CORNEAL DYSTROPHIES Optometrists Are Often the ﬁ Rst to Detect the Clues and Sleuth out the Diagnosis

NOVEMBER/DECEMBER 2019

REVIEW OF CORNEA & CONTACT LENSES

CORNEAL DISEASE ISSUE Unlocking the Mystery of CORNEAL DYSTROPHIES Optometrists are often the ﬁ rst to detect the clues and sleuth out the diagnosis. Here’s what to look for. EARN 1 CE CREDIT Page 28

Herpetic Keratouveitis Front to Back, PAGE 12

Hot Topics in Bacterial Keratitis, PAGE 14

Smart Strategies to Treat Corneal Infection, PAGE 18

Take on Neurotrophic Keratitis, PAGE 24

Residual Astigmatism After Salzmann’s, PAGE 38

The ABCs of EBMD, PAGE 40

ALSO: • THE AGE-OLD COMPLIANCE CONUNDRUM • REFLECTIONS FROM ED BENNETT • SEX AND GENDER DIFFERENCES IN DRY EYE • CONJUNCTIVAL SUTURE CONSIDERATIONS It’s amazing how something so small can make such a big impact. SMALL? PERHAPS.

SIGNIFICANT? ABSOLUTELY.

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departments features Hot Topics in News Review 6 Bacterial Keratitis Dry eye and contact lenses; Understanding common pathogens corneal pain location; scleral lens and eff ective treatments is essential terminology guide; contact lens in managing these patients with the adaptation 14 most successful results. By Christina Cherny, BS, 9 My Perspective Pratik Patel, OD, and New Contacts, Same Old Mistakes Suzanne Sherman, OD By Joseph P. Shovlin, OD Smart Strategies for The GP Experts 10 Using Antibiotics to GPs: Now and Beyond Treat Corneal Infection By Robert Ensley, OD, Understand when to initiate and Heidi Miller, OD appropriate therapy options. 18 By Fiza Shuja, OD, and 12 Corneal Consult Suzanne Sherman, OD Herpetic Keratouveitis Front to Back Take On Neurotrophic By Aaron Bronner, OD Keratitis With These Clinical Tools 38 Fitting Challenges The more it progresses, the more The “Wow” Starts Now challenging it becomes, so early 24 detection and diagnosis are key. By Cory Collier, OD By Megan Mannen, OD

40 Practice Progress CE — Unlocking The ABCs of EBMD the Mystery of By Mile Brujic, OD, and David Kading, OD Corneal Dystrophies Optometrists are often the 42 The Big Picture ﬁ rst to detect the clues A Knotty Problem 28 and sleuth out the diagnosis of corneal dystrophies. By Christine W. Sindt, OD By Mitch Ibach, OD, and Larae Zimprich, OD

At the Intersection of Sex and Dry Eye Biological diff erences aff ect a patient’s risk of dry eye, pathophysiology and treatment 34 response. By Cecelia Koetting, OD

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IN BRIEF Dry Eye: Look Beyond the Lenses ■ Researchers recently found that a conjunctival limbal autograft can he root of many contact eye from physiological dry eye. provide long-term ocular surface stability and good visual outcomes lens wearing patients’ dry Additionally, the study found the for patients with unilateral total limbal Teye symptoms may not be physiological dry eye group was stem cell defi ciency. After performing the lenses but a different etiology signifi cantly worse than both the penetrating or deep lamellar anterior keratoplasty in 44.5% of eyes, best- entirely. While contact lens wear lens-induced dry eye and asymp- corrected visual acuity improved from is an established cause of dry eye, tomatic groups in pre-corneal about 20/400 preoperatively to about a recent study found nearly half of noninvasive tear break-up time (8.2 20/70 at last follow-up. The study noted two signifi cant side eff ects: symptomatic contact lens wearers seconds in the physiological group microbial keratitis in 14.8% of eyes had symptoms of dry eye that were vs. 12.3 seconds in the contact-lens and ocular hypertension secondary to not contact lens–induced. induced group and 14.3 seconds in corticosteroid use in 25.9%. The investigation enrolled 92 par- the asymptomatic group), anterior Eslani M, Cheung AY, Kurji K, et al. Long-term outcomes of conjunctival limbal autograft in ticipants who completed the Berkeley displacement of the line of Marx and patients with unilateral total limbal stem cell defi ciency. Ocul Surf. September 6, 2019. [Epub Dry Eye Flow Chart with and superior conjunctival staining. ahead of print]. without their lenses. Other testing The asymptomatic and lens-in- ■ An Australian study determined included ocular surface exams and duced dry eye groups showed similar that corneal and intra-epidermal dry eye questionnaires. clinical signs, whereas the contact neuronal loss was more pronounced in advanced diabetic retinopathy (DR) The study divided the subjects into lens–induced dry eye and physiologi- stages, indicating a positive severity three groups: asymptomatic contact cal dry eye groups were more similar correlation between DR and diabetic lens wearers; symptomatic contact in reported symptoms. peripheral neuropathy. The corneal nerves, however, were far more sensitive lens wearers who became asymptom- Many contact lens wearers pre- to DR changes than the neuroretinal atic after they removed their lenses; senting with dryness symptoms have layers were. Corneal nerve fi ber length and symptomatic lens wearers who an underlying dry eye condition and and density were signifi cantly reduced more so in the proliferative DR group did not improve after they stopped won’t respond to treatments aimed than in the non-proliferative DR group. wearing their contacts. at changing lenses or solutions, the The researchers also found a low The investigators found 40% of researchers said. Contradictory re- correlation between intra-epidermal and corneal fi ber loss for both neurological subjects were asymptomatic, 33% sults from research studies of dry eye scores. had contact lens–induced dry eye in contact lens wearers could be due Hafner J, Zadrazil M, Grisold A, et al. Retinal and and 27% had underlying physiologi- in part to a failure to distinguish sub- corneal neurodegeneration and its association to systemic signs of peripheral neuropathy in type cal dry eye.The researchers noted the jects with symptoms resulting from 2 diabetes. Am J Opthalmol. September 19, 2019. Visual Analog Scale ratings, Ocular contact lens wear from those whose [Epub ahead of print]. Surface Disease Index and Standard symptoms have underlying causes ■ Researchers recently found a Dry Eye Patient Questionnaire unrelated to contact lens wear. potential relationship between psoriasis and keratoconus: the more scores were signifi cantly better for “It is critical for clinicians and severe the psoriasis, the greater the the asymptomatic group but did not researchers both, once a contact lens topography map changes, with the distinguish contact lens–induced dry wearer has presented with symp- association persisting both in the beginning stages of the disease and the Photo: Heidi Wagner, OD, MPH toms, to investigate further using longer it lasts. They discovered that 26 a combination of questionnaire eyes of 16 patients with psoriasis were instruments, clinical assessments and keratoconus (KC) suspects, and another two eyes already had a diagnosis of KC. objective measurements to determine Although the results do not necessarily the underlying causes or contributing mean that patients with psoriasis will factors to achieve successful patient defi nitely experience KC at some point in their lives, the researchers suggest treatment and valid, generalizable that it would be useful to conduct eye clinical study results,” the research- examinations more often for these ers wrote in their paper on the study. patients. Akcam HT, Karagun E, Iritas I, et al. Keratoconus Molina K, Graham AD, Yeh T. et al. Not all dry could be associated with psoriasis: novel eye in contact lens wear is contact lens-infi ndings from a comparative study. Cornea. Changing lenses or solutions might September 30, 2019. [Epub ahead of print]. duced. Eye Contact Lens. September 10, not affect dry eye in CL wearers. 2019. [Epub ahead of print].

6 REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 Location Plays Key Role in Understanding Corneal Pain europathic pain felt on the researchers also measured corneal They also noted that the sub-bas- periphery or in the center of epithelial thickness and sub-basal al nerve density was signifi cantly Nthe cornea may be two dis- nerve density. reduced in corneal pain patients tinct issues that respond differently The study found four patients compared with controls, and the to topical anesthesia, specifi cally if responded to topical anesthesia stroma of all study participants the pain presents without clinically (the responsive group), indicating showed activated keratocytes and visible cues, a study reports. peripheral neuropathic corneal pain, spindle, lateral and stump micro- The investigation included 27 while 10 patients showed no im- neuromas. The study observed a eyes of 14 patients who had con- provement (non-responsive group), much greater amount of microneu- tinuous severe ocular pain but with which pointed to central neuropath- romas and activated keratocytes minimal or no ocular surface signs ic corneal pain. in the responsive group compared for at least one year. The patients The investigators also reported with the non-responsive group. were also non-responsive to topical the Schirmer 1 was within normal Neuropathic corneal pain with- lubricants, steroids or cyclosporine. limits in the responsive group but out visible clinical signs does not The investigators used in vivo was signifi cantly greater in the represent typical dry eye disease, the confocal microscopy to examine non-responsive group. None of the researchers added. the central and paracentral cornea other clinical parameters or corneal Ross AR, Al-Aqaba MA, Almaazmi A, et al. Clinical and in vivo confocal microscopic features of in the patients with corneal pain epithelial thickness were markedly neuropathic corneal pain. Br J Ophthalmol. Sep- and in seven healthy controls. The different. tember 18, 2019. [Epub ahead of print].

Scleral Lens Terminology Guide Developed

onfused by scleral lens “A common language is key to jargon? If so, you’re not advancing the science and clinical Calone. With no current practice of scleral lens fi tting,” scleral lens standards, a handful they concluded in their paper on of optometrists sought to provide the effort. “The current terminolo- lens fi tting and manufacturing gy will help standardize this fi eld, defi nitions to improve uniformity helping eye care practitioners, between manufacturers and lens educators, speakers and manu- handlers. facturers to talk with the same A committee of 12 advanced language.” scleral lens clinicians used a litera- Standardized scleral lens fitting and “I am very proud of this article ture review to help them develop a manufacturing terms aim to improve because it sets the standard for the list of terms related to scleral lens clarity in the field. scleral lens industry,” Dr. Michaud fi tting and manufacturing. After says. “From now, hopefully, every experts in the fi eld were consulted addressed the general terminology stakeholder will speak the same to validate the terms and their sug- habitually applied to scleral lenses language for a better understand- gested defi nitions, a fi nal version and described terms specifi cally ing. It also highlights the evolu- was adopted by the Scleral Lens used when fi tting and manufactur- tion of the fi eld in the past years. Education Society at the end of ing scleral lenses. They then made Now, as an evolved market, scleral last year. recommendations to manufactur- lenses should rely on an offi cial The original team behind ers about the essential elements terminology.” RCCL this undertaking, led by Langis eye care practitioners need to help Michaud L, Lipson M, Kramer E, et al. The offi cial guide to scleral lens terminology. Cont Lens Michaud, OD, MSc, provided them understand the lens design Anterior Eye. September 25, 2019. [Epub ahead the defi nition of a scleral lens, and customize their fi t. of print].

REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 7 RCCL News Review REVIEW OF CORNEA & CONTACT LENSES

11 Campus Blvd., Suite 100 Newtown Square, PA 19073 Telephone (610) 492-1000 Fax (610) 492-1049 CL Patients Can Adapt Faster Editorial inquiries: (610) 492-1006 Advertising inquiries: (610) 492-1011 Email: [email protected] or new contact lens wearers, group included 10 patients on the EDITORIAL STAFF eye care practitioners typically fast schedule and 10 who were on EDITOR-IN-CHIEF Frecommend a gradual wear- the gradual schedule. Jack Persico [email protected] MANAGING EDITOR ing schedule to help patients adapt Masked investigators graded Rebecca Hepp [email protected] to lens wear. But a team of UK re- ocular surface physiology and non- ASSOCIATE EDITOR Catherine Manthorp [email protected] searchers suggests this conventional invasive tear break-up time. They ASSOCIATE EDITOR strategy may no longer be needed also recorded a range of subjective Mark De Leon [email protected] CLINICAL EDITOR with some of the latest soft contact scores at the initial visit, after 10 Joseph P. Shovlin, OD, [email protected] lens designs. hours of lens wear, four to six days ASSOCIATE CLINICAL EDITOR Christine W. Sindt, OD, [email protected] Their study, published in Contact later and 12 to 14 days later. EXECUTIVE EDITOR Lens & Anterior Eye, found The study found no difference in Arthur B. Epstein, OD, [email protected] CONSULTING EDITOR no difference in fast vs. gradual ocular surface physiology between Milton M. Hom, OD, [email protected] adaptation in patients who wore the fast and gradual adaptation GRAPHIC DESIGNER Ashley Schmouder [email protected] daily disposable hydrogel or silicon groups at any time point in either AD PRODUCTION MANAGER hydrogel (SiHy) contact lenses. lens type. The researchers also Scott Tobin [email protected] The investigation randomly found non-invasive tear break-up BUSINESS STAFF assigned patients to an adaptation time was similar at all time points PUBLISHER James Henne [email protected] schedule, either fast (10 hours of for both adaptation groups in both REGIONAL SALES MANAGER wear the fi rst day) or gradual (four lens types with the exception of Michele Barrett [email protected] REGIONAL SALES MANAGER hours on the fi rst day and two extra gradual adaptation SiHy wearers, Michael Hoster [email protected] hours each day until reaching 10 whose times were slightly longer VICE PRESIDENT, OPERATIONS Casey Foster [email protected] hours). In the hydrogel lens group, than the fast adaptation group at 24 patients were put on the fast 12 to 14 days. EXECUTIVE STAFF CEO, INFORMATION SERVICES GROUP schedule, and 21 wore their lenses The study noted the subjective Marc Ferrara [email protected] on a gradual schedule. The SiHy scores were similar across the visits SENIOR VICE PRESIDENT, OPERATIONS Jeff Levitz [email protected] and lens types with the exception SENIOR VICE PRESIDENT, CORNEAL NERVES SAFE of “lens awareness” and “ease of HUMAN RESOURCES Tammy Garcia [email protected] Upon evaluating corneal sub-bas- lens removal,” which were better VICE PRESIDENT, CREATIVE SERVICES & PRODUCTION al nerve alterations in contact in the fast group compared with Monica Tettamanzi [email protected] lens-naive silicone hydrogel lens the gradual adaptation group of VICE PRESIDENT, CIRCULATION wearers and investigating the Emelda Barea [email protected] hydrogel lens wearers at day seven. CORPORATE PRODUCTION MANAGER relationship between structural Additionally, the fast hydrogel lens John Caggiano [email protected] changes and corneal sensitivity, group reported less end-of-day researchers found that sensory EDITORIAL REVIEW BOARD discomfort 12 to 14 days compared Mark B. Abelson, MD adaptation to lens wear is not James V. Aquavella, MD with the gradual adaptation group. mediated through attenuation of Edward S. Bennett, OD “There appears to be no benefi t Aaron Bronner, OD the subbasal nerve or reduction Brian Chou, OD in daily disposable soft contact Kenneth Daniels, OD of corneal tactile sensitivity. S. Barry Eiden, OD lens adaptation for neophytes with Desmond Fonn, Dip Optom, M Optom Kocabeyoglu S, Colak D, Mocan M, et al. Sen- Gary Gerber, OD sory adaptation to silicone hydrogel contact modern contact lens material,” the Robert M. Grohe, OD lens wear is not associated with alterations researchers wrote in their paper. Susan Gromacki, OD in the corneal subbasal nerve plexus. Cornea. Patricia Keech, OD 2019;38(9):1142-6. They also noted that no underpin- Bruce Koffler, MD Pete Kollbaum, OD, PhD ning scientifi c evidence existed for Jeffrey Charles Krohn, OD the need for a gradual approach for Kenneth A. Lebow, OD Advertiser Index Jerry Legerton , OD new lens wearers. Kelly Nichols, OD Alcon ...... Cover 3 Robert Ryan, OD Bausch + Lomb ...... Page 5 Jack Schaeffer, OD Wolff sohn JS, Dhirajlal H, Vianya-Estopa M, et Charles B. Slonim, MD Menicon ...... Cover 4 al. Fast versus gradual adaptation of soft daily Kirk Smick, OD VSP ...... Cover 2, Page 3 disposable contact lenses in neophyte wearers. Mary Jo Stiegemeier, OD Cont Lens Anterior Eye. September 20, 2019. Loretta B. Szczotka, OD [Epub ahead of print]. Michael A. Ward, FCLSA Barry M. Weiner, OD Barry Weissman, OD

8 REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 MyMy Perspective Perspective By Joseph By Joseph P. Shovlin, P. Shovlin, OD OD

New Contacts, Same Old Mistakes Besides learning from the consequences, how can patients better understand compliance?

sobering report this past patients surveyed demonstrated using techniques that are easy to summer by Centers for “good” compliance and only 0.4% understand and specifi c to the Disease Control and were “fully” compliant.3 message intended, such as repeating APrevention (CDC)’s Fortunately, these behaviors are messages that minimize jargon and Morbidity and Mortality Weekly modifi able with continued efforts checking for patient understanding Report highlighted that “one-third from all of us. So, continue to of the presented points.1 of lens wearers recalled never hear- stress the risks of: Practice newsletters, text mes- ing any lens care recommendations– 1. improper wearing schedules sages and email missives to your even though most eye care providers 2. not complying with recom- patients may serve as reminders on reported sharing recommendations mended lens replacement how to avoid risky behaviors, as always or most of the time with frequencies well as why compliance is import- their patients.”1 There is hope that 3. not washing and drying hands ant and the risks of not comply- we will continue to provide ongo- before inserting and removing ing. Unfortunately, the strongest ing proper lens care education in lenses message is heard when a patient order to ward off potential risks of 4. re-using or “topping-off” lens experiences a complication, which complications, especially serious eye care solutions then provides an opportunity to get infections, but how will the estimat- 5. not cleaning properly and that patient’s attention by reviewed 45 million contact lens wearers replacing lens storage case ing what might have contributed to in the United States listen? properly or regularly their lens-related complication. As eye care professionals, we 6. not rubbing or rinsing lens- are acutely aware that improper es with approved lens care e must continue compliance wearing schedules and poor care solutions Wcampaigns with ongoing behaviors may pose devastating 7. swimming and showering in pertinent messages that sustain and risks to patients wearing contact contact lenses and exposing encourage healthy behaviors. Only lenses. Adding another dimension, them to contaminated water then can we potentially avoid the engaging in hazardous behaviors 8. sleeping in lenses when not tragic complications that often re- does not appear to be totally relat- approved to do so sult in sight-threatening experiences ed to a general lack of knowledge.2 The CDC and others have for our patients. Future studies will Risky behaviors in lens wearers done a fabulous job in providing judge just how effective compliance unfortunately abound, even when educational resources and other campaigns really are. Can they seemingly appropriate and ade- communication materials about be totally effective? Probably not, quate knowledge of lens care exists. healthy lens care habits that can be for a whole host of reasons—but The most common reasons for displayed in the offi ce and handed the fi ght must go on. It’s just too non-compliance in lens wearers or shown to patients. Employing important not to make this a major are saving money and forgetting both verbal and written messages crusade! RCCL the recommended lens replacement seems to be a more effective in schedule.2 How quickly patients communicating with patients and 1. Konne NM, Collier SA, Spangler J, Cope JR: Healthy contact lens behaviors communi- 2 seem to forget or shrug off our consumers. cated by eye care providers and recalled by warnings. In addition, the CDC has desig- patients-United States, 2018. MMWR Morb Mortal Wkly Rep. 2019;68(32):693-7. Nevertheless, non-compliant nated a week in August (prior to 2. Steele K. Contact lens compliance: a review. behavior continues to pose risks to students returning to school) the Contact Lens Update. contactlensupdate. com/2018/10/26/contact-lens-compli- our patients and hinders efforts to past few years as Contact Lens ance-a-review. October 26, 2018. Accessed maximize safety.3 Historical rates Health Week to emphasize the October 3, 2019. of non-compliance in lens wear- importance of healthy behaviors in 3. Robertson DM and Cavanaugh D: Non-compliance with contact lens wear and care ers range from 40% to 91%, but lens care. The CDC recommends practices: a comparative analysis. Optom Vis one model found that only 2% of combating poor compliance by Sci. 2011; 88(12):1402-8.

REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 9 The GP Experts By Robert Ensley, OD, and Heidi Miller, OD

GPs: Now and Beyond A conversation with proliﬁ c GP expert Ed Bennett, OD, on what these lenses still have to off er.

his year marked the hybrids and sclerals. Major im- retirement from aca- provements in manufacturing tech- demia of one of the true nology resulting in ultrathin and legends of GP lenses, Ed pseudo-aspheric peripheral designs TBennett, OD. For nearly have all been important as well. 40 years, Dr. Bennett has served as a clinician, researcher, educator, in- Are there any challenges we still dustry leader and mentor to many. face in GPs that you feel can be Recently, we picked his brain improved upon? about how the GP lens industry Of course, the elephant in the room has evolved over his career and has always been a patient’s initial what he expects for its future. comfort. Early on, I was involved Dr. Bennett with Dr. Ensley. in a number of studies looking at First off, congratulations on your the relationship between lens design retirement from the University of led to their longevity and survival? factors and comfort, and the only Missouri-St. Louis after 37 years! I certainly remember the ‘obsolete’ factor that was signifi cant was Where did you develop your comments, and I am so excited diameter. Scleral lenses ultimately passion for GP lenses? Was there a that idea never came close to supported that fi nding. particular professor or patient that fruition. Certainly, the revival—and However, we did also fi nd in inspired you? continuing improvement—of scleral another study that the use of a I’ve been a rigid lens wearer for lenses has had a signifi cant impact topical anesthetic was signifi cant in more than 52 years, and I person- and will continue to do so well into optimizing a patient’s initial experi- ally knew the benefi ts. When I was the future. ence along with how you presented fortunate enough to be a fourth- I’ve seen GP materials advance GPs to a patient. If the optometrist’s year extern in a newly developed such that we have stable and presentation to the patient was pro- contact lens research externship at wettable lenses, even in as high active and used terms such as “lens Indiana University under the super- as 200 Dk. The introduction of awareness” and “lid sensation” as vision of Drs. Sarita Soni and Irvin the HydraPEG (Tangible Science) opposed to “discomfort,” they were Borish. That was life-changing. coating allows for these lenses to be more likely to be successful. I was involved in FDA clinical worn comfortably for longer time Today’s lower edge clearance and trials for the fi rst extended-wear periods and aids with the borderline consistently smooth edge profi le de- lenses, the fi rst soft toric and, most dry eye patients. signs have resulted in well-centered, importantly, the fi rst viable gas per- better initial comfort results than meable lens, Polycon I (Art Optical In your opinion, what were the their predecessors. This is especially Lens). I was able to observe the greatest innovations in GP lens important with patients benefi ting edema dissipate in hundreds of technologies that have impacted from the vision achieved with GP polymethylmethacrylate-wearing the industry? bitoric, multifocal and keratoconus/ patients who were refi t into GP Regarding the aforementioned post-surgical designs, and I hope lenses during my three years on the scleral lenses, there are innovations this will continue. faculty at Indiana University. And I such as molded sclerals and topog- was hooked! raphy-aided, stable, hyper-Dk lens Do you think the online materials and lens coatings. There is marketplace will ever become a At one point, many opined that GP continuing improvement in ortho- competitor with GP lenses? lenses would also become obsolete. keratology (ortho-K) designs and It’s diffi cult to say at this time, but What factors do you believe have GP multifocal designs, especially my inclination is no. Obviously the

10 REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 online marketplace will continue op new GP and custom soft lens decentered optics to optimize vision to grow, but one of the strengths resources and programs. I’m still in at all distances. of GP lenses is their custom nature, an editorial position for a contact Myopia control is on the verge which simply does not lend itself lens publication, and I defi nitely of exploding onto the scene, and it easily to the online marketplace. enjoy that role. Likewise, I hope to only makes sense that ortho-K will continue to serve on the Education have a signifi cant role, as its designs GP lenses are often perceived as Committee of the Global Specialty continue to improve. And GP lenses more time consuming and diffi cult Lens Symposium. lend themselves to the augmented/ to fi t. What advice would you give The fi fth edition my text with virtual reality lenses now under de- to a practitioner wanting to build Vinita Henry, Clinical Manual of velopment, as well as possibly being their GP practice? Contact Lenses, is coming out any used as a recording device. For the practitioner desiring to day now. I’m also excited to be start building their GP practice, joining a new oversight committee Can you single out any aspect of I would fi rst encourage them to for the AAO in anticipation of your career in GP lenses that has talk to one or more of the Contact their 100th anniversary in 2022. been the most rewarding? Did Lens Manufacturer’s Association And who knows? There might be you ever think you would become (CLMA) member laboratories something else out there for me to so infl uential amongst GP lens about the services and lenses they be active in. industry? can provide. Their consultants truly Thirty-two years ago, Carl Moore, are supportive, and there is no ques- Care to offer up any projections for then-president of the CLMA, was tion too simple for them to answer. the future of GP lenses in the next taking me to the airport. He asked With the ability to take pictures 25 years and beyond? if I would be interested in becoming and videos of lenses on the eye via Certainly, scleral lenses will contin- executive director of the GPLI. iPhone slit lamp adapters, as well as ue to grow and—with the innova- Taking that position was the corneal topography, providing the tions in design including peripheral greatest professional decision I have laboratory with this information haptics as well as profi lometry— ever made and has brought me can lead to great success. they will become easier and result an enormous amount of personal The GP Lens Institute (GPLI, in higher patient success. We will satisfaction. What a joy to be able www.gpli.info) has a large num- see continued design innovations to have a passion for something and ber of online resources in all areas in presbyopia with corneal, scleral live out that passion surrounded (spherical, multifocal, toric, irregu- and hybrid multifocals, including by those who feel the same way, lar cornea, scleral and ortho-K), in- most notably the CLMA board and cluding video tutorials, calculators representatives and our outstanding and almost 100 archived webinars. GPLI advisory board—many of the There is also a lab consultants most knowledgeable GP experts in FAQs module as well as a coding the world. and billing module. It’s been a wonderful life to have been able to serve the profession in You have also served in many posi- several leadership positions and to tions and leadership roles. What are be able to author articles and text- you planning on staying involved books, but it is the opportunity to with in this next phase of life? work for the CLMA in my present I’m still keeping busy. As executive capacity that has allowed me to director of the GPLI, my intent is to have any infl uence I might pos- increase my time in helping devel- Dr. Bennett with Dr. Miller. sess—and to follow my dreams! RCCL

REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 11 Corneal Consult By Aaron Bronner, OD

Herpetic Keratouveitis Front to Back Don’t forget to check the posterior segment to catch the worst manifestation.

56-year-old female was PRELIMINARY sent in for a cornea eval- TESTING uation by her primary The patient’s Aoptometrist. He was exam showed concerned by the progression of an 1+ lid edema, 3+ increasingly severe keratitis in her injection of the right eye. Treatment was initiated conjunctiva, a four weeks ago with topical trifl u- superior super- ridine 1.0%. When the eye didn’t fi cial crescen- respond, topical tobramycin 0.3% tic marginal solution was added. Though the infi ltrate from patient had signifi cantly reduced 11 o’clock to vision, she was not in any pain. She 2 o’clock, 2+ Intense endotheliitis with placoid and partial ring had undergone cataract surgery un- diffuse epithelial precipitation of white and red blood cells on the corneal eventfully on both eyes three years edema and 4+ endothelium. earlier and only wore progressive granulomatous lenses for reading purposes. keratic precipitates in a partial ring so I questioned the patient about When corrected, the patient’s distribution. Her endotheliitis was a history of herpetic eye disease, vision was “hand motion at fi ve intense enough to cause some red which she denied, and cold sores, feet” OD and 20/25 OS. There blood cells to precipitate as well. which she had developed somewhat was no improvement with pinhole Views of the anterior chamber frequently in the past. testing on the right eye. The patient (AC) were limited, but 1+ to 2+ Though the peripheral keratitis had a full range of motion, but full white cells were graded, the iris was was unusual for the diagnosis (and evaluation of pupils and confronta- normal without segmental atro- would be more typical of herpes tion fi elds was not possible due to phy and the patient’s intraocular zoster keratouveitis), my working poor direct views of the right pupil lens was in a good position. The diagnosis was severe diffuse herpes and markedly reduced visual acuity full dilated exam showed a gross- simplex virus (HSV) endotheliitis (VA), though a consensual response ly normal but poor view of the and uveitis, as the patient had no of the left pupil when light was ap- optic nerve, retinal vessels, macula known history of zoster-based plied to the right was present. Her and retinal periphery due to poor periocular infection. She was placed intraocular pressures were 20mm corneal optics. The fellow eye was on homatropine 5% BID, Durezol Hg OD and 8mm Hg OS. unremarkable with the exception of (difl uprednate, Novartis) hourly pseudophakia. and oral acyclovir 400mg fi ve times per day and scheduled to follow-up PROBLEM the next day. She was also instruct- AND ed to discontinue topical anti-in- SOLUTIONS fective medication usage, as I felt Marked uni- that after being dosed for about lateral kera- a month, they might be causing touveitis/endo- superfi cial stress to the cornea and theliitis in an contributing little therapeutic value. adult without At subsequent follow-ups, we any other risk could see that the patient’s corneal factors is most and AC pathology was slowly re- likely herpet- sponding to therapy and vision was Superfi cial peripheral keratitis. ic in origin, gradually improving. As corneal

12 REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 optics improved, so did posterior of the possible segment views. With these better problem and its views, it became apparent that the location in the patient’s posterior segment was posterior seg- also involved to some degree. There ment, the patient was mild vitritis, an asymmetrically was maintained mildly hyperemic nerve and a small on topical ther- amount of segmented columnar oc- apy and referred clusive material in the primary and to the University secondary retinal arterioles. of Washington Given the previous diagnosis and Uveitis Clinic. now posterior involvement, acute At the clinic, retinal necrosis (ARN) needed posterior in- Improvement in corneal involvement after one week of to be considered. ARN is a rare volvement of the aggressive therapy. pathology caused by herpes viruses patient’s uveitis that produces a diagnostic triad of with diffuse retinal vessel leakage, OUTCOMES edematous necrosis of the retina, subclinical retinal edema and nerve After six months of follow-up and occlusive vasculitis/arteritis and head leakage was conﬁ rmed. The gradually tapering therapy, the pa- vitritis. It carries an extremely neg- specialist described the arteriolar tient’s panuveitis fully resolved. She ative prognosis—it’s estimated that involvement as Kyrieleis plaques, now corrects to 20/20 and is very between 20% and 85% of ARN which are a source of retinal pleased with the outcome. patients develop rhegmatogenous vasculitis associated with ARN, This case is a good reminder of retinal detachment and nearly 50% tuberculosis, syphilis toxoplasmosis an important clinical pointer. While of patients end up with a best-cor- and Mediterranean spotted fever. the scope of possible pathologies of rected VA of 20/200 following Serology tests for these pathologies herpetic eye disease is wide and the the condition.1 Due to the severity were run and subsequently found to vast majority of cases only involve be negative. the anterior segment, the disease’s The primary diagno- worst manifestation involves the sis of HSV keratouve- posterior segment. Therefore, peri- itis with possible early odic posterior evaluation of these ARN was maintained. eyes is necessary. Though it is easy Given the absence of to focus only on the anterior exam zonal retinal necrosis, a when working with impressive cas- ﬁ rm diagnosis of ARN es of anterior uveitis, the clinician was not made, so its needs to recognize that these pa- treatment protocol, thologies should not be presumed to which involves prophy- only involve the anterior segment. lactic vitreoretinal sur- Paying equal close attention to the gery, was not followed. posterior segment is critical to catch The uveitis facility panuveitis, which is associated with added a modest dose more profound and longer-lasting of oral prednisone with vision loss. RCCL a protracted taper and 1. Schoenberger SD, Kim SJ, Thorne JE, et Posterior segment involvement shows occlusive asked us to schedule al. Diagnosis and treatment of acute retinal necrosis: a report by the American Acad- arteritis of the primary retinal arterioles. These follow-ups every six emy of Ophthalmology. Ophthalmology. Kyrieleis plaques are associated with ARN. weeks. 2017;124(3):382-92.

REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 13 HOT TOPICS in Bacterial By Christina Cherny, BS, Pratik Patel, OD, and Suzanne Sherman, OD Keratitis Understanding common pathogens and eff ective treatments is essential in managing these patients with the most successful results.

acterial keratitis is a ing corneal pathogen prevalence, ABOUT THE AUTHORS serious ocular condition corneal pathogen susceptibility, Ms. Cherny is a third-year optometry that can lead to vision loss antibiotic resistance and treatment candidate at the SUNY College of Optometry, where she is Bif not treated promptly, strategy. completing an Advanced appropriately and aggressively.1 Cornea and Contact Lens micro-credential. According to the CDC, an estimat- PREVALENCE She received her ed one million clinical visits occur According to two long-term ret- undergraduate Human Biology, Health and annually in the United States due rospective case reviews of micro- Society degree at Cornell to keratitis.2 Signifi cant risk factors bial keratitis in the United States, University. She is interested in specialty contact lenses and corneal include contact lens use and ocular gram-positive organisms were the disease management. surface disease. Contact lens risk most commonly isolated bacterial factors can be further broken down group, followed by gram-negative Dr. Patel is a graduate of the SUNY College of Optometry. He completed a 6,7 into overnight lens wear, poor stor- organisms. Both studies indi- contact lens and ocular disease age hygiene and infrequent storage cated Staphylococci as the most residency at The Ohio State 2,3 University Havener Eye case replacement. prevalent gram-positive organism Institute. He is currently Treatment of bacterial keratitis and Pseudomonas species as the a clinical instructor at Weill Cornell Medicine begins with empirical manage- most frequently isolated gram-neg- Ophthalmology in New ment using frequent instillation of ative and overall organism.6,7 The York City, where his focus is anterior segment topical broad-spectrum antibiotics individual proportions of cultured management and specialty for coverage of both gram-pos- species differed slightly by study.6,7 contact lens fi tting. He is a fellow of the itive and gram-negative patho- Another study noted that methicil- American Academy of Optometry. gens. Common treatment starting lin-resistant Staphylococcus aureus Dr. Sherman is an assistant professor of points depend on the severity of (MRSA) comprised 20% of all optometric sciences in ophthalmology, director of optometric services at the the corneal ulcer and consist of isolates, while 5% of all cultured Columbia University Medical Center monotherapy with fl uoroquinolo- isolates were MRSA.6 and an assistant attending at New York–Presbyterian Hospital. nes or combination therapy with International studies show simi- She specializes in complex cephalosporins, aminoglycosides, larities and differences in bacterial and medically necessary contact lens fi ttings, vancomycin, amikacin or forti- prevalence compared with national anterior segment disease fi ed antibiotics.1,4 This increased fi ndings.8-15 Similar to the United and primary care. She is board-certifi ed by fi rst-line usage of broad-spectrum States, investigations in China, the American Board of antibiotics, however, has coincided Switzerland, South Korea, Spain Optometry and National Board of Examiners in with a signifi cant rise in the number and Colombia indicate an overall Optometry. She is a fellow of the of bacterial pathogens resistant to preponderance of gram-positive or- American Academy of Optometry, antimicrobials.5 ganisms, as well as a predominance conducts research, contributes to peer- reviewed scientifi c publications and In this review, we discuss relevant of Staphylococci and Pseudomonas presents at annual meetings. trends in bacterial keratitis, includ- individual strains.10,12,14,15 India,

14 REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 Taiwan and the tropics of Malaysia in China.8,9 In India, there has been signifi cant variability in terms of share another similarity with the a decrease in the overall prevalence antibiotic susceptibilities.6,7 Gram- United States—Pseudomonas was of gram-negative organisms, which positive isolates demonstrate 100% the single most commonly isolated differs from the increasing trends susceptibility to vancomycin over bacterial organism.8,11,13 Of notable in certain gram-negative strains time and are fairly sensitive to gen- contrast to the aforementioned observed in China and Taiwan.8,9,13 tamicin, tetracycline and trimetho- countries is Taiwan. From 2007 to Retrospective analyses conducted prim sulfamethoxazole.6,7 However, 2016, Taiwan noted gram-negative in Switzerland and South Korea in- susceptibility to fl uoroquinolones, bacteria as the most commonly iso- dicate no difference in proportions cefazolin and erythromycin is in- lated strain, followed by gram-posi- of gram-positive and gram-negative consistent.6,7 Furthermore, research- tive bacteria.13 organisms, as well as no discernible ers note a decrease in susceptibility Temporal trends in the prev- variation in causative pathogens of gram-positive organisms to alence of gram-positive strains responsible for microbial kerati- levofl oxacin and gentamicin over isolated from bacterial keratitis tis during their respective study time.6 cases varied by each respective periods.10,12 Analyses of gram-negative or- region. In the United States, there ganisms indicated excellent in vitro was a 1.13-increased odds of SUSCEPTIBILITY susceptibility of Pseudomonas to culturing MRSA for each one-year Antibiotic sensitivity is a measure fl uoroquinolones and aminoglyco- increase in culture date.6 The trends of the antibiotic concentration that sides.6,7 Fluoroquinolones are also for gram-negative organisms also will inhibit bacterial growth and effective in Serratia, Moraxella and varied considerably by region and is a predictor of the clinical re- other enteric organisms.6,7 Non- species. According to one study, sponse to antimicrobial treatment.16 Moraxella gram-negative rods the only bacterial pathogen that Techniques of bacterial culturing, exhibit better in vitro sensitivity to increased signifi cantly in propor- such as natural agar plates and cor- ceftazidime than to moxifl oxacin tion during the study period was neal scraping, are used to determine and tobramycin.6 Pseudomonas aeruginosa.7 the bacteria in question and its Internationally, studies document International trends in the sensitivity.17 Knowledge of bacte- differences in antibiotic sensitivities proportions of bacterial isolates rial susceptibility can be helpful and trends between the various re- follow a similar route, differing by to guide the selection of antibiot- gions. Gram-positive isolates have nation. There has been a signifi cant ics to achieve successful clinical a high susceptibility to vancomy- increase in gram-positive isolates outcomes.18 cin, fl uoroquinolones (including in India in recent years, in contrast Retrospective analyses of levofl oxacin, moxifl oxacin and with the decreasing trends in cer- gram-positive organisms conduct- gatifl oxacin), aminoglycosides tain gram-positive strains observed ed in the United States indicate (namely, erythromycin, gentamicin

UNITED STATES: INTERNATIONAL: 6% 3% 2% Gram-positive 6% Gram-positive 23% 31% • Staphylococcus aureus 12% • Staphylococcus spp. • Bacillus spp. 35% • Streptococcus spp. • Streptococcus spp. • Enterococcus spp. • Coagulase-negative • Corynebacterium spp. • Other 15% Staphylococci 17% • Coagulase-negative • Other gram-positive 32% • Other gram-positive Staphylococci 18%

7% Gram-negative 6% Gram-negative 6% Pseudomonas spp. 6% 26% Pseudomonas spp. 19% • • • Enterobacter spp. 43% Serratia spp. Other gram-negative • 10% • • Escherichia coli • Moraxella spp. • Acinetobacter spp. • Proteus mirabilis Other enterics 10% Serratia spp. 16% • 16% • • Haemophilus Other gram-negative 10% Klebsiella 15% • 10% • infuenzae

Strain prevalence characteristics differ markedly between the United States and international regions (comprising India, China, Switzerland, Malaysia, South Korea, Taiwan, Spain, Colombia).

REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 15 HOT TOPICS IN BACTERIAL KERATITIS

and tobramycin), chloramphenicol reported to be the most susceptible while no signifi cant annual trends and impinemen.8,9,12-15 In China, antibiotic to gram-negative bacilli, were noted in the proportions of however, there has been a decrease with an increased susceptibility to oxacillin-resistant Staphylococcus in susceptibility of gram-positive ofl oxacin observed over time.9 aureus and oxacillin-resistant coag- isolates to levofl oxacin, cefazolin, ulase-negative Staphylococci in St. ceftazidime and chloramphenicol ANTIBIOTIC RESISTANCE Louis.6,7 over time.9 Staphylococcus species This occurs when bacteria acquire Analyses in Malaysia observe in particular have a high antibiotic the ability to evade destruction by no increase in resistance rates for sensitivity to vancomycin, teico- antibiotics through spontaneous the commonly used antibiotics, planin and chloramphenicol and mutation or horizontal gene trans- although these fi ndings do not a low sensitivity to fl uoroquino- fer. Resistance is driven largely by hold true for other regions.11 In lones, such as ciprofl oxacin.8,13 overuse of antibiotics. The resis- Colombia, gram-negative organ- Susceptibility of Streptococcus tance process removes drug-sen- isms exhibit higher resistance rates pneumoniae is highest to cefazolin sitive bacteria and leaves resistant overall, while in Taiwan, resistance and lowest to ciprofl oxacin, which strains to proliferate. Causes of an- is more common in gram-posi- is mirrored by an overall trend of tibiotic resistance include the vast tive pathogens.13,15 Similar to the higher susceptibility of gram-posi- number of antibiotics prescribed, United States, the risk of culturing tive cocci to cephalosporins relative incorrect prescribing of antibiotics, MRSA in Taiwan increases with to fl uoroquinolones.8,9 extensive agricultural use of anti- time.13 This differs from fi ndings In regard to gram-negative biotics and the lack of availability in Spain and South Korea, where organisms, most are highly sensi- of new antibiotics on the market.18 no trends have been observed for tive to fl uoroquinolones (including Trends in antibiotic resistance vary methicillin-resistant strains.12,14 ciprofl oxacin and levofl oxacin), regionally, with certain bacterial Furthermore, Staphylococcus aminoglycosides (namely genta- organisms demonstrating increased species demonstrate a signifi cant micin, amikacin and tobramycin), resistance over time and other bac- increase in the proportion resistant cephalosporins (including ceftazi- terial strains exhibiting no signifi - to oxacillin over time. This is in dime and cefepime) and carbape- cant change in antibiotic resistance. contrast to the pattern seen in the nem.9,11-13 Pseudomonas species in In the United States, trends in United States.13 In Colombia and particular demonstrate excellent in antibiotic resistance have changed South Korea, moderate-to-high vitro sensitivity to fl uoroquinolo- over time and vary by region and resistance is observed for gram-neg- nes, aminoglycosides and certain bacterial strain. Resistance to moxi- ative isolates to gentamicin, cephalosporins.8,11-13 fl oxacin increases with each one- tobramycin, amikacin imipenem, Studies conducted in South year increase in the culture date, gatifl oxacin and ciprofl oxacin, as Korea and Taiwan do not show and a trend of increasing resis- well as for gram-positive isolates to signifi cant changes in antibiotic tance to gentamicin was observed Ciprofl oxacin.12,15 sensitivity over time.12,13 In compar- among gram-positive organisms. ison, analyses in China indicate a Additionally, one study found the TREATMENT STRATEGY decreasing trend of susceptibilities. risk of culturing MRSA seems to In addition to the current accepted In China, fl uoroquinolones were increase with time in San Francisco, methods used to treat microbial

Fluorescein staining shows an active The patient’s corneal ulcer is She was left with this scar after her bacterial ulcer in a patient who slept resolving. ulcer healed. in her contact lenses.

16 REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 ciprofl oxacin to fi ght off keratitis tion may help improve success rates caused by Pseudomonas aeruginosa in the treatment of corneal ulcers demonstrate the most improvement and better preserve vision in those in disease severity, with minimal affected. RCCL impact on host immune response.20 1. Bourcier T, Thomas F, Borderie V, et al. Bacterial ker- Researchers investigated ar- atitis: predisposing factors, clinical and microbiological gon cold plasma as a potential review of 300 cases. Br J Ophthalmol. 2003;87(7):834-8. 2. Collier SA, Gronostaj MP, MacGurn AK, et al. Estimated treatment for therapy-resistant burden of keratitis—United States, 2010. Morb Mortal corneal infections, specifi cal- Wkly Rep. 2014;63(45):1027-30. 3. Truong DT, Bui MT, Cavanagh HD. Epidemiology and ly for Staphylococcus aureus, outcome of microbial keratitis: private university versus This patient had irregular Staphylococcus epidermidis, urban public hospital care. Eye Cont Lens. 2018;44(Sup- pl 1):S82-6. epitheliopathy at presentation and Escherichia coli and Pseudomonas ended up having an active bacterial 4. Acharya M, Farooqui JH, Jain S, et al. Pearls and aeruginosa. Analyses indicate that paradigms in infective keratitis. Rom J Ophthalmol. infection secondary to contact lenses. 2019;63(2):119-27. argon cold plasma treatments can 5. Odonkor ST, Addo KK. Bacteria resistance to antibiotics: recent trends and challenges. Int J Biol Med Res. signifi cantly reduce various corne- 2011;2(4):1204-10. al pathogens and improve vision 6. Peng MY, Cevallos V, McLeod SD, et al. Bacterial keratitis: isolated organisms and antibiotic resistance post-treatment without damaging patterns in San Francisco. Cornea. 2018;37(1):84-7. 21 the ocular surface. 7. Hsu HY, Ernst B, Schmidt EJ, et al. Laboratory results, epidemiologic features, and outcome analyses of In another study, patients with microbial keratitis: a 15-year review from St. Louis. Am J culture-positive bacterial ker- Ophthalmol. 2019;198:54-62. 8. Das S, Samantaray R, Mallick A, et al. Types of organ- atitis—negative for fungal and isms and in-vitro susceptibility of bacterial isolates from protozoal species—received six or patients with microbial keratitis: a trend analysis of 8 years. Ind J Ophthalmol. 2019;67(1):49-53. more daily drops of potent topical 9. Lin L, Duan F, Yang Y, et al. Nine-year analysis of iso- steroids, including prednisolone lated pathogens and antibiotic susceptibilities of micro- Hyperemia can be seen in this patient. bial keratitis from a large referral eye center in southern acetate 1%, phenylephrine hydro- China. Infection and Drug Resistance. 2019;12:1295-302. keratitis, a review of recent lit- chloride 0.12%, dexamethasone 10. Bograd A, Seiler T, Droz S, et al. Bacterial and fungal keratitis: a retrospective analysis at a univer- erature indicates several novel 0.1% and prednisolone sodium sity hospital in Switzerland. Klin Monbl Augenheilkd. approaches may prove valuable for phosphate 0.5%.22 Patients on the 2019;236(4):358-65. 11. Khor HG, Cho I, Lee KRCK, et al. Spectrum of micro- the treatment of bacterial corneal high-dose steroid regimen have bial keratitis encountered in the tropics. Eye Cont Lens. infections. a 5.5-increased chance of better 2019:1542-2321. 12. Mun Y, Kim MK, Oh JY. Ten-year analysis of micro- A broad-spectrum combination visual outcomes, although patients biological profi le and antibiotic sensitivity for bacterial of polymyxin B–trimethoprim with Nocardia keratitis had poorer keratitis in Korea. PLoS ONE. 2019;14(3):e0213103. 13. Liu HY, Chu HS, Wang IJ, et al. Microbial kerati- (PT) and rifampin demonstrat- outcomes.22 Treatment of bacterial tis in Taiwan: a 20-year update. Am J Ophthalmol. 2019;205:74-81. ed increased potency, improved keratitis with high-dose steroid reg- 14. Tena D, Rodríguez N, Toribio L, et al. Infectious kerati- antibiofi lm activity and more rapid imens may prove to be an import- tis: microbiological review of 297 cases. Jpn J Infect Dis. 2019;72(2):121-3. bactericidal activity compared ant clinical tool for improved visual 15. Galvis V, Parra MM, Tello A, et al. Antibiotic resistance with PT alone for the treatment outcomes after corneal infection.22 profi le in eye infections in a reference centre in Floridab- lanca, Colombia. Arch Soc Esp Oftalmol. 2019;94(1):4-11. of Staphylococcus aureus and 16. Smaill F. Antibiotic susceptibility and resistance test- Pseudomonas corneal infections.19 working knowledge and ing: an overview. Can J Gastroenterol. 2000;14(10):871-5. This novel combination also ex- understanding of common 17. Leck A. Taking a corneal scrape and making a diagno- A sis. Comm Eye Health. 2009;22(71):42-3. hibits a lower tendency to develop pathogens and their respective 18. Ventola CL. The antibiotic resistance crisis: part 1: causes and threats. Pharm Therapeut. resistance than either individual clinical therapies and current trends 2015;40(4):277-83. 19 agent or moxifl oxacin. Increased is essential to effectively manage 19. Chojnacki M, Philbrick A, Wucher B, et al. Develop- ment of a broad-spectrum antimicrobial combination for effi cacy was also observed relative bacterial keratitis and improve the treatment of Staphylococcus aureus and Pseudomo- to commercial PT and moxifl oxa- visual outcomes in patients. Given nas aeruginosa corneal infections. Antimicrob Agents Chemother. 2018;63(1):e01929-18. 19 cin in murine models of keratitis. the widespread use of broad-spec- 20. Carion TW, Ebrahim AS, Kracht D, et al. Thymosin Thymosin beta-4 (Tβ4) is a natu- trum antimicrobials and the Beta-4 and ciprofl oxacin adjunctive therapy improves Pseudomonas aeruginosa-induced keratitis. Cells. rally occurring amino acid protein subsequent emergence of antibiotic 2018;7(10):145. that promotes wound healing and resistance, targeting various patho- 21. Reitberger HH, Czugala M, Chow C, et al. Argon cold plasma—a novel tool to treat therapy-resistant corneal host defense and reduces corneal gens with treatments that have infections. Am J Ophthalmol. 2018;190:150-63. infl ammation. Corneas treated proven effective and using novel 22. Green M, Hughes I, Hogden J, et al. High-dose steroid treatment of bacterial keratitis. Cornea. with a combination of Tβ4 and therapies adjunctively or in isola- 2019;38(2):135-40.

REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 17 SMART STRATEGIES for Using Antibiotics to Treat CORNEAL INFECTION

Understand when to initiate appropriate therapy options. By Fiza Shuja, OD, and Suzanne Sherman, OD

ccording to a recent pathogens and effective treatments with risk factors that disturb the study in Cornea, ap- is essential in managing these corneal epithelial integrity. Contact proximately one million patients with the most successful lens wear, trauma, impaired Aannual ocular medical results. defense mechanism, immunosup- visits in the United States ended up pressive medication use and altered with a bacterial keratitis diagno- BACTERIAL CONJUNCTIVITIS corneal surface structure postoper- sis.1,2 Of these patients, 76.5% re- AND KERATITIS atively are all common predispos- ceived a prescription for antibiotics Bacterial conjunctivitis is the ing factors.8,9 from their healthcare provider.1,2 second most common cause of con- The most common risk factor The cost of treating bacterial junctivitis, and it is responsible for in the US is contact lens wear. keratitis is estimated to be around 50% to 75% of conjunctivitis cases Microbial keratitis is approxi- $377 million to $857 million per in children.6 Although conjunctivi- mately 15 times more likely in year.3 Bacterial keratitis is only one tis involves the conjunctiva specifi - patients who sleep in their lenses cause of ocular infections, but it cally, it can affect the surrounding and is positively correlated with the requires immediate intervention ocular structures that can lead number of days patients wear their in order to prevent vision loss and to worsening infections, such as contact lenses without removal.8 minimize complications. keratitis, which can become serious With the increase of contact lens Viral and bacterial infections are enough to cause blindness.7 wear gloally, bacterial keratitis has the most common etiologies for In adults, a bacterial origin is less also increased accordingly.9 bacterial keratitis. A proportion of common than a viral one and is Bacterial conjunctivitis can be 71,000 cases of severe infectious characterized by bacterial over- self-limiting and resolves on its keratitis a year in America has been growth, along with infi ltration of own in one to two weeks due to estimated, a lower proportion than the conjunctival epithelial layer. non-infectious bacterial keratitis.2,4 The origin can either be from direct ABOUT THE AUTHORS To treat bacterial keratitis, prac- contact with an infected individu- titioners initiate empirical therapy al’s secretions or advanced through Dr. Shuja is an optometrist with broad-spectrum or fortifi ed organisms colonizing within the at New York–Presbyterian Hospital. antibiotics prescriptions; however, patient’s own nasal and sinus overuse has led to a pattern of re- mucosa.8 sistance that can cause diffi culty in Bacterial keratitis is an acute or Dr. Sherman is an assistant suitably managing the condition.5 chronic condition that can become professor of optometric sciences in ophthalmology This article explores the changes sight-threatening if left untreated. and director of in trends regarding corneal in- These cases can lead to stromal in- optometric services at fections and the situations where fl ammation and progressive tissue the Columbia University Medical Center and an practitioners should use antibiotic destruction, eventually causing per- assistant attending at New treatment. Understanding common foration. It is commonly connected York–Presbyterian Hospital.

18 REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 the body’s immune factors.6 Gram- rial treatment.1 Antibiotics positive cocci and Staphylococcus often accelerate clinical species are known to inhabit skin resolution and microbiolog- cells, skin glands and mucous ical remission, while also membranes. Methicillin-resistant lessening the risk of recur- Staphylococcus aureus (MRSA) rence and the development of is a well-known gram positive complications.1 cocci we always have to be on the Some prospective studies lookout for. MRSA has a caused show that delaying antibiotic an increase of vancomycin use. treatment until day three or Propionibacterium acnes (P. acnes) four will reduce the use of un- is one of the major causes of necessary medications and not postoperative endophthalmitis but affect outcomes. The practi- an uncommon cause of microbial tioner only initiated treatment This child has subcutaneous conjunctival keratitis. if the signs were worsening, membranes from a bacterial infection. When caused by dangerous shortening the course and bacterial species, such as Neisseria improving symptoms. These studies as bacterial keratitis for the best gonorrhoeae or Streptococcus pyo- all advocate that initiation of outcome.9 However, it is diffi cult genes, bacterial conjunctivitis can antibiotics after day four provides for the practitioner to quickly and be serious and sight-threatening. fi nite benefi ts.8 effectively manage patients with In rare cases, it may foreshadow a Classic antibacterial options presumed microbial conjunctivitis life-threatening systemic disease, include tobramycin, trimetho- or keratitis. Although it would be such as conjunctivitis caused by prim, ciprofl oxacin, gatifl oxacin ideal to have a confi rmed defi nitive Neisseria meningitidis.8 and moxifl oxacin.10 However, the diagnosis before initiating therapy, The most common causative widespread use of broad-spectrum bacterial pathogens can cause bacterial species are Haemophilus antibiotics has resulted in resis- irreversible corneal scarring. It infl uenza, Streptococcus pneu- tance to those typical antibiotics.10 is therefore imperative to begin moniae, Staphylococcus aureus Therefore, developing new antibi- treatment before any damage and Staphylococcus epidermidis otics with high effi cacy and safety occurs. The initiation of therapy with staphylococci, specifi cally against some resistant bacteria is must occur before an established S. aureus and coagulase-negative necessary.1 diagnosis in order to prevent visual Staphylococci (CoNS), reported disability and limit the bacterial most often.7,10 MANAGEMENT load.8 Several bacterial species simul- The primary goal when dealing Preliminary therapy is comprised taneously can cause most cases with corneal infections is always of empirical topical broad-spec- of acute bacterial conjunctivitis. to prevent loss of sight and to trum antibiotics. For routine cor- This is why practitioners use preserve corneal clarity. It is safer neal ulcers, monotherapy of topical broad-spectrum antibiotics as the to assume and, therefore, treat any fl uoroquinolones provides compa- fi rst line of ophthalmic antibacte- presentation of microbial keratitis rable therapy to combination therapy due to the enhanced Classifi cation of Bacterial Conjunctivitis8 penetration obtained Course of Onset Severity Common Organisms with commercially avail- Slow Mild to moderate Staphylococcus aureus able fl uoroquinolones.8 (days to weeks) Moraxella lacunata Fluoroquinolones can be Proteus spp. Enterobacteriaceae instilled every 30 Pseudomonas minutes to 60 minutes Acute or subacute Moderate to severe Haemophilus infl uenzae biotype III for a routine corneal (hours to days) Haemophilus infl uenzae ulcer. Streptococcus pneumoniae If the ulcer is more se- Staphylococcus aureus vere, use a loading dose Hyperacute Severe Neisseria gonorrhoeae of every fi ve minutes for (less than 24 hours) Neisseria meningitidis 30 minutes to transfer

REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 19 USING ANTIBIOTICS TO TREAT CORNEAL INFECTION

therapeutic concentration to the 1. Take a careful case stroma faster.8 history. Do not rely If monotherapy fails and/or the only on the informa- initial ulcer is large, central or tion the patient gives atypical, consider combination you. Always ask about therapies due to the additional previous contact lens gram-negative activity. In addi- use, recent activities, tion, if combination therapy fails surgeries, etc. or MRSA is suspected, initiate 2. Ask about previous fortifi ed antibiotics, including treatments. Many vancomycin. Fortifi ed antibiot- patients have already ics are compounded at increased gone to a walk-in clinic concentration. Remember that or someone who is not This patient had bacterial keratitis (top) that eventually resolved with antibiotics and was “fortifi eds” can be diffi cult to an eye care provider. left only with a small scar (bottom). obtain commercially and have If they can’t recall the greater corneal toxicity. According exact medication given, to a survey, the majority of corneal ask about the cap color specialist respondents in the United and dosage. States chose to treat corneal ulcers 3. Conduct a careful slit with fortifi ed antibiotics, specifi - lamp exam including lid cally vancomycin and tobramycin eversion and fl uorescein due to low antibiotic resistance, staining. whereas a majority of internation- 4. Use slit lamp photo- al corneal specialists respondents graphs to compare chose fl uoroquinolone treatment images at each visit. due to availability.11 5. Perform IOP measure- Clinical parameters that can be ments and dilation are helpful to monitor the response to essential. If you haven’t seen for fourth generation fl uoroquino- antibiotic treatment include blunt- a patient recently, you cannot lones to the pharmacy. ing the stromal infi ltrate perimeter, assume the posterior segment Depending on the severity of decreased density of the stromal is not involved. the infection, it is helpful to space infi ltrate, reduction of stromal ede- Once the presumed etiology is out follow-ups in order to give ma and endothelial infl ammatory determined based on case history the antibiotics time to work and plaque, reduction in anterior cham- and clinical exam, personal expe- the cornea time to heal. At the ber infl ammation, reepithelization rience shows it is most effective follow-up, closely compare the and cessation of corneal thinning.8 to use monotherapy of topical current presentation to previous In day-to-day clinical practice, fl uoroquinolones during the day slit lamp photos. Oftentimes, we work side-by-side with anterior and an added ointment at night. In clinical signs and patient symptoms segment specialists in a tertiary the offi ce, fourth generation fl uoro- will have started to improve before care setting. Over the years, we quinolones are not always avail- culture results have returned. have developed our own “smart” able; therefore, we give the patient strategies for dealing with corneal a sample of the highest-generation RISE OF THE RESISTANCE infections. drop available and a prescription Though bacterial keratitis requires treatment with antibiotics, it is Common Causes of Bacterial Keratitis8 crucial to understand how over-us- Common Uncommon ing and over-prescribing antibiotics can lead to resistance. Bacterial Staphylococcus aureus Neisseria spp. Staphylococcus epidermidis Moraxella spp. resistance to an antibiotic depends Streptococcus pneumoniae Mycobacterium spp. on the mechanism. The most Pseudomonas aeruginosa Nocardia spp. common resistance mechanism, Enterobacteriaceae Non–spore-forming anaerobes modifi cation, can involve a muta- Corynebacterium spp. tion to the target site, making the

20 REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 drug ineffective.12 Resistance can The ARMOR study monitors geographically, reinforcing the need be coded into the bacterial genes antibiotic resistance in ocular infec- for studies like ARMOR, which and then passed between colonies tions against S. aureus, CoNS, S. are conducted nationwide in the and species, allowing it to spread pneumoniae, H. infl uenzae and P. United States. Understanding the quickly.12 aeruginosa.16 From 2009 to 2013, location of bacteria can aid eye- Antibiotic resistance to penicil- methicillin resistance was shown in care providers to target the more lin can begin soon after the drug staphylococcal isolates; however, it common pathogens—S. aureus is is introduced to treat infections.13 did not increase over the fi ve years. higher in the South and lower in Factors to blame for antibiotic Bacteria such as S. pneumoniae and the West, S. pneumoniae is higher resistance include over-prescribing, H. infl uenzae were most susceptible in the Midwest and lower in the inappropriate dosing regimen, to antibiotics, whereas there was West and P. aeruginosa is higher in increased use of antibiotics in multidrug resistance in 86.8% of the Midwest and lower in the West. agriculture and increased exposure methicillin-resistant S. aureus iso- Globally, antibiotic resistance to systemic antibiotics.14,15 When lates and 77.3% of methicillin-re- continues to plague practi- practitioners prescribe, a pattern of sistant CoNS. The study also noted tioners when treating keratitis. resistance can occur if patients are a higher number of methicillin-re- Moxifl oxacin has shown increased unable to self-administer properly sistant staphylococcal infections resistance in India, despite its or discontinue medications due to in elderly patients.16 P. aeruginosa more “recent” foray in treating ocular discomfort from adverse and H. infl uenzae isolates showed bacterial infections; there was low effects.15 low resistance against most of the susceptibility of coagulase-nega- Many of the antibiotics treating antibiotics tested. tive Staphylococcus (61.2%) and the ocular surface are also used Most of the published data methicillin-resistant Staphylococcus systemically for infections, except regarding ocular pathogens is col- (53.1%) when treated with moxi- besifl oxacin, which was formulated lected from single centers; however, fl oxacin. In the US, 26% of all exclusively for ocular use to allow pathogens differ in prevalence organisms cultured were resistant lower resistance rates.14 We have seen some patients who believe Antibiotic Smart Strategies they are cured and self-discontinue Routine Corneal Monotherapy: • Equivalent to Every 30 to antibiotics early. Once this hap- Ulcer topical combination 60 minutes, pened, the infection reappeared fl uoroquinolones therapy tapered and the treatment course had to according to clinical Second • Pseudomonas be resumed. It is therefore wise for response. optometrists to prevent over-pre- generation: coverage ciprofl oxacin, • Lack some gram- More severe scribing and make sure the antibi- ofl oxacin positive activity otic treatment runs its course. presentation: Third and fourth • Improved gram- Loading dose The increase in resistant bacteria generation: positive activity every fi ve over the years has led to stud- moxifl oxacin, • Atypical minutes for ies, such as the Ocular Tracking gatifl oxacin, mycobacterial 30 minutes. Resistance in the United States levofl oxacin, coverage besifl oxacin • Limited activity Today (TRUST) and Antibiotic against MRSA Resistance Monitoring in Ocular Monotherapy Combination • Active against micRoorganisms (ARMOR) stud- for initial ulcer, therapy gram-positive and 13,14 ies. Ocular TRUST monitored unless ulcer is gram-negative S. aureus, S. pneumoniae and H. large, vision- bacteria infl uenzae when treated with fl uo- threatening or roquinolones, macrolides, amino- atypical glycosides, penicillin, dihydrofolate Failed Fortifi ed • Vancomycin gram monotherapy antibiotics +, greater coverage reductase inhibitors and polypep- or combination against MRSA tides. Ocular TRUST studies re- therapy with ported 16.8% methicillin resistance large, vision- from 2005 to 2006, which then threatening, increased to 50% by 2008.16 MRSA suspected

REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 21 USING ANTIBIOTICS TO TREAT CORNEAL INFECTION

also help resolve epithelial steroids. Clinical assessment is defects and chemical in- imperative in making the correct jury. Amniotic membrane diagnosis and managing it appro- benefi ts include reepithe- priately prevents vision loss. RCCL lization by reinforcing bas- 1. Collier SA, Gronostaj MP, MacGurn AK, et al. Es- al epithelial cell adhesion, timated burden of keratitis: United States, 2010. induction of epithelial Morb Mortal Wkly Rep. 2014;63(45):1027-30. cell migration, differenti- 2. Ballouz D, Maganti N, Tuohy M, et al. Medica- tion burden for patients with bacterial keratitis. ation and proliferation of Cornea. 2019;38(8):933–7. conjunctival and limbal 3. Smith AF, Waycaster C. Estimate of the direct and indirect annual cost of bacterial conjunctivitis epithelial progenitor cells, in the United States. BMC Ophthalmol. 2009;9:13. prevention of epithelial 4. Jeng BH, Gritz DC, Kumar AB, et al. Epidemiol- apoptosis and reduction ogy of ulcerative keratitis in Northern California. Arch Ophthalmol. 2010;128:1022–8. of keratocyte apopto- 5. Gokhale NS. Medical management approach sis. Studies have shown to infectious keratitis. Indian J Ophthalmol. Corneal scarring secondary to chronic improvement in epithelial 2008;56(3):215-20. blepharoconjunctivitis caused this case of 6. Høvding G. Acute bacterial conjunctivitis. Acta keratitis. defect, corneal haze and Ophthalmol. 2008;86(1):5-17. neovascularization when 7. Teweldemedhin M, Gebreyesus H, Atsbaha AH, et al. Bacterial profi le of ocular infections: a sys- to moxifl oxacin, while 28% of eyes were treated with amniotic tematic review. BMC Ophthalmology. 2017;17:212. Staphylococcus aureus bacterial membranes rather than antibiotics 8. American Academy of Ophthalmology. Exter- nal disease and cornea: Basic and Clinical Science isolates were resistant to ciprofl ox- alone; however, larger studies needs Course 2017-2018. 2017. 17 acin or ofl oxacin. to be conducted to analyze the full 9. Wang JJ, Gao XY, Li HZ, Du SS. The effi cacy potential of amniotic membranes and safety of besifl oxacin for acute bacterial 18 conjunctivitis: a Meta-analysis. Int J Ophthalmol. ALTERNATIVE THERAPY when treating bacterial keratitis. 2019;12(6):1027-36. There are other treatment mo- Treatment for corneal perfora- 10. Al-Mujaini A, Al-Kharusi N, Thakral A, Wali UK. Bacterial keratitis: perspective on epidemiology, dalities to consider when treating tion with doxycycline has shown clinico-pathogenesis, diagnosis and treatment. bacterial keratitis. The use of ste- improvement in animal studies. In Sultan Qaboos Univ Med J. 2009;9(2):184–95. roids in treating bacterial keratitis rabbit models, corneal perforation 11. Austin A, Schallhorn J, Geske M, et al. Empirical treatment of bacterial keratitis: an international remains a controversial issue. Early from Pseudomonas ulcers was survey of corneal specialists. BMJ Open Ophthal- use of steroids can help reduce reduced by 50% with systemic mol. 2016;2:e00047. 12. Baum J, Barza M. The evolution of antibiotic corneal stromal melt, neovascu- doxycycline use. Unfortunately, therapy for bacterial conjunctivitis and keratitis: larization and corneal scarring the lack of human studies makes it 1970-2000. Cornea. 2000;19(5):659-72. that results from the infl ammatory diffi cult to prove doxycycline as an 13. McDonald M, Blondeau J. Emerging and antibiotic resistance in ocular infections and the response against the infection. effective therapy. role of fl uoroquinolones. J Cataract Refract Surg. Instilling steroids in conjunction Collagen crosslinking, used to 2010;36(9):1588-98. 14. Thomas RK, Melton R, Asbell PA. Antibiotic re- with fortifi ed antibiotics can also treat keratoconus, has antimicro- sistance among ocular pathogens: current trends help decrease discomfort. The bial properties and can potentially from the ARMOR surveillance study (2009-2016). Clin Optom (Auckl). 2019;11:15-26. counterargument is that steroids help resolve corneal ulcers from 15. Samarawickrama C, Chan E, Daniell M. Rising delay corneal healing, leading to bacterial pathogens. Case reports fl uoroquinolone resistance rates in corneal isolates: implications for the wider use of antibi- a worse infection. Though steroid have shown an improvement in otics within the community. Infection, Disease & use leads to improvement for some symptoms and the resolution of Health. 2015;20:128-33. patients, note that the use of ste- treatment-resistant infections. 16. Asbell PA, Sanfi lippo CM, Pillar CM, et al. An- tibiotic resistance trends from ocular pathogens roids for fungal or Acanthamoeba Further trials and studies could in the US-cumulative results from the antibiotic resistance monitoring in ocular microorganisms infections can lead to terrible help establish crosslinking as a (ARMOR) surveillance study. US Ophthalmic results, such as increased loss of viable treatment for those with an- Review. 2017;10(1):35-8. vision or loss of the eye. tibiotic resistance and/or to prevent 17. Ung L, Bispo PJM, Shanbhag SS, et. al. The persistent dilemma of microbial keratitis: global 19 Studies have been performed to ocular toxicity. burden, diagnosis, and antimicrobial resistance. fi nd new adjunct therapies to treat Surv Ophthalmol. 2019;64:255-71 18. Dakhil TAB, Stone DU, Gritz DC. Adjunctive bacterial keratitis, especially with hough bacterial keratitis needs therapies for bacterial keratitis. Middle East Afr J the rise of antibiotic resistance. Tto be treated aggressively, ex- Ophthalmol. 2017;24(1):11–7. 19. Austin A, Lietman T, Rose-Nussbaumer J. Up- Amniotic membranes, typically ercise caution when using treating date on the management of infectious keratitis. used during pterygium surgery, topical therapy options, such as Ophthalmology. 2017;124(11):1678–89.

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Review Education Group partners with Salus University for those ODs who are licensed in states that require university credit. See www.reviewsce.com/events for any meeting schedule changes or updates. TAKE ON Neurotrophic With These Keratitis Clinical Tools The more it progresses, the more challenging it becomes, so early detection and diagnosis are key.

By Megan Mannen, OD

eurotrophic keratitis both centrally at the ganglion of neurotrophy.5 In fact, corneal (NK) is a potential- and peripherally at the basal confocal microscopy has been ly sight-threatening plexus. Alternatively, HSV only shown to be useful in the early Ncondition marked causes peripheral nerve damage. diagnosis of peripheral neurop- by decreased or absent corneal Patients suffering from herpes athy due to its ability to detect sensation. The condition is caused zoster ophthalmicus experience subtle reductions in corneal nerve by damage both to the trigeminal shorter corneal nerve length and density and length.6 This form of nerve along its corneal distribution lower corneal nerve count.4 The microscopy can assess small nerve and at any point in the pathway zoster virus lies dormant in the fi bers, which neuropathy affects from the ganglion to the basal trigeminal ganglion, and when it fi rst.6 Because of the link between plexus. This damage compromises reactivates along the nasociliary diabetic neuropathy and corne- corneal integrity by altering the distribution, it results in corneal al integrity, consider the role of metabolism and mitosis processes compromise.4 In both HSV and underlying neurotrophy in patients of the corneal epithelium, which VZV, these damaging effects occur with diabetes and other ocular results in reduced innate immunity quickly and have long-lasting surface disease. of the ocular surface and delayed impacts on the integrity of the Regardless of its specifi c source, healing.1,2 If allowed to progress, corneal epithelium. corneal neurotrophy is typical- damage could advance to the point Beyond viral eye disease, there ly not associated with pain or of ulceration and, in severe cases, are a variety of other causes of discomfort due to the lack of corneal perforation.1-3 NK, including repeated corneal sensation it is accompanied by. NK is easy to manage early on surgeries, chemical burns, contact These patients will, however, likely in the disease process but remains lens abuse, medications, tumors report reduced vision, especially one of the most challenging corne- and surgical complications result- as the condition becomes more al conditions to treat in its severe ing in trigeminal nerve palsies.1,5 severe. Medicamentosa is a poten- stages. This article will review Systemic disorders such as dia- tial cause of corneal neurotrophy the causes, diagnostic fi ndings betes also contribute to NK. The that should always be considered and treatments available for NK longer a patient has diabetes, the ABOUT THE AUTHOR throughout all stages of disease. more severe their corneal nerve damage might be. This mani- Dr. Mannen practices at a private optometry and TRACE IT TO THE SOURCE fests in diminished corneal tissue ophthalmology clinic in The most common etiologies sensation similar to that occur- the greater Ogden, Utah area. She completed her of NK are herpes simplex virus ring with peripheral neuropathy. residency at the Walla (HSV) and varicella zoster virus Additionally, peripheral treatment Walla Veteran Aff airs 1 Medical Center and Pacifi c (VZV). Among herpes viruses, with panretinal photocoagula- Cataract and Laser Institute. zoster causes more severe neur- tion for proliferative diabetic She is also a fellow of the American otrophy, as it may infl ict damage retinopathy worsens the degree Academy of Optometry.

24 REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 as a differential and man- different methods. Cotton aged appropriately. Topical wisps and (non-fl avored) medications most likely to dental fl oss are used most have noxious ocular surface frequently, as they are effects include anesthetics, inexpensive and readily beta-blockers and non-ste- available. roidal anti-infl ammatories Approach the unaffect- (NSAIDs). Most of these ed eye fi rst and test it in medications use benzalko- quadrants and centrally. nium chloride as the preser- Then, proceed to the other vative.7 Monitor the ocular eye and test the same zones, surface closely in glaucoma allowing the patient to grade patients using beta-blockers Fig. 1. A 51-year-old Caucasian female presented the sensitivity in comparison with progressively worsening vision in the left eye and in post-surgical patients over the last two months but no more discomfort. with its counterpart. using NSAIDs, as these are She reported using bacitracin-Polymyxin B- Relative neurotrophy is the medications most com- neomycin-hydrocortisone ophthalmic solution TID gradable using both subjec- and diclofenac BID for approximately two months monly prescribed to these while in the hospital. tive responses and observ- patients. able differences in patient Using a greater number of signs. Cells and fl are, which may blink force and recoil. For consis- medications further increases the occasionally worsen into a sterile tency, use a near uniform length risk of toxicity.7 If topical toxicity hypopyon, are often present in this of wisp or fl oss each time you test is suspected, discontinue medica- stage and can make the differenti- (~3cm is standard) to ensure equal tions and monitor the cornea for ation between microbial keratitis force is applied with each touch. improvement. Systemic medica- and neurotrophic disease more Alternatively, the Cochet-Bonnet tions have also been shown to challenging.1,2,5,8 esthesiometer is a more repeatable perpetuate corneal neurotrophy. The third and fi nal stage of and quantifi able test of aesthesia. These include antihistamines, neurotrophy involves corneal It records a patient’s response neuroleptics and antipsychotics.2 stroma ulceration. This is defi ned to contact with a nylon line on Consult primary care providers as an epithelial break with under- a scale between 0cm and 6cm.10 and consider drug cessation if lying stromal infl ammation. The A lower reading indicates more these mediations are contributing stroma is made up of organized reduced corneal sensitivity.11 to corneal compromise. collagen fi bers called lamellae. Once the stroma is penetrated, the TREATMENT STRATEGY THE THREE STAGES OF NK collagen fi brils start to degrade. Treatment of NK is based on There are three traditional clinical This damage attracts white blood disease etiology and severity. In stages of NK. The fi rst involves cells, which infi ltrate the damaged stage one, optimizing the ocu- tear dynamic alteration, punc- tissue. These immune cells proceed lar surface is the primary goal. tate epithelial erosion, superfi cial to release matrix metalloprotein- Preservative-free artifi cial tears, neovascularization and stromal ases (MMPs) and oxygen radicals, punctal occlusion and Restasis scarring. These fi ndings are which are pro-infl ammatory and (Allergan) or Xiidra (Novartis) are common and can be mistaken for cause the stroma to progressively frequently prescribed to improve other ocular surface diseases, but degrade.9 This may lead to cor- tear volume. Comorbidities, such decreased corneal sensation, lack neal melt and perforation—an as meibomian gland dysfunction, of symptoms and patient history ocular emergency that requires exposure keratitis and limbal defi - will help with the diagnosis.1,2,8 immediate attention and treatment ciency, should also be addressed to The second stage of NK is to best preserve vision and globe prevent further corneal damage. marked by a persistent epithelial integrity.1,2,8 When NK progresses to stage defect. The defect may be sur- two, closure of the defect and rounded by a loose, edematous or CLINICAL DIAGNOSIS prevention of progressive stromal boggy epithelium. Stromal edema Diagnosing NK involves evalu- thinning are the primary objec- and folds in Descemet’s membrane ating corneal sensation. Corneal tives. Use scleral lenses, bandage may also accompany these clinical aesthesia can be tested using a few soft contact lenses and amniotic

REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 25 TAKE ON NEUROTROPHIC KERATITIS WITH THESE CLINICAL TOOLS

membranes in attempts to close in cases of pure exposure keratop- to lead to direct nerve sprouting the epithelial defect. Scleral lenses athy as well. and provide a potential cure to can act as a moisture chamber to Serum-based eye drops are NK.23 offer a fl uid reservoir and buffer becoming more widely used ther- Topical steroids may be helpful against the mechanical force of apies for stages one and two of in managing neurotrophy caused the blink. Bandage contact lenses NK. These drops are created from by chemical burns; however, due provide a short-term barrier to blood samples, which are clotted, to their immunosuppression and lid friction. Amniotic membranes centrifuged and diluted with either delayed healing effects, they are contain placental tissue and, thus, sterile saline or a balanced salt considered controversial in treat- a variety of growth factors. They solution.16 All dilution prepara- ing pure NK. Further, they have have been shown to increase tions have proved useful in resolv- been found to increase the risk of corneal epithelialization, promote ing persistent epithelial defects.17 corneal melting and perforation tissue repair and heal persistent Additionally, umbilical cord se- by up-regulating collagenases, epithelial defects.12 Additionally, rum, substance P with insulin-like which leads to enhanced stromal they decrease MMPs, which growth factor 1 and nerve growth breakdown. In an effort to prevent normally reduce tissue growth factor drops are being explored as this, avoid steroids if possible.1,2,25 and turnover and, thus, infl am- future mainstream NK treatments If a steroid is necessary, pair it mation.13 Each of these therapies due to their ability to repair nerve with an appropriate antibiotic to should be combined with anti- damage.2,8,11,18,19 In fact, Oxervate keep normal fl ora from infecting microbial prophylaxis to prevent (Dompé)—a recombinant human the NK. bacterial super-infection. nerve growth factor—was recently Stage three of NK is charac- Consider a temporary lateral FDA-approved for the treatment terized by a sterile ulceration or tarsorrhaphy to heal persistent of NK. Treatment includes six melting of the stroma with the defects. A temporary tarsorrhaphy daily drops over an eight-week potential to perforate. It is pro- joins the eyelids together with course and has shown extremely moted by the prolonged presence three or four sutures. Wait until promising results in repairing of epithelial defects. Collagenase the wound resolves to release the persistent corneal defects.20 Nerve activity is up-regulated by the tarsorrhaphy, as premature suture growth factor promotes epitheli- presence of these chronic epithelial removal makes these epithelial de- al healing and increases corneal defects. This leads to thinning of fects more likely to recur.8,14 Two sensitivity.21,22 the stroma with subsequent scar- alternatives to a tarsorrhaphy are Also gaining popularity is cor- ring and warpage of the cornea a Botox injection into the levator neal neurotization, which restores if re-epithelialization occurs or, to create a temporary ptosis and corneal sensation by transferring worse— in the absence of re-ep- palpebral spring use.8,15 These sur- healthy nerve tissue to the limbus ithelialization—if progression to gical interventions may be helpful of the affected cornea. It is most perforation takes place.5 commonly performed While steroids are generally on the distal ends of avoided due to their ability to the supratrocheal and potentiate collagenase activity, supraorbital nerves.23,24 medications that down-regulate The donor nerve is drawn these enzymes can be helpful by together with the dam- decreasing potentiators of melt. aged nerve with the hope These include N-acetylcysteine, of regenerating corneal oral tetracycline antibiotics and sensation, which could medroxyprogresterone.1,9,25 take up to six months If perforation is impending or following surgery.23 has already occurred, treatment Although neurotization takes on a new level of urgency. procedures are extensive, Treatments include cyanoacrylate the least invasive tech- glue or fi brin adhesive application Fig. 2. Slit lamp exam revealed a perforated niques use cadaver nerve and amniotic membrane trans- corneal ulcer involving the inferior visual axis 23 with a collapsed anterior chamber and iris tissue or endoscopy. plantation as temporizing mea- prolapse in the left eye. Neurotization is thought sures. Adhesive options are ther-

26 REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 corneal nerve alteration: an in vivo confocal micros- keratoplasties. copy study. Ophthalmology. 2013;120(1):40-7. A penetrating 5. Chang BH, Groos EB. Neurotrophic keratitis. In: Cornea: Fundamentals, Diagnosis, and Manage- keratoplasty is ment. Elsevier; 2017:1035-42. a full-thickness 6. Petropoulos IN, Alam U, Fadavi H, et al. Rapid automated diagnosis of diabetic peripheral neu- transplant—the ropathy with in vivo corneal confocal microscopy. graft type used Invest Ophthalmol Vis Sci. 2014;55(4):2071-8. 7. Okoro CC, Amiebenomo OM, Aruotu N. Medica- in most NK mentosa keratoconjunctivitis: a case report. Afr Vis cases that lead Eye Health. 2016;75(1). 8. Sacchetti M, Lambiase A. Diagnosis and man- to perforation. agement of neurotrophic keratitis. Clin Ophthalmol. Transplants have 2014;8:571-9. 9. Ralph RA. Tetracyclines and the treatment a better chance of corneal stromal ulceration: a review. Cornea. of survival if they 2000;19(3):274-7. 10. Lambiase A, Rama P, Aloe L, et al. Management can be delayed of neurotrophic keratopathy. Curr Opin Ophthalmol. 1999;10(4):270-6. Fig. 3. The patient underwent emergency penetrating with temporizing 13,27 11. Yoon KC, You IC, Im SK, et al. Application of keratoplasty (PK) followed by a repeat PK with cataract measures. umbilical cord serum eyedrops for the treat- extraction. The culture performed prior to the first This allows time ment of neurotrophic keratitis. Ophthalmology. corneal transplant was negative for microbial growth. 2007;114(9):1637-42. Due to a persistent epithelial defect following PK, she for infl amma- 12. Kaufman SC. Anterior segment complications of herpes zoster ophthalmicus. Ophthalmology. needed multiple Prokera (Bio-Tissue) membranes, tion to subside. 2008;115(2 Suppl):S24-32. tarsorrhaphy and an amniotic membrane transplant. Unfortunately, 13. Solomon A, Meller D, Prabhasawat P, et al. Am- Post-op visual acuity was 20/400 with pinhole acuity corneal trans- niotic membrane grafts for nontraumatic corneal ranging from 20/80 to 20/200. perforations, descemetoceles, and deep ulcers. plants in neuro- Ophthalmology. 2002;109(4):694-703. 14. Mantelli F, Nardella C, Tiberi E, et al. Congeni- apeutic via tectonic improvement trophic patients are more likely tal corneal anesthesia and neurotrophic keratitis: and polymorphonuclear leukocyte to fail due to a propensity for diagnosis and management. Biomed Res Int. 2015;2015:805876. reduction, which arrests stromal continued or even worsening neu- 15. Portnoy SL, Insler MS, Kaufman HE. Surgical lysis via the inhibition of collage- rotrophy, which leads to chronic, management of corneal ulceration and perforation. 15,25,26 5 Surv Ophthalmol. 1989;34(1):47-58. nases. If ulceration continues non-healing epithelial defects. 16. Shaheen BS, Bakir M, Jain S. Corneal to worsen, follow this step with a nerves in health and disease. Surv Ophthalmol. 2014;59(3):263-85. more defi nitive conjunctival fl ap he prognosis of NK depends 17. Jeng BH, Dupps WJ Jr. Autologous serum 50% or keratoplasty. Tlargely on severity, duration eyedrops in the treatment of persistent corneal epithelial defects. Cornea. 2009;28(10):1104-8. Conjunctival fl aps are a defi n- and comorbidities. Severely neu- 18. Chikama T, Fukuda K, Morishige N, et al. itive treatment for neurotrophy rotrophic corneas are among the Treatment of neurotrophic keratopathy with substance-P-derived peptide (FGLM) and insulin-like but come at a signifi cant burden most diffi cult corneal pathologies growth factor I. Lancet. 1998;351(9118):1783-4. to visual potential. They promote to effectively manage, as sight is 19. Yanai R, Nishida T, Chikama T, et al. Potential new modes of treatment of neurotrophic keratopa- healing by providing fi brovascular threatened and the potential for thy. Cornea. 2015;34(Suppl 11):S121-7. tissue rich in growth factors. The recurrence is high. The primary 20. Bonini S, Lambiase A, et al. Phase II ran- domized, double-masked, vehicle-controlled primary goal is to preserve globe objectives for appropriate man- trial of recombinant human nerve growth integrity. Conjunctival tissue is agement should be to optimize the factor for neurotrophic keratitis. Ophthalmology. 2018;125(9):1332-43. not susceptible to the same mech- ocular surface, close epithelial de- 21. Bonini S, Lambiase A, Rama P, et al. Topical anisms that lead to neurotrophic fects and reduce collagenase activ- treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology. 2000;107(7):1347-51. disease and, thus, the potential for ity. Careful attention to the many 22. Lambiase A, Rama P, Bonini S, et al. Top- perforation is eliminated. Flaps are facets of neurotrophy should be ical treatment with nerve growth factor for corneal neurotrophic ulcers. N Engl J Med. reserved for chronic ulcers with given to provide optimal patient 1998;338(17):1174-80. poor visual prognoses because al- care, maintain ocular integrity and 23. Koaik M, Baig K. Corneal neurotization. Curr Opin Ophthalmol. 2019;30(4):292-8. though the conjunctival fl ap tissue ultimately preserve vision. RCCL 24. Terzis JK, Dryer MM, Bodner BI. Corneal neuroti- thins, it remains vascularized, lim- zation: a novel solution to neurotrophic keratopathy. Plast Reconstr Surg. 2009;123(1):112-20. 14 1. Bonini S, Rama P, Olzi D, et al. Neurotrophic kera- iting best-corrected visual acuity. 25. Jhanji V, Young AL, Mehta JS, et al. Manage- titis. Eye (Lond). 2003:17(8):989-95. Once neurotrophy advances to ment of corneal perforation. Surv Ophthalmol. 2. Semeraro F, Forbice E, Romano V, et al. 2011;56(6):522-38. Neurotrophic keratitis. Ophthalmologica. perforation, treatment depends 26. Setlik DE, Seldomridge DL, Adelman RA, et al. 2014:231(4):191-7. The eff ectiveness of isobutyl cyanoacrylate tissue largely on size. Small perforations 3. Srinivasan S, Lyall DAM. Clinical Gate. Neuro- adhesive for the treatment of corneal perforations. can be glued, while large per- trophic keratopathy. clinicalgate.com/neurotroph- Am J Ophthalmol. 2005;140(5):920-1. ic-keratopathy/. August 3, 2015. 27. Nurözler AB, Salvarli S, Budak K, et al. Results forations are generally repaired 4. Hamrah P, Cruzat A, Dastjerdi MH, et al. Unilateral of therapeutic penetrating keratoplasty. Jpn J with patch grafts or penetrating herpes zoster ophthalmicus results in bilateral Ophthalmol. 2004;48(4):368-71.

REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 27 1 CE Credit (COPE APPROVED)

Unlocking the Mystery of Corneal Dystrophies Optometrists are often the ﬁ rst to detect the clues and sleuth out the diagnosis. Here’s what to look for. By Mitch Ibach, OD, and Larae Zimprich, OD

orneal dystrophies are a Four main corneal dystrophies af- light, tearing or a gritty, sandy-like group of progressive infect the superfi cial cornea: epithelial feeling. Oftentimes, a patient’s heritable conditions that, basement membrane dystrophy symptoms can be exacerbated upon Cover time, cause bilateral (EBMD), Meesmann dystrophy, awakening due to the detachment pathology. The manifestations, Reis-Bucklers dystrophy and Thiel- of damaged epithelium, which may which are commonly deposits of Behnke dystrophy. The epithelium, cause signifi cant pain. Once this oc- material in the anterior cornea and approximately 50µm thick, serves as curs, the cornea may become prone cell atrophy in the posterior cornea, a barrier to provide protection and to recurrent corneal erosion (RCE). are not associated with trauma, in- allow the diffusion of oxygen from Approximately 10% of patients fection or infl ammation; rather, they the tear fi lm. All of these dystro- with EBMD experience recurrent are secondary to genetic mutations.1 phies can compromise the epitheli- corneal erosions and, conversely, Although corneal dystrophy is a um, which often leads to pain and 50% of patients with RCE evidence rare condition, the familial im- irregular astigmatism, which causes EBMD in the contralateral eye.3 pact makes diagnosis and appro- poor visual outcomes. Although EBMD is one of the priate counseling of the utmost Epithelial basement membrane most common corneal dystro- importance. dystrophy. EBMD is a bilateral, phies, it may present in a variety This review aims to unlock the though often asymmetric, condition of ways. Slit-lamp examination of mystery of corneal dystrophies characterized by thickening and a patient with EBMD may reveal by discussing prevalence, genetic redundancy of the corneal epithe- bilateral subepithelial microcysts, patterns, slit lamp clues, treatments lial basement membrane and the chalky patches, thickened gray and other pertinent points to help abnormal adhesion to the basal epi- areas that resemble fi ngerprints clinicians better diagnose and care thelial cells. It is not uncommon for or map-like lesions—giving us the for these patients. patients to be asymptomatic or even term “map-dot-fi ngerprint” dys- Classifi cation of corneal dys- unaware they have the condition. ABOUT THE AUTHORS trophies is routinely based on the There are reported cases of affected corneal layer. A recent EBMD with studied point muta- Dr. Ibach is a residency- trained optometrist at epidemiologic retrospective analysis tions in the TGFβI gene on chromo- Vance Thompson Vision of managed care patients revealed some 5 in an autosomal dominant in Sioux Falls, SD. He specializes in anterior a prevalence of a single corneal pattern; however, some feel that it segment surgical care, dystrophy at 0.13%.1 Endothelial is more of a degeneration rather including cataracts, corneal 2 diseases, glaucoma and dystrophies were the most common than a true dystrophy. The genetic refractive surgeries. (60.4% of the total) followed by an- inheritance pattern is rather weak, Dr. Zimprich is the current terior dystrophies (15.6%). Lastly, which leads some people to believe optometry resident at stromal dystrophies were identifi ed it is a degeneration associated with Vance Thompson Vision, 1 where she will specialize as the least frequent. However, aging, dry eye and trauma. in ocular disease as well 26% of cases in this study were Patients who are symptomatic as comanagement of refractive, cataract, corneal listed as “unspecifi ed” dystrophies. may complain of blurred vision due and glaucoma surgeries. She ANTERIOR CORNEAL to induced irregular astigmatism, recently graduated from Massachusetts DYSTROPHIES mild to severe pain, sensitivity to College of Pharmacy and Health Sciences.

28 REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 trophy. These fi ndings are confi ned curled fi laments within Bowman’s to the epithelial layer, and negative membrane on confocal microsco- staining in a whorl-like pattern can py, which is pathognomonic for be observed with the instillation of Thiel-Behnke.4 fl uorescein. RCEs may occur in all epithelial Meesmann dystrophy. This is and Bowman’s dystrophies due an autosomal-dominant epitheli- to ruptured cysts and an unstable al corneal dystrophy. Meesmann epithelium; however, they are more Central epithelial basement dystrophy typically manifests from a common in Reis-Bucklers and Thiel- membrane dystrophy on high young age and is caused by a defect Behnke dystrophies.4 Otherwise, magnifi cation. in the KRTI2 gene, which leads to typical symptoms such as glare, thickening of the epithelial basement light sensitivity and blurred vision membrane, similarly to EBMD.4 are generally mild. However, slit-lamp examination reveals bilateral, small, punctate TREATMENT OF ANTERIOR or bubble-like intraepithelial cysts DYSTROPHIES concentrated in the interpalpebral The primary therapy goal in region. patients with epithelial basement Reis-Bucklers and Thiel-Behnke membrane or Bowman’s dystrophies dystrophies. These are Bowman’s is to maintain the integrity of the layer dystrophies caused by muta- ocular surface. EBMD in a patient with a history of fi ngernail trauma. tions in TGFβI that manifest later in A patient who is mildly symp- life compared with Meesmann cor- tomatic may be managed conserva- toward restoring the epithelium and neal dystrophy.4 Corneal examina- tively with lubrication. If symptoms decreasing patient pain, so place- tion in a patient with Reis-Bucklers worsen, medical treatments such as ment of a bandage contact lens or or Thiel-Behnke dystrophy may punctal plugs, hyperosmotic agents amniotic membrane on the cornea reveal subepithelial deposits of hy- and topical or oral anti-infl amma- is common. For any patient with an aline-like material that damage and tories can be added. Although not epithelial defect wearing a bandage eventually replace Bowman’s layer.2 a cure, patients can be fi t in scleral lens, add a topical antibiotic for The cornea may also show dense lenses. These lenses completely infection prophylaxis. Topical and/ gray-white subepithelial opacities vault over the cornea to protect the or oral anti-infl ammatories can centrally that worsen with age. fragile epithelium while correcting decrease matrix-metalloproteinase-9 Although clinically similar, they vision compromised by irregular (MMP-9) as well as speed up heal- can be differentiated from one an- astigmatism. ing and prevent recurrent erosions. other by the characteristic fi nding of The treatment of RCEs is tailored In a small study of seven patients

Release Date: November 15, 2019 activity has been planned and implemented by the Postgraduate Institute Expiration Date: November 15, 2022 for Medicine and Review Education Group. Postgraduate Institute for Estimated time to complete activity: 1 hour Medicine is jointly accredited by the Accreditation Council for Continuing Jointly provided by Postgraduate Institute for Medical Education, the Accreditation Council for Pharmacy Education, Medicine and Review Education Group. JOINTLY ACCREDITED PROVIDERTM and the American Nurses Credentialing Center, to provide continuing INTERPROFESSIONAL CONTINUING EDUCATION education for the healthcare team. Postgraduate Institute for Medicine is Educational Objectives: After completing this activity, the participant should be better able to: accredited by COPE to provide continuing education to optometrists. • Identify the most common traits as well as the characteristic signs and Faculty/Editorial Board: Mitch Ibach, OD, Vance Thompson Vision, Sioux symptoms related to corneal dystrophies. Falls, SD, and Larae Zimprich, OD, Vance Thompson Vision. • Consider the diff erential diagnosis for corneal dystrophies. Credit Statement: This course is COPE approved for 1 hour of CE credit. • Perform the necessary elements of the patient history, ocular Course ID is 65002-AS. Check with your local state licensing board to see examination/vision testing and laboratory testing required to diagnose corneal dystrophies. if this counts toward your CE requirement for relicensure. • Distinguish the diff erent types of corneal dystrophies most commonly Disclosure Statements: encountered by optometrists, with at least a cursory understanding of Dr. Ibach receives consulting fees from Aerie, Alcon, Avedro, Glaukos, their genetic inheritance. Ocular Therapeutix and fees for non-CME/CE services from Aerie and • Provide, or otherwise obtain, the ocular and systemic treatment that the patient requires. Glaukos; and has ownership interest in Equinox. Dr. Zimprich has no disclosures. Target Audience: This activity is intended for optometrists engaged in Managers and Editorial Staff : The PIM planners and managers have the care of patients with corneal dystrophies. nothing to disclose. The Review Education Group planners, managers and Accreditation Statement: In support of improving patient care, this editorial staff have nothing to disclose.

REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 29 UNLOCKING THE MYSTERY OF CORNEAL DYSTROPHIES

with traumatic RCEs who were characterized by bilateral treated with a combination of amorphous hyaline deposits topical steroid and oral doxy- that present within the fi rst de- cycline, all patients’ epithelial cade of life. It is an autosomal defects healed in 10 days or less dominant dystrophy that has a with no recurrence of erosion mutation in the TGFβI gene.4 for at least three months.5 Symptoms include glare and All of these treatments sup- photophobia, with decreased port the stability of the ocular vision as it progresses. Patients surface, but they won’t cure the normally do not experience condition. A more permanent vision loss until later in life. approach is surgical interven- The cornea will show small Reis-Bucklers dystrophy with central grayish tion. Superfi cial keratectomy, opacities in Bowman’s layer. breadcrumb-like hyaline de- where the epithelium is deposits in the central superfi cial brided with or without excimer and mucopolysaccharides within the stroma that spare the limbus. In the laser phototherapeutic keratectomy stroma.4 later phase, these deposits increase (PTK), may be considered for super- In affected patients, the cornea in number, enlarge and extend fi cial abnormalities of the cornea. demonstrates bilateral corneal deeper into the stroma. RCEs may These can be used to polish corneal opacities that extend throughout also occur. Treatment options in- irregularities or opacities within the thickness of the stroma. A key clude PKP or deep anterior lamellar the anterior 10% to 20% of the slit-lamp differentiator for MCD is keratoplasty. cornea.6 that the stromal opacities commonly Lattice corneal dystrophy. extend out to the limbus. As the Caused by a mutation in TGFβI STROMAL DYSTROPHIES condition progresses, the opacities gene, this dystrophy manifests as The stroma represents the thick- coalesce and guttata can develop amyloid deposits located in the an- est layer of the cornea, measuring within the endothelium, both lead- terior stroma.2 The deposits appear about 450µm. It is made up of ing to a poor visual outcome within as refractile lines centrally in the dense, regular connective tissue the fi rst three decades of life. These anterior stroma, while the peripher- that contains keratocytes, colla- patients are commonly diagnosed at al cornea remains largely unaffected. gen, ground substance and water. an early age and can experience at- Later, these refractile lines progress Stromal dystrophies reside deep tacks of irritation and photophobia. into stromal opacifi cations, which within the cornea and are typically Further testing will reveal a slightly can cause patients to be symptomat- treated in a conservative manner; thinner than average stroma. ic with blurred vision. Some patients but if stromal opacifi cation presents, Therapeutic options are limited to may lack the typical appearance of treatment options are limited. tinted contact lenses and lu- Multiple stromal dystrophies can brication, which help reduce affect the cornea, but the most com- symptoms only to a certain mon are macular dystrophy, gran- extent. The sole treatment ular dystrophy, lattice dystrophy, is penetrating keratoplasty Avellino dystrophy and Schnyder (PKP), which is a full-thick- dystrophy. ness corneal transplant that Macular corneal dystrophy replaces the damaged tissue. (MCD). This is the least common Lamellar keratoplasty is yet the most visually impairing typically not indicated due stromal dystrophy. Despite its to its high rate of disease re- classifi cation, MCD can also affect currence because it involves Descemet’s membrane and the removing only the anteri- endothelium. Caused by mutations or cornea and may leave in the CHST6 gene, MCD is the a damaged endothelium 4 only autosomal recessive stromal attached to the graft. Granular dystrophy type 2 (Avellino dystrophy and is associated with an Granular corneal dys- dystrophy) showing a central combination of aggregation of glycosaminoglycans trophy. This condition is line and circular opacities.

30 REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 the stromal disease and only experi- ly affected, a corneal graft ence symptoms from RCEs.2 may be indicated.2 Initially, management is focused on treating any RCEs that occur; ENDOTHELIAL but if the opacities become visually DYSTROPHIES signifi cant, PKP may be indicat- The endothelial cell layer ed. Unfortunately, there is a high represents the most pos- rate of recurrence of lattice cor- terior corneal layer. The neal dystrophy within the graft.4 endothelium is approx- For surface irregularities, PTK is imately 5µm thick and indicated. Opacities deep within the borders on its basement stroma cannot be treated by PTK membrane, Descemet’s. Lattice dystrophy on high magnifi cation. Note because of the depth of involve- This boundary layer’s the progressive corneal haze. ment. Patients risk corneal haze and main function is to reg- overall decreased vision the deeper ulate corneal hydration the ablation depth. with active fl uid transport Avellino corneal dystrophy. Also to maintain a mostly known as granular corneal dystro- dehydrated stroma. phy type 2, Avellino is a combina- Three main corneal dys- tion of granular and lattice corneal trophies affect the posteri- dystrophies that is caused by a or cornea: Fuchs’ endo- mutation in the TGFβI gene.2 The thelial dystrophy (FECD), affected cornea presents with white- posterior polymorphous gray granular deposits within the dystrophy (PPCD) and anterior stroma, while the mid-pos- congenital hereditary Schnyder corneal dystrophy with an overlying scleral contact lens. terior stroma has lattice-like lesions endothelial dystrophy that move more centrally with age. (CHED). In all three, the endothelial fl uid equilibrium is disrupted and In the late phase, an overall haze pump function is disrupted, leading corneal edema ensues. Corneal can present throughout the cornea. to an imbalance of hydration and edema results in loss of visual acuity Management includes copious resultant corneal edema. and visual quality for patients where lubrication, anti-infl ammatories or Fuchs’ endothelial corneal dys- glare and haloes become a frequent- PKP. trophy. This is the most common ly cited visual disruption. In late Schnyder corneal dystrophy. This of all the corneal dystrophies in the stage FECD with chronic corneal normally presents within the fi rst United States with a prevalence of edema, patients may develop painful decade of life, with multiple fi ne approximately 4% of the popula- bullae (blisters), which over time polychromatic crystal deposits that tion over age 40.1 Fuchs’ dystrophy can alter the anterior corneal shape tend to form in a ring shape near the is inherited in an autosomal domi- and epithelial integrity. limbus. These deposits are caused by nant pattern, affecting women more Posterior polymorphous corneal an accumulation of cholesterol and than men. dystrophy. This autosomal dom- phospholipids that have a strong In FECD patients, the endothelial inant corneal dystrophy results association with systemic hypercho- “pump” cells atrophy, leaving a in abnormal vesicles with deep lesterolemia.7 Patients under the age fewer number of healthy pumping gray corneal haze at the level of of 40 with this presentation should cells and corneal guttata (areas Descemet’s and endothelium. The have their fasting serum cholesterol devoid of endothelial cells with pathophysiology is thought to occur and triglyceride levels measured. thickened Descemet’s). Two hall- during gestation, and its ocular signs Schnyder corneal dystrophy mark endothelial cell morphology most commonly manifest in early is caused by a mutation in the changes in FECD are pleomorphism childhood. In the corneal develop- UBIAD1 gene and is rare.4 Surgical (irregular change to cell shape) ment of patients with PPCD, the en- intervention is seldom needed, as vi- and polymegathism (irregular cell dothelial layer is lined with variable sion is typically unaffected until lat- growth). As the endothelial cells amounts of epithelium-like squa- er in life when the opacities become reduce in number and pump ability mous cells.4 The additional cell lay- more central. If vision is signifi cant- continues to worsen, the corneal ers cause band-like adhesions and

REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 31 UNLOCKING THE MYSTERY OF CORNEAL DYSTROPHIES

an abnormally thickened Descemet’s keratoplasty is preferred over a membrane. The abnormal cell bands PKP. Endothelial keratoplasties are can extend from the cornea and ad- a better option due to less induced here to the iris, leading to peripheral astigmatism, avoidance of incre- anterior synechiae, putting PPCD mental suture removal, lowered patients at risk for glaucoma.4 risk of rejection and better visual Corneal edema typically isn’t acuity potential compared with progressive in patients with PPCD, PKP.8 Descemet’s stripping endo- but if vision in late childhood and thelial keratoplasty and Descemet’s early adulthood worsens, clinicians membrane endothelial keratoplasty should initiate ancillary tests and a (DMEK) are the two most common- treatment plan to reduce edema. ly performed endothelial keratoplas- Congenital hereditary endothelial ties in the United States. Although Fuch’s dystrophy with early corneal dystrophy (CHED). The least com- both provide superior visual acuity edema. Note the classic orange peel mon of the endothelial dystrophies, results to PKP, DMEK has better vi- appearance on the endothelium. CHED has two distinctly recogniz- sual acuity potential with a quicker surgical treatment approaches. able forms: CHED1 and CHED2.4 visual recovery.9,10 When keratoplasty is necessary, A distinguishing factor of both anterior dystrophies require a CHED1 and CHED2 is bilateral ptometry plays a signifi cant full-thickness or anterior lamellar thickened corneas with a ground Orole for patients with corneal transplant; but for patients with glass appearance present at birth or dystrophies because the initial diag- posterior dystrophies, an endothe- infancy, which is different in onset nosis and referral, when necessary, is lial keratoplasty should be the fi rst from other endothelial dystrophies.4 often made by an OD. choice. CHED1 (autosomal dominant) The optometrist’s fundamental Corneal dystrophies are rare, but patients manifest progressive cor- task for the diagnosis and manage- correctly diagnosing these condi- neal edema, tearing and photopho- ment of corneal dystrophies is to tions changes the eye care landscape 4 bia, but do not have nystagmus. fi rst determine which corneal layer for a whole family. RCCL CHED2 (autosomal recessive) tends is affected. Along with the case 1. Musch DC, Niziol LM, Stein JD, Kamyar RM, Sugar to be non-progressive, but presents history, regular corneal topogra- A. Prevalence of corneal dystrophies in the United with nystagmus plus occasional phies and corneal imaging can help States: estimates from claims data. Invest Ophthalmol Vis Sci. 2011 Sep 1;52(9):6959-63. deafness (corneal dystrophy-per- to monitor for change and aid in 2. Krachmer J, Mannis M, Holland E (eds.). Cornea. ceptive deafness, a.k.a., Harboyan the decision-making for manage- 2nd ed, Vol 1. Philadelphia, PA: Elsevier; 2005: 898- syndrome).4 ment. Keep in mind that anterior 902. 3. Jager RD, Lamkin JC. The Massachusetts Eye and dystrophies most commonly lead to Ear Infi rmary Review Manual for Ophthalmology. 3rd SURGICAL OPTIONS more RCEs and opacifi cation, while ed. Philadelphia: Lippincott Williams & Wilkins; 2005. 4. Klintworth GK. Corneal dystrophies. Orphanet J If any of these endothelial dystro- posterior dystrophies are associated Rare Dis. 2009 Feb 23;4:7. phies result in progressive visual with more progressive corneal ede- 5. Dursun D, Kim MC, Solomon A, Pfl ugfelder SC. Treatment of recalcitrant recurrent corneal erosions loss, relieving stromal edema is the ma. This tenet dictates medical and with inhibitors of matrix metalloproteinase-9, doxy- most common treatment approach. cycline and corticosteroids. Am J Ophthalmol. 2001 Jul;132(1):8-13. Hyperosmotics may provide short- 6. Paparo LG, Rapuano CJ, Raber IM, et al. Photo- term relief in select patients, but for therapeutic keratectomy for Schnyder’s crystalline corneal dystrophy. Cornea. 2000 May;19(3):343-7. patients with progressing dystro- 7. Bagheri N, Wajda B (eds.). The Wills Eye Manual. phies, the best long-term treatment 7th ed. Philadelphia: Wolters Kluwer; 2017. is a surgical approach. 8. Lee WB, Jacobs DS, Musch DC, et al. Descemet’s stripping endothelial keratoplasty: safety and out- For CHED1 and CHED2, due to comes: a report by the American Academy of Oph- stromal ground glass opacifi cation, thalmology. Ophthalmology. 2009 Sep;116(9):1818-30. 9. Tourtas T, Laaser K, Bachmann BO, et al. Descemet PKP is the surgical option of choice membrane endothelial keratoplasty versus Descemet because corneal edema is less of a stripping automated endothelial keratoplasty. Am J Ophthalmol. 2012 Jun;153(6):1082-90. 4 concern. 10. Hamzaoglu EC, Straiko MD, Mayko ZM, et al. The In PPCD and FECD, in which sur- fi rst 100 eyes of standardized Descemet stripping automated endothelial keratoplasty versus standard- gical intervention is more dictated Posterior polymorphous dystrophy in ized Descemet membrane endothelial keratoplasty. by corneal edema, an endothelial a 17-year-old male. Ophthalmology. 2015 Nov;122(11):2193-9.

32 REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 CE TEST ~ NOVEMBER/DECEMBER 2019 1. All of the following are caused by a mutation in the 4. Which of the following is an autosomal recessive c. Decreased number of cells. TGFβI gene, except: inherited dystrophy? d. Overproduction of cells. a. Epithelial basement membrane dystrophy. a. CHED1. b. Macular dystrophy. 8. Which of the following dystrophies is associated with b. Schnyder corneal dystrophy. c. Granular dystrophy. c. Granular dystrophy. an increased risk for glaucoma? d. Epithelial basement membrane dystrophy. a. Fuchs’ endothelial dystrophy. d. Lattice dystrophy. b. Posterior polymorphous dystrophy. 5. Which corneal dystrophy is characterized by amyloid c. Lattice dystrophy. 2. What percentage of patients with epithelial basement deposits within the anterior stroma? d. Granular dystrophy. membrane dystrophy experience recurrent corneal a. Granular dystrophy. erosions? b. Meesmann dystrophy. 9. Which of the following dystrophies is associated with c. Reis-Bucklers dystrophy. a. 10%. d. Lattice dystrophy. nystagmus? b. 30%. a. CHED2. c. 50%. 6. Which of the following dystrophies is associated with b. Posterior polymorphous dystrophy. d. 70%. hypercholesteremia? c. Macular dystrophy. a. Fuchs’ endothelial dystrophy. d. Avellino dystr b. Macular dystrophy. ophy. 3. Phototherapeutic keratectomy may be indicated for 10. Descemet’s membrane endothelial keratoplasty is which of the following dystrophies? c. Epithelial basement membrane dystrophy. d. Schnyder dystrophy. indicated for which of the following dystrophies? a. Fuchs’ endothelial dystrophy. a. Lattice dystrophy. b. Congenital hereditary endothelial dystrophy. 7. What is the correct deﬁ nition of pleomorphism? b. Avellino dystrophy. c. Macular dystrophy. a. Irregular change to cell shape. c. Epithelial basement membrane dystrophy. d. Epithelial basement membranedystrophy. b. Irregular cell growth. d. Fuchs’ endothelial dystrophy.

EXAMINATION ANSWER SHEET Mail to: Jobson Healthcare Information, LLC, Attn.: CE Processing, 395 Hudson Street, 3rd Floor New York, New York 10014 Unlocking the Mystery of Corneal Dystrophies Valid for credit through November 15, 2022 Payment: Remit $20 with this exam. Make check payable to: Jobson Healthcare Information, LLC. Online: This exam can also be taken online at www.reviewsce.com. Upon passing the Credit: This lesson is approved for 1 hour of CE credit. Course ID is 65002-AS. exam, you can view your results immediately and download a real-time CE ceriticate. Jointly provided by Postgraduate Institute for Medicine and Review Education Group. You can also view your test history at any time from the website. Salus University has sponsored the review and approval of this activity. Directions: Select one answer for each question in the exam and completely darken the appropriate circle. A minimum score of 70% is required to earn credit. Processing: There is a four-week processing time for this exam.

Answers to CE exam: Post-activity evaluation questions: Rate how well the activity supported your achievement of these learning objectives: 1. A B C D 1=Poor, 2=Fair, 3=Neutral, 4=Good, 5=Excellent 2. A B C D 11. Identify the most common traits as well as the characteristic signs and symptoms related to corneal dystrophies. 1 2 3 4 5 3. A B C D 12. Consider the differential diagnosis for corneal dystrophies. 1 2 3 4 5 4. A B C D 13. Perform the necessary elements of the patient history, ocular examination/vision testing and laboratory testing required to 1 2 3 4 5 5. A B C D diagnose corneal dystrophies.

6. A B C D 14. Distinguish the different types of corneal dystrophies most commonly encountered by optometrists, with at least a cursory 1 2 3 4 5 understanding of their genetic inheritance. 7. A B C D 15. Provide, or otherwise obtain, the ocular and systemic treatment that the patient requires. 1 2 3 4 5 8. A B C D 16. Based upon your participation in this activity, do you intend to change your practice behavior? (choose only one of the 9. A B C D following options) 10. A B C D A I do plan to implement changes in my practice based on the information presented. B My current practice has been reinforced by the information presented. Rate the quality of the C I need more information before I will change my practice. material provided: 17. Thinking about how your participation in this activity will influence your patient care, how many of your patients are likely to benefit? 1=Strongly disagree (please use a number) 2=Somewhat disagree 18. If you plan to change your practice behavior, what type of changes do you plan to implement? (check all that apply) 3=Neutral A Apply latest guidelines B Change in pharmaceutical therapy C Choice of treatment/management approach D Change in current practice referral E Change in non-pharmaceutical therapy F Change in differential diagnostics 4=Somewhat Agree G Change in diagnostic testing H Other, please specify: 5=Strongly agree 19. How confident are you that you will be able to make Identifying information (please print clearly): 22. The content was evidence- your intended changes? based. A very confident B somewhat confident First Name C unsure D not confident Last Name 1 2 3 4 5 20. Which of the following do you anticipate will be the Email 23. The content was balanced primary barrier to implementing these changes? The following is your: Home Address Business Address and free of bias. A Formulary restrictions Business Name B Time constraints 1 2 3 4 5 Address C System constraints City State 24. The presentation was clear D Insurance/financial issues and effective. E Lack of interprofessional team support ZIP F Treatment related adverse events Telephone # - - 1 2 3 4 5 G Patient adherence/compliance Fax # - - H Other, please specify: By submitting this answer sheet, I certify that I have read the lesson in its entirety and 21. Additional comments on this course: completed the self-assessment exam personally based on the material presented. I have not obtained the answers to this exam by fraudulent or improper means.

Signature: ______Date: ______Please retain a copy for your records. LESSON 118824, RO-RCCL-1119

REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 33 AT THE Intersection of Sex AND Dry Eye Biological diff erences aff ect a patient's risk of dry eye, pathophysiology and treatment response. By Cecelia Koetting, OD

hile sex differences meibomian glands, nasolacrimal likely to undergo LASIK refractive may not matter duct and tear fi lm. surgery, which carries an elevated for many things in In addition, men and women risk of post-op DED and neuro- Weye care, they can experience pain differently, which pathic pain. Animal studies show have a signifi cant impact on dry impacts the number of patients females have a higher prevalence of eye disease (DED), according to seeking care for DED and expe- neuropathic pain related to DED.1 the Tear Film and Ocular Surface riencing symptom improvement. Gender- and sex-specifi c medica- Society’s (TFOS) Dry Eye Workshop Studies show that men have a tions, such as hormone replacement II (DEWS II) report.1 In addition to higher pain tolerance than women, therapy and oral contraceptives, can sex, hormones and gender have also with explanations ranging from also increase the risk of DED. been identifi ed as factors that can sociocultural gender roles to brain affect DED diagnosis and treatment. neurochemistry differences.3,4 Thus, SIGNS & SYMPTOMS SEE-SAW In the absence of a decent com- male patients are less likely to The female sex reports more prehensive report discussing the complain of DED symptoms and severe symptoms as measured by biological sex differences at a are less likely to seek treatment or the Ocular Surface Disease Index cellular and molecular level, TFOS be compliant with treatment. When and the Symptom Assessment commissioned one by the Institute they do, they tend to have a greater Questionnaire in Dry Eye. Increased of Medicine to help develop a better decrease in symptoms following visual quality indicators and feelings understanding.2 The report docu- LipiFlow (TearScience) treatment.1 of depression accompany this in- ments several biological differences Alternately, females may present crease in symptoms.1 The increase in between the sexes that manifest with symptom complaints that may reporting and scoring of symptoms themselves in the anatomy, physi- not match their ocular signs. by females may, in part, be why ology and pathophysiology of the Here’s how sex, gender and hor- they are diagnosed an average of six lacrimal gland, cornea, conjunctiva, mones affect a patient’s risk for, and years younger than male patients.1 diagnosis of, dry eye. Tear osmolarity testing has be- Work with the Right Definitions come common in many optometric RISKY BEHAVIOR offi ces and can aid in diagnosing The most important first step is understanding the difference between Overall, the female sex has a higher and managing DED. The DEWS sex and gender. The DEWS II report risk of DED, and women are diag- uses the term sex to classify organ- nosed an average of six years young- ABOUT THE AUTHOR isms, generally as male or female, 1,5-8 er than their male counterparts. Dr. Koetting is the referral according to reproductive organs Additionally, certain gender-re- optometric care and and functions assigned by chro- lated behaviors and habits can lead externship program mosomal complement. Gender is a coordinator at Virginia Eye person’s self-representation as male to a higher risk of DED, such as the Consultants in Norfolk, VA. or female, which is often rooted in use of cosmetics and contact lens She is a fellow of the AAO and a trustee of the Virginia biology but also shaped by environ- wear, which is higher in women Optometric Association. ment and experience.1 than men. Women are also more

34 REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 II report noted that both males and females experience increased tear osmolarity during aging.1 Incorporating tear osmolarity testing in all older patients may lead to increased and earlier diagnosis of DED patients who may otherwise not have been identifi ed. Neutral lipids are unstable when spread over an aqueous subphase and will collapse, forming lipid This postmenopausal female patient droplets that leave the aqueous has chronic dry eye and bilateral portion of the tear fi lm unprotected, Salzmann’s nodules. allowing for rapid evaporation.9,10 This layer is stabilized by the lower Goblet cells found within the overall when it comes to goblet cell polar lipid sublayer, so too few conjunctiva are important because density loss even when compro- polar or too many neutral lipids they produce and secrete mucins, mised by chronic infl ammation. can cause a tear fi lm imbalance.9,10 which in turn hydrate and lubri- Males’ higher goblet cell count is DEWS II researchers note that cate the surface of the eye, helping also likely related to their higher meibomian gland expression of to control chronic infl mmation.11 prevalence of conjunctival infl am- specifi c polar lipids in meibum was Mucin regulation is targeted by mation related to allergies.1 lower in both middle aged males allergy and infl ammatory mediators DEWS II also found women and females.1 Specifi c neutral lipid that alter the function and sur- experience a depression of goblet expression in meibum was higher vival of the goblet cells.11 Allergic cell count around the time of ovu- in older males and females.1 Both conjunctivitis leads to an increase lation.1 Knowing that females who of these results correlate with the in mucin production, while the are ovulating will have cyclically fi nding that the lipid layer is thicker opposite occurs with DED.11 With worse dry eye, it may be helpful to and less contaminated in males chronic infl ammation, infl ammatory individualize their DED treatment older than age 45.1 It also explains, cytokines cause decreased goblet cell and increase their use of medication in part, why in males in the third de- survival, leading to decreased mucin around their mensturation cycle. cade of life experience their highest production.11 Goblet cell density and pro- rate of decreased tear break-up time The DEWS II report notes that duction is also affected by other and females in their seventh.1 males have higher goblet cell count, infl ammatory processes such as Within the last few years, more suggesting males may fare better superior limbic keratoconjunctivitis, clinicians have started to which is more prevalent use meibography to assess MEIBOGRAPHY COMPARISON BY SEX in women.1 patient’s meibomian gland Pterygia, which orig- function and structure. inate in the conjunctiva The TFOS researchers and extend onto the behind DEWS II found cornea, exhibit areas of that although males have goblet cell hyperplasia a higher prevalence of Right and left meibography of a 75-year-old female and can occur from many asymptomatic meibomian patient with no diagnosed systemic comorbidities. things, such as ultraviolet gland dysfuction (MGD), radiation, infl ammatory they have greater lid disorders and chronic oc- margin abnormality and ular surface irritatiton.12 gland drop out after age The DEWS II report fi nds 70.1 This may explain that pterygia occur more why males have greater often in males but cause Right and left meibography of a 75-year-old male decrease in symptoms patient with no diagnosed systemic comorbidities. Note greater discomfort in following LipiFlow the male patient of the same age has less gland damage, females.1 It is important treatment.1 truncation and atrophy. to keep this in mind when

REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 35 AT THE INTERSECTION OF SEX AND DRY EYE

when on estrogen alone and a Androgen is also important for 30% increased incidence when corneal and conjunctival cell repro- on estrogen in combination with duction and synthesis. Defi ciency progesterone/progestins.5 can lead to poor wound healing, corneal dystrophies and increased GET TO KNOW HORMONES conjunctival and corneal staining.1 Our endocrine system helps us Studies exploring topical and sys- develop and regulate the ocular temic applications show an im- surface and adnexa. Hormones play provement in DED signs and symp- an important role in this system, toms in both men and women.1 including androgen, estrogen, Estrogen and progesterone. progestin, estrogen, glucocorticoids, Unlike androgen, less is understood growth hormone IGF-1, insulin and about the roles of estrogen or pro- thyroid hormones. gesterone in ocular surface function. Androgen. This hormone helps No intra-tissue data currently exists; This female patient reported severe in the development and function however, both hormones have been symptoms, despite signs of only 1+ superficial punctate keratitis. of the lacrimal glands, meibomian detected in human tears, correlating glands, cornea and conjunctiva. The with serum levels in premenopausal treating pterygia and making surgi- lacrimal gland is an androgen target females.1 Estrogen receptors are cal decisions. Even if male patients organ that uses the hormone to found in the meibomian glands, may be asymptomatic, don’t forego help with cellular architecture, gene lacrimal gland, cornea, bulbar con- the discussion of the risks of pro- expression, protein synthesis, im- junctival and tarsal plate.1 gression and don’t delay treatment mune activity and fl uid and protein Estrogen plays an important role of underlying causes. secretion.1 within our immune system, the Comorbidities, although wide- Shortage can cause lacrimal extent of which differs signifi cantly ly reported in multiple studies to gland dysfunction and aqueous tear based on concentration and tissue increase the risk of DED, have defi ciency. Women have a decrease type. This hormone promotes the not been directly studied when it in serum androgen and increased production of B-cells and antibod- comes to sex-related differences. primary lacrimal gland defi ciency ies, a subset of T-cells, dendritic Research shows lupus, Sjögren’s during menopause, pregnancy, cells, M2 macrophages and regula- syndrome, rosacea, anxiety, hay fe- lactation and with use of estrogen tory cytokines.1 ver, depression, pelvic pain, irritable containing oral contraceptives. Reports on the effect of estro- bowel syndrome and chronic pain Sjögren’s patients, more common- gen and progesterone on DED are syndrome are all associated with ly women than men, have a greater varied depending on the study and DED.1,5 Clinically, most agree with androgen defi ciency within their co-factors such as autoimmune this and have noted increased DED lacrimal tissues related to the elevat- conditions.1 Although studies show incidence in patients who suffer ed pro-infl ammatory cytokines IL-1, positive effects of topical testoster- from these comorbidities. Worth TNF-α and IL-6.1 This androgen one on MGD and DED, it is cur- noting is that an all-male study also defi ciency impairs lacrimal gland rently only available via compound- found an increased rate of DED in function, which is a risk factor for ing pharmacies.9 Allergan submitted those exhibiting high blood pressure lacrimal gland infl ammation and a patent and initiated a Phase II and benign prostatic hyperplasia.6 aqueous-defi cient DED.1 study in 2015, but nothing has been These conditions are not typically The meibomian gland complex is published at this time. Similarly, linked with DED, and we may be also an androgen target organ, stim- compounded estradiol suspension overlooking these patients. ulating tissue function and suppress- or a mixture containing testosterone Both sexes have an increased risk ing keratinization.1 Androgen stim- and progesterone are used by some of DED with the use of antidepres- ulates the ontologies responsible for practitioners to treat DED off label. sants, although women are more lipid biosynthesis and cholesterol, Glucocorticoids. Functioning as likely to use them. Not surprisingly, fatty acid, phospholipid and steroid a regulator of the infl ammatory women who are postmenopausal dynamics.1 Androgen defi ciency is response and immunosuppressive and on hormone therapy had a a risk factor for the development of hormone, glucocorticoid and its 70% increased incidence of DED MGD and evaporative DED. synthetic partners are important in

36 REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 anti-infl ammatory activity. roids. This option also allows for Thyroid. An imbalance of thyroid Glucocorticoid’s effects on the oc- control of the drug’s concentration, hormones T3 and T4 has a nega- ular surface and adnexa are concen- helping to decrease concern for tive effect on the lacrimal gland, tration dependent and have a higher complications with longer-term use. tear fi lm and ocular surface.1 These level of anti-infl ammatory activity in Growth hormone, IGF-1 and hormones help to promote lipid males than females.1 The ocular sur- Insulin. The latter of these hor- and protein synthesis along with face of the mucosa is immunopro- mones, secreted by the acinar cells tissue growth.1 Females are more tected in part by the autocrine effect within the lacrimal gland, is found prone to thyroid diseases such as in epithelial cell and fi broblasts within the human tear fi lm and its Hashimoto’s thyroiditis and Graves’ caused by production of cortisol receptor, IGF-1, is found on the disease. These patients are also more from endogenous glucocorticoid.1 human ocular surface. Growth hor- likely to have Sjögren’s syndrome. With a better understanding mone and IGF-1 may help within of these hormones’ role in DED, the meibomian glands to regulate ur understanding of DED has researchers have developed and growth and function.1 Oevolved signifi cantly in the continue to develop new treatments. Insulin helps with corneal wound last 10 years, as has our diagnostic Topical glucocorticoids are already healing by promoting tissue main- technology and treatment options. widely used to control infl amma- tenance.1 Diabetic patients have Understanding the underlying cause tion-associated DED. A phase IV delayed corneal healing in part and how sex and gender impact the study recently fi nished, but has not because their tears exhibit increased physical, hormonal and behavioral published results, on topical hydro- IGF-binding protein 3, which may differences are crucial to ensure an cortisone 0.335% (Softacort, Thea attenuate the IGF-1 receptor signal appropriate treatment approach. RCCL Pharmaceuticals) to treat chronic necessary for tissue maintenance. 1. Sullivan D, Rocha E, Aragona P, et al. TFOS DEWS DED and ocular infl ammation. Diabetes patients often suffer II sex, gender, and hormones report. Ocul Surf. Another ongoing study is looking at from DED due to the autoimmune 2017;15(3):284-333. 2. Institute of Medicine (US) Committee on Under- the effects of intravenous glucocor- destruction of the lacrimal gland standing the Biology of Sex and Gender Diff erences: Exploring the Biological Contributions to Human ticoid on the tear fi lm in eyes with from antigen cross activity with the Health: Does Sex Matter? Washington, DC: The thyroid-associated ophthalmopathy. pancreas in Type 1 diabetes. DED in National Academies Press; 2001. 3. Mogil, Jeff rey S. Sex diff erences in pain and pain With the currently available patients with Type 2 diabetes is both inhibition: multiple explanations of a controversial phenomenon. Nat Rev Neurosci. 2012;13(12):859. topical steroids, clinicians should hormonal and metabolic in nature 4. Ruau D, Liu LY, Clark JD, et al. Sex diff erences in take the preservatives within the stemming from the defective insulin reported pain across 11,000 patients captured in electronic medical records. J Pain. 2012;13(3):228- drug into consideration, as many action and hyperglycemia. 34. 5. Schaumberg DA, Sullivan DA, Buring JE, Dana with DED are also sensitive to these. Sex hormones are thought to in- MR. Prevalence of dry eye syndrome among US Compounding pharmacies are a fl uence the levels of insulin receptor, women. Am J Ophthalmol. 2003;136(2):318-26. 6. Schaumberg DA, Dana R, Buring JE, Sullivan great alternative for preparation of suggesting higher levels of sex hor- DA. Prevalence of dry eye disease among US men: estimates from the Physicians’ Health Studies. Arch preservative-free topical corticoste- mones lower the action of insulin Ophthalmol 2009;127:763e8. within ocular tissues. Patients with 7. Paulsen AJ, Cruickshanks KJ, Fischer ME, et al. Dry eye in the beaver dam off spring study: preva- insulin resistant conditions such as lence, risk factors, and health-related quality of life. polycystic ovary syndrome, preg- Am J Ophthalmol. 2014;157(4):799-806. 8. Muoz B, West SK, Rubin GS, et al. Causes of blind- nancy, anti-androgen therapy and ness and visual impairment in a population of older Americans: The Salisbury Eye Evaluation Study. androgen insensitivity syndrome Arch Ophthalmol. 2000;118(6):819-25. have increased DED symptoms. 9. Green-Church K, Butovich I, Willcox M, et al. The international workshop on meibomian gland dys- Animal studies looking at sys- function: report of the subcommittee on tear fi lm lipids and lipid-protein interactions in health and temic replacement or topical insulin disease. Invest Ophthalmol Vis Sci. 2011;52(4):1979- treatment show that signs of DED 93. 10. Shrestha R, Borchman D, Foulks G, et al. Analysis and wound healing defects can be of the composition of lipid in human meibum from normal infants, children, adolescents, adults, and reversed. Current use of autologous adults with meibomian gland dysfunction using serum, which contains insulin and 1H-NMR spectroscopy. Invest Ophthalmol Vis Sci. 2011;52(10):7350-8. growth factors, is an effective treat- 11. Dartt DA, Masli S. Conjunctival epithelial and This poorly controlled diabetic goblet cell function in chronic infl ammation and ment for severe DED and conditions ocular allergic infl ammation. Curr Opin Allergy Clin patient is treated for chronic associated with it, although it is Immunol. 2014;14(5):464-70. severe DED and neurotrophic 12. Golu T, Mogoantă L, Streba CT, et al. Pterygium: keratoconjunctivitis, which has led to widely underused due to prepara- histological and immunohistochemical spects. Rom recurrent corneal abrasions. tion and storage inconveniences. J Morphol Ebryol. 2011;52(1):153-8.

REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 37 Fitting Challenges By Cory Collier, OD

The “Wow” Starts Now Correcting residual astigmatism can be the diff erence between a good visual outcome and a great one.

t can be easy to get lost in the cus- both the right and left eyes was the tomization options available with Custom Stable Elite (Valley Contax) scleral lenses. While most help -2.00D/45.00D/16.8mm with stan- Icreate healthy and comfortable dard limbal and scleral zones [+6 lenses, front toric vision correction (fl at)/-4 (steep)]. stands out from the rest. Sometimes, Following 30 minutes of settling, it can be the difference between a central clearance OD was 250µm satisfi ed patient and a loyal patient. with approximately 75µm of clearance over the most elevated corneal THE CASE nodule located in the mid-peripheral A 73-year-old female presented for a The fl at meridian “O” is rotated 30 cornea, and the limbal clearance was second opinion on her contact lens degrees to the left, and the front cylinder roughly 25µm in all quadrants. The vertical reference is at 6 o’clock OS. correction. The patient’s chief com- scleral zone displayed mild edge lift plaint was poor visual quality in her Although the patient had poten- along the fl at meridian (this design right eye due to glare and ghosting. tial for improved vision based on uses two laser-marked “Os” to She was diagnosed with Salzmann’s the results of the over-refraction, indicate the fl at meridian) with align- nodular corneal degeneration 15 the current piggyback lens design ment along the steep meridian. years earlier and has been wearing made this unlikely for two reasons. The fl at meridian was rotated 25 corneal gas permeable (GP) lenses First, decentration would continue degrees to the right using the hori- for over 40 years. She was refi t with to be a major limiting factor as the zontal meridian as a reference. The a piggyback lens system three years nodules displaced the lens. Even with left eye displayed 200µm centrally earlier to improve the centration of piggybacking, the current centration with 50µm of clearance over the her lenses. Lately, however, she has was not adequate. This decentration most elevated corneal nodule located been experiencing frustration as a re- was likely contributing to the glare in the superior-nasal peripheral sult of her visual symptoms. She was symptoms as her pupil approached cornea. The limbal clearance was full interested in any contact lens option the limits of her optic zone. In at roughly 25µm in all quadrants. that would improve visual quality. addition, if true residual astigmatism The scleral zone displayed moderate Slit-lamp examination revealed were present, a front toric corneal edge lift along the fl at meridian with superior nasal, elevated gray-blue design would be diffi cult to stabilize alignment along the steep meridian. nodules consistent with her corneal due to the superior corneal nodules The fl at meridian was rotated 30 degeneration diagnosis. The ocular displacing the lens inferiorly. It also degrees to the left. Both lenses were surface was otherwise unremarkable. has unpredictable rotational stability, well centered. The patient’s GP lenses were as the lens edge contacts the corneal A spherical over-refraction of highly decentered inferior temporal nodules with each blink. +1.50 OD and +1.25 OS improved in both eyes. The superior nasal nod- After reviewing possible approach- vision to 20/30+ OD and OS and ules appeared to play a role in decen- es, a scleral lens was the best option. 20/30+2 OU. A sphero-cylindrical tration, as they displaced the lenses This would provide the opportunity over-refraction yielded +1.75- inferior and temporal in both eyes. for GP optics, centration indepen- 0.75x050 OD and +1.50-0.75x130 Acuities were measured at 20/40 dent of corneal anatomy, a larger OS. This resulted in acuities of 20/20 OU. A +0.50 spherical over-refrac- optic zone to limit interaction with OU. Over-keratometry was per- tion improved vision to 20/30 OU, mydriasis in low lighting and the formed with a spherical result, ruling and a sphero-cylindrical over-refrac- opportunity to incorporate a stable out lens fl exure as the potential cause tion improved it to 20/20 OU. It was front toric correction if needed. of the cylindrical over-refraction. unclear if lens decentration, fl exure Based on these results, the or true residual astigmatism was DIAGNOSTIC FITTING following lenses were ordered: resulting in the toric over-refraction. The diagnostic lens chosen for -0.25-0.75x025 (25-degree right

38 REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 rotation)/45.00D/16.8mm/limbal tion, she had noticed a reduction in when scleral toricity can be used to clearance zone: standard/scleral glare while driving at night. Her acu- stabilize the lens. When toric scleral landing zone: +4 (fl at)/-2 (steep) OD ities were 20/20 OU, and her central zones are appropriate, the interaction and -0.50-0.75x160 (30-degree left clearances were 200µm and 150µm between the toricity in the shape of rotation)/45.00D/16.8mm/limbal in the right and left eyes, respectively. the lens and the toricity of the sclera clearance zone: standard/scleral land- Roughly 25µm of clearance over the creates rotational stability. This al- ing zone: +2 (fl at)/-2 (steep) OS. most elevated nodules, full limbal lows for stability without the added Both lenses were modifi ed in the clearance and scleral alignment was weight or thickness. A diagnostic set fl at meridian of the scleral zone to observed in both eyes. Rotation was with standard toricity is extremely compensate for edge lift, while the consistent with previous measures. helpful in determining the lens power steep meridians were left standard. The patient returned for her one- to order. By carefully measuring the The over-refraction axis was adjust- month follow-up with continued rotation of the diagnostic lens, the ed to compensate for lens rotation. clarity and comfort. The fi t was over-refraction axis can be properly unchanged, and her ocular surface compensated. DISPENSING tolerated lens wear well. Considering the right eye of the The patient returned one week later. patient in this case, the diagnostic As is typical in our offi ce, the pa- DISCUSSION lens was rotated 25 degrees to the tient’s lenses were inserted, and she Scleral lenses offer excellent stability right; thus, the axis of the over-re- was given approximately 30 minutes on the eye. With this stability comes fraction was modifi ed from 50 for them to settle. the ability to incorporate front toric degrees to 25 degrees. Note that Upon entering the exam room, vision correction with predictable this compensation is performed on the patient said, “I have one word rotational stability. the over-refraction, not the manifest for you—‘Wow!’” She went on to Front toric scleral lenses can be refraction. We anticipate the ordered comment that she couldn’t recall the stabilized through prism ballast- lens will rotate the same amount last time her vision felt so crisp and ing and toric scleral shape. When of degrees as the diagnostic lens. If clear. Her acuities were 20/20 OU a front toric correction is added this is the case, the axis will align as with a plano over-refraction in both to a lens with a symmetrical scler- intended. Some scleral lens designs eyes. The central fi t of both lenses al zone design, the lens must be provide additional rotation assess- was consistent with the diagnos- balanced using prism ballasting to ment lens markings to ensure that tic fi t. The fl at meridian markings minimize lens rotation. The amount the predicted rotation with the diag- were rotated to the same degree as of recommended ballasting varies nostic lens is the observed rotation they were in the diagnostic fi tting. based on lens design. The ballast can with the ordered lens. Within this lens design, an additional be increased if unstable rotation is During the diagnostic fi tting pro- vertical laser mark was placed at the observed; however, keep gravity and cess, I always perform both spherical anticipated 6 o’clock position for a oxygen availability in mind. and sphero-cylindrical over-refrac- simple axis check. The patient was With the ballast adding weight to tions to gauge the patient’s best-cor- educated on all pertinent wear and the inferior portion of the lens, infe- rected acuity and identify meaningful care instructions. rior decentration can be problematic amounts of residual astigmatism (I when excess amounts of prism are consider a front toric when residu- FOLLOW-UP incorporated. In addition, the thick- al astigmatism is 0.75 or greater). The patient returned a week later ness of the inferior lens can present By addressing meaningful residual having worn her lenses for seven challenges with oxygen availability astigmatism, we are able to aid our hours. She praised her visual quality, to the inferior cornea. Use the least patients in achieving their full visual reporting excellent initial and lasting amount of ballast to stabilize the lens potential and improving their overall comfort and vision with a daily aver- and high- to hyper-Dk materials. quality of vision and satisfaction age wear time of 12 hours. In addi- A more favorable situation arises with their lenses. RCCL

REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 39 Practice Progress By Mile Brujic, OD, and David Kading, OD

The ABCs of EBMD Although the presentation of epithelial basement membrane dystrophy may be subtle, its visual outcomes may not be.

pithelial basement mem- EBMD patients can minimize brane dystrophy (EBMD) their need for glasses with the may be more common appropriate lens prescription. Ethan we think. Literature In mild cases, a soft contact lens suggests that it affects 2% to 3% can accomplish this. Although no of the global population.1,2 This clear guidelines exist for soft lens is probably an underestimate, as selection, higher modulus lenses, EBMD is sometimes overlooked such as silicone hydrogel options, because of how subtle its clinical work well for these patients. With appearance can be. Here’s how to ever-advancing technologies, spot and manage it. we now have a handful of daily disposable lens options that are sil- CLINICAL PRESENTATION icone hydrogel. For more moder- EBMD happens when the base- Fig. 1. Epithelial thickness map shows ate or severe corneal irregularities ment membrane (BM) extends thinning where the map pattern is located. secondary to EBMD, oftentimes a into the corneal epithelium. Basal rigid surface is required to renor- corneal epithelial cells produce fi lm and ocular surface. If any ab- malize the optics entering the eye. abnormal BM cells, leading to the normalities exist, it is critical to treat Small-diameter gas permeable lenses region’s irregularity.2-4 As this occurs, them appropriately. In the presence work well for EBMD patients. If a the epithelium becomes uneven of a normal tear fi lm and ocular sur- patient has a diffi cult time wearing over the irregularly heaped areas of face, lubrication via artifi cial tears, this lens, a hybrid may be an appro- membrane, creating the elevations punctal plugs, Lacriserts or a combi- priate alternative. Scleral lenses are clinically seen as areas of negative nation of the three may be used. also an option and correct corneal staining and patterns of mapping, A major concern for patients with irregularities through the post-lens dots and fi ngerprints. Elevated EBMD is recurrent corneal ero- solution reservoir and lens surface. epithelium due to BM irregularities is sion. Preventative measures include thinner than corresponding non-el- lubrication in the evening with bland CASE STUDY evated epithelial tissue. This can be and hyperosmotic saline ointments. A 45-year-old male presented with easily seen with AS-OCT (Figure 1). More aggressive strategies to reduce a chief complaint of blurred vision. As EBMD progresses, it can cause the risk of recurrent events include He noted that everything “seemed a progressive reduction in BCVA. epithelial debridement and photo- blurry” and driving at night was be- Unfortunately, often this leads to therapeutic keratectomy.5-7 coming much more diffi cult for him. variability in vision because of poor In the event of a recurrent erosion, He reported that his glasses were tear fi lm qualities over the corneal the goal is to rehabilitate the cornea. re-made three times but the prescrip- irregularities and variability in the In mild cases, a bandage contact tion was never correct. His manifest irregular patterns observed on the lens can help the cornea heal. If the refraction was different than what cornea. These patients’ refractive erosive event is more severe, consider was in his glasses. His VA was 20/25 errors can vary with manifest refrac- an amniotic membrane.8 OU. tions over separate visits. Usually For patients who have a diffi cult The posterior segment examina- this is seen as changes in the axis and time seeing well and experience fl uc- tion was unremarkable. The patient’s amount of astigmatism measured. tuating vision, there are several con- corneas were remarkable for signif- tact lens options that can improve icant mapping patterns that were VISION OPTIMIZATION the visual experience by renormaliz- visible when viewed with a cobalt EBMD management strategies focus ing surface irregularities to create a blue light and a written #12 fi lter on promoting the health of the tear smooth, regular optic surface. after fl uorescein was placed on the

40 REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 surface of the eyes (Figure 2). EBMD better than it had been in years. He patients have elevated regions on the commented on how sharp every- corneal surface that appear darker thing looked. We ordered lenses or black when compared with the with the appropriate powers and surrounding cornea because they are Hydra-PEG (Tangible Science) not adequately covered by the tear coating to optimize the hydrophilic fi lm (Figure 3). properties of the lens surface and The patient was educated on the steepened the landing zone in the reason for his reduced and variable steep meridian by two steps. vision. We discussed treatment op- With the lenses, the patient’s tions, and he wanted to proceed with VA was 20/20 OU. In addition to lenses to improve his vision. He was improved vision and visual quality, fi t with scleral lenses of the following the patient commented on how parameters: -2.00/16.5mm diame- comfortable the lenses felt. He was ter/4200 sagittal depth/toric scleral taught appropriate wear and care Fig. 2. Normal fl uorescein pattern over landing zone OU. practices before the lenses were the cornea. After the lenses were worn for 30 dispensed. minutes, the central corneal clear- The patient noted good comfort and surgical remedies, presents an ances measured with a horizontal and vision at his one-week fol- important opportunity to intervene scan were 220µm OD and 240µm low-up. His vision was 20/15 OU in an EBMD patient’s life and help OS. There was adequate limbal with no notable over-refraction. He optimize their vision for the best out- clearance, and the landing zone was continues to fi nd success with scleral comes. You just need to know where slightly fl at in the steep meridian. lens wear and experience clearer to start and how to proceed. RCCL The steep meridian was oriented vision. 1. Hillenaar T, van Cleynenbreugel H, Remei- vertically on the eye with a marking jer L. How normal is the transparent cornea? indicating it was located at the 6 specialty contact lens improved Eff ects of aging on corneal morphology. o’clock position. The over-refraction Athe quality of this patient’s Ophthalmology. 2012;119(2):241-8. 2. Waring GO 3rd, Rodrigues MM, Laibson was -0.50 SPH 20/15 OD and -0.25 vision and could be the solution for PR. Corneal dystrophies. I. Dystrophies of SPH 20/15 OS. others like him. Practicing appro- the epithelium, Bowman’s layer and stroma. With the diagnostic lenses, the priate treatment methods, includ- Surv Ophthalmol. 1978;23(2):71-122. 3. Labbé A, Nicola RD, Dupas B, et al. patient reported that his vision was ing advanced contact lens fi ttings Epithelial basement membrane dystrophy: evaluation with the HRT II Rostock Cornea Module. Ophthalmology. 2006;113(8):1301-8. 4. Karpecki PM, Shechtman DL. Put an end to EBMD. Rev Optom. 2008;145(3). 5. Reidy JJ, Paulus MP, Gona S. Recurrent erosions of the cornea: epidemiology and treatment. Cornea. 2000;19(6):767-71. 6. Vo RC, Chen JL, Sanchez PJ, et al. Long- term outcomes of epithelial debridement and diamond burr polishing for corneal epithelial irregularity and recurrent corneal erosion. Cornea. 2015;34(10):1259-65. 7. Lee WS, Lam CK, Manche EE. Photothera- peutic keratectomy for epithelial basement membrane dystrophy. Clin Ophthalmol. 2016;11:15-22. 8. Miller DD, Hasan SA, Simmons NL, et al. Fig. 3. Negative staining associated with Recurrent corneal erosion: a comprehensive EBMD. review. Clin Ophthalmol. 2019;13:325-35.

REVIEW OF CORNEA & CONTACT LENSES | NOVEMBER/DECEMBER 2019 41 The Big Picture By Christine W. Sindt, OD

A Knotty Problem Sutures pose a challenge for contact lens ﬁ tting, necessitating an elevation-speciﬁ c design.

n 18-year-old male with defect was closed within days. The tachment, cornea and conjunctival Stevens-Johnson syn- patient remained on all postop- procedures. It undergoes hydrolytic drome presented after erative antibiotics, steroids and degradation and has been known Aglaucoma tube explan- glaucoma meds during scleral lens to elicit infl ammatory reactions. tation secondary to tube exposure wear. At follow up, the suture tails Granulomas may form around vic- and endophthalmitis. The patient were splayed out under the scleral ryl conjunctival/scleral sutures. was suffering from a persistent lens haptic; however, there was no It is a braided material, which ac- corneal epithelial defect and was staining or erosion of the conjunc- counts for the splayed appearance referred for scleral lens fi tting to tival tissue. seen in this patient. He will need to aid in corneal healing of his only Contact lenses are commonly fi t be refi t with a new elevation-spe- remaining eye. over ocular sutures. When doing so, cifi c lens design once the suture is The conjunctival wound had it is important to follow the patient absorbed and the surgical infl am- been closed with three running 8-0 closely for suture erosion, which mation is reduced. vicryl sutures with episcleral bites may be a vector for infection. Ethilon (nylon) is a non-absorb- to anchor to the underlying sclera. Vicryl (polyglactin 910) is an able monofi lament material com- There was a suture knot with long absorbable suture that holds its monly used for corneal transplants. tails under the conjunctival fl ap. tensile strength for approximately This material will remain in the An elevation-specifi c lens was 21 days and is completely absorbed cornea until removed. Fortunate- created with extra clearance over within 56 to 70 days. It is used for ly, it is inert, with minimal tissue the knot and the corneal epithelial subcutaneous tissue, muscle reat- reaction. RCCL

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*Compared to SYSTANE® BALANCE Lubricant Eye Drops. References: 1. Korb D, Blackie C, Meadows D, Christensen M, Tudor M. Evaluation of extended tear stability by two emulsion based artifi cial tears. Poster presented at: 6th International Conference of the Tear Film and Ocular Surface: Basic Science and Clinical Relevance; September 22-25, 2010; Florence, Italy. 2. Moon SW, Hwang JH, Chung SH, Nam KH. The impact of artifi cial tears containing hydroxypropyl guar on mucous layer. Cornea. 2010;29(12):1430-1435. 3. Davitt WF, Bloomenstein M, Christensen M, Martin AE. Effi cacy in patients with dry eye after treatment with a new lubricant eye drop formulation. J Ocul Pharmacol Ther. 2010;26(4):347-353. 4. Willcox MDP, Argueso P, Georgiev GA, et al. TFOS DEWS II tear fi lm report. Ocul Surf. 2017;15:366-403. 5. Ketelson H, Rangarajan R. Pre-clinical evaluation of a novel phospholipid nanoemulsion based lubricant eye drop. Invest Ophthalmol Vis Sci. 2017;58:3929. 6. Ogundele A, Ketelson H, et al. Preclinical evaluation of a novel hydroxypropyl-guar phospholipid nanoemulsion lubricant eye drop for dry eye disease. Poster presented at: The 36th World Ophthalmology Congress (WOC); June 16-19, 2018; Barcelona, Spain. 7. Craig J, Nichols K, Akpek E, et al. TFOS DEWS II defi nition and classifi cation report. Ocul Surf. 2017;15:276-283. 8. Lane S, Paugh J, et al. An Evaluation of the in vivo Retention Time of a Novel Artifi cial Tear as Compared to a Placebo Control. Invest Ophthalmol Vis Sci. 2009;50(13):4679. 9. Benelli U. Systane® lubricant eye drops in the management of ocular dryness. Clin Ophthalmol. 2011;5:783-790. 10. Torkildsen G. The eff ects of lubricant eye drops on visual function as measured by the Inter-blink interval Visual Acuity Decay test. Clin Ophthalmol. 2009;3:501-506.