CRO Vol. 26.3 by MediConcept

CRO

ONLINE EDITION

Clinical & Refractive Optometry Online VOLUME 26, NUMBER 3, 2015

CLICK HERE TO DOWNLOAD AND PRINT THIS ISSUE Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care The Inflammation Game: Unlocking the Enigma of the Inflamed Eye A Comprehensive Review of Diabetic Keratopathy Unknown Adverse Visual Effects of Gabapentin

See additional safety information on page 118

Clinical&Refractive Optometry: Online Edition Editorial Board • Volume 26, Number 3, 2015

Editor-in-Chief

Associate Editor

Yvon Rhéaume, OD Montreal, Quebec

Richard Maharaj, OD Toronto, Ontario

Leonid Skorin, Jr., OD, DO, MS Albert Lea, Minnesota

Editors Emeriti John Jantzi, OD Vancouver, British Columbia

Brad Almond, OD Calgary, Alberta

Barbara Caffery, OD Toronto, Ontario

Contributing Editors Jean Bélanger, OD Montreal, Quebec

Paul Dame, OD Calgary, Alberta

Gerald Komarnicky, OD Vancouver, British Columbia

Rodger Pace, OD Waterloo, Ontario

Scott D. Brisbin, OD Edmonton, Alberta

Danielle DeGuise, OD Montreal, Quebec

Bart McRoberts, OD Vancouver, British Columbia

Maynard Pohl, OD Bellevue, Washington

Lorance Bumgarner, OD Pinehurst, North Carolina

Pierre Forcier, OD Montreal, Quebec

Ron Melton, OD Charlotte, North Carolina

Barbara Robinson, OD Waterloo, Ontario

Louis Catania, OD Philadelphia, Pennsylvania

Guy Julien, OD Montreal, Quebec

Langis Michaud, OD Montreal, Quebec

Jacob Sivak, OD, PhD Waterloo, Ontario Randall Thomas, OD Concord, North Carolina

Publication Staff Publisher Lawrence Goldstein

Managing Editor Mary Di Lemme

Senior Medical Editor Evra Taylor

Layout Editor Colin MacPherson

Graphics & Design Mediconcept Inc.

Mission Statement Clinical & Refractive Optometry: Online Edition is a peer-reviewed professional journal dedicated to the publishing and disseminating of COPE approved CE credit scientific articles. The contents of each issue are composed of a mixture of original: state-of-the-art/ technical, therapeutic/clinical, or practice management articles which are of particular interest to and use by practicing optometrists. Participants achieving 70% or more on the questionnaires that accompany each of the articles in the journal, will receive a course credit certificate.

About This Issue This online issue of CRO (Clinical & Refractive Optometry) is being sent to you at no charge with the compliments of the CSCRO (Canadian Society of Clinical & Refractive Optometry). Each of the scientific articles contained in this issue have been approved by COPE for 1-hour of CE credit and are available at a cost of $25 per course. To take any of the CE credit courses in this issue, please follow the instructions on the test questionnaire pages. Please note that you can upgrade to a print edition subscription to CRO (Clinical & Refractive Optometry) which includes prepaid CE credit courses in every issue. For more details and to subscribe, please see the subscription upgrade offer on the next page.

Clinical&Refractive Optometry: Online Edition Contents • Volume 26, Number 3, 2015

CE CREDIT ARTICLES 80 Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care Richard Maharaj, OD INTRODUCTION: Dr. Maharaj began his presentation by stating that during his longstanding practice he has seen a large number of dry eye patients, specifically dry eye patients with ocular surface diseases. His point of view is that when an optometrist sees a particular disease day in and day out, it alters their perspective. One of the focuses of Dr. Maharaj’s work is how osmolarity fits into the primary eye care arena.

The Inflammation Game: Unlocking the Enigma of the Inflamed Eye David Ng, OD; Duc Le, OD INTRODUCTION: Dr. Ng and Dr. Le began their presentation by noting that they would be presenting five Case Reports of patients who recently presented in their clinic with various forms of ocular inflammation. These cases ranged from basic to complex, and in all cases finding the correct diagnosis and instituting the most effective treatment plan was essential. The purpose of this presentation was to share their diagnostic process and treatment approaches.

A Comprehensive Review of Diabetic Keratopathy Amiee Ho, OD; Pauline F. Ilsen, OD ABSTRACT: Diabetes can affect almost all structures of the eye, particularly the cornea, causing a condition known as diabetic keratopathy. Diabetic keratopathy stems from chronic hyperglycemia due to the abnormal glucose metabolism of diabetic patients. It involves all layers of the cornea including corneal nerves and the pre-corneal tear film. The aim of this paper is to provide a comprehensive overview of potential corneal findings that have been observed in patients with diabetes.

110 Unknown Adverse Visual Effects of Gabapentin Dawn N. Tomasini, OD, Jennifer Tribley-Grill, OD, Miriam M. Rolf, OD

Clinical & Refractive Optometry: Online Edition is published 4 times per year by Mediconcept. The Journal is made available to all optometrists on www.crojournal.com. Advertising insertion orders and copy must be received before the first day of the preceding month for which the advertising is scheduled. While the editorial staff of Clinical & Refractive Optometry: Online Edition exercises great care to ensure accuracy, we suggest that the reader consult the manufacturer’s instructions before using products mentioned in this publication. The views contained in the Journal are those of the respective authors and not of the Publisher. Please direct all correspondence to: Mediconcept Editorial & Sales Office 2113 St. Regis, Suite 250 Dollard-des-Ormeaux, Quebec Canada H9B 2M9 Tel.: (514) 447-1110 E-mail: info@mediconcept.ca Printed in Canada. All rights reserved. Copyright © 2015 Mediconcept. The contents of the publication may not be mechanically or electronically reproduced in whole or in part without the written permission of the publisher. All drug advertisements have been cleared by the Pharmaceutical Advertising Advisory Board.

ABSTRACT: Gabapentin, commonly known as Neurontin® is a medication used in the treatment of seizures and pain control. Traditionally, its ocular side effects have been limited to blurred vision, diplopia and impairment of ocular motilities. Over the past decade, anti-epileptic drugs similar to gabapentin have been linked to severe visual field constriction. The following case substantiates that gabapentin can cause reversible visual field defects, as well as affect central visual acuity.

BOOK REVIEW

117 Visual Impairment: A Global View by Heather McLannahan Reviewed by: Emily Bjore, OD; Leonid Skorin, Jr., OD, DO

NEWS & NOTES

118 Contact Lens Researchers Test New Lens to Slow the Progression of Myopia; Tonomate Disposable Applanation Prism Now Available in Canada

ISSN: 1705-4850; Date of Issue: October/November 2015

Cover Image: Corneal abrasion with severe confluent SPK. Courtesy of: Dr. David Ng and Dr. Duc Le

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Clinical & Refractive Optometry: Online Edition is pleased to present this continuing education (CE) article based on a presentation given by Dr. Richard Maharaj at the CRO 2015 Meeting in Toronto, Ontario in which he discussed the increasingly important role of tear osmolarity in optometric practice. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to the page 86 for complete instructions.

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care Richard Maharaj, OD, FAAO

INTRODUCTION Dr. Maharaj began his presentation by stating that during his longstanding practice he has seen a large number of dry eye patients, specifically dry eye patients with ocular surface diseases. His point of view is that when an optometrist sees a particular disease day in and day out, it alters their perspective. One of the focuses of Dr. Maharaj’s work is how osmolarity fits into the primary eye care arena. His primary interests are the intrinsic and extrinsic risk factors associated with ocular surface diseases and his presentation concentrated on the history and relevance of tear film osmolarity — and its role in optometric care.

SUGGESTING AN ALTERNATIVE TEAR FILM MODEL Dr. Maharaj described the various layers of the tear film: the lipid, mucus and aqueous layers delivered by the meibomian glands, the goblet cells, and the lacrimal and accessory glands respectively. The goal of a stable tear film is based on the perfect interaction between these layers, as well as the optimal interface between these layers and the lid mechanics (Fig. 1). A large part of this is the sensory motor component of the ocular surfaces. In cases of dry eye or other surface diseases, typically the patient presents by saying, “I'm uncomfortable. I feel gritty, I feel sandy.” They often describe some form of discomfort, prompting the question of the underlying cause. Dr. Maharaj stated that he examines this query in terms of three major categories. Pathology is first and foremost. Both pathological and age-related changes conspire to break down the ocular surface. The second element is environmental or external factors and the third being anatomical considerations, involving an examination

Maharaj — Clinic Director, eyeLABS, Brampton, Ontario; Staff Optometrist, Humber River Regional Hospital - York/Finch Eye Associates, Toronto, Ontario Correspondence to: Dr. Richard Maharaj, 7900 Hurontario, Suite 406, Brampton, ON L6Y 0P6; E-mail: rmaharaj@eyelabs.ca

CRO: Online Edition 26:3, 2015

of the blink mechanism. It’s not a perfect vertical movement; in fact, there are torsional, tangential and vertical movements of both the upper and lower eyelid. It’s a very complex series of mechanisms that add up to a perfect blink; and in fact, the majority of dry eye sufferers, more than 60% of them, have some form of lid dysfunction or blink closure; rather, the lack thereof. What may be defined as lagophthalmos in some cases may not, in fact, be so obvious. What’s more, these microanatomical changes at the level of the blink have a huge impact. Depending on the ethnicity of the patient and their age, and with various activities, these movements can change. Dr. Maharaj underscored the fact that optometrists tell their patients about the 20/20/20 rule, trying to drive home the message that the anatomy of the blink matters.

ENVIRONMENTAL FACTORS In terms of external environmental factors, seasonal allergens in the air definitely have an impact on dry eye disease. For a dry eye patient who has a less than perfect tear film, allergens may be the tipping point: they may represent the element that shifts a patient from being asymptomatic to symptomatic, as a large part of the disease exists in the asymptomatic stage. Another important aspect is the effect of the office environment on the blinking process. In a large room, patients can undertake preventive measures such as artificial tears as they know in advance that their eyes are going to get irritated. Foreign bodies such as microparticulates including make-up, dust, epidermis and devitalized epithelium, are evident in patients’ tear film all the time. The following question arise: Should we address this? Is it normal? In a healthy eye with a healthy tear film, that may not be necessary; however, said Dr. Maharaj, how does an optometrist know if a patient has a healthy tear film? Here, diagnostics play a significant role. Contact lenses are an obvious additional environmental factor, and represent an etiology for which practitioners are, in fact, responsible. Currently, optometrists are using single use and reusable lenses, and are adding different solutions and playing with various materials. However, as Dr. Maharaj pointed out, a contact lens is still a foreign

Stable Tear Film Maintenance Lacrimal Gland Anatomical

Meibomian Gland

Aqueous Lipid Mucin

Goblet Cells Stable Tear Film Lid Blinking Sensory Motor Lid Closure

Chemical Composition of Human Tear & Plasma

Tear Clearance & Spread

↓ Evaporation

Water Solids (total) NA+ K+ CLHCO3Ca2+ Glucose Total protein Amino Acids Urea

TEARS

PLASMA

98.2% 1.8% 142meq/l 15-29meq/l 120-135meq/l 26meq/l 2.29mg/100ml 3-10mg/100ml 0.6-2g/100ml 8g/100ml 0.04mg/100ml

94% 6% 137-142meq/l 5meq/l 102meq/l 24.3meq/l 80-90mg/100ml 6.78g/100ml 20-40mg/100ml Dr. Vijay Joshi, MS, MBBS Ophthalmology

Fig. 1 Proper interaction between tear film layers is vital to a stable tear film.

Fig. 2 Human tear and plasma share similar chemistry.

body being introduced into patients’ eyes. They’re being used for good reason and with good intent, with a body of science behind them, but the fact remains that a foreign body will be recognized by one’s body as foreign, contributing to inflammation and therefore an immunological response will be triggered. All of the above are extrinsic factors that contribute to patient discomfort.

way. This is relevant considering that eyes are constantly bathed in this solution that's being produced by the body, so any changes in it make a difference. Inorganic salts in particular — microproteins — contribute heavily to the measurement of tear osmolarity. Tears contain hormones, which is why, in female patients in their fifties who are going through menopause, start to see the onset in their dry eye symptomology. It may in fact be related, and the endorphins that contribute to the sense of pain are also present. The lipid layer is the interface between tears and the air, but the mucin layer is the scaffolding that gives tears their structure. Secretory mucins at the ocular surface interact with epithelial receptors that, so if there is dysfunction in the corneal epithelium or in those receptors, this may indicate a dysfunction in the scaffolding. Figure 2 illustrates a parallel between blood plasma and tears, showing very similar values. Regarding blood chemistry testing and how relevant it is in overall systemic health, Dr. Maharaj proposed the question, is the same level of scrutiny helpful for ocular surface diseases? His response answer is that it is indeed.

PATHOLOGICAL AND CHRONOLOGICAL CHANGES Dr. Maharaj highlighted the challenge of lid wiper epitheliopathy. He feels that it is an interesting concept and pathology as, like dry eye, it can start in an asymptomatic phase; indeed, in most cases, it does. Staining is one of the best methods of early testing to help identify the condition; he suggested it for at-risk patients (contact lens wearers, tight lids, obvious and non-obvious MGD patients, etc.). Friction at the lid wiper and ocular surfaces is the key to the dry eye symptomology— and the driving force behind the inflammatory cascade at the ocular surface. Currently, practitioners are seeing a departure from the model of three discrete tear film layers: the mucin, the lipid and the aqueous, with the aqueous making up the bulk of the layers. The literature is reflecting a shift away from the classical type of “sandwich,” with the aqueous in the middle, the lipid on top and the mucin on the bottom. In an alternate tear film model, a glycocalyx transmembrane emanates through the layers and is anchored to the epithelium. The question arises, “Does the chemical composition of tears affect dry eye progression and is this important?” Dr. Maharaj pointed out that there are several components that the industry is examining very closely. Physicians have relied heavily on lab work, including blood testing, and a shift in direction when it comes to tear chemistry is occurring in much the same

DRY EYE DISEASE AND OCULAR WELLNESS The prevalence of dry eye disease has been stated in a number of different ways, depending on how it is defined in the various clinical studies. However, Dr. Maharaj postulated about a unified way of defining dry eye disease such as is done with glaucoma or macular degeneration. Is there a reliable metric that can be used in the primary care arena that helps to define it — because if so, he pointed out, these numbers might actually fall into slightly more agreement.

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care — Maharaj

Knowing that in optometric practice dry eye disease is second only to cataracts in terms of prevalence, it's a huge cohort. Dr. Maharaj posed the following questions for consideration: how is it being managed? Are practitioners doing anything different than they were five or ten years ago? Even with the growing number of options in contact lenses and care solutions, the dropout rates by contact lens wearers due to discomfort hasn't changed when considering all of these advances, a decline in dry eye disease should be evident. Dr. Maharaj suggested that a key piece of the puzzle might be missing.

TEAR OSMOLARITY PAST AND PRESENT The history of tear osmolarity began with the late Jeff Gilbard who was, in Dr. Maharaj’s opinion, well ahead of his time. As early as 1978, he proposed that hyperosmolarity is the driving force behind ocular surface disease. He published papers on the correlation between high incidences of eye osmolarity and decreased corneal epithelial glycogen, and conjunctival goblet cell density. In an inverse relationship, the higher the tear osmolarity, the more change in the goblet cell morphology was seen. In 1989, he determined that hyperosmolarity was, in fact, coincident in patients that had good lacrimal gland function but meibomian gland orifices closure. This was the first time anybody had the suggested that hyperosmolarity was actually a major culprit in dye eye disease. Gilbard's work was finally recognized and catapulted to its current status.

DEFINITION AND MEASUREMENT OF OSMOLARITY Osmolarity is the measure of solute concentration. Its unit of measure is osmoles per liter, or in the case of the tear film milliosmoles per liter because the value is so very low. Surprisingly, there are three methods of measuring osmolarity. The first, which does not seems to suit the primary eye care setting, is the freezing point depression. When a particular material is frozen — for instance, water — it freezes at 0 degrees. If the solute level or the osmolarity of that solution is higher, the freezing point drops and that point of depression, that delta between 0 and the freezing temperature, can be extrapolated to osmolarity. The sample requires 0.2 uL so it's still rather large but it can be done, and it is used in lab testing, stated Dr. Maharaj. The converse is also true. The second method — vapor pressure — can also be tested to correlate to osmolarity. Again, the mechanism is extremely complex and it doesn't lend itself very well to primary care; however, there are several institutions that use vapor pressure to measure osmolarity — not tear osmolarity, as it uses quite a large sample size.

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The third method is commonly recognized and used: electrical impedance. The conductivity of the fluid is changed and it is proportional to the osmolarity or concentration of the solution. It actually requires a very small sample of approximately 50 nL, which is perfect because only a small amount of tears is available, about 17 uL. It has been available through TearLabTM testing for some time.

OSMOLARITY VERSUS OSMOLALITY As a differentiation between osmolality, and osmolarity, osmolality refers to the solute concentration per kilogram; it's the solvent measured as a solid as opposed to a liquid. Tear film never solidifies therefore in this discussion, stated Dr. Maharaj, osmolality and osmolarity are synonymous. These two words can be used interchangeably; however, in the literature it is referred to as osmolarity. In the DEWS (International Dry Eye Workshop) report in 2007, tear osmolarity was actually incorporated as part of the definition of dry eye disease. The IOP at or above which practitioners should be concerned in glaucoma patients is 21, an extremely important recognized benchmark; it has helped to identify glaucoma patients far earlier — and, in Dr. Maharaj’s view, the specificity and sensitivity in optometry practices have increased as a result of that. Knowing that the prevalence of dry eye disease is significantly greater than that of glaucoma, and that there is a metric that has been included in the definition, it does make sense that practitioners can delve into this disease through their patient base and see if there is preventative action they can take. Patients who test above 308 milliosmoles per liter do, in fact, have the disease. Tear osmolarity is the global marker agreed upon by both ODs and MDs alike, which is a rarity, but in the presence of a measure that is so strong, it begs further exploration. It is elevated in the diabetic population and in patients on chronic glaucoma medication who are exposed to BAK on a regular basis. The dry eye disease population is paralleled only by that of diabetes in the United States, with some 25 million people affected.

ROLE OF OSMOLARITY IN DRY EYE DISEASE The 308 mOsms/L figure was derived from a 2010 study by Michael Lemp, published in 2011 (Fig. 3). It postulated and confirmed that above 308 mOsms/L, one sees an increase in inflammation and apoptosis, as well as a breakdown in useful homeostasis. However, the question remains, what causes dry eye disease hyperosmolarity? Compared to other markers such as tear break-up time, Schirmer's and the ocular surface increase index, osmolarity has much greater sensitivity and specificity. In Dr. Lemp’s paper, above the cutoff of 308, sensitivity was at

Defining the Disease At 308 mOSm/L cutoff • Specificity = 88% and Sensitivity = 75% At 315 mOSm/L cutoff • Specificity = 92% and Sensitivity = 73% • PPV 85% - i.e. “The % of time a metric > 308 mOsm/L will actually be DED Recall • Sensitivity % of persons who actually have the disease. • Specificity % of persons who do not have the disease. • Positive Predictive Value is the percent of people with a positive test who have the disease. • Negative Predictive Value is the percent of people with a negative test who do not have the disease.

Observed Differences in Hyperosmolarity & Normal Participants =< 308 mOsm/L

> 308 mOsm/L

Avg osmolarity

297 +/- 7

323 +/- 17

Inter-eye difference

6 +/- 6

17 +/- 16

McDonald ASCRS 2013- Osmolartiy Prevalence Study (from Donnenfeld)

Fig. 3 Using sensitivity and specificity to define dry eye disease.

Differences in Hyperosmolar & Normal Participants =< 308 mOsm/L > 308 mOsm/L Overall population

52%

48%

Pts reporting 3 or more DED symptoms

49%

51%

Reporting less than 3 DED 54% symtpoms (Asymptomatic)

46%

McDonald ASCRS 2013- Osmolartiy Prevalence Study (from Donnenfeld)

Fig. 5 Dry eye symptoms in hyperosmolar and normal patients.

70% and specificity was at 88%. Specificity indicates that the number of patients who test negative is high; therefore, if it's good at determining who doesn't have it, it's good at determining who does have it. As osmolarity increases, so does specificity. Furthermore, in the second best measure, ocular surface disease index, in Dr. Lemp’s research the agreement still wasn't as high as with osmolarity.

PREVALENCE OF DRY EYE DISEASE Dr. Eric Donnenfeld began a prevalence study in 2012, which was taken over by Dr. Marguerite McDonald in 2013. It comprised approximately 9,000 patients sequentially, excluding those who had been artificial teared within two hours of testing. Their demographics and history were taken followed by a series of yes or no questions. The patients were then classified as either having dry eye disease or having normal or low osmolarity.

Fig. 4 Comparing hyperosmolar and normal participants.

Of particular interest, Dr. Maharaj stated, was that for patients who had normal osmolarity, below 308, the inter-eye difference was actually quite low at ±6. For patients above 308, the inter-eye difference is actually fairly significant, at 17±16 (Fig. 4). A similar trend was that the inter-eye difference above the 308 threshold increases. At the same time, osmolarity tended to be higher in the more painful eye. Dr. Maharaj noted that these are now regarded as trends to look for. In patients with dry eye disease, often one eye feels worse than the other. Furthermore, it's quite possible that after measuring their osmolarity, the delta is actually in favour of the eye that is more uncomfortable. Figure 5 presents rates of symptomatology in hyperosmolar and normal patients. Fifty percent of those with normal osmolarity reported three or more dry eye-like symptoms; therefore, 50% were experiencing some other disease causing their symptomology. Close to half of these 9,000 dry eye patients were silently suffering and were only uncovered by the osmolarity testing, stated Dr. Maharaj. The salient point is that patients who are symptomatic and have abnormal tear film still need to get run through for diagnosis. In addition, they need to be examined for corneal health, staining and other standard testing for other possible contributing factors.

RELATIONSHIP BETWEEN OSMOLARITY AND MEIBOMIAN GLAND DYSFUNCTION Dr. Anthony Bron et al in the UK have put forth the concept of a solute gradient of the tear film, using a tear prism model: it has a thick base and a thin apex, with solute concentration in osmolarity highest at the apex and lower at the base. As a result, there is a driving force from

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care — Maharaj

tear film to the lid margin and therefore the meibomian gland orifice (MGO) forcing solutes towards the lid margin and into the MGO. This may in fact be a key mechanism in the genesis of MGD demonstrating its origin in hyperosmolar environments.

IMPACT OF DRY EYE ON OPTOMETRIC PRACTICE Dr. Maharaj mentioned that the average dry eye patient is female, over age 30, is a contact lens wearer, and uses a computer. This demographic also fits the profile of the decision-makers in families. These are patients who, if they’re well taken care of and identified in the asymptomatic phase, can be steered clear of a disease that will induce anxiety, depression, and a whole cascade of events that can be life altering — and his first-hand experience bears witness to this. Regarding contact lens dropouts, the number in recent years is 30% in the first year of wear alone, despite advances in contact lens materials and solutions.

DRY EYE DISEASE IN SURGICAL PATIENTS William Trattler MD did a retrospective study called the PHACO study which examined 272 eyes of 136 patients for incidence of DED in a surgical population. Using the ITF, the International Task Force classification on dry eye, almost 63% of patients had abnormal break-up times; 21% had an abnormal Schirmer's score; and almost 77% were positive for corneal staining, 50% of which had central staining. 87% of the dry eye patients identified were asymptomatic. This potentially represents a high number of patients emerging post-surgery with postoperative dryness. In many cases DED is present preoperatively and not adequately managed. In a small internal study at his clinic in Brampton of approximately 100 patients, looking at their ocular surface disease index, and fluorescein staining, 23% of post-cataract patients developed dry disease, who were normal preoperatively. The literature cites postoperative dry eye prevalence anywhere from 8% to 52%. In light of these negative surgical effects, Dr. Maharaj posed the question, is there room for optometrists to do more to these patients pre-surgically in order to identify them properly?

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PREVENTIVE MEASURES FOR DRY EYE DISEASE The TearLab™ detection test for dry eye disease has been on the market for a while. It comprises a detection system, with a simple applicator and disposal test cards that produce the result number. In July 2015, i-Pen® was launched by I-MED Pharma as another point of detection test, again using a simple single, disposable chip. Rather than being housed in a charger, it is a hand-held battery operated device which is very simple to operate. It gives the reading in less than 5 seconds and patients are very comfortable during the test procedure. Dr. Maharaj stated that the modern focus of medical endeavours is prevention. This raises the issue of when to initiate preventative measures in dry eye disease management like diagnostic testing which may impact early intervention and treatment, as has already happened in diseases like glaucoma and macular degeneration, for example. Dr. Maharaj remarked that surgical patient remains under the optometrist’s care, and always will be, the optometrist’s patient. His view is that ODs are “lending” the person to ophthalmology to perform a surgical medical procedure — and that patient will return to the OD. The chances are, he stated, that if there are any complications, it will flow through the optometrist’s office, and it is incumbent upon ODs to manage the situation.

CONCLUSION Dr. Maharaj concluded his presentation by commenting that the contact lens landscape is rapidly evolving. Google, for instance, is now hoping to develop a contact lens that measures blood glucose. Additionally, he asserted that the modulus of that lens will be slightly higher than current options, and the coefficient of friction will probably be higher. The ways in which this and other contact lens advances will impact optometric practice should impact the overall management of the ocular surface as a consequence. He feels strongly that tear chemistry will play an increasingly major role in the future of eye care, and that what worked five or ten years ago should not, in fact, work in the upcoming five or ten years. If it does, he opined, the chances are that doctors of optometry and ophthalmologists alike are doing something wrong. ❏

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QUESTIONNAIRE Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care Richard Maharaj, OD, FAAO 1. ❑ ❑ ❑ ❑

What percentage of dry eye sufferers have some form of lid dysfunction? More than 40% More than 50% More than 60% More than 80%

2. ❑ ❑ ❑ ❑

All of the following statements about dry eye disease are true, EXCEPT: It can start in the asymptomatic phase Contact lenses are an environmental factor in dry eye etiology Make-up is one of several foreign bodies that are evident in patients’ tear film all the time Most patients present for the first time with advanced dry eye disease

3. ❑ ❑ ❑ ❑

All of the following statements about tear osmolarity and dry eye disease are true, EXCEPT: Andropause may trigger the onset of dry eye symptomatology Menopause may trigger the onset of dry eye symptomatology Microproteins contribute to the measurement of tear osmolarity Dropout rates by contact lens wearers due to discomfort haven’t changed

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Which osmolarity indicates dry eye disease? 150 milliosmoles per liter 270 milliosmoles per liter 308 milliosmoles per liter 400 milliosmoles per liter

5. ❑ ❑ ❑ ❑

Which of the following ocular conditions is most prevalent? Dry eye disease Glaucoma Blepharitis Keratitis

6. ❑ ❑ ❑ ❑

In glaucoma patients, an IOP at or above which level is concerning to practitioners? 15 21 25 30

7. ❑ ❑ ❑ ❑

In Dr. Lemp’s research, osmolarity above the cut-off of 308 milliosmoles per liter, specificity was at what percentage? 55% 60% 78% 88%

8. ❑ ❑ ❑ ❑

All of the following characteristics describe the typical dry eye patient, EXCEPT: Female Over age 30 Contact lens wearer Extended contact lens wearer

9. ❑ ❑ ❑ ❑

Which of the following is the rate of contact lens dropout in the first year of wear? 20% 25% 30% 35%

10. ❑ ❑ ❑ ❑

In Dr. Trattler’s research, what percentage of dry eye patients were identified as asymptomatic? 42% 55% 72% 87%

26:3, 15

4. ❑ ❑ ❑ ❑

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care — Maharaj

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Clinical & Refractive Optometry: Online Edition is pleased to present this continuing education (CE) article based on a presentation given by Dr. David Ng and Dr. Duc Le at the CRO 2015 Meeting in Toronto, Ontario in which they discussed the diagnostic process and treatment approaches to five cases of ocular inflammation ranging from basic to complex. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to the page 94 for complete instructions.

The Inflammation Game: Unlocking the Enigma of the Inflamed Eye David Ng, OD; Duc Le, OD

INTRODUCTION Dr. Ng and Dr. Le began their presentation by noting that they would be presenting five Case Reports of patients who recently presented in their clinic with various forms of ocular inflammation. These cases ranged from basic to complex, and in all cases finding the correct diagnosis and instituting the most effective treatment plan was essential. The purpose of this presentation was to share their diagnostic process and treatment approaches.

CASE STUDIES Case #1 The first case involved a 12-year-old boy with sore, itchy eyes for the past week. His lids were stuck together with yellow mucus upon wakening. His mother administered Visine® allergy drops with no improvement. The patient was not on any other medications; he denied have allergies to ragweed, pollen or dust mites. Vision was 6/6 (20/20) in each eye; however, he had bilateral lid erythema (Fig. 1A) with grade 1 conjunctival papillae and positive Dennie's lines. Dr. Ng wanted to prescribe loteprednol etabonate ophthalmic suspension 0.2% (Alrex®, Bausch & Lomb, Vaughan, ON), which the patient’s mother rejected; she wanted to use olopatadine hydrochloride ophthalmic solution 0.1% (Patanol®, Alcon Canada, Mississauga, ON). Dr. Ng prescribed olopatadine hydrochloride ophthalmic solution 0.2% (Pataday®) once a day for the next two months, to carry him through allergy season. The following day the patient returned with much more redness and a high degree of discomfort. D. Ng; D. Le — Assistant Clinical Professor, University of Waterloo, School of Optometry, Waterloo, ON and New England College of Optometry, Boston, MA Correspondence to: Dr. David Ng, 500 Sheppard Avenue East, Suite 204, North York, ON M2N 6H7; E-mail: drdavidng@drdavidng.com

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The patient’s mother was concerned that her son was allergic to the olopatadine hydrochloride and she noted that the product insert stated that it was not approved for children under the age of 18; in Canada, it's actually 16. Dr. Ng added artificial tears and cold compresses, and advised the patient to stop rubbing his eyes. His suggestion for Alrex was rejected by his mother as it was a steroid; therefore, the patient was placed on ketotifen fumarate ophthalmic solution 0.035% (Zaditor®, Alcon Canada, Mississauga, ON). At the one-week follow up the patient presented with near normal lids. However, he was still complaining of some itchiness and showed mild conjunctival papillae. Alrex was suggested again and accepted by his mother. A subsequent follow-up was insignificant. Alrex was discontinued once all signs and symptomatology disappeared. Pataday was continued until the end of the allergy season. Dr. Ng pointed out that when patients present with severe seasonal allergies, referencing the local pollen forecast can help determine which anemophilous plants are the causative sources of their allergy. Seasonal allergic conjunctivitis can be responsible for itching, redness, burning, swelling, hyperemia, chemosis, and mucoid or watery discharge. It is critical to quickly treat allergies to avoid permanent tissue damage; using the inflammatory cascade as a guide, one has only 24 hours within which an antihistamine/mast cell stabilizer will be most effective (Fig. 1B). The late phase is beyond 24 hours and this is where steroids really excel. Dr. Ng

External

Fig. 1A Seasonal allergic conjunctivitis.

Corticosteroids Inhibit Multiple Early Points of the Inflammatory Cascade Mast Cell Membrane Phospholipids Early-Phase Mediators

Mast Cell Stabilizers (MCS)1 Work Here

Corticosteroids

Most Combination Antihistamines/MCS1 Work Here

Late-Phase Mediators

Phospholipase A2 Activity Arachidonic Acid

Histamine Heparin Proteases PAF (trytase, chymase)

Cyclooxygenase Pathway

NSAIDs Work Here

Lipoxygenase Pathway Hydroperoxides (5-HPETE)

Antihistamines1 Work Here Prostaglandins (PGF2a, PGD2, PGE2)

Prostacyclin (PGI2)

Thromboxane A2 (TXA2)

HHT, MDA

Leukotnense (SRS-A, LTB4)

Adapted with permission from Slonim CB. Rev Ophthalmol 2000: 101-112.

Fig. 1B Importance of early intervention in allergy treatment.

stated that in his practice it is very rare that patients come to the office within the first 24 hours of the initial allergy symptoms. For allergies with no signs, prescribing an antihistamine/mast cell stabilizer is fine. In mild to moderate cases, when patients present with itchiness that affects their lifestyle, a steroid should be prescribed. The initial dosing is four times a day for two weeks; twice a day for one to two more weeks; then switch to a mast cell stabilizer/antihistamine. With steroid use, he monitors the patient’s IOP every two weeks. Case #2 A 32-year-old female consulted with her family physician for upper lid itching for the past month. The family doctor had prescribed hydrocortisone 1% to be used sparingly one to four times a week. The patient stated that her condition had worsened greatly and that her eyelids had become increasingly swollen in the past two days (Fig. 2). According to Dr. Ng, this was a classic case of eyelid dermatitis with scaly, itchy skin causing intense rubbing and scratching. Most often patients have dermatitis or eczema on other parts of their body with associated other systemic conditions such as asthma, hay fever and allergies.

The most common cause of eyelid dermatitis is contact dermatitis, seen in 74% of cases. Dermatologists conducted a study to determine the length of time it takes before a patient who had contact dermatitis or eyelid dermatitis received the correct diagnosis. The study found that the average time for the correct diagnosis was seven years. During this time patients often seek help from multiple specialties such as general medicine, dermatology, ophthalmology, and optometry. With regard to treatment, some practitioners suggest an antibiotic steroid - tobramycin and dexamethasone ophthalmic (Tobradex®, Alcon Canada, Mississauga, ON); however, the skin has already been made more sensitive due to the inflammation, so adding an antibiotic is not advisable. Ideally, pointed out Dr. Ng, the treatment of choice would be an immunomodulating agent such as tacrolimus topical ointment (Protopic®, Astellas Pharma Canada, Markham, ON) and pimecrolimus cream, 1% (Elidel®, Valeant Canada, Laval, QC). These are preferred treatments because they don't cause skin atrophy. Fluorinated steroids thin the skin, stated Dr. Ng. He stated that physicians should be mindful of the fact that some patients will have access to fluorinated steroid creams and ointments prescribed by their family physician

The Inflammation Game: Unlocking the Enigma of the Inflamed Eye — Ng, Le

“Swollen Lids”

Fig. 2 Eyelid contact dermatitis.

“Peek a Boo”

Fig. 3 Nonspecific episcleritis

Table I Episcleritis vs Scleritis Diagnostics

Episcleritis

Scleritis

Incidence

41 / 100 000 / Year

3.4 / 100 000 / Year

Phenylephrine 2.5 % Test

Blanch Significantly

Minimal Blanching

Location

Focal: Simple or Nodular Anterior & Posterior Forms

Less Focal

Colour

Bright Red

Deeper Purple Red

Pain

+++ Often Deep Radiating

Age

Younger

Older: 4-6th Decade

Systemic Involvement

+++

Onset Days

More Acute: 1-2 days

Gradual over several

Sight Threatening

++++

Approx. 50%

for other areas of their body, and will self-treat their eyelid areas. The steroid absorption rate depends on the thickness of the skin. Eyelid skin is extremely thin, with a high absorption rate around 30% to 40% compared to other parts of the body. For example, steroid absorption in the forearm is about 1% and the palms of the hand is 0.1%. Steroids arrest keratinocyte proliferation, collagen synthesis, and inhibition of fibroblasts and hyaluron enzymes. This in turn causes thinning of the skin. A small animal study comparing loteprednol against betamethasone (a potent steroid) and hydrocortisone (a mild steroid) showed that loteprednol did not produce statistical thinning of the skin. Products other than OTC hydrocortisone are available for lid inflammation. Loteprednol etabonate ophthalmic ointment 0.5% (Lotemax®, Bausch & Lomb, Vaughan, ON) is now available, which has minimal to no skin atrophy. This allows practitioners to manage eyelid contact dermatitis quickly and effectively. Dr. Ng stated that loteprednol etabonate ophthalmic ointment bid for

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4-5 days is usually all that is needed to manage most cases of eyelid contact dermatitis. Once the eyelid swelling is eliminated one should discontinue the steroid and switch to a daily application of a hypoallergenic facial cream. Case #3 Mr. R. presented with a red, painful left eye with photophobia for which he was taking Tylenol for the pain (Fig. 3). He reported similar episodes in the past. He had a routine eye exam 6 months previous and reported that his eye health was normal. The diagnosis of nonspecific episcleritis was made and Dr. Ng prescribed loteprednol 0.5% susp Q2H for three days then QID for five days. At the one-week follow-up, the patient had no more pain nor light sensitivity, however the eye redness had minimal improvement compared to the initial presentation. The patient was told to continue Lotemax QID and Maxidex ung HS was added for two weeks. At the two-week follow-up, the patient had total resolution and blood work obtained from his family physician was negative for any inflammatory markers. The eye redness was more sectoral and was more indicative of episcleritis than scleritis (Table I). Dr. Ng noted that the data states it is roughly ten times more likely to be episcleritis. However, episcleritis is benign, whereas scleritis is actually sight-threatening, so knowing the differences is very critical. In each of the preceding cases, steroids were an essential component of the successful treatments, which brings up the question of how safe are steroids. At this point the audience was polled on their greatest concerns about the use of topical ophthalmic steroids in general. Of the three main side effects typically associated with steroids (elevated IOP/steroid-induced glaucoma, infection i.e., HSK, and cataract) the majority of respondents indicated IOP elevation was their chief concern. Dr. Ng and Dr. Le then discussed the relative risks of steroids and IOP elevation. It was noted that the older

Slit Lamp

48 Hr Follow Up

Limbal

Updated Treatment Protocol

Fig. 4 (A) Corneal abrasion with severe confluent SPK. (B) Corneas 48 hours after initiating treatment (C) Effects of limbal keratoconjunctivitis. (D) Suggested treatment protocol for vernal keratoconjunctivitis.

ketone-based steroids are more prone to causing IOP spikes, whereas the newer ester-based ones are much less likely to do so. Dr. Mansour Armaly’s 1965 study using dexamethasone 0.1% dosed three times a day for roughly four weeks showed that the vast majority of patients, 66%, had no intraocular pressure response at all. Any rise in pressure would manifest within two weeks, which gave rise to the two-week rule with which most practitioners are familiar. Approximately one-third of the subjects had a moderate increase in IOP somewhere between 6 mm and 10 mm. However, a very small subgroup, roughly 5%, were very high responders, with an increase in IOP greater than 16 mm. Dr. Gary Novack did a study in 1998 comparing IOP response of loteprednol (0.5% and 0.2%) and Pred Forte® (prednisolone acetate ophthalmic suspension, USP, 1%, Allergan Canada, Unionville, ON) over a four-week

period. A significant response was any rise in IOP greater than 10 mmHg over baseline. Only 1.7% of subjects on loteprednol 0.5% (Lotemax) had increased IOP over 10 mm after one month, compared to 6.7% of subjects on Pred Forte. With the lower dose of loteprednol 0.2%, only 0.8%, showed an increase versus the 0.7% placebo group. This was a rigorously controlled double-blind randomized trial, demonstrating that risk of an IOP increase was significantly lower with the ester-based loteprednol than the ketone-based Pred Forte. As a result, Dr. Le and Dr. Ng stressed that all steroids can safely be used as long as necessary for disease management with careful monitoring for the IOP responders. Even for the responders or those requiring long-term steroid therapy it may be possible to treat with loteprednol 0.2% due to the exceptionally low response rate that was essentially equivalent to placebo.

The Inflammation Game: Unlocking the Enigma of the Inflamed Eye — Ng, Le

Slit Lamp Findings

Fig. 5 Slit lamp revealed 3++ fine KPs

Case #4 A 19-year-old Asian male presented to Dr. Le’s office having been diagnosed with corneal abrasion in the right eye at another eye doctor's office. He reported having had a similar occurrence in his left eye in the previous month. He was treated both times with gatifloxacin ophthalmic solution, 0.3% (Zymar®, Allergan Canada, Unionville, ON) for two weeks. He now returned with his third occurrence in the past month with severe left eye pain and blurring which are now causing headaches. Slit lamp examination showed severe confluent SPK, particularly in the left eye (Fig. 4A). Severe upper lid follicles/papillae were present, with a copious mucoid discharge, much worse in the left eye. After being shown Figure 4, the audience was polled and asked what treatment they would recommend. The majority of respondents choose loteprednol 0.5% susp. Dr. Le then outlined the actual treatment used. The patient was started on loteprednol 0.5% susp every two hours for two days, in addition to loteprednol 0.5% ung overnight, along with non-preserved artificial tears every hour while awake, cold compresses, and counselled to avoid rubbing the eyes. As the patient’s corneas were quite severely compromised, Dr. Le elected to follow up in 48 hours. At the follow-up appointment, the patient reported good compliance with loteprednol susp and nonpreserved artificial tears, but had not yet begun use of the ointment as it was not in stock at his local pharmacy. Slit lamp exam showed remarkable improvement compared to his initial visit (Fig. 4B). The patient had an excellent response to the Lotemax suspension alone. Treatment was tapered to three times a day for two weeks, and then two times a day for another 2 weeks. The Lotemax ointment at night was continued. At one-month follow-up, his left eye had cleared up and returned to baseline. The presentation and clinical findings in this case were consistent with vernal keratoconjunctivitis or vernal keratoconjunctivitis (VKC), a rare form of

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severe ocular allergy. It affects both eyes but it can be asymmetrical, and can have a chronic course than can last for years. Onset is usually in a younger age group, around puberty, typically peaking between 11 and 13 years of age. It rarely occurs over age 20, which made the diagnosis challenging in this case. Nearly 75% of these cases occur in males, with a 50% family history association of atopic disease. Three main forms of VKC (limbal, tarsal and mixed with elements of both) were discussed. The tarsal form produces giant papillae, greater than 1 mm in diameter, typically on the upper lids. The limbal form has a few different characteristics, mostly centered on the limbus, including infiltrates, Trantas dots and elevation of the limbus (Fig. 4C). Dr. Le cited the following quotation: “The chronic nature of the disease makes VKC potentially devastating to its sufferers and can lead to corneal ulcers, keratoconus and permanent visual impairment without aggressive, long term therapy.” Abelson, MB, McLaughlin, J. VKC and the Allergy Rogues Gallery. Review of Ophthalmology Feb. 2012: 80-83. Revophth.com. The clinical signs of VKC include corneal changes ranging from mild SPK to shield ulcers; conjunctival hyperemia, chemosis and a ropey, stringy mucous or serous discharge may be present. Clinical symptoms include severe itching, foreign body sensation, photophobia, and morning misery. In Dr. Le’s case, very little itching and more foreign body sensation was reported by the patient which made the diagnosis more difficult. Dr. Le then outlined some suggested treatment protocols (Fig. 4D), emphasizing that these protocols were more of a guideline and that there is an art to treatment as with most disease management. In this case, due to this patient’s presentation, Dr. Le used a modified limbal protocol, which involved more aggressive and prolonged treatment rather than the palpebral VKC protocol. Case #5 The final case of the meeting involved a 36-year-old male who presented with acute onset of redness and blurred vision in the right eye a week earlier. The left eye then became “blurred” 2 days earlier. The patient initially sought treatment with his family physician who prescribed moxifloxacin (Vigamox® Alcon Canada, Mississauga, ON) a day earlier. He then presented to Dr. Le because his condition continued to deteriorate with increased “clouding” of vision, worsening in bright light and persistent throbbing ocular pain for which he was taking Aleve. He did not initially report any previous medical history but later noted back pain that was attributed to a musculoskeletal injury. His best-corrected visual acuity was slightly diminished at 6/12 (20/40) OD, 6/12 (20/30) OS. His pupils, motility and DFE appeared to be normal. Slit lamp revealed 3++ fine KPs OU and moderate circumlimbal flush (Fig. 5). No flare was present, but the patient had

inferior synechiae in his left eye. His IOP was slightly asymmetrical: slightly higher on the right than on the left. Based on the findings, Dr. Le diagnosed bilateral anterior uveitis or iritis. Dr. Le then polled the attendees on their treatment of choice and the consensus among respondents was aggressive treatment with a potent steroid – in this case Pred Forte used hourly to start. This was a case of anterior non-granulomatous uveitis, a non-infectious inflammation of the iris and ciliary body. It is relatively rare with 8 per 100,000 incidence in the U.S. annually. More than half of cases have an idiopathic etiology. Of the remaining 30% to 50% of cases, the next most common cause of uveitis is the HLA B27 family of diseases. This includes ankylosing spondylitis, reactive arthritis and inflammatory bowel disease. These conditions, along with sarcoidosis and syphilis should be ruled out if the iritis is recurrent or bilateral. Dr. Le then discussed three major problems associated with untreated iritis: posterior synechiae, peripheral anterior synechiae and CME, and stressed the need for aggressive treatment in order to stop their progression. Posterior synechiae leads to pupil block; peripheral anterior synechiae leads to angle closure, and CME will result in central vision loss. Dr. Le stated that the first course of action is to treat with the strongest steroid available to optometrists locally. In Ontario the drug of choice would be Pred Forte. However, Dr. Le noted some evidence to suggest that Lotemax gel may be as effective as Pred Forte mainly because of dose uniformity. Given its favourable side effect profile it can be used as a substitute for Pred Forte. At the time of the meeting, Lotemax gel was not yet available in Ontario but Dr. Le mentioned that he was looking forward to testing it for himself. Dr. Le then discussed recommended treatment protocols with aggressive pulse dosing initially and tapering slowly, beginning when a 2 grade improvement in symptoms are observed. Steroid ointment was suggested as an adjunct for overnight coverage which could potentially shorten the treatment course. Special emphasis was placed on treatment until the condition had completely resolved as some forms of uveitis (for example, HLA-B27) can have a mean duration of attacks of up to six weeks. Should the condition not begin to resolve within a few weeks, reassessment may be necessary and additional medication may be needed. When treating for such a long period of time, IOP has to be monitored, but treatment does need to continue for as long as necessary to prevent long-term complications and relapses. Dr. Le also discussed the importance of tapering the medication very gradually, particularly if the patient has been on a long

course of therapy. An example of the final stages of a taper was given to illustrate the concept of a more gradual discontinuation, with a dosing schedule of TID for five days, BID for 4-5 days, then QD for four or five days with careful monitoring for rebound inflammation. Dr. Le outlined the actual treatment for his case. In addition to Pred Forte q1h, Dr. Le added Maxidex® ophthalmic ung qhs (dexamethasone, Alcon Canada, Mississauga, ON) and recommended cyclopentolate for cycloplegia. Homatropine is a better cycloplegic, but Dr. Le mentioned previous difficulty with obtaining it locally as the reason for choosing cyclopentolate. Cycloplegia is very useful as it prevents posterior synechiae and increases patient comfort. For cases with more severe inflammation, an oral NSAID may be added for additional anti-inflammatory activity. Due to the bilateral presentation and additional symptoms (back pain), Dr. Le also advised a work-up with the patient’s family physician to rule out HLA-B27 conditions and scheduled a follow up in 72 hours. At the next follow-up the patient reported significant improvement in comfort and redness, although the right eye remained significantly blurred. Dr. Le observed a 1-step reduction in KPs OU and resolution of the posterior synechiae OS without the use of cyclopentolate as the patient had not yet been able to obtain it. At this point, Dr. Le elected to continue the tapering schedule without the cyloplegia and to continue the oral NSAID (Aleve). At follow-up Day 9, the patient reported almost complete resolution of his back pain. The KPs had completely resolved OU, but the right eye remained slightly blurry, with a +0.75 DS needed to achieve 6/6 (20/20). In hindsight, Dr. Le mentioned that Optical Coherence Tomography to check for cystoid macular edema would have been helpful as the vision was reduced slightly in the right eye. The patient was given instructions for a final taper and asked to return if his symptoms worsened again.

CONCLUSION All of these cases involved inflammatory disease ranging from very common to less common conditions that can present to the primary care optometrist. Often these patients have been treated elsewhere unsuccessfully before arriving in the optometrist’s office. In all cases a rapid resolution was achieved once the correct diagnosis was made and management was initiated. These cases highlight the utility of topical ophthalmic steroids and the important role of optometrists in the diagnosis, treatment and management of a wide range of inflammatory conditions in a primary care setting. ❏

The Inflammation Game: Unlocking the Enigma of the Inflamed Eye — Ng, Le

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QUESTIONNAIRE The Inflammation Game: Unlocking the Enigma of the Inflamed Eye David Ng, OD; Duc Le, OD 1. ❑ ❑ ❑ ❑

For patients on steroids, how frequently does Dr. Ng monitor IOP? Every week Every two weeks Every three weeks Every four weeks

2. ❑ ❑ ❑ ❑

Contact dermatitis is seen in what percentage of patients with eyelid dermatitis? 27% 43% 64% 74%

What is the average length of time it takes before a patient with contact dermatitis or eyelid dermatitis to receive the correct diagnosis? Three years Four years Six years Seven years

❑ ❑ ❑ ❑

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What is the absorption rate for eyelid skin? 20% to 30% 30% to 40% 40% to 50% 60%

5. ❑ ❑ ❑ ❑

All of the following are side effects of topical ophthalmic steroids, EXCEPT: Ocular edema Elevated IOP Infection Cataract

6. ❑ ❑ ❑ ❑

All of the following statements about vernal keratoconjunctivitis (VKC) are true, EXCEPT: In the chronic form, it can last for years It is asymmetrical in the majority of cases The majority of cases appear in males It rarely occurs over age 20

7. ❑ ❑ ❑ ❑

Clinical symptoms of VKC include all of the following, EXCEPT: Photophobia Foreign body sensation Severe itching Ocular redness

8. ❑ ❑ ❑ ❑

The patient in Case #5 presented with all of the following symptoms, EXCEPT: Migraine Persistent throbbing ocular pain Blurred vision Acute onset of redness

9. ❑ ❑ ❑ ❑

Episcleritis occurs more commonly than scleritis, by what percentage? Two times Five times Ten times Fifteen times

10. ❑ ❑ ❑ ❑

In Case #4, the patient had all of the following clinical signs and symptoms, EXCEPT: Severe left eye pain Foreign body sensation Blurring in the left eye Mucoid discharge

26:3,15

4. ❑ ❑ ❑ ❑

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care — Maharaj

CLICK HERE TO PRINT THIS CE CREDIT ARTICLE AND TEST

Clinical & Refractive Optometry: Online Edition is pleased to present this continuing education (CE) article by Dr. Amiee Ho and Dr. Pauline F. Ilsen entitled A Comprehensive Review of Diabetic Keratopathy. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 108 for complete instructions.

A Comprehensive Review of Diabetic Keratopathy Amiee Ho, OD; Pauline F. Ilsen, OD

ABSTRACT Background: Diabetes can affect almost all structures of the eye, particularly the cornea, causing a condition known as diabetic keratopathy. Diabetic keratopathy stems from chronic hyperglycemia due to the abnormal glucose metabolism of diabetic patients. It involves all layers of the cornea including corneal nerves and the pre-corneal tear film. Excess glucose circulating in the tear film changes the tear composition and chemistry. Chronically, tear film abnormalities contribute to the development of ocular surface defects, cornea neuropathy, and lacrimal gland damage. The combination of excess glucose and amino acids produce advance glycation end products which deposits in the epithelium resulting in changes in epithelial cell morphology and basement membrane. Stromal damage is rare but there are cases reported. Alterations in endothelial cell morphology and permeability are observed, along with wrinkling of Descemet’s membrane. Finally, corneal neuropathy secondary to chronically elevated glucose leads to decreased corneal sensitivity which paves the way for the development of various degrees of diabetic neurotrophic keratopathy. Traditional and new treatments are discussed, as well as risk factors, differentials, and complications. The aim of this paper is to provide a comprehensive overview of potential corneal findings that have been observed in patients with diabetes. Conclusion: It is important for clinicians to be conscious that diabetes can lead to corneal disease. Diabetic keratopathy is hypothesized to be a highly prevalent A. Ho — Resident, West Los Angeles VA Healthcare Center, Los Angeles, CA; P.F. Ilsen — Professor, Southern California College of Optometry, Los Angeles, CA Correspondence to: Dr. Pauline F. Ilsen, Marshall B. Ketchum University, West Los Angeles Veterans Affairs Healthcare Center, Optometry Clinic (123) Bldg. 304, Room 2-123, 11301 Wilshire Blvd., Los Angeles, CA 90073; E-mail: Pauline.Ilsen@va.gov This article has been peer reviewed.

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condition but manifestations are frequently under recognized and under diagnosed. More awareness of DK can help clinicians address, manage and treat diabetic patients appropriately during routine comprehensive diabetic eye examinations.

INTRODUCTION Diabetic keratopathy (DK) was observed as early as 1858 by a French physician, Francois, who noted corneal and anterior segment abnormalities in diabetic mellitus (DM) patients. He observed that wound healing was delayed and there was an increased risk of ocular infection with this population.1 Reports of this kind were scattered and isolated until 1967 when Collier published a comprehensive review article in attempts to focus on corneal pathology in diabetic patients. His emphasis was, however, on whether or not pathopneumonic forms of keratopathy existed and if they did, what signs can be used as an early diagnostic indication of diabetes.2 In 1981, Richard Schultz published Diabetic Keratopathy which was the first paper to focus on corneal abnormalities reported through clinical observations in diabetic patients examined through a two-year period of time.3 This landmark article paved the way for the plethora of research interest and growing clinical awareness of this disease. It is believed that there is a high incidence of DK but it is rarely diagnosed4 and largely underreported.5 An estimation of 1/36,7 to 47% to 64%3 of all diabetic patients have some form of DK. One study claims that 2/3 of all DM patients, at minimum, have some form of corneal epithelial lesions alone.6 Because DK is largely not considered serious or pathological it is mostly overlooked.5 In addition, it is often difficult to confirm that corneal changes are solely due to diabetes and not another disease process.5 Therefore, epidemiological estimations tend to vary and have large ranges. A summary of ocular manifestations of diabetic keratopathy is presented in Table I.

REVIEW OF CORNEAL ANATOMY The cornea is an avascular tissue that is highly organized and very precisely arranged, dedicated to refracting and transmitting light. It is subdivided into three basic layers and two membranes: epithelium, Bowman’s layer, stroma,

Table I Ocular manifestations of diabetic keratopathy • Decrease tear break up time (TBUT) • Symptomatic dry eyes • Decreased • Epithelial defects • Superficial punctate keratitis • Persistent epithelial erosion/defects • Lacrimal gland damage • Decreased tear production/lacrimation • Decreased reflex tearing • Abnormal Schirmer test • Reduction in blink rate • Less inclined to use artificial tears • Decreased corneal healing/wound repair • Delayed re-epitheliazation • Increased epithelial fragility • Decreased corneal sensitivity • Epithelial edema

• Stromal edema • Endothelial edema • Recurrent corneal erosion • Increase risk of infection • Reduction in corneal transparency • Transient stroma edema • Corneal lattice degeneration • Various forms of keratitis • Stromal ulceration (rare) • Stromal melting (rare) • Stromal perforation (rare) • Stromal scarring (rare) • Polymegathism • Pleomorphism • Wrinkling of descemet’s membrane • Diabetic neurotrophic keratopathy • Blurry vision

Descemet’s membrane and endothelium.8 In addition, the pre-corneal tear film and the epithelial basement membrane are also equally important contributors to maintaining corneal integrity. Each layer has its own critical role in maintaining structure and function. Diabetes can disrupt the delicate balance of all the layers. Corneal defects secondary to diabetes will be dissected and discussed in the following subsequent sections. Recent developments have discovered a new corneal layer, Dua’s layer.9 Much is unknown about this layer, especially how diabetes affects it, therefore, for simplicity sake, it will not be discussed in this paper.

THE PRE-CORNEAL TEAR FILM Although the tear film is not part of the cornea, it has an undeniable value in maintaining a healthy corneal epithelium.10 It functions as a smooth ocular surface and serves as the first barrier against foreign substances.11 Therefore, it plays an integral role in the susceptibility of developing diabetic keratoepitheliopathy. The pre-corneal tear film is comprised of an intricate balance of multiple biochemical components with intertwining interactions that are still not completely understood. Current research supports the idea that the tear film is more of a mixture rather than the traditionally hypothesized segregation of layers.10 To simplify the discussion for the purpose of this paper, the tear film will be considered separate entities as the lipid, aqueous and mucin layers. The superficial lipid layer functions to prevent pre-mature evaporation, providing tear film stability. Immediately beneath is the thick aqueous layer which “consists of water, electrolytes, proteins, peptide growth factors, immunoglobulins, cytokines, vitamins, antimicrobials, and hormones secreted by the lacrimal

glands.”12,13 These components help the tear film maintain constant pH, proper osmolarity,14,15 defend against infection via microbes,16 stimulate wound healing and immune modulation,17,18 and provide protection against reactive oxygen species.11,16 A thin mucin layer is sandwiched between the cornea and the aqueous layer which helps attach the hydrophilic aqueous layer to the hydrophobic epithelial cells of the cornea.19,20 Common diabetic complications like hyperglycemia and diabetic neuropathy both contribute to tear film abnormalities. Hyperglycemia and Tear Film Hyperglycemia causes excess glucose to deposit in tears, changing tear film composition and chemistry.21-23 Studies have determined non-uniform lipid layer21 and significant goblet cell loss22,23 as the most significant byproducts of having an abnormal tear composition and chemistry. A healthy lipid layer is able to reduce the rate of evaporation by 90% to 95%, therefore, any reduction in thickness can cause evaporative dry eye, dry eye symptoms10 and a reduced tear break up time (TBUT).21,22,24-26 In a study with Seifart et al, “tear break up time in nearly all diabetics tested was found to be less than 10 seconds, a finding only seen in 5.8% of controls.”24 Moreover, because of profound goblet cell loss, mucin, a key component of the tear film that helps “facilitate tear spreading and stability,” is reduced.22,23 Both lipid and mucin disruptions play a role in the reduction of TBUT in diabetic eyes.22 When the delicate balance of the tear film is altered, the quality of the tear film decreases which reduces tear stability and its inherent ability to coat the epithelial layer.22,23,24,27 With time this can cause ocular discomfort and epithelial disease.25 Depending on the severity, epithelial defects compromise the healing ability of the cornea.26 Studies have found a correlation between lower TBUT values and “peripheral neuropathy and poorly controlled disease.”22 Diabetic Neuropathy and Tear Film Peripheral neuropathy is a common complication in DM patients. Corneal nerves are considered a peripheral nerve. Corneal neuropathy leads to DK, therefore DK is a manifestation of peripheral neuropathy.28 Patients who develop DK secondary to neuropathy have decreased corneal sensitivity. Corneal sensation plays a critical role in instigating awareness of desiccation. When signals are dampened due to neuropathy, patients are not cognizant of any ocular surface dryness issues (Fig. 1). This insensitivity has negative impact on reflex tearing23,29 and produces tear secretion abnormalities.26,30-33 Even a minute decrease in sensitivity is enough to significantly reduce reflex tearing.29 Other studies have found a reduction in blink rate,25 a decrease in lacrimation,22,26,29,30,34-42 and even less of a tendency to use artificial tears.43 In addition,

A Comprehensive Review of Diabetic Keratopathy — Ho, Ilsen

Diabetes Mellitus Diabetic neuropathy

Hyperglycemia

Corneal sensitivity

Changes in tear composition/chemistry Non-uniform lipid

Goblet cell loss

TBUT

Tear spreading/stability

Reflex tearing/lacrimation Tear secretion abnormalities Blink rate

Evaporative dry eye Dry eye symptoms Epithelial disease Compromised/Delayed healing

Use of ATs Damage to lacrimal gland (chronic)

Fig. 1 Proposed mechanism for the development of evaporative dry eye in diabetes mellitus

Diabetes Mellitus Hyperglycemia Sugar + Amino acis

}

Maillard Reaction (High heat)

Advanced Glycation End (AGE) Product Deposits in epithelium Changes in epithelial cells & basement membrane Diabetic Keratoepitheliopathy Fig. 2 Proposed mechanism for the development of diabetic keratoepitheliopathy

“longstanding disease may cause damage to the microvascular supply to the lacrimal gland, impairing lacrimation.”44 Studies that assessed tear secretion with the Schirmer test reported “diminished wetting”22,37 while a few studies that that used the Cotton Thread test have found no difference in tear secretion21,37 and also reported normal TBUT values.37 Further research must be conducted to support or deny these findings. Corneal neuropathy will be discussed more extensively in the corneal neuropathy section.

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Corneal Epithelium The corneal epithelium is the first protective tissue barrier from foreign objects and organisms along with resisting exchange of fluids from the outside world to the deeper corneal layers.38,45 The epithelium is comprised of 5 to 7 layers that sit on top of a basement membrane. The top 2 to 3 layers are known as the superficial cells that are comprised of flattened squamous cells held together by tight junctions. Immediately beneath are 2 to 3 layers of polyhedral cells, also known as the wing cells. Both these layers sit on top of the basal epithelium, which are comprised of a single layer of columnar cells. Together, the three different layers securely rest on top of the basement membrane via hemidesmosomes.8 DK affects epithelial cell morphology and causes disruptions to the basement membrane. The Maillard reaction secondary to hyperglycemia is the main mechanism responsible for these epithelial changes.5,26,33,40,46-56 Maillard Reaction and Epithelium Excess sugar molecules bind with amino acids, which are naturally found in our bodies, and in a non-enzymatic reaction, purely under high heat, these two molecules undergo the Maillard reaction to produce advanced glycation end (AGE) products (Fig. 2). A study conducted by Zou et al. discovered that AGE products were observed through all layers of the cornea but were most concentrated in the epithelial layers and decreased in more posterior layers. A suggested theory proposes that the metabolism of the avascular cornea primarily depends on the aqueous humor. “Therefore, AGEs could be cleared more easily in the posterior than in the anterior part of the cornea because the posterior part is next to the aqueous humor.”57 Moreover, another study found a higher expression of AGE productions, AGE receptors, and transcription factor

CORNEAL STROMA

Diabetes Mellitus Hyperglycemia Glucose Glycolysis

Aldose Reductase

Krebs Cycle

Sorbitol

ETC

Overhydrate Endo Cell Endo Swell Slow down Krebs Cycle ATP Endo Pump Morphological Permeability Changes Changes

Fig. 3 Proposed steps in the development of corneal endothelial dysfunction in diabetes mellitus

nuclear factor kappa-B (NF-kB) in the lacrimal glands which produce tears bathing the epithelium.58 These findings suggest AGE product deposition is most detrimental and localized to more anterior corneal structures like the epithelium and the basement membrane. AGE product deposition in the epithelium causes abnormalities in cell shape40,46-50 and structure.5,51-53 In addition to epithelial damage, excess AGE deposition creates a hypertonic basement membrane causing increased fluid permeability and abnormal thickening.5,26,33,50-52,54-56 These abnormalities lead to hemidesmosome disruptions resulting in poor adhesion of regenerating epithelial cells to basal cells.26,31,33,40,51,55 A study by Tabatabay et al found a general reduction of hemidesmosomes in patients with diabetes compared to non-diabetic patients.54 Recurrent corneal erosion,3,26,50,59-62 slower wound repair,26,33,50 superficial punctate keratitis/persistent epithelial defects26,59,61 delayed re-epithelialization5 and increased epithelial fragility26,62 are commonly observed with diabetic patients. Moreover, AGE disruptions impair the defense properties and barrier functions of the epithelium,38,63,45 making it 5.4 times more permeable to water and ionic substances38 which ultimately causes epithelial edema.50,60 Weakened corneal defenses increase risk of developing corneal infections like fungal keratitis, which is more commonly reported in diabetic patients.64-66

Diabetic alterations to the corneal stroma are rare and have not been extensively studied. Some documented findings include: wide spaced stromal collagen fibril matrix which reduces corneal transparency,67,68 transient stromal edema, corneal lattice degeneration, various forms of keratitis.26 In extreme cases, stromal ulceration,34 melting, perforation and scarring62,69 have been reported. The potential mechanisms of these findings are unclear.

CORNEAL ENDOTHELIUM The endothelium is a thin single-celled layer that forms the barrier between the anterior chamber and Descemet’s membrane.8 “A major function of the corneal endothelium is to maintain corneal transparency by regulating corneal hydration” and creating a selective barrier for the passage of certain nutrients into the cornea.8,70,71 In order to accomplish these tasks, the endothelium must have the proper anatomic and metabolic support. The endothelial cell surface is extensively lined with microvilli, significantly increasing the surface area for a vast number of protein pumps that helps actively drive aqueous in or out of the cornea.70,72,73 In addition, the lateral endothelial cell-to-cell surfaces are held together by tight junctions which help establish a barrier against ions and aqueous. “Finally, ultrastructural analysis of endothelial cells show a lot of mitochondria which mean they are metabolically active.”8 Damage to endothelial morphology and permeability is observed with diabetics. As a result, corneal edema becomes a byproduct of endothelial dysfunction.26,59,61 Morphological Changes to Endothelium Normal glucose metablism begins with glycosis, then the Krebs cycle and finally the electron transport chain to ultimately produce ATP for energy. However, excess sugar over-saturates the normal pathway and instead, gets shunted into the sorbitol pathway. Glucose is reduced by the enzyme aldose reductase and produces sorbitol in excess. Sorbitol ends up depositing in the endothelial cells which osmotically draws in more solvent to quench the overabundance of solute, overhydrating the cells, causing swelling. Swelling slows down critical cellular metabolism, particularly the krebs cycle, consequently causing a drop in ATP. Endothelial pump function decreases as a result of the drop in ATP.74 Failure of pump function can lead to death of the cell, which decreases cell density.61,75-78 When endothelial cell density decreases, the existing cells change in shape (pleomorphism) and size (polymegathism) to cover the lost area.48,61,67,68,75,76,77 Permeability Changes to Endothelium With enough extensive decline in cell density to prompt pleomorphism and polymegathism, endothelial cellular pump function is jeopardized and endothelial permeability

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Stage 1 • Superficial/epithelial

Stage 2 • Epithelial breakdown

Stage 3 • Stromal involvement • Ulcer/melting/perforation Fig. 4 Proposed mechanism for the development of corneal stromal disease in diabetes mellitus

becomes compromised. Loss of the selective permeability function of the endothelium, allows aqueous from the anterior chamber to influx past the endothelium and into the stroma, leading to corneal edema (thickening) (Fig. 3).79-82 A study with Busted suggested that increased corneal thickness “may be one of the earliest changes detectable in the diabetic eye”79 and associated with “increased HbA1c and blood glucose levels, and severe retinal complications.79,80 One study even found a correlation between having diabetes for over 10 years and corneal thickening81 but findings are not confirmed at this point.79 Possibly due to the chronicity of endothelial damage and stromal swelling, wrinkling of Descemet’s membrane is commonly noted in diabetic patients, with a predilection to females.26,79,83,84 This phenomenon is commonly observed as a natural aging change but they seem to appear earlier in diabetics.84 “Wide spaced collagen fibrils in Descemet’s membrane” might also contribute to the wrinkling/decreased transparency of the corneal tissue.67,68

CORNEAL NEUROPATHY Corneal nerves originate from the ophthalmic division of the trigeminal nerve. It becomes the long posterior ciliary and anterior ciliary nerves, creates a limbal annulus and “enter the cornea in a radial pattern.”8 It transverses the anterior third of the stroma, parallel to the epithelium, eventually making a sharp 90 degree turn to pierce through bowman’s layer and into the epithelium to

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emerge with exposed naked free nerve endings. The cornea is “one of the most densely innervated tissues of the body.”8 Corneal nerves are a type of peripheral nerve tissue. Diabetes can develop peripheral neuropathy which involves corneal nerves, causing a decrease in corneal sensitivity.31 Corneal neuropathy secondary to diabetes or, neurotrophic keratopathy, is a “degenerative corneal disease characterized by impairment of corneal sensitivity associated with epithelial breakdown, deficiency in healing process leading to corneal ulceration, and subsequent vision loss.”62 Aside from hyperglycemia, diabetics also suffer from abnormal lipid composition; both conditions are deleterious to corneal sensitivity. Hyperglycemia and Corneal Sensitivity Excess glucose produces excess sorbitol which prevents the production of certain phospholipids critical for calcium ion channels to function, ultimately decreasing nerve conduction speed.21,85 In addition, sorbitol accumulates “within the lamellae of the Schwann cell [causing] eventual mechanical compressive or toxic damage to the axon”26,85 Finally, disarray and disorder of corneal nerve fibers due to abnormal blood sugar levels is also hypothesized to contribute to desensitization.6,26 Abnormal Lipid Composition and Corneal Sensitivity Abnormal lipid composition is theorized to “interfere with the normal maintenance of the myelin sheaths, ultimately leading to a partial demyelination of the nerve.”26,85 Demyelination leads to loss of corneal sensation.

DIABETIC NEUROTROPHIC KERATOPATHY Decreased corneal sensitivity is the gateway to developing diabetic neurotophic keratopathy. The mechanism starts with decreased corneal sensation which reduces the patient’s awareness of dryness and other corneal disorders. Chronic inattention to ocular surface desiccation limits the patient’s ability to remedy the problem. Aqueous, lipid and mucus production continue to decrease along with blink rate25 due to the dampened corneal sensation. As a result, various forms of epithelial defects begin to appear. With time, epithelial conditions worsen, and the damage reaches deeper layers of the epithelium as well as into the stroma and endothelial layers. Corneal infection, susceptibility to corneal trauma,34 decreased wound healing,86-89 ulceration34 and scarring are what lie at the end of this process.21,28,62,69 Diabetic neurotrophic keratopathy can present as three different stages (Fig. 4). Stage 1 is characterized by Rose Bengal staining of the palpebral conjunctiva, decreased tear break up time, and superficial punctuate keratitis. Chronic forms of stage 1 will present with superficial vascularization, stromal scarring, and epithelial

Diabetes Mellitus Abnormal lipid

Hyperglycemia Glucose Aldose Reductase

Disorder of corneal nerve fiber

Demyelination of nerve

Sorbitol Production of PL (ion channels)

Compressive/Toxic damage Corneal sensitivity

Conduction speed

Unaware of dryness Blink rate

Aqueous/lipid/mucin Epithelial defects

• Corneal infection/trauma • ↓ Wound healing • Corneal ulcers • Corneal scarring Fig. 5 Proposed contributions to reduced corneal sensitivity and its complications in diabetes mellitus

hyperplasia. Stage 2 includes epithelial break down (oval or circular), a hazy and edematous cornea with loose epithelial cells which poorly adhere to bowman’s layer and smooth, rolled edges of defect without epithelial growth. Stage 3 is the end stage, presenting with stromal involvement, ulceration, melting, perforation, and secondary infection. It is found that at this end stage, sometimes topical treatment, with antibiotics or steroids can increase the risk of a perforation.62,69 Studies by Rosenberg have found that “a reduction of long nerve fiber bundles was noted to have occurred already in patients with mild to moderate neuropathy” long before patients subjectively reported a reduction in sensitivity.90 Rosenberg further discovered “corneal mechanical sensitivity was reduced only in patients with severe neuropathy.”90 When highly sensitive instruments were used to assess corneal sensitivity, objective findings would precede subjective symptoms. These results suggest that clinicians should always consider DK with neuropathic potential and diabetic neurotrophic keratopathy for patients who develop unexplained corneal epithelial disease and ulcers.69 There is a correlation between diabetic polyneuropathy and keratopathy. Polyneuropathy dampens peripheral

sensation, involving corneal sensation.28,91 As corneal sensation decreases, epithelial, stromal and endothelial lesions begin to develop (Fig. 5). More severe corneal findings indicate a more severe case of keratopathy. Therefore, reduced corneal sensitivity is believed to be a symptom of polyneuropathy.3,22,23,25,29,36,37,90 By association, it can be assumed that corneal sensitivity is related to the diabetic severity, patients with cornea desensitization were reported to exhibit more severe retinopathy and to have longer disease duration.29,36

TREATMENT OPTIONS Standard Treatments The conventional treatments are based on the severity of the DK. Ultimately, the goal of treatment is to retain a well lubricated ocular surface to prevent desiccation. Any ocular surface compromise could lead to infections and ulcerations.62 For mild epitheliopathies, preservative free topical lubricants might suffice. For more advanced stages with presentation of recurrent corneal erosions or ulcerations, using a bandage contact lens, patching, tarsorrhaphy, or induced ptosis and construction of a conjunctival flap can

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Table II Treatment options for diabetic keratopathy Standard Treatments • Preservative free topical lubricants • Bandage contact lens • Patching • Tarsorrhaphy • Induced ptosis • Conjunctival flap • Topical antiobiotic • Topical steroid

New Treatments • Topical insulin-like growth factor-1 and substance P • Topical insulin • Topical nerve growth factor (NGF) • Opioid growth factor (OGF) • Aldose Reductase Inhibitors (ARI) • Oral nicergoline • Oral aminoguanidine • Oral goshajinkigan

be considered as options.62 Based on the severity of corneal compromise, a topical antibiotic and/or steroid treatment might help, but studies have found variable responses. Lockwood found no response with topical treatment69 while Hyndiuk found improvement.34 New Treatments Unlike the standard treatments, which target the signs and symptoms of DK, the new treatments for DK focus on the underlying mechanism and molecules that are responsible. Most of these treatments are still in their experimental phases and are not currently used in clinical practice. Only oral goshajinkigan is available for public use. Based on a variety of study outcomes, these new experimental treatments show an astounding prospect of hope to the future treatment of DK.62 Topical insulin-like growth factor-1 and substance P: Studies have found that concurrent use of a topical insulin-like growth factor-1 and substance P have synergistic effects on the cornea, promoting epithelial migration on donor organ corneal cultures.62,92 Clinical use of these peptides have demonstrated usefulness in the “prevention of superficial punctuate keratopathy in diabetic patients after cataract surgery”93 and have been shown to help “rapid epithelial resurfacing in patients with persistent corneal epithelial defects.”94 Topical insulin: Studies have shown that instilling topical insulin on ocular surfaces “stimulates hepatotatic migration of human epidermal keratinocytes”95 which in turn aids in healing ulcers94,96 and burns.97 Topical Nerve Growth Factor (NGF): NGF has been found to “promote survival and growth of sympathetic and sensory neurons and differentiation of neurons in the central nervous system.”98 In addition, NGF also has an influence on the immune system,99 studies have found NGF active in controlling ocular inflammation and “corneal epithelial proliferation and differentiation.”62 According to a study with Bonini et al, NGF drops “improved corneal sensitivity and promoted corneal epithelial healing,” in addition to improving visual acuity and “healing of corneal ulcers” in eyes with “both moderate and sever neurotrophic keratitis within 12 to 42 days of NGF treatment.”100

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Opioid growth factor (OGF): OGFs “has been identified in both eukaryotes and prokaryotes as a potent inhibitor of cell replication.101-103 Zagon et al used naltrexone (OGF antagonists) on rabbit corneal epithelium cultures to show an increase in cell proliferation.104,105 Naltrexone has been shown to heal “corneal epithelial wounds in uncontrolled type 1 diabetic rodents at rates equal to or surpassing that in normal controls.”106 In addition, “naltrexone has been reported to be effective in normalizing tear production and corneal sensitivity in diabetic rats.”104,106 Aldose Reductase Inhibitors (ARI): “Aldose reductase (AR) is the rate-limiting enzyme in the polyol pathway in which glucose is converted to sorbitol.”26 Excess sorbitol deposits onto corneal epithelium, causing epithelial defects and abnormalities.26 Various studies used topical ARI’s on patients with diabetic keratopathy finding a reduction in “corneal changes after they have occurred, and [a limitation to] the development of these corneal changes when compared with untreated controls in both animals and humans.”26,107 Oral nicergoline: “Nicergoline is an ergoline derivative known to cross the blood-brain barrier and is now widely and safely used to treat cognitive impairment from stroke and degenerative dementia.”108,109 In addition, recent studies have also found that taking oral nicergoline for approximately 2 weeks have “increased corneal wound healing rate in 50 rat eyes.”110 Oral Aminoguanidine: Aminoguanidine is an antioxidant that studies have found to be “effective in inhibiting AGE formation” which, in turn, minimizes AGE product’s damaging deposition on corneal epithelium.5 Additionally, aminoguanidine “ameliorate[s] attachment of corneal epithelial cells to basement membrane” which reduces the occurrence of new/recurrent epithelial erosions, improves wound repair and decreases epithelial fragility.5 Oral Goshajinkigan: Goshajinkigan is a natural Chinese remedy which is composed of a mixture of crude extracts from 10 different herbs available in pill or powder form. Goshajinkigan is believed to have “aldose reductase inhibitor activity”111 and found to “improve ocular surface disorders in patients with insulin-dependent diabetes mellitus.”41 Table II provides a summary of the treatment options for diabetic keratopathy.

RISK FACTORS By default, patients with the diagnosis of diabetes mellitus are automatically at risk for developing neurotrophic keratopathy34,69 and “endothelial dysfunction that leads to increased corneal thickness.81 The duration of time a patient has diabetes is a risk factor for developing any sort of abnormal corneal sensitivity.26 In particular, having more than 5 years of insulin dependent type of

Table III Differential diagnosis of diabetic keratopathy Differential Diagnosis In General • Natural aging changes • Trauma • Extended contact lens wearer/abuse Epithelium • Dry eye syndrome • Superficial punctate keratitis • Autoimmune disorder

Stroma • Corneal stromal dystrophy • Corneal infection • Corneal scars • Corneal toxicity to medications or chemicals Endothelium • Guttata • Fuch’s endothelial dystrophy

diabetes mellitus is a risk factor for decreased epithelial nerve density and developing abnormal stromal nerve architecture, which paves the way for neurotrophic keratopathy.112 In addition, having poor control of diabetes puts the patient at risk for having abnormal corneal sensitivity, endothelial findings,26 and worsened dry eye symptoms.27,44 Moreover, later stages of diabetic retinopathy increases the risk for corneal epithelial fragility,32 abnormal corneal thickness (thicker in earlier stages of diabetes and becomes more thin as the disease progresses),81 severe reductions in tear secretion23 and abnormal corneal sensitivity.29,113 Finally, the severity of diabetic keratopathy becomes a risk factor for having an abnormal lipid layer and dry eye findings.21,63

DIFFERENTIAL DIAGNOSIS In general, it is unlikely that all corneal anomalies can be attributed purely to diabetic changes; rather, diabetes should be viewed as an additional contributing factor or risk factor in the development of corneal disease. Therefore, it is helpful to consider several differential diagnoses in order to properly diagnose, treat and manage patients (Table III). On the top list of differentials for general corneal abnormalities would be natural aging changes, trauma or extended contact lens wearer or abuse.26 These three differentials can account for a variety of corneal changes that might mimic diabetic keratopathy. When dissecting the corneal by layers, any tear film or epithelial irregularity can be attributed to dry eye problems, superficial punctate keratitis, or an autoimmune disorder. For endothelial irregularities, guttata or Fuch’s endothelial dystrophy must be considered. In terms of stromal changes, corneal sensitivity and neuropathy issues, various types of stromal dystrophies, corneal infections leaving stromal scars, and potential corneal toxicity to medications or chemicals should be ruled out.26,34,62,67-69

COMPLICATIONS Since DK leaves the cornea in a more fragile state, the cornea is more susceptible to ocular insults. Some

Table IV Ocular complications with diabetic keratopathy Surgical Cataract surgery • Delayed/poor healing • Corneal edema • Cloudy corneal epithelium • New/recurrent epithelial erosion • Corneal epitheliopathy • Superificial punctate keratitis • Persistent clinical corneal changes • Severely reduced tear break up time • Predisposition to bacterial and fungal infection LASIK • Poor refractive outcomes • Epithelial complications • Epithelial ingrowth • Neovascularization of iris and angle

Vitrectomy/PRP • Prolong/recurrent epithelial defects Trauma • Corneal abrasion • Deeper damage • Recurrent corneal erosion Contact Lenses • Microbial keratitis • Corneal ulcer • Ocular infection • Increased lens spoliation • Resistance to corneal edema • Non-resolving corneal edema

common ocular insults include ocular surgeries (i.e., cataract, LASIK, vitrectomies), trauma and contact lenses (Table IV). Cataract Surgery Post-ocular surgery patients with diabetes have a higher susceptibility to surgical stress and delayed healing,60 especially after cataract surgery.74 Some documented cases of post-cataract surgical complications include: corneal edema,5 cloudy corneal epithelium,5 poorly healing corneal epithelial surface,5 new/recurrent epithelial erosion,5,60 corneal epitheliopathy or superficial punctate keratitis,92 persistent clinical corneal changes,3 severely reduced tear break up time,114 predisposition to bacterial and fungal infections.5,62 LASIK The first study to report on the outcomes of LASIK on diabetic subjects found “poor refractive outcomes and epithelial complications in 47% of diabetic patients.”115 Fraufelder et al. theorized that having a pre-existing corneal condition, like DK, helps explain the high rate of complications. Other studies have reported increased frequency of epithelial ingrowth post-LASIK.115-119 Despite these alarming reports, another study conducted by Cobo-Soriano et al. found “no significant difference in refractive outcomes between diabetic patients and controls; only five diabetic patients out of 44 developed epithelial complications, all of which fully resolved without complication.”120 All the aforementioned studies failed to distinguish the rate of complications occurring among the well controlled diabetics verse the poorly controlled, which can account for the conflicting data. In a case report conducted by Ghanbari and Ahmadieh, LASIK was performed on a proliferative diabetic

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retinopathy (PDR) patient which resulted in extensive neovascularization of the iris and angle within 1 month post-surgery.121 In addition, a study with Halkiadakis et al performed LASIK on “24 tightly controlled diabetic patients. None of these patients displayed any significant epithelial complications and all ended up with a postoperative visual acuity (VA) of 20/20. The foregoing notwithstanding, 28% of these individuals ultimately required enhancements compared to 10% of non-diabetic patients.”122 Based on these reports, LASIK appears to be relatively safe in well controlled diabetics and highly contraindicated in patients with a history of PDR. Vitrectomy/PRP Several studies have found evidence to support corneal complications post-vitrectomy is more common among diabetic patients. A study with Foulks reported that nearly all of the 14 vitrectomy patients that exhibited some form of corneal complication had diabetes30 while another study with Perry found that 83% of patients were diabetic60 and yet another study with Brightbill found all subjects were diabetic.123 Not only is there an increase rate of corneal complications but “one study showed 9 of 13 with prolonged or recurrent epithelial defects30 while another reported that about a quarter exhibited prolonged or recurrent epithelial problems following surgery.”124 In addition, dry eye complaints were also more commonly reported post PRP (panretinal photocoagulation), “suggesting that damage to long cilicary nerves may occur during the procedure.22,27,125 Trauma Ocular insult in the form of corneal abrasions has been noted to cause more damage in diabetics vs non-diabetics.53 The abrasions are deeper, possibly due to the increased epithelial fragility62,126 leading to detachment of the basement membrane.53 Once the basement membrane is disrupted, this paves the way for recurrent corneal erosions to occur.3,26,50,59,60,61,62 Contact Lenses Many studies have found an increased risk of contact lens related complications with diabetic patients. Studies reported an increase incidence of contact lens related microbial keratitis in diabetics, which is even more prevalent in extended wearers.127,128 Another study showed that three out of the four aphakic patients with hydrogel lenses that ended up developing a corneal ulcer were diabetic.129 As mentioned earlier, there is an excess amount of glucose in the tear film21-23 that already disrupts tear function and corneal epithelium, adding a contact lens into the equation further complicates matters to increase the risk of ocular infection and “increased lens spoliation.”83 Finally, the combined results of two studies by O’Donnell and March concluded that “current daily wear contact lenses are a safe option for vision correction

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in diabetic patients” because the studies found no difference between contact lens induced complications between diabetics and non-diabetics wearing hydrogel daily soft contact lenses.130,131 Some studies discovered that diabetic corneas are more resistant to corneal edema under hypoxic conditions verses control subjects. This phenomenon is thought to occur “due to the effects of hyperglycemia on cornea hydration.”132-134 Additionally, in the case that the cornea does overcome the hyperglycemia to become edematous, due to abnormalities in corneal endothelium, diabetic patients do not as easily recover from contact lens induced corneal edema as compared to non-diabetics.126,132,133

CONCLUSION In summary, patients with diabetes have abnormal glucose metabolism which can affect all layers of the cornea, precorneal tear film and corneal nerve tissue. Depending on the extent and layers of corneal involvement, patients can experience a variety of symptoms like dry eyes, recurrent corneal erosion, slower wound healing, blurry vision, decreased corneal sensation and corneal neuropathy. Common signs that can be found in diabetic patients can include decreased TBUT, SPK staining, persistent epithelial erosion, corneal edema, stromal opacities/abnormalities, polymegathism and pleomorphism. Since corneal edema is potentially one of the earliest changes measurable in the diabetic eye and is often linked to increased HbA1C levels, increased blood glucose levels and severe retinal complications, including pachymetry as part of the comprehensive diabetic eye exam might be beneficial to both the patient and the clinician for disease management. Diabetic Keratopathy is a growing concern; therefore, it is important for eye care providers to scrutinize the cornea as diabetes can be a contributing factor to corneal disease. ❏

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Francois J, Brabandere J. Facteurs influencant la cicatrisation des plaies chirurgicales de la cornèe. Annèe thèrap et clin en Ophth IX, 1958, p. 1961. Collier MM. La pathologie cornèenne des diabètiques. Bull Soc Ophthalmol Fr 1967; 67: 105. Schultz RO, Van Horn DL, Peters MA, et al. Diabetic keratopathy. Trans Am Ophthalmol Soc LXXIX (1981): 180-199. Wylegala E, Mocko L, Woyna-Orlewicz A, Teper S, Orzechowska-Wylegala B. Diabetic complications within ocular surface. Polski Merkuriusz Lekarski 2006; 21(125): 495-497. Kaji Y. Prevention of diabetic keratopathy. Br J Ophthalmol 89 (2005): 254-255. Rao GN. Dr. P. Siva Reddy Oration: Diabetic Keratopathy. Indian J Ophthalmol 1987; 35(5-6): 16-36. Ioli-Spada G. Ulterior contributo allo studio della cherato distrofia epiteliale punctata diabetic. Boll Ocul 1964; 43: 775. Smolin G, Foster CS, Azar DT, Dohlman CH. Smolin and Thoft’s The Cornea: Scientific Foundations and Clinical Practice. Philadelphia: Lippincott Williams & Wilkins, 2005. Print. Dua HS, Faraj LA, Said DG, Gray T, Lowe J. Human Corneal Anatomy Redefined: A Novel Pre-Descemet’s Layer (Dua’s Layer). American Academy of Ophthalmology 2013; 120(9): 1778-1785.

10. Tasman, William, and Edward A. Jaeger. Duane’s Ophthalmology. Philadelphia, PA: Lippincott Williams & Wilkins, 2006. 11. Bron AJ, Tiffany JM, Gouveia SM, et al Functional aspects of the tear film lipid layer. Exp Eye Res 2004; 78: 367 12. Johnson ME, Murphy PJ. Changes in the tear film and ocular surface from dry eye syndrome. Prog Ret Eye Res 2004; 23: 449. 13. Holly FJ, Lemp MA. Tear physiology and dry eyes: Review. Surv Ophthalmol 1997; 22: 69. 14. Carney LG, Hill RM. Human tear pH. Diurnal variations. Arch Ophthalmol 1976; 94: 821. 15. Bachman WG, Wilson G. Essential ions for maintenance of the corneal epithelial surface. Invest Ophthalmol Vis Sci 1985; 26: 1484. 16. de Souza GA, Godoy LM, Mann M. Identification of 491 proteins in the tearfluid proteome reveals a large number of proteases and protease inhibitors. Genome Biol 2006; 7: R72. 17. Sommer A. Effects of vitamin A deficiency on the ocular surface. Ophthalmology 1983; 90: 592. 18. Schultz G, Khaw PT, Oxford K, et al. Growth factors and ocular wound healing. Eye 1994; 8: 184. 19. Argüeso P, Gipson IK. Epithelial mucins of the ocular surface: Structure, biosynthesis and function. Exp Eye Res 2001; 73: 281. 20. Argüeso P, Guzman-Aranguez A, Mantelli F, et al, Association of cell surface mucins with galectin-3 contributes to the ocular surface epithelial barrier. J Biol Chem 2009; 284: 23037. 21. Inoue K, Satoshi K, Ohara C, Numaga J, et al. Ocular and systemic factors relevant to diabetic keratoepitheliopathy. Cornea 2001 20(8): 798-801. 22. Dogru M, Katakami C, Inoue M. Tear function and ocular surface changes in noninsulin-dependent diabetes mellitus. Ophthalmology 2001; 108: 586-592. 23. Yoon KC, Im SK, Seo MA. Changes in tear film and ocular surface in diabetes mellitus. Korean J. Ophthalmology. 2004; 18: 168-174. 24. Seifart U, Strempel I. The dry eye and diabetes mellitus. Ophthalmologe. 1994; 91(2): 235-239. 25. Inoue K, Okugawa K, Amano S, et al. Blinking and superficial punctate keratopathy in patients with diabetes mellitus. Eye 2004; 19(4): 418-421. 26. Herse PR. A review of manifestations of diabetes mellitus in the anterior eye and cornea. Am J Optom Physiol Opt 1988; 65(3): 224-230. 27. Ozdemir M, Buyukbese MA, Cetinkaya A, Ozdemir G. Risk factors for ocular surface disorders in patients with diabetes mellitus. Diabetes Research and Clinical Practice 2003; 59: 195-199. 28. Schultz RO, Peters MA, Sobocinski K, Nassif K, Schultz KJ. Diabetic keratopathy as a manifestation of peripheral neuropathy. Am J Ophthalmol 1983; 96(3): 368-371. 29. Saito J, Enoki M, Hara M, et al. Correlation of corneal sensation, but not of basal or reflex tear secretion, with the stage of diabetic retinopathy. Cornea 2003: 22: 15-18. 30. Foulks GN, Thoft RA, Perry HD, Tolentino FI. Factors related to corneal epithelial complications after closed vitrectomy in diabetics. Arch Ophthalmol 1979; 97: 1076-1078. 31. Chung H, Tolentino FI, Cajita VN, Acosta J, Refojo MF. Re-evaluation of corneal complications after closed vitrectomy. Arch. Ophthalmol 1988; 106(7): 916-919. 32. Saini JS, Khandalavla B. Corneal epithelial fragility in diabetes mellitus. Can J Ophthalmol 1995; 30: 142-146. 33. Hatchell DL, Magolan JJ Jr, Besson MJ, Goldman AI, Pederson HJ, Schultz KJ. Damage to the epithelial basement membrane in the corneas of diabetic rabbits. Arch Ophthalmol 1983; 101: 469-471. 34. Hyndiuk RA, Kazarian EL, Schultz RO, Seideman S. Neurotrophic corneal ulcers in diabetes mellitus. Arch Ophthalmol 1977; 95: 2193-2196.

35. Morax V. Encycl fr Ophth IV, p 278, 1905. 36. Schwartz DE. Corneal sensitivity in diabetics. Am J Ophthalmol 1974; 91: 174. 37. Goebbels M. Tear secretion and tear film function in insulin dependent patients with diabetes. Br J Ophthalmol 2000; 84: 19-21. 38. Goebbels M, Spitznas M, Oldendoerp J. Impairment of corneal epithelial barrier function in diabetics. Graefes Arch Clin Exp Ophthalmol 1989; 227:142-144. 39. Stolwijk TR, van Best JA, Boot JP, Lemkes HHPJ, Oosterhuis JA. Corneal epithelial barrier function after oxybuprocaine provocation in diabetes. Invest Ophthalmol Vis Sci 1990; 31: 436-439. 40. Hosotani H, Ohashi Y, Yamada M, et al. Reversal of abnormal corneal epithelial cell morphologic characteristics and reduced corneal sensitivity in diabetic patients by aldose reductase inhibitor, CT-112. Am J Ophthalmol 1995; 119: 288-294. 41. Nagaki Y, Hayasaka S, Hayasaka Y, et al. Effects of goshajinkigan on corneal sensitivity, superificial punctate keratopathy and tear secretion in patients with insulin-dependent diabetes mellitus. Am J Chinese Med 2003; 31(1): 103-109. 42. Ishida N, Rao GN, del Cerro M, et al. Corneal nerve, alterations in diabetes mellitus. Arch Ophthalmol. 1984; 102: 1380-1384. 43. Nepp J, Abela C, Polzer I, Derbolav A, Wedrich A. Is there a correlation between the severity of diabetic retinopathy and keratoconjunctivitis sicca? Cornea 2000; 19(4): 487-491. 44. Kaiserman I, Kaiserman N, Nakar A, Vinker S. Dry eye in diabetic patients. Am J Ophthalmol 2005; 139: 498-503. 45. Gekka M, Miyato K, Nagai Y, et al. Corneal epithelial barrier function in diabetic patients. Cornea 2004; 23: 35-37. 46. Tsubota K, Yamada M. The effect of aldose reductase inhibitor on the corneal epithelium. Cornea 1993; 12: 161-162. 47. Meyer LA, Ubels JL, Edelhauser HF. Corneal endothelial morphology in the rat. Effects of aging, diabetes, and topical aldose reductase inhibitor treatment. Invest Ophthalmol Vis Sci 1988; 29: 940-948. 48. Matsuda M, Awata T, Ohashi Y, et al. The effects of aldose reductase inhibitor on the corneal endothelial morphology in diabetic rats. Curr Eye Res 1987; 6: 391-397. 49. Ohguro N, Matsuda M, Ohashi Y, et al. Topical aldose reductase inhibitor for correcting corneal endothelial changes in diabetic patients. Br J Ophthalmol 1995; 79: 1074-1077. 50. Sato E, Mori F, Igarashi S, et al. Corneal advanced glycation end product increase in patients with proliferative diabetic retinopathy. Diabetes Care 2001; 24(3): 479-482. 51. Azar DT, Spurr-Michaud SJ, Tisdale AS, et al. Altered epithelialbasement membrane interactions in diabetic corneas. Arch Ophthalmol 1992; 110: 537-540. 52. Taylor HR, Kimsey RA. Corneal epithelial basement membrane changes in diabetes. Invest Ophthalmol Vis Sci 1981; 20: 548-553. 53. Kenyon K, Wafai Z, Michels R, et al. Corneal basement membrane abnormality in diabetes mellitus. Invest Ophthalmol Vis Sci 1978; 17(suppl): 245. 54. Tabatabay CA, Bumbacher M, Baumgartner B, et al. Reduced number of hemidesmosomes in the corneal epithelium of diabetics with proliferative vitreoretinopathy. Graefes Arch Clin Exp Ophthalmol 1988; 226: 389-392. 55. Azar DT, Spurr-Michaud SJ, Tisdale AS, et al. Decreased penetration of anchoring fibrils into the diabetic stroma. A morphometric analysis. Arch Ophthalmol 1989; 107: 1520-1523. 56. Ljubimov AV, Huang Z, Huang GH, et al. Human corneal epithelial basement membrane and integrin alterations in diabetes and diabetic retinopathy. J Histochem Cytochem 1998; 46: 1033-1041. 57. Zou C. Advanced glycation end products and ultrastructural changes in corneas of long-term streptozotocin-induced diabetic monkeys. Cornea 2012; 31(12): 1455-1459.

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58. Alves M, Calegari VC, Cunha DA, Saad MJ, Velloso LA, Rocha EM. Increased expression of advanced glycation endproducts and their receptor, and activation of nuclear factor kappa-B in lacrimal glands of diabetic rats. Diabetologia 2005; 48: 2675-2681. 59. Owen CG, Newsom RSB, Rudnicka AR, Ellis TJ, Woodward G. Vascular response of the bulbar conjunctiva to diabetes and elevated blood pressure. Ophthalmology 2005; 112: 1801-1808. 60. Perry HD, Foulks GH, Thoft RA, et al. Corneal complications after closed vitrectomy through the pars plan vitrectomy. Arch Ophthalmol 1978; 96: 1401-1403. 61. Schultz RO, Matsuda M, Yee RW, et al. Corneal endothelial changes in Type I and Type II diabetes mellitus. Am J Ophthalmol 1984; 98(4): 401-410. 62. Abdelkader H, Patel DV, McGhee CNJ, Alany RG. New Therapeutic approaches in the treatment of diabetic keratopathy: a review. Clin Exp Ophthalmol 2011; 39: 259-270. 63. Yokoi N, Nhya A, Komuro A, et al. Effects of aldose reductase inhibitor CT-112 on the corneal epithelial barrier of galactose-fed rats. Curr Eye Res 1997; 16: 595-599. 64. Alfonso EC, Rosa RH, Jr. Fungal keratitis. In: Krachmer JH, Mannis MJ, Holland HJ, eds. Cornea. St. Louis: Mosby; 1997: 1253-1265. 65. Gapinathan U, Garg P, Fernandes M, Sharma S, Athmanathan S, Rao G. The epidemiological features and laboratory results of fungal keratitis. Cornea 2002; 21(6): 555-559. 66. Bharathi MJ, Ramakrishnan R, Vasu S, Meenakshi R, Palaniappan R. Epidemiological characteristics and laboratory diagnosis of fungal keratitis. A three-year study. Indian J Ophthalmol 2003; 51(4): 315-321. 67. Rehany U, Ishii Y, Lahav M, et al. Collagen pleomorphism in Descemetâ&#x20AC;&#x2122;s membrane of streptozotocin-induced diabetic rats: an electron microscopy study. Cornea. 2000; 19: 390-392. 68. Rehany U, Ishii Y, Lahav M, et al. Ultrastructural changes in corneas of diabetic patients: an electron-microscopy study. Cornea 2000; 19: 534-538. 69. Lockwood A, Hope-Ross M, Chell P. Neurotrophic keratopathy and diabetes mellitus. Eye 2006; 20: 837-839. 70. Maurice DM. The structure and transparency of the cornea. J Physiol (Lond) 1957; 136: 263. 71. Dikstein S, Maurice D. The metabolic basis to the fluid pump in the cornea. J Physiol (Lond) 1972; 221: 29-41. 72. Svedbergh B, Bill A. Scanning electron microscopic studies of the corneal endothelium in man and monkeys. Acta Ophthalmol (Copenh) 1972; 50: 321-336. 73. Hodson S, Miller F. The bicarbonate ion pump in the endothelium which regulates the hydration of rabbit cornea. J Physiol (Lond) 1976; 263: 563-577. 74. Choo MM, Prakash K, Soong T, et al. Corneal changes in Type II diabetes mellitus in malaysia. Int J Opthalmol 2010; 3(3): 234-236. 75. Roszkowska AM, Tringali CG, Colosi P, Squeri CA, Ferreri G. Corneal endothelium evaluation in type I and type II diabetes mellitus. Ophthalmologica 1999; 213(4): 258-261. 76. Inoue K, Kato S, Inoue Y, Amano S, Oshika T. The corneal endothelium and thickness in type II diabetes mellitus. Jpn J Ophthalmol 2002; 46(1): 65-69. 77. Shenoy R, Khandekar R, Bialasiewicz A, Al Muniri A. Corneal endothelium in patients with diabetes mellitus: a historical cohort study. Eur J Ophthalmol 2009; 19(3): 369-375. 78. Sudhir RR, Ramon R, Sharma T. Changes in the corneal endothelial cell density and morphology in patients with Type 2 diabetes mellitus: a population-based study, Sankara Nethralaya Diabetic Retinopathy and Molecular Genetics Study. Cornea 2012; 31(10): 1119-1122. 79. Busted N, Olsen T, Schmitz O. Clinical observations on the corneal thickness and the corneal endothelium in diabetes mellitus. Br J Ophthalmol 1981; 65: 687-690.

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80. Su DHW, Wong TY, Wong W, et al. Diabetes, hyperglycemia, and central corneal thickness. Ophthalmology 2008; 115(6): 964-968. 81. Saini JS, Mital S. In vivo assessment of corneal endothelial function in diabetes mellitus. Arch Ophthalmol 1996; 114(6): 649-653. 82. Lee JS, Oum BS, Choi HY, Lee JE, Cho BM. Differences in corneal thickness and corneal endothelium related to duration in diabetes. Eye 2006; 20(3): 315-318. 83. Rubenstein MP. Diabetes, the anterior segment and contact lens wear. Contact Lens J 1987; 15: 4-11. 84. Henkind P, Wise GN. Descemetâ&#x20AC;&#x2122;s wrinkles in diabetes. Am J Ophthalmol 1961; 52: 371. 85. Alberti KG, Press CM. The biochemistry of the complications of diabetes mellitus. In: Keen H, Jarrett J, eds. The complications of diabetes. London; Edward Arnold, 1982; 231-270. 86. Mishima S. The effects of the denervation and stimulation of the sympathetic and the trigeminal nerve on the mitotic rate of the corneal epithelium in the rabbit. Jpn J Ophthalmol 1957; 1: 65-73. 87. Alper MG. The anesthetic eye: an investigation of changes in the anterior ocular segment of the monkey caused by interrupting the trigeminal nerve at various levels along its course. Trans Am Ophthalmol Soc 1975; 72: 323-365. 88. Araki K, Ohashi Y, Kinoshita S, et al. Epithelial wound healing in the denervated cornea. Curr Eye Res 1994; 13: 203-211. 89. Baker KS, Anderson SC, Romanowski EG, et al. Trigeminal ganglion neurons affect corneal epithelial notype: influence on type VII collagen expression in vitro. Invest Ophthalmol Vis Sci 1993; 34: 137-144. 90. Rosenberg ME, Tervo TMT, Immonen IJ, et al. Corneal Structure and sensitivity in type 1 diabetes mellitus. Invest Ophthalmol Vis Sci 2000; 41: 2915-2921. 91. Schultz RO, Peters MA, Sobocinski K, et al. Diabetic corneal neuropathy. Trans Am Ophthalmol 1983; 131: 107-124. 92. Nakamura M, Kawahara M, Morishige N, et al. Promotion of corneal epithelial wound healing in diabetic rats by the combination of a substance P-derived peptide (FGLM-NH2) and insulin-like growth factor-1. Diabetologia 2003; 46: 839-842. 93. Chikamoto N, Chikama T, Yamada N, Nishida T, Ishimitsu T, Kamiya A. Efficacy of substance P and insulin-like growth factor-1 peptides for preventing postsurgical superficial punctate keratopathy in diabetic patients. Jpn J Ophthalmol 2009; 53: 464-469. 94. Rosenthal SP. Acceleration of primary wound healing by insulin. Arch Surg 1968; 96: 53-55. 95. Benoliel AM, Kahn-Perles B, Imbert J, Verrando P. Insulin stimulates haptotactic migration of human epidermal keratinocytes through activation of NFkappa B transcription factor. J Cell Sci 1987; 110: 2089-2097. 96. Van Ort SR, Gerber RM. Topical application of insulin in the treatment of decubitus ulcers: a pilot study. Nurs Res 1976; 25: 9-12. 97. Pierre EJ, Barrow RE, Hawkins HK. Effects of insulin on wound healing. J Trauma 1998; 44: 342-345. 98. Levi-Montalcini R. The nerve growth factor 35 years later. Science 1987; 237: 1154-1162. 99. Levi-Montalcini R, Aloe L, Alleva E. A role for nerve growth factor in nervous, endocrine and immune system. Prog Neuroendocrinimuunol 1990; 1: 1-10. 100. Bonini S. Lambiase A, Rama P, Capriogli G, Aloe L. Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology 2000; 107: 1347-1352. 101. Zagon IS, McLaughlin PJ. The role of endogenous opioids and opioid receptors in human and animal cancers. In: Plotnikoff AJ, Murgo AJ, Faith RE, Wybran J, eds. The role of endogenous opioids and opioid receptors in human and animal cancers. Caldwell, NJ: CRC, 1991; 343-356.

102. Zagon IS, McLaughlin PJ. Opioid growth factor receptor in the developing nervous system. In: Zagon IS, McLaughlin PJ, eds. Opioid growth factor receptor in the developing nervous system. Vol. 1. London: Chapman and Hall, 1993: 39-62. 103. Zagon IS, McLaughlin PJ. Identification of opioid peptides regulating proliferation of neurons and glia in the developing nervous system. Brain Res 1991; 542(2): 318-323. 104. Zagon IS, Klocek MS, Sassani JW, McLaughlin PJ. Dry eye reversal and corneal sensation restoration with topical naltrexone in diabetes mellitus. Arch Ophthalmol 2009; 127: 1468-1473. 105. Cheng F, McLaughlin PJ, Banks WA, Zagon IS. Passive diffusion of naltrexone into human and animal cells and upregulation of cell proliferation. Am J Physiol Regul Integr Comp Physiol 2009; 297: R844–R852. 106. Klocek MS, Sassani JW, McLaughlin PJ, Zagon IS. Topically applied naltrexone restores corneal re-epithelialization in diabetic rats. J Ocul Pharmacol Ther 2007; 23: 89-102. 107. Ohashi Y, Matsuda M, Hosotani H, Tano Y, Ishimoto I, Fukuda M, Manabe R: Aldose Reductase Inhibitor (CT-112) eye drops for diabetic corneal epitheliopathy. Am J Ophthalmol 1988; 105: 233-238. 108. Nishio T, Sunohara N, Furukawa S, Akiguchi I, Kudo Y. Repeated injections of nicergoline increase the nerve growth factor level in the aged rat brain. Jpn J Pharmacol 1998; 76: 321-323. 109. Giardino L. Giuliani A, Battaglia A, Carfagna N, Aloe L, Calza L. Neuroprotection and aging of the cholinergic system: a role foor the ergoline derivative nicergoline (Sermion). Neuroscience 2002; 109: 487-497. 110. Kim S-Y, Choi J-S, Joo C-K. Effects of nicergoline on corneal epithelial wound healing in rat eyes. Invest Ophthalmol Vis Sci 2009; 50: 621-625. 111. Shoji M, Sato H, Hirai Y, et al. Pharmacological effects of Gosha-jinki-gan-ryo extract: effects on enxperimental diabetes. Folia. Pharmacol. Jpn. (Nippon Yakuri Zasshi) 1992; 99: 143-152. 112. He J, Bazan HE. Mapping the nerve architecture of diabetic human corneas. Ophthalmology 2012; 119(5): 956-964. 113. Rogell GD. Corneal hypesthesia and retinopathy in diabetic mellitus. Ophthalmology 1980; 87: 229-233. 114. Fujishima H, Shimazaki J, Yagi Y, et al. Improvement of corneal sensation and tear dynamics in diabetic patients by oral aldose reductase inhibitor, ONO-2235: a preliminary study. Cornea 1996; 15: 368-372. 115. Fraufelder FW, Rich LF. Laser-assisted in situ kerato-mileusis complications in diabetes mellitus. Cornea 2002; 21(3): 246-248. 116. Gimbel HV, van Westenbrugge JA, Anderson Penno EE, et al. Simultaneous bilateral laser in situ keratomileusis: safety and efficacy. Ophthalmology 1999; 106: 1461-1467. 117. Wang MY, Maloney RK. Epithelial ingrowth after laser in situ keratomileusis for the correction of myopia. Am J Ophthalmol 2000; 129: 746-751.

118. Stulting RD, Carr JD, Thompson KP, Waring GOIII, Wiley WM, Walker JG. Complications of laser in situ keratomileusis for the correction of myopia. Ophthalmology 1999; 106(1): 13-20. 119. Jabbur NS, Chicani CF, Kuo IC, O’Brien TP. Risk factors in interface epithelialization after laser in situ keratomileusis. J Refract Surg 2004; 20:343-348. 120. Cobo-Soriano R, Beltran J, Baviera J. LASIK outcomes in patients with underlying systemic conditions. Ophthalmology 2006; 113: 1118-1124. 121. Ghanbari H, Ahmadieh H. Aggravation of proliferative diabetic retinopathy after laser in situ keratomileusis. J Cataract Refract Surg 2003; 29: 2232-2233. 122. Halkiadakis I, Belfair N, Gimbel HV. Laser in situ keratomileusis in patients with diabetes. J. Cataract Refract. Surg. 2005; 31: 1895-1898. 123. Brightbill FS, Myers FL, Bresnick GH. Postvitrectomy keratopathy. Am J Ophthalmol 1978; 85: 651-655. 124. Mendelcorn MS, Blankenship G, Machemer R. Pars plana vitrectomy for the management of severe diabetic retinopathy. Am J Ophthalmol 1976; 81: 561-570. 125. Riss B, Binder S. Corneal sensitivity after photocoagulation for diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 1981; 217: 143-147. 126. Herse PR. Recovery from contact lens-induced edema is prolonged in the diabetic rabbit cornea. Optom Vis Sci 1990; 67: 466-470. 127. Eichenbaum JW, Feldstein M, Podos SM. Extended-wear aphakic soft contact lenses and corneal ulcers. Br J Ophthal 1982; 66: 663-666. 128. Schein OD, Glynn RJ, Poggio EC, Seddon JM, Kenyon KR. The relative risk of ulcerative keratitis among users of dailywear and extended-wear soft contact lenses a case-control study. N Engl J Med 1989; 321: 773-778. 129. Spoor TC, Hartel WC, Wynn P, Spoor DK. Complications of continuous-wear soft contact lenses and corneal ulcers. Br J Ophthamol 1984; 102: 1312-1313. 130. O’Donnell C, Efron N, Boulton AJM. A prospective study of contact lens wear in diabetes mellitus. Ophthal Physiol Opt 2001; 21(2): 127-138. 131. March W, Long B, Hofmann W, Keys D, McKenney C. Safety of contact lenses in patients with diabetes. Diabetes Technol Ther 2004; 6(1): 49-52. 132. Skaff A, Cullin AP, Doughty MJ, Fonn D. Corneal swelling and recovery following wear of thick hydrogel contact lenses in insulin-dependent diabetics. Ophthal Physiol Opt 1995; 15: 287-297. 133. Weston BC, Bourne WM, Polse KA, Hodge DO. Corneal hydration control in diabetes mellitus. Invest Ophthalmol Vis Sci 1995; 36: 586-595. 134. McNamara NA, Brand RJ, Polse KA, Bourne WM. Corneal function during normal and high serum glucose levels in diabetics. Invest Ophthalmol Vis Sci 1998; 39: 3-17.

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QUESTIONNAIRE A Comprehensive Review of Diabetic Keratopathy Amiee Ho, OD; Pauline F. Ilsen, OD 1. ❑ ❑ ❑ ❑

A healthy lipid layer is able to reduce the rate of evaporation by what percentage? 45%-50% 65%-75% 80%-90% 90%-95%

2. ❑ ❑ ❑ ❑

In one study, tear break-up time in nearly all diabetics tested was found to be which of the following? Less than 5 seconds Less than 10 seconds Less than 15 seconds Less than 20 seconds

3. ❑ ❑ ❑ ❑

Patients with diabetic keratopathy may exhibit all of the following characteristics, EXCEPT: Increased use of artificial tears Decrease in lacrimation Decreased use of artificial tears Reduction in blink rate

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All of the following are characteristics of Stage 1 diabetic neuropathic keratopathy, EXCEPT: Superficial vascularization Stromal scarring Ulceration Epithelial hyperplasia

5. ❑ ❑ ❑ ❑

All of the following are differentials for general corneal abnormalities, EXCEPT: Natural aging changes Family history of the condition Trauma Extended contact lens wear

6. ❑ ❑ ❑ ❑

One study found poor refractive outcomes and epithelial complications in what percentage of diabetic patients? 39% 47% 55% 62%

7. ❑ ❑ ❑ ❑

Standard treatments for diabetic keratopathy include all of the following, EXCEPT: Induced ptosis Oral antibiotic Topical steroid Topical antibiotic

8. ❑ ❑ ❑ ❑

All of the following are ocular complications with diabetic keratopathy, EXCEPT: Superficial punctate keratitis Corneal edema Delayed/poor healing Increased blink rate

9. ❑ ❑ ❑ ❑

Corneal thickening is associated with all of the following, EXCEPT: Having diabetes for over five years Increased HbA1c levels Severe retinal complications Increased blood glucose levels

10. ❑ ❑ ❑ ❑

Which of the following types of patients are likely to have Descemet’s membrane? Patients > age 70 Patients with diabetes for over ten years Females Males

26:3, 15

4. ❑ ❑ ❑ ❑

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Clinical & Refractive Optometry: Online Edition is pleased to present this continuing education (CE) article by Dr. Dawn N. Tomasini, Dr. Jennifer Tribley-Grill and Dr. Miriam M. Rolf entitled Unknown Adverse Visual Effects of Gabapentin. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 115 for complete instructions.

Unknown Adverse Visual Effects of Gabapentin Dawn N. Tomasini, OD, FAAO Jennifer Tribley-Grill, OD, FAAO Miriam M. Rolf, OD, MS, FAAO

ABSTRACT Gabapentin, commonly known as Neurontin® is a medication used in the treatment of seizures and pain control. Traditionally, its ocular side effects have been limited to blurred vision, diplopia and impairment of ocular motilities.1,2 Over the past decade, anti-epileptic drugs similar to gabapentin have been linked to severe visual field constriction. Vigabatrin, commonly known as Sabril® is a gamma-aminobutyric acid (GABA)transaminase inhibitor similar in chemical structure to gabapentin, has numerous reports confirming symptomatic and asymptomatic irreversible and severe peripheral visual constriction.3,4 In May 2006, the first case report linking gabapentin to severe visual field loss as well as severe visual field constriction was published in the British Journal of Medicine.5 The following case substantiates that gabapentin can cause reversible visual field defects, as well as affect central visual acuity.

INTRODUCTION Gabapentin, commonly known as Neurontin® (Pfizer Inc., New York, NY), is a widely used drug to control epileptic seizures and neuropathic pain.1 More recently, gabapentin has been approved by the FDA for the treatment of restless leg syndrome under the trade name of Horizant® (gabapentin enacarbil, XenoPort, Inc. Santa Clara, CA).6 Having only mild side effects, it is generally well tolerated by patients. Ocular side effects are rare and may include

D.N. Tomasini, J. Tribley-Grill, M.M. Rolf — VA Hudson Valley Healthcare System, Optometry Service, Wappingers Falls, NY Correspondence to: Dr. Dawn N. Tomasini, VA Hudson Valley Healthcare System, Optometry Service, 41 Castle Point Road, Wappingers Falls, NY 12590; E-mail: dawn.tomasini@va.gov This article has been peer-review.

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blurred vision, diplopia and impairment of ocular motilities. Anti-epileptic drugs similar to gabapentin have been linked to severe visual field constriction. Vigabatrin, commonly known as Sabril® (Lundbeck, Deerfield, IL), is a gammaaminobutyric acid (GABA)-transaminase inhibitor which is similar in chemical structure to gabapentin. Numerous reports have confirmed symptomatic and asymptomatic, irreversible and severe peripheral visual constriction with the use of vigabatrin.2-4 In May 2006, the first case report linking gabapentin to such severe visual field loss was published in the British Medical Journal.5

CASE REPORT A 54-year-old white male presented to the VA Hudson Valley for his initial optometry exam to renew his glaucoma medications. He had been diagnosed previously with low tension glaucoma four years prior by another VA facility, and had a history of bilateral inferior argon laser trabeculoplasty. His current medications were Timoptic® (timolol maleate ophthalmic solution, Merck & Co., Whitehouse Station, NJ) 0.5% BID OU and Xalatan® (latanoprost ophthalmic solution, Pfizer Inc., New York, NY) QHS OU. Medical history was significant for scleroderma with associated Sjögren’s disease, hyper tension, hyperlipidemia, depression, and post-traumatic stress disorder. To treat these conditions, the patient was taking felodipine, prednisone, oral pilocarpine, gabapentin, methotrexate, topiramate, penicillamine, salsalate and citalopram. Initial visual field testing in October 2004 was unreliable but indicated only mild scattered defects OU with a high number of false negatives. When repeated, a dramatic bilateral concentric constriction was noted with dense, absolute defects. Multiple subsequent visual field tests after June 2005 revealed repeatable dense bilateral visual field constrictions with a stable moderately reduced visual acuity, which varied from 6/9 (20/30) to 6/21 (20/70) (Figs. 1, 2). The severity of the visual field loss was not consistent with the patients’ optic nerve cupping, documented as a 0.60 cup to disc ratio, which had healthy rim tissue and was devoid of notches or other glaucomatous abnormalities (Figs. 3, 4). Despite severe visual field constriction, which at times was reduced to almost

Fig. 1 Initial visual field OD in 2004 and following gabapentin use in 2005.

Fig. 2 Initial visual field OS in 2004 and following gabapentin use in 2005.

Fig. 3 Fundus photo OD showing normal cupping and healthy rim tissue.

Fig. 4 Fundus photo OS showing normal cupping and healthy rim tissue.

10 degrees, the patient did not report any problems with peripheral vision or ambulation, nor were any visual field deficits obvious to the clinician. In May 2006, a case report was published in the British Medical Journal linking gabapentin to visual field loss. Given this new information and the inconsistency between the dense bilateral visual field loss and the large, but healthy, optic nerve cupping, the patient agreed to stop the gabapentin to determine if his visual fields would improve (Figs. 5, 6). In less than two months, a marked improvement in the visual field defects was noted in the left eye. No change was noted in the right eye despite the patientâ&#x20AC;&#x2122;s subjective improvement in vision. Within six months of discontinuation of gabapentin, the patientâ&#x20AC;&#x2122;s visual field improved dramatically, left eye more so than right eye (Figs. 7, 8). In fact, after twelve months without gabapentin, visual fields had almost completely returned to normal in both eyes and visual acuity improved to 6/6 (20/20) in each eye. With the resolution of visual field defects, normal tensions and large but stable and healthy optic nerve

cupping, the patient was taken off his glaucoma medication. Since 2006, his ocular status has remained stable and he is currently monitored annually. At the time of examination optical coherence tomography (OCT) was unavailable.

DISCUSSION Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter of the central nervous system. It is abundant in the retina and is primarily used by the amacrine cells as well as one or more classes of horizontal cells.2 GABA is synthesized from glutamate in the presynaptic nerve terminal. It is released into the synaptic cleft in a vesicle, which crosses the synapse to bind with GABA receptors on the post-synaptic neuron. In the retina, there are three types of GABA receptors: A, B and C. GABA-C receptors are highly sensitive to GABA; the neurotransmitter can initiate a response even at low doses and then initiate a sustained response to GABA. This is in opposition to the temporary response seen with GABA-A receptors.2 In the peripheral retina, antibodies to GABA

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Fig. 5 Visual field OD 7/2006 prior to discontinuing Gabapentin.

Fig. 6 Visual field OS 7/2006 prior to discontinuing Gabapentin

Fig. 7 Visual field OD six months after discontinuing Gabapentin.

Fig. 8 Visual field OS six months after discontinuing Gabapentin.

stain heavily in the inner plexiform layer and the amacrine cells.2 Horizontal cells do not stain in the periphery, but have reported to stain in the foveal area.2 Subpopulations of amacrine and horizontal cells, bipolar cells, interplexiform cells, Muller cells and retinal ganglion cells have all been described as GABAergic.2 Gabapentin is an antiepileptic drug initially created to mimic the structure of GABA. Gabapentin increases the available amount of GABA and therefore creates an anti-anxiety and anti-convulsive effect.1,2 In 1994, it was approved by the FDA as an adjunctive medication for the control of partial seizures.1 In 2002, its FDA approval expanded to include the treatment for post-herpetic neuralgia and other painful neuropathies. Restless leg syndrome was added to the list of approved conditions for gabapentin use in 2011.6 Gabapentin also has been used “off-label” for the prevention of migraine headaches and for the treatment of bipolar disorder, anxiety disorders including depression, obsessive compulsive disorder, and insomnia. It has been considered well-tolerated with minimal side effects including dizziness, drowsiness and peripheral edema. There has only been one reported case of peripheral visual field constriction associated with its use in 2006.5 Another antiepileptic drug, vigabatrin, is an irreversible GABA-transaminase inhibitor that gives an antiepileptic effect by enhancing inhibitory transmission in the brain, thereby increasing the levels of GABA at synapses.2,7 Vigabatrin’s chemical structure is very similar to that of gabapentin. While approved for use in the United Kingdom, Canada and Australia in the 1990s, the United States Food and Drug Administration initially denied its approval in 1998.8 However, in 2009, the US approved

vigabatrin for the treatment of infantile spasms in pediatric patients and for medically refractory complex partial seizures in adults. Despite its chemical similarity to gabapentin, its side effects extend beyond dizziness and somnolence which are known to occur with gabapentin. Symptoms of vision abnormalities were reported in approximately 30% of patients taking vigabatrin.2 Since the late 1990s, it has been documented to cause symptomatic and asymptomatic visual field constriction. More importantly, this visual field loss has been found to be irreversible despite cessation of the drug (Table I). The exact mechanism by which vigabatrin causes visual field constriction is unclear. Its effect on GABA is most prominent in the retina where drug concentrations are 18.5x higher than in the brain.7 Abnormal ERGs produced in patients on vigabatrin all showed depression of the scotopic b-wave, suggesting a toxic effect on retinal Muller cells.2,9 Muller cells make up a large portion of retinal cells and function to maintain the balance and integrity of the retina and its layers. They are the primary responders in times of retinal injury or stress.10 Muller cell density is higher in the central retina as compared to the peripheral retina. Therefore, damage to Muller cells results in peripheral visual field loss and spares the central field.10 Although no central visual field defects have been noted in the literature, subnormal vision was reported in 50% of children treated with vigabatrin.11 While on gabapentin, the patient’s visual acuity fluctuated between 6/9 (20/30) and 6/21 (20/70). Once the gabapentin was discontinued, the patient’s vision gradually improved to 6/6 (20/20) within ten months and has remained stable. The damage incurred by the central Muller cells can be evident in the reduction of central visual acuity. The amount

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Table I Comparison of vigabatrin, gabapentin and topiramate.

of visual field loss seems to be affected by the duration of treatment with vigabatrin as well as the total dose.12 Genetic predisposition is another variable under study.2 Prior to 2014, visual field defects were only associated with vigabatrin and not other GABAergic drugs.7 In January of 2014, topiramate, also known as TopamaxÂŽ,

(Janssen Pharmaceuticals, Inc, Titusville, NJ) another commonly prescribed medication used to treat epilepsy, amended its side effects to include reversible visual field defects of unknown origin.13 As with vigabatrin, the mechanism of action for topiramate is mostly unknown. It is thought to block sodium dependent voltage channels

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as well as augment the activity of GABA at GABA-A transmitter sites while inhibiting carbonic anhydrase.14 This mechanism of action is similar in that both vigabatrin and gabapentin also produce GABAergic effects. It is thought that the persistence of GABA in the retina may lead to levels of toxicity, which may cause the visual defects noted.12 Since vigabatrin and topiramate are known to cause visual field defects, it seems logical that gabapentin, a drug with a similar mechanism of action and chemical structure, could also have the ability to produce visual field defects and reduction in central visual acuity due to toxicity. Vigabatrin, topiramate and gabapentin all cause an increase of GABA levels in the retina. It is possible that these increased GABA levels are toxic to the Muller cells, which are less numerous in the peripheral retina. With damage to these cells, bilateral and concentric visual field loss occurs. The central retina also becomes affected, resulting in a reduction of visual acuity. The difference between these medications seems to be that the visual field constriction caused by vigabatrin is not reversible while the constriction caused by gabapentin and topiramate is reversible.15 It is unclear as to why gabapentin caused visual field loss as well as a decrease in central visual acuity in our patient. Possibilities include drug-drug interaction, drug toxicity or even a genetic predisposition. These unknowns require further investigation.

awareness of the visual side effects of gabapentin and promote research to determine the etiology of its retinal toxicity. New practice guidelines for monitoring patients taking gabapentin may need to be established. ❏

CONCLUSION

11.

Antiepileptic drugs have become more widely used to treat a variety of conditions. Of those, gabapentin has generally been considered a relatively safe, well-tolerated medication with minimal side effects. However, it may have under-reported visual consequences. This case demonstrates severe visual field constriction and reduced central visual acuity in a patient taking gabapentin for thirteen years. Our patient’s visual field loss is almost identical to visual field loss documented with vigabatrin and topiramate, other similar antiepileptic drugs with known neurotoxic effects. This case should increase the

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REFERENCES 1. 2. 3. 4. 5. 6. 7.

8. 9. 10.

12. 13. 14. 15.

Neurontin® [package insert]. New York, NY: Pfizer 2011. Roff Hilton EJ, Hosking SL, Betts T. The effect of antiepileptic drugs on visual performance. Seizure 2004; 13: 113-128. Sabril [package insert], Deerfield, IL: Lundbeck 2013. Moorthy RS, Valluri S. Ocular toxicity associated with systemic drug therapy. Opin Ophthalmology 1999; 10(6): 438-446. Bekkelund SI, Lilleng H, Tonseth S: Gabapentin may cause reversible visual field constriction. British Medical Journal 2006; 332: 1193. Horizant® [package insert], Santa Clara, CA: XenoPort 2013. Sills GJ, Butler E, Forrest G et al. Vigabatrin, but not gabapentin or topiramate, produces concentration–related effects on enzymes and intermediates of the GABA shunt in rat brain and retina. Epilepsia 2003; 44(7): 886-892. Kalviainen R, Nousiainen I. Visual field defects with vigabatrin epidemiology and therapeutic implications. CNS Drugs 2001; 15(3): 217-230. Daneshvar H, Racette L, Coupland SG et al. Symptomatic and asymptomatic visual loss in patients taking vigabatrin. Ophthalmology 1999; 106:1792-1798. Goldman, Daniel. Muller glial cell reprogramming and retina regeneration. Nature Reviews Neuroscience 2014; 15: 431-442. Westall CA, Logan WJ, Smith K et al. The Hospital for Sick Children, Toronto. Longitudinal ERG study of children on vigabatrin. Doc Ophthalmol 2002; 104: 133-149. Hardus P, Verduin W, Engelsman M et al. Visual field loss associated with vigabatrin: quantification and relation to dosage. Epilepsia 2001; 42: 262-267. Topamax® [package insert], Titusville, NJ: Janssen Pharmaceuticals, Inc. 2014. Mandal A, Chatterjee S, Bose S, Ganguly G. Ocular adverse effects of topiramate: two case reports. Indian Journal of Pharmacology 2008; 40(6): 278-280. Best JL, Acheson JF. The natural history of vigabatrinassociated visual field defects in patients electing to continue their medication. Eye 2005; 19: 41-44.

26:3, 15

COPE-APPROVED CE CREDIT APPLICATION FORM

INSTRUCTIONS FOR 1 HOUR OF

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QUESTIONNAIRE Unknown Adverse Visual Effects of Gabapentin Dawn N. Tomasini, OD, FAAO; Jennifer Tribley-Grill, OD, FAAO; Miriam M. Rolf, OD, MS, FAAO 1. ❑ ❑ ❑ ❑

Gabapentin has been FDA approved for the treatment of all of the conditions, EXCEPT: Restless leg syndrome Epileptic seizures Paresthesia Neuropathic pain

2. ❑ ❑ ❑ ❑

All of the following are possible ocular side effects of gabapentin, EXCEPT: Blurred vision Night blindness Diplopia Impairment of ocular mobilities

3. ❑ ❑ ❑ ❑

In the Case Report presented, visual field testing revealed all of the following, EXCEPT: Mildly scattered defects OU Bilateral concentric constriction Moderately reduced visual acuity Dramatically reduced visual acuity

Unknown Adverse Visual Effects of Gabapentin — Tomasini et al

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❑ ❑ ❑ ❑

In the Case Report presented, all of the following statements describe the patient’s condition following discontinuation of gabapentin, EXCEPT: Improvement in visual field Improved visual acuity Normal tensions Reduced visual acuity OS

5. ❑ ❑ ❑ ❑

Gabapentin is used for the following disorders, EXCEPT: Anxiety disorders Schizophrenia Insomnia Migraine headaches

6. ❑ ❑ ❑ ❑

All of the following have been reported as possible symptoms of visual abnormalities associated with vigabatrin, EXCEPT: Approximately 10% Approximately 20% Approximately 30% Approximately 40%

7. ❑ ❑ ❑ ❑

All of the following statements about vigabatrin are true, EXCEPT: It has been reported to cause reversible visual field loss It has been reported to cause visual field constriction Its effects are most prominent in the retina No central visual field defects have been reported in the literature

8. ❑ ❑ ❑ ❑

Subnormal vision has been reported in what percentage of children taking vigabatrin? 15% 30% 40% 50%

9. ❑ ❑ ❑ ❑

In the Case Report presented, once the gabapentin was discontinued, the patient’s vision gradually improved to what level within 10 months? 20/20 (6/6) 20/25 (6/7.5) 20/30 (6/9) 20/32 (6/9.5)

10. ❑ ❑ ❑ ❑

Topiramate has been known to cause nystagmus in what percentage of patients? 11% 15% 20% 25%

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Book Review Visual Impairment: A Global View. Edited by Heather McLannahan. Pp 93. Soft cover with colored illustrations. Oxford University Press, 2008, ISBN: 978-0-1992-3731-9, US$46.97. Over two billion people worldwide, about one-third of the global population, have a vision impairment which can be corrected with a variety of treatment modalities from spectacles to refractive surgical techniques. This book helps to explain the reasons for visual impairment anatomically and optically. It also shines a light on the livelihood and socioeconomic status of individuals afflicted with poor vision. This book is a part of a series geared as a source for students to study from around the world at a school called The Open University. This is a primarily undergraduate school located in the United Kingdom that uses modern distance learning for adult education. Some of the other titles of this series include Water and Health in an Overcrowded World, Alcohol and Human Health and Screening for Breast Cancer. Visual Impairment: A Global View has 93 pages consisting of six chapters. Each chapter is broken down into sections, which helps transition from one topic to the next. At the end of each chapter, there are statements that briefly summarize the contents of each section. Within the sections are questions, notated with a light purple diamond, followed by an immediate answer, notated with a dark purple diamond. These questions are meant to provoke critical thinking. There are also boxes with further explanations of concepts in light blue and vignettes in light green. There are numerous figures containing pictures or diagrams to help visualize the meaning of the topic at hand. There are also a number of icons in the margin to help the reader capitalize on topics they just learned. They specify materials needed for each activity (paper, calculator, etc). A DVD is included which should be watched at certain intervals of the written text. A DVD icon within the text lets the reader know when to view the video. The various videos include how lenses focus, the development of soft contact lenses, how a laser works in refractive surgery, global inequalities in eye treatment and a personal story told by Derek Child. Mr. Child explains that even though he lost all his sight at age 29, he was still able to return to a demanding job. He did this by learning the skills of long cane and guide dog training, using low vision device scanners, computers and pocket file portable devices and learning Braille. The opening chapter starts with a global view of sightrelated problems and populations, while the next couple of chapters dive into anatomy of the eye and the optics of vision. The book later focuses on common refractive errors and ways to correct them. It then gives a brief synopsis of the most common medical conditions which can cause vision loss, including cataracts, glaucoma, age-related macular

degeneration, diabetic retinopathy and eye infections. Each chapter has a different author or authors that have expertise and knowledge in each of the specific disciplines. Even though there is a slight disruption of the bookâ&#x20AC;&#x2122;s flow between each chapter, there is no redundancy of information. The nature of this book is suitable for someone who is interested in the eye and how it works. In fact, the author comments in the introduction that it was written for a course at a primarily undergraduate university in the United Kingdom, The Open University, for first year students. As expected, a first year college student may not have any scientific background nor would they need to for understanding this text. It is clear and concise, yet explains all the background scientific concepts behind each topic in a way that is easy to read and readily comprehended. It offers and recommends various extra materials besides the text, in activities, videos, questions or summaries, to engage the reader. However, this book would not be as helpful as a reference for an ophthalmic clinician. It does not give the detail needed for diagnoses nor does it have any information regarding treatment. Since this bookâ&#x20AC;&#x2122;s main emphasis is vision loss and how it affects the individual, we expected to find information on low vision devices and appliances. Although there was a mention of some devices used by Mr. Child on the DVD video, we would suggest another section or even chapter regarding how to use and recommend some simple and inexpensive low vision devices and treatments for those people that live with impaired vision not correctable by standard lenses or surgery. This book has many beneficial features to aid a student or individual who is interested in the eyes and how vision works yet may not have a scientific background in optometry or ophthalmology. It is an informative generalized overview in a format that is very easy to read. This book is not geared to an eye care clinician as it does not contain the detail needed for diagnosis of eye diseases nor does it contain needed information for the treatments of common ocular conditions. On the other hand, it would be a good book for a professional to have as a reference for interested patients or undergraduate students who are considering pursuing a career in optometry or ophthalmology. Reviewed by: Emily Bjore, OD Yankee Eye Clinic Eagan, MN Leonid Skorin, Jr., DO, OD, MS, FAAO, FAOCO Mayo Clinic Health System Albert Lea, MN

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News and Notes Contact Lens Researchers Test New Lens to Slow the Progression of Myopia Vision scientists at the Centre for Contact Lens Research at the University of Waterloo’s School of Optometry and Vision Science are testing a new type of contact lens that could slow the progression of myopia. The novel lens design uses “smart optics” to prevent the eye from compensating for out of focus rays of light, stabilizing the prescription at an early age. Traditionally, myopic patients were prescribed a slightly out of focus prescription to force their eyes to work. “We know now that actually has the opposite effect and causes the eye to grow even more as it tries to compensate, resulting in an increased amount of myopia” says Lyndon Jones, director of the Centre for Contact Lens Research. The key here is to have a lens that projects light rays evenly across the curved retina so that the eye doesn’t need to change or grow. When the eye views close objects like books or computer screens, the image in the center of the eye is in focus, but the edges project just past the retinal surface. The eye compensates by growing longer, but then images of normally distanced objects project just short of the retina, causing the person to experience short-sightedness. More than 94% of Singapore’s population currently suffers from myopia – a staggering statistic that has professionals worried. It’s not the average case of myopia we’re worried about, but the increasing number of extreme cases,” says Jones, also a Professor in the School of Optometry and Vision Science at Waterloo. “Myopia leads to blindness and other eye complications like glaucoma, macular degeneration and retinal detachment.” For more information, visit www.cclr.uwaterloo.ca. Tonomate Disposable Applanation Prism Now Available In Canada Keeler has introduced a new disposable applanation prism, Tonomate, to facilitate safe and fast Goldmann applanation tonometry. Tonomate prisms are manufactured to the high quality associated with the Keeler brand and designed to fit most applanation tonometer prism holders. Each prism is individually packed in sterile packaging and can be fitted easily without requiring direct contact. The prism is discarded after use to streamline eye examinations and prevent the cross-infection of diseases between patients that can be transmitted via the tear film. Tonomate prisms are ideal for use with D-KAT, Keeler’s digital applanation tonometer. D-KAT is available in R-type and T-type variants for -H- style slit lamps and as a Z-type model for Z-style slit lamps. It features fewer moving parts compared to conventional applanation tonometers and an LED display makes it easy to read in the dark. For more information about Tonomate prisms and D-KAT, visit www.keelerusa.com or contact your authorized Keeler representative.

Indications and clinical use: LOTEMAX® Gel (loteprednol etabonate ophthalmic gel 0.5% w/w) is indicated for the treatment of postoperative inflammation and pain following cataract surgery. • The safety and efficacy of LOTEMAX® have not been studied in pediatric patients (<18 years of age) and the product should not be used in these populations. Contraindications: • Suspected or confirmed infection of the eye: viral diseases of the cornea and conjunctiva including epithelial herpes, simplex keratitis (dendritic keratitis), vaccinia, and varicella; untreated ocular infection of the eye; mycobacterial infection of the eye and fungal diseases of ocular structures. • Hypersensitivity to LOTEMAX® or any ingredient in the formulation or container, or to other corticosteroids. Relevant warnings and precautions: • LOTEMAX® Gel is indicated for short-term treatment only (up to 14 days). If LOTEMAX® Gel is used for 10 days or longer, intraocular pressure (IOP) should be closely monitored. • The use of steroids after cataract surgery may delay wound healing. • Prolonged use of corticosteroids may result in cataract and/or glaucoma formation. Should not be used in the presence of glaucoma or elevated IOP, unless absolutely necessary and close ophthalmologic monitoring is undertaken. • LOTEMAX® Gel includes benzalkonium chloride. • Should not be used in pregnant or lactating women unless the benefit to the mother clearly outweighs the risk to the infant/child. For more information: Please consult the Product Monograph at http://www.bausch.ca/en-ca/our-products/ rx-pharmaceuticals/lotemax-gel-loteprednoletabonate-ophthalmic-gel-05-w-w for complete dosing instructions, warnings, precautions, adverse events and patient selection criteria. The Product Monograph is also available by calling 1-888-459-5000.

Bausch & Lomb Canada, Vaughan, Ontario L4K 4B4 © Valeant Canada LP ®/TM are trademarks of Bausch & Lomb Incorporated or its affiliates.

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