracts.” Also, way that all modern phaco in some parts of the world, machines are trending,” it’s not possible to set up a he says. “It’s very rare that fully equipped phaco sur- you have things that are re- gery suite, and other op- usable, and this serves to tions need to be explored. drive costs up, not down.” — MSICS allows you to Manual Small Incision use a sutureless incision, Cataract Surgery which Dr. Mamalis says adds to its feasibility in the As a viable alternative to developing world. “Sutures phaco, MSICS uses little to add an expense and take no ultrasound energy and is increased surgical time very economical. to place,” he says. “When MSICS involves the use you’re in a setting where of a scleral tunnel incision. there are a large number While the incision itself is Figure 1. In the Dominican Republic, patients wait in long lines to of cataract patients and only about 5 to 6 mm long, be evaluated. Dr. Newsom says that doing surgery quickly and you have to do surgery as effi ciently is important where there are a large number of it’s created in such a way quickly and efficiently as cataract patients, and eliminating the need for sutures allows for that it becomes larger as it rapid surgery. possible, eliminating the nears the anterior chamber. need for sutures allows for This aids in the removal rapid surgery.” of the natural lens, which is accom- protect the endothelium, since the Dr. Crandall emphasizes that plished using a syringe or a glide. surgeon doesn’t need to use ener- MSICS still has a place in the United The syringe creates suction, while gy to break it up. Dr. Mamalis says States. “In Utah, we treat refugees the glide uses pressure to gently that the incision is actually wider and people in the Navajo Nation, force the lens out. One of the other as you’re coming out of the ante- and at least once or twice we see a benefi ts, proponents say, is that su- rior chamber. “The advantage here dense, white cataract or a morgag- tures aren’t required with this tech- is that you don’t have to disassem- nian cataract. Those are unlikely to nique, due to the small incision. ble a hard lens nucleus,” he says. be phacoable, so we’ll go ahead and Here’s a closer look at MSICS’ ad- — MSICS can be economical. “The perform an extracap,” he says. vantages, disadvantages, potential instrumentation for extracap in- • MSICS disadvantages. While pitfalls and results. cludes things that can be used mul- MSICS is inexpensive and effec- • MSICS’ advantages. While tiple times,” says Dr. Newsom. This tive, there are disadvantages to the not as technologically advanced reusability helps keep the technique technique. A cornerstone of MSICS as modern cataract removal, some inexpensive. This is one of the main is that the cataract can be removed surgeons say that MSICS—some- reasons that MSICS is such a viable whole. However, this can sometimes times called extracapsular cataract option for those in the developing prove to be more complicated than extraction—has several advantages. world. Comparatively, Dr. Mamalis it sounds. “Even though it’s called — MSICS can effectively re- says there are challenges associated small-incision, you still make a fairly move cataracts without energy, with using phaco in the developing large incision through the sclera and therefore minimizing endothe- world. “Since it’s relatively expensive, the cornea,” Dr. Mamalis says. lial damage. “Extracap applies a there are diffi culties in just getting Dr. Newsom notes other possible lot less trauma to the corneal en- the phacoemulsification machine, incision issues: “If you’re going into dothelial cells,” says Dr. Newsom. he says. “There’s a significant ex- the sclera, you’re going to have to — MSICS allows the cataract to be pense involved with the necessary do a peritomy or go through the removed whole, which also helps tubing, packs and tips.” Dr. New- conjunctiva in some way,” he says.

April 2019 | reviewofophthalmology.com | 55

054_rp0419_f5.indd 55 3/22/19 12:34 PM Cover Cataract Patients

REVIEW Focus Hunter T. Newsom, MD “You’re going to be cutting blood vessels at the limbus and pulling the conjunctiva, and that introduces blood and [the need for] cautery. The eye is going to look a lot redder and more injected.” For the entry wound, Dr. Mamalis prefers a scleral frown incision. “You want to make sure that, as you’re making the scleral incision, you’re at the correct depth and that the inside opening is large enough to allow you to remove the relatively large lens nucleus,” he says. The capsulotomy size can also be a challenge. “Whether you’re doing a can-opener type opening or a con- tinuous capsulorhexis, it can be dif- fi cult to get the large cataract out of the bag and into the anterior cham- ber,” says Dr. Newsom. As a result, Dr. Mamalis says, the surgeon needs to make a capsulorhexis that’s large enough to get the nucleus out of the Figure 2. Minor surgery is conducted on a patient in the Dominican Republic by bag whole. Dr. Newsom suggests us- Hunter Newsom, MD, and his team. ing Trypan blue to help accurately perform the capsulorhexis. damaged or try to come out of the just can’t measure it].” Another consideration is that since wound, which can potentially create In reference to his past work in the extracapsular surgery preceded a hemorrhage.” He adds that there’s Dominican Republic, Dr. Newsom the advent of phacoemulsification, more corneal edema and infl amma- says IOL selection was a challenge. it’s not usually taught to surgeons tion, and that healing is slower for “Determining what type of lens pow- anymore, especially in the United extracapsular surgery compared to er to put in the eye and measureing States. “Newer surgeons don’t do a phaco. astigmatism is diffi cult,” he says. “We lot of extracapsular surgeries,” says In terms of astigmatism, there’s didn’t have the precision of our usual Dr. Mamalis. “To be honest, a lot of only so much that can be done in keratometry measurements.” When our residents aren’t trained on many certain countries. “In the develop- comparing the developing world to extracapsular cases, so it’s unfamiliar ing world, you know there’s going to the United States, he likens the IOL territory to them.” Dr. Crandall adds, be a huge amount of astigmatism, selection-process to getting a pair “It’s hard to teach people this tech- but the cataract is gone and they of shoes; he says that, in the United nique. The problem is that the rate of can see again [which is the most im- States you can choose from many seeing patients with non-phacoable portant aspect of the surgery],” says different numbered sizes, but in the cataracts in the U.S. is small.” Dr. Newsom. Dr. Crandall agrees, developing world, he says, you may • Pitfalls. A few MSICS trouble saying, “The priority is to restore only have sizes small, medium and spots to watch out for include com- vision. We’re talking about people large, “You have what you have, and plications with the procedure itself who are seeing light perception; all there’s not a big selection to choose and the rate of postop astigmatism. they can see is light or dark. First and from,” he says. Dr. Newsom discusses some po- foremost, we’re interested in get- • MSICS results. In a study that tential complications to be aware of. ting patients back on the chart and compared the effi cacy and visual re- “You have all kinds of chamber-depth walking around. It’s not that we don’t sults of two different MSICS meth- issues,” he says. “You’ve got every- care about astigmatism, but when ods, called “modified Blumenthal thing coming up and it tends to bang you have 500 people who have light- and Ruit,” it was found that MSICS on the cornea. With extracap, every- perception cataracts, and you have produces good visual outcomes thing is shallower, and the iris can get fi ve days to perform procedures, [you and only minor complications.1 Af-

56 | Review of Ophthalmology | April 2019

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REVIEW Focus

ter three months, corrected visual In surgery, surgeons say certain United States who may not be able acuity in the Blumenthal group was patient presentations might ben- to undergo phaco, Dr. Newsom says 0.73 (just under 20/25) and 0.69 (a efit from the use of the miLoop. that the miLoop allows him to make little better than 20/32) in the Ruit “MiLoop is useful for people who on-the-spot decisions as to whether group.1 The average postoperative have a very dense, hard, leathery phaco will be too strenuous for a astigmatism was 0.87 ±0.62 D and nucleus that’s diffi cult to disassem- given eye, and therefore shouldn’t 0.86 ±0.62 D for the Blumenthal ble and would require a lot of phaco be used to perform cataract surgery. and Ruit groups, respectively, while energy,” Dr. Mamalis says. “MiLoop is a very interesting option mean surgically induced astigmatism Doctors agree that these patients that I think everyone should have was 0.55 ±0.45 D and 0.50 ±0.44 D, could have issues associated with access to in the operating room,” he respectively.1 Otherwise, noted com- extended phaco time, so in an ef- says. “I want [miLoop] there, ready plications included minimal hyphe- fort to see how gently the device to be opened, so that as I’m doing mas and corneal edema.1 could tackle the nucleus, Dr. Cran- my initial assessment I can deter- dall aided in the creation of the Mi- mine whether I need it based on the The miLoop yake/Apple technique. Using the case, intraoperatively. MiLoop has technique, they confi rmed that the eliminated any reason for a potential Surgeons say the miLoop device, device was very zonular- and cap- extracap.” from Zeiss, can help streamline some sular-bag friendly. “The beauty of Dr. Mamalis says that the miLoop of the steps of MSICS. the miLoop is that it can be used can also be used as a training tool. The miLoop is a relatively inex- [to break up] really hard cataracts,” “MiLoop could allow doctors who pensive and disposable instrument Dr. Crandall says, “since the energy don’t have experience making a made of nitinol, a strong material; is kept away from the bag and the scleral-corneal incision to disassem- it can be injected through a small, zonules. It’s a great skill to know.” ble a nucleus into multiple, smaller clear corneal incision. Once injected, Dr. Mamalis feels that an advan- pieces,” he says. the fi lament loop extends under the tage of the miLoop is that the sur- • Disadvantages. Since it’s the anterior capsule and goes around the geon doesn’t have to make a scleral only device of its kind, Dr. Mamalis nucleus to the equator and then the tunnel. “You can disassemble a hard says there’s a learning curve. “The posterior surface. As the loop is with- nucleus into small pieces that you device works wonderfully but, like drawn, it cuts through the nucleus, can remove through a clear corneal any other technology, it has to be bisecting it. The device can then be incision,” he says. When consider- used properly and it’s important that used to rotate the nucleus and fur- ing the usefulness of the device in people are trained to use it,” he says. ther break it into quarters or even the developing world, he adds that Dr. Mamalis says visualization can smaller pieces. Doctors say no phaco it’s helpful to be able to use a small, be an issue, and there’s also a need to is needed, just a manual irrigation/ clear corneal incision. “Anything have an intact capsule. “Sometimes aspiration handpiece. you can do to make the incision what’s diffi cult with the miLoop is smaller, especially in a developing- that if you have a really dense nucle-

Zeiss world setting, is helpful,” he says. us, once the loop goes behind it, you Dr. Crandall adds that there are sometimes can’t visualize it well,” he two advantages to using the miLoop says. “Also, if you’ve got some tears in international settings. “One is in the anterior capsule or you’ve got that you have the ability to use a an anterior capsular extension, you small incision, since you can break may want to reconsider the use of the nucleus in half, which can be the miLoop.” critical,” he says. “Two, you can use • Technique tips. To get a better Figure 3. miLoop ensnares the lens. foldable lenses.” He also states that handle on the miLoop, Dr. Mama- since the miLoop incision is smaller lis suggests employing the Miyake/ • Advantages. As an alterna- than a conventional, 10-mm extra- Apple technique to view it in action, tive to phaco, some surgeons say cap incision, there may be less in- using a cadaver eye. “You take a do- miLoop is a viable tool for managing duced astigmatism to worry about nated, human cadaver eye and sec- non-phaco candidates in the United postop, though the difference would tion it coronally, at the equator, and States and for medical missions in be small. glue the anterior segment of the eye the developing world. When it comes to patients in the to a glass slide,” he says. “That al-

58 | Review of Ophthalmology | April 2019

054_rp0419_f5.indd 58 3/22/19 12:35 PM EXAM LANE SOLUTIONS lows for simultaneous videoing both can be performed on the machine anteriorly and posteriorly, which is so that it’s working consistently,” he very helpful when you’re evaluating says. Dr. Newsom adds that certain UNIQUE COMBO devices like the miLoop.” This has complications of phaco might be enabled Dr. Mamalis to video the too much for surgeons in less-well- device as it’s sectioning the nucle- equipped countries, as well. “There CHAIR & STAND us, and see what’s happening to the are limited options readily available capsular bag and the zonules. He to fi x a problem,” he says. “If you notes that there are also many vid- have healing issues in the cornea eos available online that can show because of increased phaco energy, you how to use the loop. you probably don’t have access to Using enough viscoelastic is also corneal transplants. There’s also important. “Adequately use visco- limited access to specialists who can elastic to ensure that the loop is go- potentially treat a patient that might ing underneath the anterior capsule have endothelial damage as a result properly and then coming around of extended phaco time.” the equator,” explains Dr. Mamalis. Dr. Crandall expands on this idea, “Make sure that you’re going all the saying, “If you’re in a developing way around the nucleus without snag- country and you have one of these ging or getting caught on anything in big, expensive machines and a light order to break the nucleus into mul- bulb burns out, what are you going tiple pieces and disassemble it.” to do? They don’t have the back-ups • miLoop results. In a random- that we do.” For this reason, doc- ized, controlled study, where sev- tors say that even donated phaco ma- eral of the researchers were em- chines can be problematic. ployees or consultants for the maker That said, MSICS looks to contin- of miLoop, Iantech, the safety and ue as the main form of cataract re- effi cacy of surgery with the miLoop moval in the developing world, with was assessed in moderate to severe miLoop poised to fi nd its niche. Dr. cataracts. The study found that Mamalis says that patients with a miLoop fragmented every dense relatively dense nucleus would ben- nucleus within the capsular bag.2 efi t from both of these techniques, The miLoop filament completely too. He adds that there’s a large transected the nucleus without any overlap in MSICS candidates and centrifugally directed instrument miLoop candidates, and if properly A complete solution forces that would stress or stretch done, you can get very good results the capsular bag, the researchers using either. “[MSICS and miLoop said. In advanced cataracts and are] very friendly to the cornea,” to optimize space cases involving weak zonules, there Dr. Mamalis says. “They will allow were no instances of zonular dialysis you to remove a relatively dense or anterior/posterior capsule tears.2 nucleus without requiring the high and functionality at an ultrasound energy that’s necessary Looking Ahead when performing phaco.” affordable price Though cataract surgeons in the Drs. Newsom, Mamalis and United States almost exclusively use Crandall report no fi nancial disclo- MANUFACTURED IN NORTH AMERICA phaco, Dr. Mamalis says reliable sures in the products discussed. phaco is still difficult to access in 1. Kongsap P. Visual outcome of manual small-incision cataract the developing world, and alterna- surgery: Comparison of modifi ed Blumenthal and Ruit techniques. International Journal of Ophthalmology 2011;4:1:62-5. tives will always be welcome. “[For 2. Ianchulev T, Chang DF, Koo E, et al Microinterventional endocapsular nucleus disassembly: Novel technique and results phaco to be feasible] you need to be of fi rst-in-human randomised controlled study. British Journal of in a situation where maintenance Ophthalmology 2019;103:176-180. 250 Cooper Ave., Suite 100 Tonawanda NY 14150

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054_rp0419_f5.indd 59 3/22/19 12:35 PM Glaucoma Management

REVIEW Edited by Kuldev Singh, MD, MPH, and Peter A. Netland, MD, PhD

Diagnosing Angle Closure: Gonioscopy vs. OCT Both approaches offer advantages in terms of convenience and accuracy, but gonioscopy still remains the gold standard.

Sunita Radhakrishnan, MD, San Francisco

lthough primary open-angle gold standard; the sensitivity of the patient, making the patient wait for A glaucoma is more common than van Herick test to detect angle closure gonioscopy by the ophthalmologist primary angle-closure glaucoma, the was only 58 to 79 percent.1 might be considered disruptive to the latter has higher visual morbidity, schedule. Furthermore, it’s possible including blindness. Precursor stages Gonioscopy Pros and Cons to misdiagnose the angle status, even of primary angle-closure glaucoma when you perform gonioscopy— are characterized by iridotrabecular Gonioscopy is the gold standard especially if you don’t do it very contact of at least 180 degrees of the for diagnosing angle closure. As often. For example, a pigmented angle, which can be detected with a glaucoma specialist, I specifically Schwalbe’s line might be mistaken gonioscopy. check the angle with gonioscopy on for the trabecular meshwork, creating Unfortunately, angle-closure dis- a regular basis. It does require an the erroneous impression of an open ease is often missed. Most patients anesthetic, but it usually takes less angle when the angle is actually with this condition don’t have symp- than a minute. In addition to providing closed. Similarly, if the trabecular tomatic attacks of angle closure that a quick 360-degree assessment of meshwork is very pale, it can be might prompt them to seek eye care. the angle width—with and without diffi cult to determine the condition Even when a patient presents for an indentation—peripheral anterior of the angle structures. There are eye exam, gonioscopy may not al- synechiae can be detected, the degree some workarounds to help with this, ways be performed. The van Herick of trabecular meshwork pigmentation such as the corneal wedge technique test, which estimates the peripheral can be observed, and abnormalities that can help you identify Schwalbe’s anterior chamber depth relative to such as neovascularization of the angle line, but the fact is, sometimes even the peripheral corneal thickness, and angle recession can be diagnosed. with gonioscopy it can be difficult is commonly used to decide which However, gonioscopy has some lim- to tell what’s going on in the angle. patient should undergo gonioscopy. itations. It’s a subjective technique (Of course, the more you do it, and The most significant problem with that requires contact with the eye the more familiar you are with these this approach is that it doesn’t have a and slit lamp illumination, both of issues, the more likely you are to make high enough sensitivity and specifi city which can artificially widen the an accurate assessment.) to catch all patients with angle closure. angle. It’s also not performed as of- In one study, the van Herick test, per- ten as recommended. One reason Weighing the Alternatives formed by technicians, residents and for this may be that in clinics where attendings, was compared to gonios- technicians perform the initial slit These considerations—and the copy performed by attendings as the lamp assessment and then dilate the reality that many cases of closed

60 | Review of Ophthalmology | April 2018 This article has no commercial sponsorship.

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Both gonioscopy and anterior-segment optical coherence tomography have pros and cons An extensive power range, with when it comes to assessing the condition of the angle. five magnification settings from 6x to 40x. Standard on all ELIELITE TE angles are not being caught—open • Ultrasound biomicroscopy. slit lamps. the door to other ways of assessing UBM uses high-frequency ultrasound the angle that might bypass some and gives excellent cross-sectional of gonioscopy’s limitations. These views of the angle structures, inclu- include: ding the ciliary body. However, it’s • The scanning peripheral cumbersome to use on a routine depth analyzer. This instrument basis and requires a highly skilled (not available in the United States) operator to perform the scans. Those

uses visible light to automatically scan considerations make it unsuitable from the optical axis to the limbus, for use as a screening tool for angle estimating the distance between the closure.

cornea and the iris and quantifying it Anterior segment OCT is another into different grades. It’s an easy-to- cross-sectional imaging modality that use, non-contact method to indirectly can visualize the anterior chamber estimate the angle width, but the and angle structures. However, unlike technology doesn’t have high enough UBM, OCT is an optical technology; IMAGING specifi city to be a good alternative to it can’t penetrate the iris pigment The S4OPTIK H5 ELITE slit lamp gonioscopy.2,3 epithelium, so the ciliary body can’t comes digital ready. Combine • The Pentacam. The Pentacam be viewed. The Visante OCT (Carl with the S4OPTIK all-in-one digital uses a rotating Scheimpfl ug camera Zeiss Meditec) uses a wavelength of camera to acquire exceptional still and provides cross-sectional images 1310 µm, which is ideal for visualizing and video images. of the anterior chamber, but it’s not angle structures; but, unfortunately, able to visualize the angle recess itself. the Visante is no longer being Instead, it makes some extrapolations manufactured. Retina-focused OCT based on the corneal surface and iris instruments that are widely available, surface to draw conclusions about the such as Carl Zeiss Meditec’s Cirrus, angle recess. Heidelberg’s Spectralis and Optovue’s 250 Cooper Ave., Suite 100 Tonawanda NY 14150 Sensible equipment. Well made, well priced .

060_rp0419_gm.indd 61 3/22/19 4:04 PM Glaucoma

REVIEW Management

Gonioscopy vs. OCT: Pros and Cons physiological state of the angle, giving us a better sense of the true condition Gonioscopy OCT of the angle. Subjective Objective • It can quantify angle width Rapid 360-degree assessment Time-consuming; not practical for scanning 360 and changes occurring with pu- degrees with current FDA-approved devices pil dilation. Another useful test Requires contact; some patients Non-contact; comfortable for patient related to angle closure is seeing cannot tolerate contact procedures how the angle opens (or closes) as 360-degree assessment Cross-sectional view; not practical for scanning the pupil reacts to greater or lesser 360 degrees illumination. Both gonioscopy and Requires illumination Can be performed in the dark OCT can be used to evaluate this, but OCT allows us to quantify the amount Can detect other causes of elevated Cannot assess angle features other than angle width of change. IOP such as pigment dispersion or • OCT detects more angle angle recession closure than gonioscopy. Iron- Indentation possible, revealing PAS, Indentation not possible ically, one reason that OCT has low plateau confi guration specificity when used to assess the Limited information about the anterior Snapshot of entire anterior chamber in one scan angle in studies is that it actually chamber detects more angle closure than goni- Scleral spur can be misidentifi ed Scleral spur can’t be identifi ed in up to 30 percent of oscopy, which is treated as the gold if trabecular meshwork is pale or angle images standard for comparison. Schwalbe’s line is pigmented Being able to detect more angle Angle width measurement is Angle width measurement is objective, but vari- closure than gonioscopy can certainly subjective ability can be high be seen as a good thing. However, angle closure on OCT doesn’t al- ways mean that the patient should Avanti, can also be used to image the image the angle in the dark without immediately be treated. In fact, even anterior segment, but these use light illumination would, in theory, allow us patients with gonioscopic angle clo- wavelengths between 800 and 900 to screen patients much more easily. sure don’t always require treatment. µm that don’t penetrate the angle In fact, when anterior segment OCT In the case of primary angle closure as well. As a result, the images are was first developed, it was seen as suspects who are usually asymptoma- less detailed in the angle region than a very promising way to screen for tic and have no abnormality other those produced by the Visante OCT. angle closure. than angle closure, the American Nevertheless, it’s usually possible to This approach has some clear Academy of Ophthalmology’s Pre- tell whether the iris and cornea are potential advantages over gonioscopy. ferred Practice Patterns leaves touching. Those include: decisions about treatment up to the Probably the primary reasons these • It’s easy to use. OCT doesn’t doctor, saying that treatment with instruments are seldom used for require an ophthalmologist with ex- iridotomy in this situation “may be angle analysis is because of workfl ow pertise in performing gonioscopy to considered.” Therefore, using OCT in the clinic. They’re normally used diagnose iridotrabecular contact. alone isn’t suffi cient to decide how a after the patient has been dilated, • It’s comfortable for the patient. patient should be treated. However, and they usually require an additional In contrast, gonioscopy requires it can help to identify individuals who external lens for imaging the front of touching the eye, which patients should be checked more carefully for the eye. Nevertheless, I have seen generally prefer to avoid. a problem in the future. some doctors use retinal OCT to • It may produce fewer artifacts. • It may detect the likelihood of assess the angle. As mentioned earlier, to perform future angle closure better than gonioscopy you need slit lamp gonioscopy. Interestingly, one study The AS-OCT Advantage illumination and you have to touch looked at patients who were classifi ed the eye, both of which can artifi cially as having open angles by gonioscopy, Although gonioscopy is the gold widen the angle. With OCT there’s no but classifi ed as having closed angles standard for angle assessment, a need to touch the eye, and because it with OCT.4 The study found that noncontact technology that could can be done in the dark it reveals the after four years, 17 percent of the

62 | Review of Ophthalmology | April 2019

0060_rp0419_gm.indd60_rp0419_gm.indd 6262 33/22/19/22/19 4:044:04 PMPM patients in this category that returned problematic, for a number of reasons: and inferior quadrants is challenging for follow-up had developed closed • Anterior segment OCT isn’t because the eyelid gets in the way.) angles in two or more quadrants (as widely available. That means the In contrast, gonioscopy provides in- classified by gonioscopy), and 10 equipment most appropriate for formation about the entire angle. percent developed angle closure in evaluating the angle isn’t available in Of note, there is a new swept- three or more quadrants. many practices. source, 1310-µm OCT instrument not Although this finding was based • Most OCT scans (used for eval- approved in the United States that on only the 62 percent of the original uating the optic nerve and retina) does allow 360-degree measurement patient sample that returned for are performed after the patient of the angle. So far, there’s no data to follow-up at year four, this is signifi - has been dilated. Even if you de- suggest that this technology is superior cant. On gonioscopy, these people cide to use OCT technology that’s to gonioscopy, but in theory it might appeared to have open angles. Yet not optimized for viewing anterior be a viable alternative for detecting some went on to develop closed an- segment structures, this use may not angle closure. (However, even where gles, and OCT picked up on that be- be convenient in terms of patient fl ow. this technology is available, it doesn’t fore closure was visible on gonioscopy. appear to be replacing gonioscopy.) If a patient appears to have open • Quantifying the angle requires angles, most ophthalmologists won’t subjective input about the location be checking periodically to see if the Even when relying of the scleral spur. The scleral spur angle is closing. That leaves these in- primarily on can be diffi cult to identify with OCT dividuals open to future trouble— in up to 30 percent of images. This is trouble that might be prevented by gonioscopy to assess a problem if you’re trying to quantify an OCT scan. the angle, AS-OCT the opening of the angle using OCT; Ironically, this potential advantage the person doing the measurement to scanning with anterior segment serves several very has to decide where the scleral spur OCT wouldn’t be particularly useful useful purposes. is, resulting in variability in the out- to me, because as a glaucoma spe- come depending on that decision. cialist, I perform gonioscopy on all In addition, when assessing change of my patients on a regular basis— over time, one can’t be sure that even if the angle has appeared to be • OCT only measures a tiny the same region is being scanned, open in the past. If all seems well, I fraction of the angle. Primary angle and measurement variability can be check them every three or four years; closure is defi ned in the Academy’s introduced due to differences in the if they’re borderline, I check them Preferred Practice Patterns as being iris structure at different locations. every year. However, if OCT is able to characterized by iridotrabecular For these reasons, I don’t routinely catch some patients at risk for future contact for at least 180 degrees. use OCT for quantitative analysis of trouble, patients that gonioscopy isn’t (Iridotrabecular contact is defi ned as the angle. able to identify, this could be useful the posterior trabecular meshwork for a doctor who doesn’t perform not being visible using static goni- Population-based Screening gonioscopy very often. It might pro- oscopy.) This is relevant when com- vide a warning that this patient needs paring OCT and gonioscopy, because One important concern is that we’d to be checked periodically, despite the OCT typically only scans a slice from like to have an instrument that can appearance of an open angle. (That four quadrants. Essentially, you’re easily act as a screening tool in the could mean referring the patient to seeing the condition of the angle in general population to fi nd individuals a glaucoma specialist who’s more four degrees out of 360. with angle closure. Aside from comfortable with regular gonioscopy Since the defi nition of angle closure needing a technology that’s simple screening.) is iridotrabecular contact over at least to use, a major consideration here 180 degrees, we conclude that if two is having high specificity in order OCT Disadvantages of four OCT scans show a closed to avoid too many false positives. angle, that indicates at least 180 Generally, a specificity of 95 to 98 Despite its advantages, at a prac- degrees of closure. (Trying to base percent has been recommended for tical level in the clinic, using OCT the conclusion on a larger number screening, along with a sensitivity of as an alternative for examining of scans can be problematic. Among at least 85 percent.5,6 If a technology the condition of the angle can be other issues, scanning the superior has high sensitivity and low specifi city,

April 2019 | reviewofophthalmology.com | 63

0060_rp0419_gm.indd60_rp0419_gm.indd 6363 33/22/19/22/19 4:044:04 PMPM Glaucoma

REVIEW Management

Sensitivity and Specifi city of OCT in Different Studies them understand the problem, but I’ve found that showing the patient Sensitivity (percent) Specifi city (percent) a picture of his or her own angle Nolan et al, 20077 98 55.4 compared to an open angle is most Lavanya et al, 20082 88.4 62.9 effective. Then I can explain how Nongpiur et al, 20138 98 78 angle closure attacks can happen and how an iridotomy might help. Zhang et al, 20143 73 87 • OCT can be helpful in situ- Dabasia et al, 20159 87 87 ations where gonioscopy isn’t Kochupurakal, 2016 10 91 12 feasible. Occasionally a patient will present with a hazy cornea, making it will fl ag most patients as having a the primary tool with anterior seg- angle visualization difficult or im- closed angle, including many who ment OCT reserved as an adjunct possible; OCT can still provide a don’t actually have it, burdening the technology. Even when relying view of the angle. Also, some patients health-care system. primarily on gonioscopy to assess the are unable to tolerate a contact lens This is an area in which OCT doesn’t angle, AS-OCT serves several very placed on the eye. OCT can allow do well. Studies of OCT used for useful purposes: angle evaluation without touching the detection of angle closure have shown • OCT can help to determine eye. widely varying results in comparison the cause of the angle closure. In the fi nal analysis, OCT is a great to gonioscopy, with specifi city ranging OCT is useful for identifying the adjunct, but there’s no substitute for from 12 to 87 percent—although it’s mechanism(s) behind the angle performing gonioscopy. important to note that the defi nition closure. The various mechanisms of of angle closure isn’t uniform across primary angle closure often coexist; Dr. Radhakrishnan is a glaucoma the studies. In addition, fi nding angle they include pupillary block, high specialist at the Glaucoma Center closure on OCT doesn’t always imply lens vault, thick peripheral iris, and of San Francisco and research di- the need for immediate treatment. an anteriorly positioned ciliary body rector at the Glaucoma Research Given these facts, I don’t believe OCT (although the last can’t be seen and Education Group, also in San can be justifi ed as a screening tool for with OCT—only with ultrasound Francisco. She reports no relevant angle closure out in the community. biomicroscopy). OCT can also reveal fi nancial disclosures. OCT’s usefulness as a screening causes of secondary angle closure, 1. Johnson TV, Ramulu PY, Quigley HA, Singman EL. Low tool does increase, however, if the such as supraciliary fl uid that’s push- sensitivity of the Van Herick method for detecting gonioscopic screening is being done in the offi ce ing the iris-lens diaphragm forward. angle closure independent of observer expertise. Am J Ophthalmol 2018;195:63-71. (i.e., opportunistic screening) rather It’s important to know this because 2. Lavanya R, Foster PJ, Sakata LM, et al. Screening for narrow than out in the world, especially in the appropriate treatment varies angles in the Singapore population: Evaluation of new noncontact screening methods. Ophthalmology 2008;115:10:1720-7, 1727. settings where gonioscopy may not be depending upon the cause of the e1-2. feasible. In the clinic, a higher false- problem. 3. Zhang Y, Li SZ, Li L, Thomas R, Wang NL. The Handan Eye Study: Comparison of screening methods for primary angle positive rate may be acceptable. In • OCT is excellent for patient closure suspects in a rural Chinese population. Ophthalmic that environment, high sensitivity—a education. In my practice, people Epidemiol 2014;21:4:268-75. 4. Baskaran M, Iyer JV, Narayanaswamy AK, et al. Anterior limited number of false negatives— often come in for a second opinion segment imaging predicts incident gonioscopic angle closure. is more important. However, in this about whether they should receive a Ophthalmology 2015;122:12:2380-4. 5. Stamper RL. Glaucoma Screening. J Glaucoma 1998;7:3:149- setting the cost and availability of laser iridotomy. In most cases they’re 50. OCT is a limitation. If there’s ade- totally asymptomatic; a general 6. Thomas R, Parikh R, Paul P, Muliyil J. Population-based screening versus case detection. Indian J Ophthalmol quate expertise, gonioscopy is a faster, ophthalmologist or an optometrist 2002;50:3:233-7. cheaper, way to assess the angle and has noted their closed angle and 7. Nolan WP, See JL, Chew PT, et al. Detection of primary angle closure using anterior segment optical coherence tomography in make treatment decisions in a patient suggested the iridotomy. Patients Asian eyes. Ophthalmology 2007;114:1:33-9. who is already in the clinic. fi nd that idea scary when they haven’t 8. Nongpiur ME, Haaland BA, Friedman DS, et al. Classifi cation algorithms based on anterior segment optical coherence heard of it before, so they come to a tomography measurements for detection of angle closure. glaucoma specialist to fi nd out if this Ophthalmology 2013;120:1:48-54. OCT as an Adjunct 9. Dabasia PL, Edgar DF, Murdoch IE, Lawrenson JG. Noncontact is correct. screening methods for the detection of narrow anterior chamber In my experience, the approach Of course, I could show them a angles. Invest Ophthalmol Vis Sci 2015;56:6:3929-35. 10. Kochupurakal RT. Role of optical coherence tomography that’s most effective for angle drawing or generic photo of a normal in assessing anterior chamber angles. J Clin Diagn Res. assessment is to use gonioscopy as angle versus a closed angle to help 2016;10:4:NC18–NC20.

64 | Review of Ophthalmology | April 2019

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RP0419_Santen.indd 1 3/21/19 10:20 AM Retinal Insider

REVIEW Edited by Carl Regillo, MD, and Yoshihiro Yonekawa, MD

Be Prepared for Pediatric Patients Pediatric retina patients’ ocular anatomy can pose unique challenges.

Yoshihiro Yonekawa, MD, Boston

hen working with pediatric pa- syndrome, familial exudative vitreo- I aim to look there fi rst, since we don’t W tients, it can be easy to fall into retinopathy (FEVR), X-linked retino- know when the child will decide that the trap of simply considering them schisis and incontinentia pigmenti, and this isn’t fun anymore. Some children small adults. From the ophthalmic sequelae of developmental anatomic fi nd it entertaining when I look for ani- examination to operating on complex anomalies like persistent fetal vascu- mals or cartoon characters inside their pediatric pathology, some differences lature, optic disc pits and colobomas. eyes. It usually helps to have the par- become apparent quickly, while some When diagnosing these conditions, ents working with you also, as they may are subtle and require knowledge in say, 3-year-olds running circles have the child’s favorite toys or tablet beforehand in order to tackle these around the exam chair, the approach videos that they can use as distractions. unique cases. In this article, I’ll review we take is quite different than a typical When in doubt, and when faced with some of the challenges of diagnosing adult funduscopic exam. Neonates are possibly blinding or life-threatening and treating children with retinal con- typically easy to overpower, especially conditions, we must remember to have ditions, and explain how to optimize if they are swaddled. You will need ad- a low threshold to proceed with an outcomes as much as possible. ditional hands to stabilize a child that’s examination under anesthesia. approaching several months of age. Imaging technologies can also aug- A Different Exam Toys with bright lights and which make ment our ophthalmoscopic exam. This noises can also help children focus, and includes modalities such as widefi eld The differential diagnosis for chil- you can move these toys in the direc- scanning laser ophthalmoscopy imag- dren with retinal pathology is different tion you would like them to look. ing and ultrasonography. SLO imag- than it is for adults. The most common For patients between 1 and 3, things ing, such as with the Optos camera, is diagnoses we encounter in adult clinics get interesting, and your approach of- quick, comfortable and great for imag- are age-related macular degeneration, ten depends on the child’s personality ing the peripheral retina, where many diabetic retinopathy, vein occlusions, and developmental stage. First, you pediatric retinopathies may reside. macular hole, epiretinal membrane have to win the child’s trust, and you A peripheral retinal exam is diffi cult and retinal detachment. In pediatric can’t go wrong with a high-fi ve to initi- even for adults to tolerate, and B-scan retina, however, we take care of pre- ate your interaction. I like to set the ultrasonography can supplement the mature neonates with retinopathy of ophthalmoscope light low, and allow peripheral ophthalmoscopic exam in a prematurity in the neonatal intensive the child to sit on the parent’s lap. I comfortable way in children. care unit, older kids with traumatic quickly look at the red refl ex fi rst, as Our understanding of the genetic retinal detachment, genetic conditions that alone can provide tons of informa- basis of diseases continues to expand. such as sickle cell retinopathy, Stickler tion. If I suspect an area of pathology, Identifying the genetic cause for he-

66 | Review of Ophthalmology | April 2019 This article has no commercial sponsorship.

066_rp0419_retina.indd 66 3/22/19 12:46 PM A A

B B

Figure 1. Widefi eld fl uorescein angiography. (A) Widefi eld imaging Figure 2: Oral fl uorescein angiography. (A) For children who cannot captures the peripheral pathology in this child with familial tolerate intravenous injection of fl uorescein, the dye can be exudative vitreoretinopathy. There is temporal dragging of the ingested to obtain late-phase angiograms. This is a child with retinal vasculature and a peripheral traction retinal detachment sickle cell retinopathy. (B) Oral fl uorescein angiography shows without overlying hyaloidal organization. (B) Widefi eld fl uorescein peripheral nonperfusion and neovascularization temporally. angiography demonstrates hyperfl uorescence consistent with leakage from the vasculature.

reditary retinal diseases facilitates di- and distinguish Coats’ disease vs. reti- very formed and adherent to the reti- agnosis, prognostication and how we noblastoma vs. capillary hemangiomas. nal surface. Here’s how these factors follow and treat patients. However, However, many children won’t toler- can affect surgery, and how to account genetic testing can be expensive, chal- ate an intravenous injection of fl uores- for them. lenging in terms of insurance, and it cein. One useful trick, then, is to have • Anatomic differences. The pro- can take weeks to months to obtain children drink the dye, and then take portions of the ocular structures in results. A cost-effective, quick and the images approximately 20 minutes young children are different from an meaningful way to uncover a potential later. Oral FA is a great way to acquire adult’s—for instance, the lens is rela- genetic condition is to examine family late-phase angiograms (Figure 2).4 tively large and the pars plana is small members. Not only will this approach Note that you can’t obtain early and (Figure 3). The extent of the difference provide a better understanding of your mid frames, so the diagnostic capaci- depends on the patient’s age. For in- patient’s condition, but you may iden- ties are relatively limited compared stance, if we created a typical scleroto- tify early pathology in family members to intravenous FA. For children too my 3.5 to 4 mm posterior to the limbus that may be treatable.1 young for imaging in clinic, widefi eld in a neonate as we do for adults during Another diagnostic gem for many FA can be performed under anesthe- vitrectomy, we would slice through pediatric retinal conditions is widefi eld sia. Also note that fl uorescein is dosed retina and the result would be disas- fl uorescein angiography (Figure 1).2,3 by weight in children.5 trous. Typically, for children younger Many of the diagnoses listed at the top than 1, we enter 1 mm posterior to of the article are primary or secondary Surgical Considerations the limbus; for kids between 1 and retinal vasculopathies, and detailed im- 2 years of age, we enter 1 to 2 mm aging of the peripheral retinal vascula- In pediatric retina surgery, remem- posterior; and for children who are ture is key in making the correct diag- ber two important concepts: 1) a young between 2 and 3 years old, we enter 2 nosis and subsequent treatment plan. child’s ocular anatomy is different from to 3 mm posterior to the limbus. We It’s essential, for example, to identify an adult’s; and 2) the child’s vitreous is enter 3 mm posterior for most other

April 2019 | reviewofophthalmology.com | 67

066_rp0419_retina.indd 67 3/22/19 12:46 PM Retinal

REVIEW Insider

children. These are rough adults because you can guidelines, and we always readily separate the vitre- examine the eye carefully ous from the retinal sur- beforehand to make sure face, followed by fl attening the pars plana is available of the retina, retinopexy for entry. This is because and tamponade. In chil- the pediatric patient’s ocular dren, however, it can be anatomy can be altered by impossible to completely the underlying pathology. remove the vitreous. An A prime example is persis- RRD repair without ad- tent fetal vasculature. There dressing the traction and can be segments of retina Figure 3. Thoughtful trocar placement for young children. This without removing the that developed, or became 2-month-old with familial exudative vitreoretinopathy is undergoing scaffold for proliferative pulled, very anteriorly by vitrectomy. Note that the sclerotomies are made directly in the sclera vitreoretinopathy means a the ciliary processes. If we without cannulas, because the surgical space is limited. In this patient, lower success rate. Chil- the sclerotomies are created 1 mm posterior to the limbus, unlike the go through the pars plana in dren are less likely to usual 3.5 to 4 mm in older patients. The temporal sclerotomy is also those areas, we could nick displaced superiorly, to avoid an anterior tractional retinal detachment adhere to proper postop the retina and cause an in- in the superotemporal quadrant. positioning as well, which operable rhegmatogenous means that you can’t count retinal detachment. we lose our view—and if we lose our on the tamponade to work properly. While pediatric eyes are smaller, view, we can’t operate. To help with It’s for these reasons that we prefer their crystalline lenses are proportion- this situation, there are certain non- scleral buckling to fi x RRDs in children ately larger. We always have to be cog- contact viewing systems that allow (Figure 4). Scleral buckles don’t rely nizant of the lens as we work in the the lens to sit higher off of the cornea. on the vitreous being separated, and tight intraocular space (unless we are There are also specifi c pediatric retinal you don’t have to rely on positioning. removing the lens for very anterior surgery lenses that are smaller in diam- In fact, almost all primary RRDs in retinal detachments). To decrease the eter than their adult counterparts. children would do great with a nicely risk of lenticular trauma, in the begin- • Scleral buckles are your best placed scleral buckle. Primary buck- ning of the surgery we aim our instru- friends. For most vitreoretinal sur- ling is a fading art, but remains a main- ments more posteriorly, but away from geons, vitrectomy is now the go-to stay of pediatric RD surgery.5 any anteriorized retina. It’s also a good method for repairing primary rheg- • No margin for error. The child’s practice to slow down and be delib- matogenous retinal detachment in formed vitreous poses challenges for erate when inserting and removing adults. Vitrectomy usually works in tractional retinal detachments also. instruments, especially In adults with diabetic curved ones. TRDs or PVR retinal de- • Visualization. One tachments, the general of the practical issues approach is to release the with young children is membranes, but if the that their eyes are small- membranes are too in- er, so we have to hold our trinsic to the retina and instruments closer to- can’t be peeled, you can gether. As we note above, perform a retinectomy the sclerotomies are cre- (especially for PVR) to cut ated closer to the limbus, the stiff retina and flat- so that again decreases ten the retina with brute the distance between our force. You can’t take that right and left hands. Be- approach in children, cause we hold our instru- Figure 4. The formed and adherent vitreous, as well as the inability to though. For a child with ments closer together, it’s position reliably, make scleral buckle the ideal surgical modality to treat a TRD from conditions easier to hit the viewing rhegmatogenous retinal detachment in children. This child had an open like ROP, Norrie disease lens with our instruments. globe repair and subsequently developed a retinal detachment, which or FEVR, the goal is to If we hit the viewing lens, was repaired with a primary encircling buckle. (Continued on page 73)

68 | Review of Ophthalmology | April 2019

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Akorn Consumer Health 57 Kala Pharmaceuticals 17, 18 S4OPTIK 59, 61 Phone (800) 579-8327 Phone (781) 996-5252 Phone (888) 224-6012 www.akornconsumerhealth.com Fax (781) 642-0399 [email protected] www.kalarx.com Bausch + Lomb 21-25, 35, 36 Santen Inc. USA 65 Phone (800) 323-0000 Keeler Instruments 5 Phone (415) 268-9100 Fax (813) 975-7762 Phone (800) 523-5620 Fax (610) 353-7814 Fax (510) 655-5682 Beaver-Visitec International, Inc. 27 www.santeninc.com Phone (866) 906-8080 Lombart Instruments 51 Fax (866) 906-4304 Phone (800) 446-8092 www.beaver-visitec.com Fax (757) 855-1232 Shire Ophthalmics 75, 76 www.shire.com Focus Laboratories, Inc. 12 Ocular Therapeutix, Inc. 7, 8 Phone (866) 752-6006 Phone (877) 628-8998 Fax (501) 753-6021 www.ocutx.com Sight Sciences 43 www.focuslaboratories.com Phone (877) 266-1144 Omeros 10-11 [email protected] Glaukos 15 Phone (206) 676-5000 Phone (800) 452-8567 Fax (206) 676-5005 www.sightsciences.com www.glaukos.com

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ROPH0419.indd 69 3/17/19 10:55 PM 069_rp0419_adindex.indd 69 3/22/19 1:51 PM Research Review REVIEW

Researchers Delve into Orbital Lymphoma

group of investigators from sev- vival of 41 percent and 32 percent, birth weights less than 1,251 g, who A en different centers around the respectively). were born at 22 to 35 weeks’ gesta- world came together to investigate tion, were monitored during all in- and characterize the clinical features Am J Ophthalmol 2019;199:44-57. hospital examinations to determine of subtype-specifi c orbital lymphoma. Olsen TG, Holm F, Mikkelson LH, Rasmussen PK, Coopland SE, et al. birth characteristics associated with The retrospective, interventional the absence of ROP, and identify case series collected patient data from Identifying Babies at Low Risk those who would be considered low January 1, 1980 through December For Developing ROP risk for subsequent ROP treatment. 31, 2017, comprising 797 patients The infants underwent 4,113 ROP with a histologically verified orbital Most premature infants don’t end examinations between 31 and 47 lymphoma. The primary endpoints up developing retinopathy of prema- weeks’ postmenstrual age; 1,153 ex- were overall survival, disease-specifi c turity. However, due to difficulties ams found no ROP, and 456 infants survival and progression-free survival. in determining those at risk, sensi- showed no ROP prior to study center The median age was 64 years, and tive screening procedures for prema- discharge. There was no ROP in 59 51 percent of patients (n=407) were ture infants persist after NICU dis- percent of infants of 27 to 33 weeks male. charge—even in infants without ROP. gestation age compared to 15 percent The researchers report that most of In a recent study, which took place in of infants younger than 27 weeks at the lymphomas were of B-cell origin North American neonatal intensive- the time of hospital discharge. Larg- (98 percent, n=779). Extranodal mar- care units, doctors sought to under- er birth weight and higher gestation- ginal zone B-cell lymphoma (EMZL) stand the factors associated with pre- al age were significantly associated was the most frequent subtype (57 mature infants being at low risk, and with absence of ROP in a multivari- percent, n=452), followed by diffuse to identify those who wouldn’t benefi t ate analysis of infants born between large B-cell lymphoma (DLBCL) (15 from continued ROP monitoring post 27 and 33 weeks gestation. percent, n=118), follicular lymphoma hospital discharge. The study concluded by identifying (FL) (11 percent, n=91), and mantle Currently, screening for ROP characteristics that are associated with cell lymphoma (MCL) (8 percent, begins at 32 weeks postmenstrual low likelihood of developing ROP. n=66). Localized, Ann Arbor stage age and continues every one to two These factors include infants at 27 IE EMZL and FL were frequently weeks until the retinal vessels have weeks’ gestational age or greater treated with external beam radiation matured, which is around 40 weeks. who have a birth weight of at least therapy. DLBCL, MCL and dissemi- Only 5 percent of at-risk infants are 750 g. The researchers add that if nated EMZL and FL were primarily eventually treated, however. The ROP hasn’t been detected by the time treated with chemotherapy. EMZL evaluations are seen as uncomfort- the infant is discharged, continued and FL patients had a markedly bet- able for the infant and can pose a surveillance would have limited value. ter prognosis (10-year disease-specifi c burden to ophthalmologists, since survival of 92 percent and 71 percent, physicians with ROP experience JAMA Ophthalmology respectively) than DLBCL and MCL are limited. 2019;137:160-166 patients (10-year disease-specifi c sur- In the study, 1,257 infants with Wade K, Ying G, Baumritter A, et al.

70 | Review of Ophthalmology | April 2019 This article has no commercial sponsorship.

0070_rp0419_rr.indd70_rp0419_rr.indd 7070 33/22/19/22/19 3:203:20 PMPM 071_rp0419_wills.indd 71 What isyourdiagnosis? furtherworkupwouldyoupursue?Thediagnosis appearsonp. 72. OU withoutdiscedemaorpallor. Dilated fundusexaminationdemonstratedablondewithmaculardrusenineacheye.Thecup-to-discratiowas 0.4 There wasnoproptosisbyHertelexophthalmometryandhypesthesia.Colorplateswere7/8OD8/8OS. otherwise normal.Externalexaminationwasremarkablefor3mmofnon-fatigablerightuppereyelidptosis fi Examination spine forwhichhereceivedpalliativeexternalbeamradiotherapy. Familyhistoryandsocialwerenon-contributory. therapy forrecurrencein2006andenzalutamide(anti-androgen)therapy. In2012,thepatientdevelopedmetastasesto pertension. Healsopreviouslyhadprostateadenocarcinomamanagedbyradicalprostatectomyin2005,followedradio- Medical History proximal muscleweakness. with aright-sidedheadache.Thepatientdeniedchangesinvision,diplopia,fever, jawclaudication,scalptendernessor Presentation Kyle McKey, MD, Tatyana Milman, MD, CarolL.Shields, MD headache. A 75-year-old forevaluationofptosisanda manpresentstoWills elds were full in both eyes. Extraocular motility demonstrated a 20-percent limitation of upgaze of the right eye, but was elds werefullinbotheyes.Extraocularmotilitydemonstrateda20-percentlimitationofupgazetherighteye,butwas the uppereyelid. showing blepharoptosisof photograph Figure 1.External

Anterior segment examination showed an age-related nuclear sclerotic cataract OU, but was otherwise unremarkable. Anterior segmentexaminationshowedanage-relatednuclearscleroticcataractOU,butwasotherwiseunremarkable. On examination,bestcorrectedvisualacuitywas20/40ODand20/25OS.Pupilswerenormal,confrontation Current medicationsincludedmetoprolol,digoxin,glimepiride,atorvastatin,omeprazole,leuprolideandenzalutamide. Past ocularhistorywasunremarkable.medicalincludedatrialfi brillation, typeIIdiabetesmellitusandhy- A 75-year-old Caucasianmalepresentedwithoneweekofpainful,progressive,constantrightblepharoptosisassociated REVIEW Wills Eye Wills Eye Resident CaseSeries Edited byJasonFlamendorf, MD April 2019 | reviewofophthalmology.com (Figure 1) |

71 . 3/22/19 3:50 PM 071_rp0419_wills.indd 72 magnification x100).C: The neoplasticnucleiexpress prostateadenocarcinoma marker NKX3.1(originalmagnification x100). demonstrates nestsofatypicalcellswithavaguely arrangement inadenselyfi cribriform brotic stroma(hematoxylin-eosin;original Figure 3. A: Spiculesofboneassociatedwithdensefibrosis (hematoxylin-eosin;originalmagnifi cation x50).B. Highermagnifi number oftumors. the ageof60,metastasescomprised10percenttotal comprising 7percentofallorbitaltumors.Inadultsover orbit weretheseventhmostcommontypeoforbitallesion, Eye HospitalOncologyService,metastatictumorstothe a reviewof1,264patientswithorbitaltumorsfromtheWills with reactivechanges,surrounded onstrated fragmentsoflamellarbone gregate. Microscopicevaluationdem- tissue measuring12x115mminag- ments offirm,grayanddarkbrown the periostealreactionwasextensive. found toextendtheorbitalapex,and with longrongeurs.Thetumorwas and thetumorwasremovedpiecemeal affected rightorbitwasperformed, rior rectusmuscle.Orbitotomyofthe involving theorbitalroofandsupe- heterogenous massintherightorbit, without contrastshowedthesamesize MRI ofthebrainandorbitswith tion andcorticalthinning(Figure2). orbit, withassociatedperiostealreac- superior posterioraspectoftheright tissue subperiostealmasswithinthe which showeda2.3x2.20.7cmsoft CT scanoftheorbitswithoutcontrast, Workup, DiagnosisandTreatment 72 13 percentofallorbitaltumorsreportedintheliterature. Discussion aspiration biopsytechniques. tastasis withrefi cancer, as wellasimprovementinourabilitytodetectme- be duetoanincreaseinthemediansurvivalofpatientswith tumors totheorbithasincreasedinrecentyears;thismay REVIEW Grossly, themassconsistedoffrag- Ancillary imagingstudiesincluded Metastatic orbital lesions account for approximately 1 to Metastatic orbitallesionsaccountforapproximately1to | ReviewofOphthalmology Resident CaseSeries nementofancillarystudiesand fi 2 The reported incidence of metastatic Thereportedincidenceofmetastatic 3 The most common types of Themostcommontypesof | April2019 androgen receptors. androgen receptors. neoplastic cellsexpressedNKX3.1and nohistochemical stainsshowedthatthe geographic necrosis(Figure3).Immu- mitotic fi trating malignantcellswithfrequent by nests,islandsandbandsofinfil- orbital roof. the area ofthesuperiorrectus andlevator superioriswithadjacentbonyreaction ofthe Figure 2.CoronalsectionofaCTscantheorbitsshowing homogenousenlargement in ne-needle ne-needle gures, apoptoticbodiesand 1 In In eton andlocallymphnodes. Skeletal metastasesarepre- metastatic disease,mostfrequently involvingtheaxialskel- States annually. approximately 27,000cancer-related deathsintheUnited carcinoma remainsanoften-lethaldiseaseaccountingfor carcinoma. Despitesuchadvances,metastaticprostate several advancesinourabilitytotreatmetastaticprostate new casesin2015.Inthepastdecade,therehavebeen in malestheUnitedStates,withanestimated220,800 prostate carcinomas. cancer tometastasizetheorbitincludebreast,lungand Prostate carcinomahasawell-recognized patternof Prostate carcinomaisthemostcommonmalignancy 4 1-3 ment. to anoncologistforsystemicmanage- noma totheorbit,promptingreferral patient’s knownprostateadenocarci- were compatiblewithmetastasisofthe and immunohistochemicalfindings The combined clinical, morphologic The combinedclinical,morphologic cation 3/22/19 3:50 PM Retinal

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dominantly osteoblastic (95 percent (Continued from page 68) 0.08 percent, and assuming that we of cases) and preferentially involve the release all the traction without mak- treat each eye as being independent of spine, pelvis and femur. These lesions ing any retinal breaks, and certainly the other by redraping, rescrubbing, are found in up to 84 percent of pa- no retinectomies. This is because in regowning, etc., the risk for bilateral tients with advanced disease. Metasta- an adult you can almost always fl atten endophthalmitis is equivalent to 1 pa- sis to the orbit is rare, occurring in less the retina by resorting to cutting it and tient in 1,500,000 to 10,000,000 bilat- than 1 percent of patients with prostate being aggressive with the peeling. In eral surgeries.6 On the other hand, the carcinoma.5 children, however, it’s almost impos- risk for anesthesia-related mortality in In general, the presenting symptoms sible to fl atten the retina completely children is as high as 1 in 10,000, 10 to of orbital metastasis include propto- due to the adherent vitreous and in- 100 times higher for all-cause mortal- sis, pain, diplopia, decreased vision tense membranes, so a small iatrogenic ity; it’s even higher in neonates, and and ptosis.3,6 Pain is more common in retinal break in a TRD in a young child higher still in premature neonates.6 prostate carcinoma because it tends to can lead to an inoperable eye. So the risk of mortality with a second spread to the orbital bone and perios- Since the stakes are high in these pe- anesthesia session is many times higher teum where there are sensory nerves diatric TRD surgeries, the old saying, than the risk of developing bilateral rather than orbital soft tissue. Bony le- “perfect is the enemy of good” couldn’t endophthalmitis. sions are usually osteoblastic and may be any more true. The goal is to release In these instances, we recommend simulate a meningioma, especially if the traction without making breaks, considering simultaneous bilateral sur- the sphenoid bone is affected. The and then rely on the retinal pigment gery to decrease the risk of mortality rapid development of osteoblastic or- epithelium to gradually pump the sub- and progression of blinding disease. bital lesions in an elderly male is highly retinal fl uid out and reattach the retina We have previously published guide- suggestive of metastatic prostate car- over time. If you must drain subretinal lines for this practice.6 We love focus- cinoma.3 fl uid or hemorrhage, it’s a good idea to ing on patients’ eyes, but we also need Nearly all prostate cancers are car- drain externally through a sclerotomy, to take a step back when our patients cinoma, specifi cally adenocarcinoma, as opposed to the internal retinotomies are ill and assess the entire patient to and can range from well-differentiated that we’re used to making in adults. optimize outcomes—for both the vi- to very poorly differentiated. Recogni- • Think of the entire patient, sion and the life of the patient. tion of metastatic prostate carcinoma not just the eyes. Some children and Ultimately, we have to approach pe- is important, since it can be managed adults are at very high risk for anes- diatric patients and their unique eyes safely and effectively with hormonal thesia-related morbidity and mortality. thoughtfully. Pediatric retina surgery therapy. Prostate carcinoma is a ra- Perhaps the highest risk as a general is a gratifying fi eld, because you’re po- diosensitive malignancy, so treatment group would be ROP infants, who are tentially saving vision for the next 100 for orbital disease usually consists of likely to have multiple severe co-mor- years of the young patient’s life. There’s radiotherapy combined with hormonal bidities.2 These children also tend to nothing like telling a mother that her therapies.3 have bilateral, progressive pathology. baby is going to be able to see. In summary, we describe a patient Over the course of several days, an in- with metastatic prostate adenocarci- fant with ROP can progress from 20/20 Dr. Yonekawa is a retina surgeon at noma to the orbit, who presented with potential as a stage 4A retinal detach- Massachusetts Eye and Ear and di- painful blepharoptosis and limitation ment to hand-motion vision as a stage rects the pediatric retina surgery pro- of extraocular motility. This case high- 4B detachment. So how do we address gram at Boston Children’s Hospital. lights the importance of medical his- bilateral, progressive disease in sick He will be joining Mid Atlantic Retina tory in guiding diagnostic workup and patients? Do we schedule two separate and Wills Eye Hospital in Philadelphia management. surgeries and potentially double the later this year. anesthesia risk, while watching the sec- 1. Kashani AH, Learned D, Nudleman E, et al. High prevalence 1. Shields JA, Shields CL, Scartozzi R. Survey of 1,264 patients of peripheral retinal vascular anomalies in family members of with orbital tumors and simulating lesions. Ophthalmology ond eye progress? patients with FEVR. Ophthalmology 2014;121:1:262-268. 2004;111:997-1008. 2. Yonekawa Y, Thomas BJ, Thanos A, et al. The cutting edge of 2. Demirci H, Shields CL, Shields JA, et al. Orbital tumors in the Bilateral ophthalmic surgery is usu- retinopathy of prematurity care: Expanding the boundaries of older adult population. Ophthalmology 2002;109:243-248. ally not performed in the United States. diagnosis and treatment. Retina 2017;37:12:2208-2225. 3. Ahmed SM, Esmaeli B. Metastatic tumors of the orbit and 3. Kang KB, Wessel MM, Tong J, et al. Ultra-widefi eld imaging for ocular adnexa. Current Opinion in Ophthalmol 2007;18:405-13. The main theoretical risk is bilateral the management of pediatric retinal diseases. J Pediatr Ophthal- 4. Park JC, Eisenberger MA. Advances in the treatment of meta- mol Strabismus 2013;50:5:282-288. endophthalmitis, which indeed would 4. Nayak BK, Ghose S. A method for fundus evaluation in children static prostate cancer. Mayo Clin Proc 2015;90:1719-33. with oral fl uorescein. Br J Ophthalmol 1987;71:12:908-909. 5. Long MA, Husband JES. Features of unusual metastases from be devastating. However, the risk for 5. Yonekawa Y, Fine HF. Practical pearls in pediatric vitreoretinal prostate cancer. Br J Radiol 1999;72:933-41. surgery. Ophthalmic Surg Lasers Imaging Retina 2018;49:8:561. 6. Shields JA, Shields CL, Brotman HK, et al. Cancer metastatic endophthalmitis after vitrectomy has 6. Yonekawa Y, Wu WC, Kusaka S, et al. Immediate sequential to the orbit. Ophthalmic Plast Reconstr Surg 2001;17:346-354. bilateral pediatric vitreoretinal surgery: An international multicenter been reported to be 0.03 percent to study. Ophthalmology 2016;123:8:1802-1808.

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0071_rp0419_wills.indd71_rp0419_wills.indd 7733 33/22/19/22/19 3:513:51 PMPM SAVE THESE DATES 3RD YEAR RESIDENTS CONTINUING SPECIALIZED EDUCATION 3RD YEAR RESIDENT PROGRAMS & WET LAB Dear CSE 3rd-Year Resident Program Director and Coordinator, We would like to invite you to review the upcoming 3rd-Year Ophthalmology Resident Programs and Wet Lab for 2019 in Fort Worth, Texas. The programs offer a unique educational opportunity for third-year residents by providing the chance to meet and exchange ideas with some of the most respected thought leaders in ophthalmology. The programs are designed to provide your residents with a state-of-the-art didactic and wet lab experience. The programs also serve as an opportunity for your residents to network with residents from other programs. After reviewing the material, it is our hope that you will select and encourage your residents to attend one of these educational activities, which are CME accredited to ensure fair balance. Best regards, Review Education Group

Third-Year Resident Wet Lab Programs 2019:

August 2-3 August 16-17 August 23-24 September 20-21 Fort Worth, TX Fort Worth, TX Fort Worth, TX Fort Worth, TX

www.revophth.com/ResEdu2019

For more information: Visit the registration site above or Email: [email protected] • Call: Denette Holmes 866-627-0714

Courses are restricted to US-based 3rd-year residents enrolled in a US-based ophthalmology resident program and within their third year at the time of the course. There is no registration fee for these activities. Air, ground transportation in Forth Worth, hotel accommodations and modest meals will be provided through an educational scholarship for qualified participants.

Satisfactory Completion - Learners must complete an evaluation form to receive a certifi cate of completion. Your chosen sessions must be attended in their entirety. Partial credit of individual sessions is not available. If you are seeking continuing education credit for a specialty not listed below, it is your responsibility to contact your licensing/certifi cation board to determine course eligibility for your licensing/certifi cation requirement. Physicians - In support of improving patient care, this activity has been planned and implemented by Amedco LLC and Postgraduate Healthcare Education. Amedco LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team

TM JOINTLY ACCREDITED PROVIDERTM Credit Designation Statement - Amedco designates this live activity for AMA PRA Category 1 Credits . Physicians should claim only the INTERPROFESSIONAL CONTINUING EDUCATION credit commensurate with the extent of their participation in the activity.

Endorsed by: Jointly provided by: Supported by an independent medical education grant from: ® REG Review of Ophthalmology (Review Education Group) Alcon VGUVGFOIMIFC[ HQNFVJGJWOCPRNCUOCGZRQUWTGCV the recommended human ophthalmic dose [RHOD], based on VJGCTGCWPFGTVJGEWTXG=#7%?NGXGN 5KPEGJWOCPU[UVGOKE GZRQUWTGVQNKƂVGITCUVHQNNQYKPIQEWNCTCFOKPKUVTCVKQPQH:KKFTC Rx Only CVVJG4*1&KUNQYVJGCRRNKECDKNKV[QHCPKOCNƂPFKPIUVQVJG risk of Xiidra use in humans during pregnancy is unclear. Animal Data BRIEF SUMMARY: .KƂVGITCUVCFOKPKUVGTGFFCKN[D[KPVTCXGPQWU +8 KPLGEVKQP Consult the Full Prescribing Information for complete product VQTCVUHTQORTGOCVKPIVJTQWIJIGUVCVKQPFC[ECWUGF information. an increase in mean preimplantation loss and an increased INDICATIONS AND USAGE KPEKFGPEGQHUGXGTCNOKPQTUMGNGVCNCPQOCNKGUCVOIMI Xiidra® NKƂVGITCUVQRJVJCNOKEUQNWVKQP KUKPFKECVGFHQTVJG FC[TGRTGUGPVKPIHQNFVJGJWOCPRNCUOCGZRQUWTGCV VTGCVOGPVQHVJGUKIPUCPFU[ORVQOUQHFT[G[GFKUGCUG &'&  the RHOD of Xiidra, based on AUC. No teratogenicity was QDUGTXGFKPVJGTCVCVOIMIFC[ HQNFVJGJWOCP DOSAGE AND ADMINISTRATION RNCUOCGZRQUWTGCVVJG4*1&DCUGFQP#7% +PVJGTCDDKV Instill one drop of Xiidra twice daily (approximately 12 hours an increased incidence of omphalocele was observed at the CRCTV KPVQGCEJG[GWUKPICUKPINGWUGEQPVCKPGT&KUECTF NQYGUVFQUGVGUVGFOIMIFC[ HQNFVJGJWOCPRNCUOC VJGUKPINGWUGEQPVCKPGTKOOGFKCVGN[CHVGTWUKPIKPGCEJG[G GZRQUWTGCVVJG4*1&DCUGFQP#7% YJGPCFOKPKUVGTGFD[ Contact lenses should be removed prior to the administration +8KPLGEVKQPFCKN[HTQOIGUVCVKQPFC[UVJTQWIJ#HGVCN0Q QH:KKFTCCPFOC[DGTGKPUGTVGFOKPWVGUHQNNQYKPI 1DUGTXGF#FXGTUG'HHGEV.GXGN 01#'. YCUPQVKFGPVKƂGFKP administration. the rabbit. CONTRAINDICATIONS Lactation 6JGTGCTGPQFCVCQPVJGRTGUGPEGQHNKƂVGITCUVKPJWOCP Xiidra is contraindicated in patients with known hypersensitivity VQNKƂVGITCUVQTVQCP[QHVJGQVJGTKPITGFKGPVUKPVJG milk, the effects on the breastfed infant, or the effects on milk RTQFWEVKQP*QYGXGTU[UVGOKEGZRQUWTGVQNKƂVGITCUVHTQO formulation. ocular administration is low. The developmental and health ADVERSE REACTIONS DGPGƂVUQHDTGCUVHGGFKPIUJQWNFDGEQPUKFGTGFCNQPIYKVJ Clinical Trials Experience the mother’s clinical need for Xiidra and any potential adverse Because clinical studies are conducted under widely varying effects on the breastfed child from Xiidra. conditions, adverse reaction rates observed in clinical studies Pediatric Use of a drug cannot be directly compared to rates in the clinical 5CHGV[CPFGHƂECE[KPRGFKCVTKERCVKGPVUDGNQYVJGCIGQH VTKCNUQHCPQVJGTFTWICPFOC[PQVTGƃGEVVJGTCVGUQDUGTXGF years have not been established. KPRTCEVKEG+PƂXGENKPKECNUVWFKGUQHFT[G[GFKUGCUGEQPFWEVGF YKVJNKƂVGITCUVQRJVJCNOKEUQNWVKQPRCVKGPVUTGEGKXGFCV Geriatric Use NGCUVFQUGQHNKƂVGITCUV QHYJKEJTGEGKXGFNKƂVGITCUV  No overall differences in safety or effectiveness have been 6JGOCLQTKV[QHRCVKGPVU  JCFŰOQPVJUQHVTGCVOGPV observed between elderly and younger adult patients. GZRQUWTGRCVKGPVUYGTGGZRQUGFVQNKƂVGITCUVHQT NONCLINICAL TOXICOLOGY approximately 12 months. The majority of the treated patients Carcinogenesis, Mutagenesis, Impairment of Fertility YGTGHGOCNG  6JGOQUVEQOOQPCFXGTUGTGCEVKQPU Carcinogenesis: Animal studies have not been conducted TGRQTVGFKPQHRCVKGPVUYGTGKPUVKNNCVKQPUKVGKTTKVCVKQP VQFGVGTOKPGVJGECTEKPQIGPKERQVGPVKCNQHNKƂVGITCUV dysgeusia and reduced visual acuity. Other adverse reactions Mutagenesis: .KƂVGITCUVYCUPQVOWVCIGPKEKPVJGin vitro TGRQTVGFKPVQQHVJGRCVKGPVUYGTGDNWTTGFXKUKQP #OGUCUUC[.KƂVGITCUVYCUPQVENCUVQIGPKEKPVJGin vivo conjunctival hyperemia, eye irritation, headache, increased mouse micronucleus assay. In an in vitro chromosomal lacrimation, eye discharge, eye discomfort, eye pruritus and aberration assay using mammalian cells (Chinese sinusitis. JCOUVGTQXCT[EGNNU NKƂVGITCUVYCURQUKVKXGCVVJGJKIJGUV Postmarketing Experience concentration tested, without metabolic activation. 6JGHQNNQYKPICFXGTUGTGCEVKQPUJCXGDGGPKFGPVKƂGFFWTKPI Impairment of fertility: .KƂVGITCUVCFOKPKUVGTGFCV postapproval use of Xiidra. Because these reactions are KPVTCXGPQWU +8 FQUGUQHWRVQOIMIFC[ reported voluntarily from a population of uncertain size, it is not HQNFVJGJWOCPRNCUOCGZRQUWTGCVVJG always possible to reliably estimate their frequency or establish TGEQOOGPFGFJWOCPQRJVJCNOKEFQUG 4*1& QH a causal relationship to drug exposure. NKƂVGITCUVQRJVJCNOKEUQNWVKQP JCFPQGHHGEVQP Rare cases of hypersensitivity, including anaphylactic reaction, fertility and reproductive performance in male and bronchospasm, respiratory distress, pharyngeal edema, swollen female treated rats. tongue, and urticaria have been reported. Eye swelling and rash have been reported. USE IN SPECIFIC POPULATIONS Pregnancy /CPWHCEVWTGFHQT5JKTG75+PE5JKTG9C[.GZKPIVQP/# There are no available data on Xiidra use in pregnant women to (QTOQTGKPHQTOCVKQPIQVQYYY:KKFTCEQOQTECNN KPHQTOCP[FTWICUUQEKCVGFTKUMU+PVTCXGPQWU +8 CFOKPKUVTCVKQP Marks designated ®CPFvCTGQYPGFD[5JKTGQTCPCHƂNKCVGFEQORCP[ QHNKƂVGITCUVVQRTGIPCPVTCVUHTQORTGOCVKPIVJTQWIJ 5JKTG75+PE5*+4'CPFVJG5JKTG.QIQCTGVTCFGOCTMUQT IGUVCVKQPFC[FKFPQVRTQFWEGVGTCVQIGPKEKV[CVENKPKECNN[ TGIKUVGTGFVTCFGOCTMUQH5JKTG2JCTOCEGWVKECN*QNFKPIU+TGNCPF relevant systemic exposures. Intravenous administration of .KOKVGFQTKVUCHƂNKCVGU NKƂVGITCUVVQRTGIPCPVTCDDKVUFWTKPIQTICPQIGPGUKURTQFWEGF Patented: please see JVVRUYYYUJKTGEQONGICNPQVKEGRTQFWEVRCVGPVU an increased incidence of omphalocele at the lowest dose .CUV/QFKƂGF5

RRP0419_ShireP0419_Shire PI.inddPI.indd 1 33/14/19/14/19 10:1710:17 AMAM :KKFTCOC[RTQXKFG .#56+0)4'.++'( UVCTVKPICUGCTN[CUYGGMU

1PGFTQRKPGCEJG[GVYKEGFCKN[CDQWVJQWTUCRCTV &KUECTFVJGUKPINGWUGEQPVCKPGTKOOGFKCVGN[CHVGTWUG

Indication Xiidra® NKƂVGITCUVQRJVJCNOKEUQNWVKQP KUKPFKECVGFHQTVJG %JQQUG:KKFTCƂTUVHQTRCVKGPVU VTGCVOGPVQHUKIPUCPFU[ORVQOUQHFT[G[GFKUGCUG &'&  YKVJUKIPUCPFU[ORVQOUQH Important Safety Information &T['[G&KUGCUG :KKFTCKUEQPVTCKPFKECVGFKPRCVKGPVUYKVJMPQYPJ[RGTUGPUKVKXKV[ VQNKƂVGITCUVQTVQCP[QHVJGQVJGTKPITGFKGPVU :KKFTCTGFWEGFU[ORVQOUQHG[GFT[PGUUCV +PENKPKECNVTKCNUVJGOQUVEQOOQPCFXGTUGTGCEVKQPUTGRQTVGF YGGMUKPQWVQHUVWFKGUCPFKPCNNUVWFKGU KPQHRCVKGPVUYGTGKPUVKNNCVKQPUKVGKTTKVCVKQPF[UIGWUKC CVCPFYGGMU:KKFTCCNUQKORTQXGFUKIPU CPFTGFWEGFXKUWCNCEWKV[1VJGTCFXGTUGTGCEVKQPUTGRQTVGF QHKPHGTKQTEQTPGCNUVCKPKPICVYGGMUKPQWV KPVQQHVJGRCVKGPVUYGTGDNWTTGFXKUKQPEQPLWPEVKXCN QHUVWFKGU1 J[RGTGOKCG[GKTTKVCVKQPJGCFCEJGKPETGCUGFNCETKOCVKQP 6JGUCHGV[CPFGHƂECE[QH:KKFTCEQORCTGF G[GFKUEJCTIGG[GFKUEQOHQTVG[GRTWTKVWUCPFUKPWUKVKU VQXGJKENGYGTGUVWFKGFKPRCVKGPVUKP 6QCXQKFVJGRQVGPVKCNHQTG[GKPLWT[QTEQPVCOKPCVKQPQHVJG YGNNEQPVTQNNGFYGGMVTKCNU1 UQNWVKQPRCVKGPVUUJQWNFPQVVQWEJVJGVKRQHVJGUKPINGWUG EQPVCKPGTVQVJGKTG[GQTVQCP[UWTHCEG %QPVCEVNGPUGUUJQWNFDGTGOQXGFRTKQTVQVJGCFOKPKUVTCVKQP %JGEMKVQWVCV:KKFTC'%2EQO QH:KKFTCCPFOC[DGTGKPUGTVGFOKPWVGUHQNNQYKPI administration. 5CHGV[CPFGHƂECE[KPRGFKCVTKERCVKGPVUDGNQYVJGCIGQH [GCTUJCXGPQVDGGPGUVCDNKUJGF

For additional safety information, see accompanying Brief Summary of Safety Information on the adjacent page and Full Prescribing Information on Xiidra-ECP.com.

Reference: 1. Xiidra [Prescribing Information]. Lexington, MA: Shire US.

©2018 Shire US Inc., Lexington, MA 02421. 1-800-828-2088. All rights reserved. SHIRE and the Shire Logo are trademarks or registered trademarks of - ˆÀi* >À“>ViṎV>œ`ˆ˜}ÃÀi>˜`ˆ“ˆÌi`œÀˆÌÃ>vwˆ>Ìið >ÀŽÃ`iÈ}˜>Ìi`® >˜`Ò>ÀiœÜ˜i`LÞ- ˆÀiœÀ>˜>vwˆ>Ìi`Vœ“«>˜Þ°-{ÓÓÇä£äÉ£n

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