CROQ Vol 1 Number 5

Page 1

CROQ ONLINE EDITION

Clinical Refractive & Optometry Quebec EDITION

VOLUME 1, NUMÉRO 5, 2016

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Tous les articles sont accrédités par l’OOQ pour des crédits UFC de catégorie A

Principles of Dry Eye Disease Tear Dysfunction and Osmolarity AREDS2 Controversies and Facts Diagnosis and Treatment of Ocular Surface Conditions: Focus on Allergy


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Clinical

&Refractive Optometry Quebec

Comité de rédaction • volume 1, numéro 5, 2016 Rédacteur en chef

Rédacteur en chef adjoint

Rédacteur en chef adjoint

Dr Yvon Rhéaume Montréal, Québec

Dr Richard Maharaj Toronto, Ontario

Dr Leonid Skorin, Jr. Albert Lea, Minnesota

Collaborateurs à la rédaction Dr Brad Almond Calgary, Alberta

Dre Danielle DeGuise Montréal, Québec

Dr Langis Michaud Montréal, Québec

Dr Jean Bélanger Montréal, Québec

Dr Pierre Forcier Montréal, Québec

Dr Rodger Pace Waterloo, Ontario

Dr Scott D. Brisbin Edmonton, Alberta

Dr John Jantzi Vancouver, Colombie-Britannique

Dr Maynard Pohl Bellevue, Washington

Dr Lorance Bumgarner Pinehurst, Caroline du Nord

Dr Geral Komarnicky Vancouver, Colombie-Britannique

Dre Barbara Robinson Waterloo, Ontario

Dre Barbara Caffery Toronto, Ontario

Dr Bart McRoberts Vancouver, Colombie-Britannique

Dr Jacob Sivak Waterloo, Ontario

Dr Louis Catania Philadelphie, Pennsylvanie

Dr Ron Melton Charlotte, Caroline du Nord

Dr Randall Thomas Concord, Caroline du Nord

Équipe éditoriale Éditeur Lawrence Goldstein

Directrice gérante Mary Di Lemme

Éditrice médicale Evra Taylor

Mise en page Colin MacPherson

Graphisme et design Mediconcept Inc.

Notre énoncé de mission Clinical & Refractive Optometry Quebec est une revue d’optométrie évaluée par les pairs produite en éditions imprimée et en ligne. La revue a pour mandat de publier des articles cliniques et scientifiques approuvés par COPE qui ont été accrédités par l’Ordre des optométristes du Québec (OOQ) et sont offerts comme cours donnant droit à des crédits UFC de catégorie A. Le contenu de cette publication est composé d’articles qui présentent une utilité ou un intérêt particuliers pour les praticiens professionnels des soins de la vue au Québec. Les participants qui répondent aux tests-questionnaires UFC contenus dans la revue et qui obtiennent une note de 50 % ou plus recevront un certificat de crédit UFC personnalisé par courriel.

Pourquoi la revue est-elle publiée en anglais ? Les règles concernant les crédits d’éducation permanente au Québec ont été amendées. Dorénavant, les articles de revue donnant droit à des crédits UFC qui ont été approuvés par COPE, le conseil créé par The American Regulatory Board of Optometry (ARBO), peuvent être offerts en version imprimée et en ligne aux optométristes du Québec pour des crédits UFC de catégorie A. Il est important de rappeler cependant que tous ces articles ont été à l’origine rédigés, approuvés et accrédités en anglais et ne peuvent être traduits ou reproduits dans une autre langue. Pour cette raison, tous les cours donnant droit à des crédits UFC de catégorie A offerts dans cette publication sont présentés en anglais avec l’approbation de l’Ordre des optométristes du Québec (OOQ).


Clinical

&Refractive Optometry Quebec

Contenu • volume 1, numéro 5, 2016 ARTICLES DE CRÉDITS UFC

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Principles of Dry Eye Disease: Diagnosis, Treatment and Management Pavan Avinashi, OD INTRODUCTION: Dr. Avinashi began his presentation by highlighting that dry eye disease certainly represents a major opportunity in optometric practice. Since 2007, when the Delphi panel issued a true definition of dry eye disease, it’s been a constant and continual evolving paradigm shift in the approach to treating dry eye. It’s no longer simply about giving a sample of an artificial tear and instructing the patient to use a hot compress at home with a towel and some warm water, which was and still is, common practice.

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Tear Dysfunction and Osmolarity: Tales from the Trenches Richard Maharaj, OD INTRODUCTION: Dr. Maharaj began his presentation by stating that he would be discussing new treatment options for dry eye, also referred to as tear dysfunction, comprising three areas: 1) Clinical approaches to diagnostics in terms of the ocular surface in tear dysfunction; 2) Several case studies revolving around treatment options; and 3) How to apply tear osmolarity testing in the primary eye care arena. He noted that he feels the concept of osmolarity is going to be gaining momentum with new diagnostics coming onto the market and may even differentiate how we traditionally have looked at tear film osmolarity.

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AREDS2 Controversies and Facts: Delving Deeper into our Knowledge on Eye Health Bernard Hurley, MD INTRODUCTION: Dr. Hurley described the objectives of his presentation: To recognize the impact age-related macular degeneration (AMD) has on Canadians; identify the risk factors associated with AMD; discuss the impact and limitations of the AREDS and AREDS2 studies; recognize the role of ocular vitamin supplementation in the management of patients; understand the status and limitations of pharmacogenetic testing today; and, finally, apply some of these to patients in everyday practice.

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Clinical & Refractive Optometry Quebec est publié six fois par année par Mediconcept. La revue est accessible à tous les optométristes praticiens du Québec à www.crojournal.com. Les commandes d’annonces et les textes doivent être reçus avant le premier jour du mois qui précède la date de publication. L’équipe éditoriale de Clinical & Refractive Optometry Quebec prend un grand soin pour assurer l’exactitude du contenu, mais nous recommandons toujours aux lecteurs de consulter les directives du fabricant avant d’utiliser les produits mentionnés dans nos pages. Les vues exprimées dans la revue sont celles des auteurs respectifs et non de l’éditeur. Veuillez faire parvenir toute correspondance à : Mediconcept Rédaction et service des ventes 3484, boul. des Sources, bureau 518 Dollard-des-Ormeaux, Québec Canada H9B 1Z9 Tél. bureau : (514) 245-9717 Courriel : info@mediconcept.ca Imprimé au Canada. Tous droits réservés. Copyright © 2016 Mediconcept. Le contenu de cette publication ne peut être reproduit par voie mécanique ou électronique en tout ou en partie sans l’autorisation écrite de l’éditeur. Toutes les publicités de médicaments ont été approuvées par le Conseil consultatif de publicité pharmaceutique.

Diagnosis and Treatment of Ocular Surface Conditions: Focus on Allergy Paul M. Karpecki, OD INTRODUCTION: Dr. Karpecki began his presentation by noting that he established his first dry eye clinic in 1997 and in the first ten years of ocular surface disease, there wasn’t a lot to teach about dry eye disease as we were learning as we went along. In addition, there wasn't much practitioners could do for success. In fact, he noted, his success rate was probably less than fifty percent. In a survey conducted before he joined Kentucky Eye Institute, approximately 96% to 98% of patients said they were satisfied or very satisfied with their treatment results. Dr. Karpecki mentioned that in the last six or seven years, great strides have been made in the management of the ocular effects of dry eye disease and allergies.

ISSN: 2369-498X; Date de ce numéro : Octobre/Novembre 2016

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Image de Couverture : Scleral contact lenses have been proven effective in severe dry eye disease. Gracieuseté de : Dr. Pavan Avinashi



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Clinical & Refractive Optometry Quebec is pleased to present this continuing education (CE) article by Dr. Pavan Avinashi, Hollyburn Eye Clinic, Vancouver, BC. This article has been approved for 1 Category A, UFC credit in Ocular Health by the Ordre des Optométristes du Québec. In order to obtain your credit, please refer to page 178 for complete instructions.

Principles of Dry Eye Disease: Diagnosis, Treatment and Management Pavan Avinashi, OD

INTRODUCTION Dr. Avinashi began his presentation by highlighting that dry eye disease certainly represents a major opportunity in optometric practice. Since 2007, when the Delphi panel issued a true definition of dry eye disease, it’s been a constant and continual evolving paradigm shift in the approach to treating dry eye. It’s no longer simply about giving a sample of an artificial tear and instructing the patient to use a hot compress at home with a towel and some warm water, which was and still is, common practice. First, he noted, that’s very mild superficial palliative care; and second, it’s not really treating or managing the problem. When patients are shown that something can be done above and beyond that, with a willingness to investigate things further, and that there are a lot of options in managing dry eye disease, they’re a lot more committed to the practitioner, with a greater degree of trust which will increase their retention and referral rates, as well.

PATIENT COMMUNICATION ABOUT DRY EYE DISEASE According to the literature, ocular surface disease occurs in as low as 10% of the general patient population to as much as 70% according to one Japanese publication. A common rule of thumb, said Dr. Avinashi, is that it occurs in almost one third of people who consult with an optometrist. The salient question, though relates to how many are being recognized and managed. Dry eye is a multi-factorial disease affecting people’s comfort, lifestyle and visual stability. Dr. Avinashi explains to his patients that the condition is associated with increased osmolarity, which is the tear composition, and that the underlying problem with dry eye disease is

P. Avinashi — Hollyburn Eye Clinic, Vancouver, BC Correspondence to: Dr. Pavan Avinashi, Hollyburn Eye Clinic, 1516 Marine Drive, West Vancouver, BC V7V 1H8 E-mail visualperformance@hotmail.com This article has been peer reviewed.

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inflammation. It’s not somebody stating that in the past few days they’ve had slight dryness in their eyes. Rather, these are patients who have tried various drops and have been suffering for years, with fluctuating vision as a result. When Dr. Avinashi diagnoses someone with episodic, chronic or recalcitrant dry eye disease, he feels it’s essential to tell them three things. Number one, that dry eye is a disease. If it’s not labelled as such, it’s not given the importance that it deserves. Number two, it’s crucial to mention that dry eye disease is chronic and progressive; it’s not something that will go away forever. It may go away for a while, it may be suppressed or managed, but it’s going to be there persistently. If these factors aren’t stressed, patients may not be on board for compliance for what is being managed or recommended. Number three, he always emphasizes to them that the underlying problem with dry eye disease is inflammation. He does this because the treatment modality of introducing oral omega-3 topical steroids, cyclosporine or anything else of that nature is justified by trying to manage the inflammation as well. In addition, sometimes patients associate the inflammation more with chronic conditions so this way at least there’s a correlation.

TEAR FILM MATRIX COMPOSITION In terms of the tear film, Dr. Avinashi stated, it’s essential to remember that the mucous layer has glycocalyx which act as a type of “cotton candy” to the corneal film. This is extremely important because with dry eye disease, when that gets compromised it also leads to apoptosis of the epithelial tissue and constant chronic conditions. Additionally, it’s where osmolarity can have a huge effect on stabilizing tear film at that level of the cornea and tear film. Dr. Avinashi explains to his patients that the tear film has many purposes but it’s a complex composition of many different elements that have to be addressed. Hence, when we’re mentioning things such as osmolarity nowadays, it’s an index of the composition of the tear film in the eyes. Regarding symptoms, one aspect that is always undermined is visual stability. One study showed that tear instability can constitute up to 20% of visual variability. When a patient complains of visual instability, dry eye disease can’t be ruled out. Risk factors include age,


Table I Systemic diseases associated with dry eye Inflammatory – Fibromyalgia, RA, SLE, Scleroderma, Osteoarthritis – Sarcoidosis, Raynaud’s, OCP – Thyroid Disease, Sjögren’s Neural – Bell’s Palsy, Compressive Lesions – IIIrd or Vth Nerve Damage/Disorders Hormonal – Post Menopause, Pregnancy – Rosacea

Infectious – Chlamydia, HZ, Viral URI Metabolic – Diabetes Mellitus, Amyloidosis – Vitamin A Deficiency Developmental – Ectodermal Dysplasia – Ichthyosis, Alacrima Medical/Therapeutic – Antihistamines, Decongestants – Sedatives, Anti-depressants – Beta Blockers, Diuretics – OCB, HRT Fig. 1 Tear film instability: a key underlying cause of dry eye disease.

female gender, contact lenses, medications, and autoimmune disease. Regarding medications, Dr. Avinashi noted that many medications have dry eye symptoms as a side effect, for instance, antihistamines.

SYSTEMIC DISEASES AND DRY EYE DISEASE While there are many systemic diseases associated with dry eye disease (Table I), Dr. Avinashi highlighted one that is often overlooked: diabetes. Depending on the studies being considered, 54% to 60% of all diabetics have some level of ocular surface disease. With these patients, cataracts and retinopathy are the main concern, rather than the ocular surface.

TEAR FILM AND OSMOLARITY There are two different categories of dry eye disease: aqueous deficient dry eye and evaporative dry eye. The proportion of patients with a level of evaporative dry eye as a component is close to 100%. While Dr. Avinashi has seen the reported figure as low as 60%, it’s generally considered to be 80%; however, he has read and believes that it’s close to 100%. It may not be in the earlier stages but at some point it’s going to develop into that. So the question that remains is whether or not optometrists are managing their patients correctly in light of this. By sending them home with the aqueous supplement tear and nothing else, are these patients being managed properly? The tear film is a causative mechanism of ocular surface disease. When the tear film becomes unstable, the epithelial tissue is breached and the layers are adversely affected which in turn causes a chronic cycle of inflammation (Fig. 1). This leads to local drying or hyperosmolarity of the exposed surface. This leads to a discussion of the second kind of causative mechanism. Osmolarity testing has been in existence for some time; however,

there is controversy about how valid the index is. Just in the last five years, more and more studies have been conclusive in the fact that this is actually a big parameter that has to be addressed, or at least looked at from the diagnostic perspective or a patient education perspective. The bottom line, noted Dr. Avinashi, is that a hyperosmolar tear film is an indication of an inflammatory environment. With an aqueous deficient tear flow and an unstable tear film, this leads to a hyperosmolar environment, which leads to cellular death, which leads to inflammation and it becomes a vicious cycle. Tear osmolarity on the ocular surface causes a decrease in aqueous production, so a hyperosmolar condition or environment innately decreases the aqueous and lipid production, evaporation is increased, and this causes an upregulation of inflammatory mediators. This accelerates the entire cycle of disease and it becomes an overall toxic environment for the tear film.

DIAGNOSTIC AND SCREENING TOOLS Dr. Avinashi stated that it’s critical to have a classification system for dry eye disease because that’s going to be the basis on which a treatment plan is developed. Furthermore, a comparison is needed when treating these patients six months or 12 months down the line. Screening for dry eye disease should comprise symptoms as well as signs. One of the best tools is a formalized questionnaire for dry eye disease, examples of which are the Ocular Surface Disease Index (OSDI) and the Dry Eye Questionnaire (DEQ). Another widely used questionnaire is the Canadian Dry Eye Assessment Guide (CDEA). Dr. Avinashi strongly suggests these as an introduction to dry eye management. While it may seem rudimentary and tedious, if the staff become involved and are educated

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on administering these questionnaires, they can provide a plethora of information. For example, the CDEA, a numeric value that helps guide the level of dryness, the severity of what the patient is experiencing from a personal perspective. This type of index with objective numbers is extremely valuable; whether it’s 3 months, 6 months or 12 months down the line, the questionnaire can be revisited and the number has a comparative value. Patients would return six months later asking what their number was and wanted to repeat the questionnaire to see if their situation had improved over the last visit. As a result, Dr. Avinashi came to the realization that its value was more for the patients as much as anything else. Furthermore, he emphasized that practitioners should look at more than tear breakup time. Everting the eyelids and expressing the meibomian glands should be standard tests done when managing dry eye disease patients. There are a lot of diagnostic tools and methods that can be used simply and inexpensively. Tear breakup time is the most commonly used test, measured with fluorescein. The use of fluorescein also helps give an indication of any type of epitheliopathy or punctate erosion of the cornea. However, with more practice, Dr. Avinashi also recommends using lissamine green. It greatly helps with further understanding the level of devitalized and desquamatized tissue of both the cornea and conjunctiva. He posed the question, “Knowing that essentially 80% if not 100% of ocular surface disease is evaporative, are optometrists currently doing a good job in evaluating meibomian glands?” The diagnostic approach has vastly changed in the last few years with the introduction of the Oculus Keratograph® (Arlington, WA). Regarding meibography, Dr. Avinashi mentioned that Innova (Laval, QC) has an excellent machine; and Topcon (Boisbriand, QC) has a great attachment. These imaging tests indicate the level of congestion through a black and white composite; they non-invasively measure tear breakup time and blink rate. The degree of meibomian gland atrophy can now be measured in terms of stages 1, 2 and 3. InflammaDry®, manufactured by Rapid Pathogen Screening Inc. (Sarasota, FL), is distributed by two companies in Canada. It’s an MMP-9 inflammatory marker test and it recently received FDA approval. It is another easy-toadminister, in-office diagnostic tool to help with the management of dry eye disease patients. One of its drawbacks, though, is that it produces a lot of false negatives.

TEAR OSMOLARITY As a key diagnostic tool, osmolarity testing provides a single biophysical measurement that denotes the balance of inputs and outputs. It’s now becoming increasingly accepted by many key opinion-makers and researchers across North America as being critical in the diagnosis of ocular surface disease management. Osmolarity has a

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greater sensitivity and specificity than other diagnostic tests and its objective number is critical in deciding on the treatment approach. A systematic review of 164 peer-reviewed articles related to the diagnostic value of tear osmolarity found that 72% were favourable and supported tear osmolarity as a diagnostic tool for DED. Numerous additional publications have underscored it as an excellent tool to use. Now, after many years, said Dr. Avinashi, there is another viable resource to use, a testing device produced by I-MED, a Canadian company. This testing device is so economical that if a practitioner is thinking even remotely to try getting into dry eye disease management, it’s almost a necessity to have in one’s practice. Even in the National Dry Eye Disease Guidelines for Canadian Optometrists (published in the Canadian Journal of Optometry, Vol. 76, Suppl 1, 2014), it actually says on the subject, “Tear film osmolarity is the most accurate single test for dry eye disease, but should not be used in isolation,” of course. It’s similar to the importance of tracking and setting goals in IOPs in glaucoma. Anytime Dr. Avinashi has a new patient for cataract surgery or a LASIK consultation, he measures osmolarity preoperatively and postoperatively. With any patient going into contact lenses, he uses this measure as part of his workup and assessment as it may guide in how he recommends contact lenses, as well. Osmolarity is measured in milliosmoles per litre and the statistical mean high normal value is 300 mOSm/L. Another element to consider is if there’s a variance in the osmolarity reading. Sometimes a reading in one eye is 290 and the other one is 302, which is still within normal and healthy range, but with that degree of variance between the two eyes, inflammation is producing the result. There are two major osmolarity testing devices on the market: The TearLab Osmolarity System® (TearLab Corporation, San Diego, CA) and i-Pen® (I-MED Pharma, Montreal, QC) a small hand-held device which Dr. Avinashi has used in his practice and has found to be very convenient and easy to use. He reported that he has found it a lot easier to use than TearLab and it has recently been made available to Canadian optometrists. With its favorable cost, he considers it a valuable asset. The difference between the two tests is that TearLab utilizes temperature controlled impedance measurements to provide indirect assessment of osmolarity, whereas i-Pen uses impedance measurements, but these are based on the extracellular fluid in the tear film. Dr. Avinashi stated that his staff uses this measurement process as part of the pre-test and the readings are very quick, especially with the i-Pen.

MANAGEMENT OF DRY EYE DISEASE As per the Canadian Optometry Guidelines, the goals are to reduce symptomology, return the tear film to a healthier state, and decrease the frequency of symptoms. While


Table II Comparative chart of artificial tears Preserved Tears

Gels/Ointments

Non-Preserved

Various Preservatives

Refresh Optive Advanced Refresh Optive Fusion Refresh Tears Refresh Ultra Tears Naturale Systane Ultra Systane Balance GenTeal HypoTears Liposic TheraTears Isopto Tears

Refresh Liquigel Tear-Gel GenTeal Gel Systane Gel Lacri-Lube Liposic Gel Tears Naturale PM HypoTears Ointment DuoLube Ointment

Refresh Plus Refresh Celluvisc Refresh Endura Refresh Unit Dose Bion Tears TheraTears Tears Naturale Free Systane Ultra Preservative Free i-drop HYLO Drops / Gel i-drop Pur i-drop Pur Gel

Purite BAK Polyquad Cetrimide Sodium Perborate

Certain artificial tears specifically address lipid tear film deficiencies – emulsion formula. Some have wound healing properties. Gentle, more acceptable preservatives with least disruption to the corneal surface are available.

practitioners may not be able to wholly fix a patient, but they can reduce the symptomology and definitely reduce the progression. With episodic cases, said Dr. Avinashi, this is where palliative care is standard. Using artificial tears and hot compresses is very important. Non-ocular considerations are sometimes overlooked for the sake of brevity, to get the patient out of the chair, or to encourage them to buy glasses, versus actually managing their disease. Patients’ medications, diet, level of alcohol consumption, whether or not they smoke, and environmental factors play an enormous role as well. In Vancouver, particularly, there are frequent climate changes, and Dr. Avinashi finds that with the higher pollen count he has a lot more patients with dry eye disease visiting his clinic.

ARTIFICIAL TEARS Dr. Avinashi is an avid advocate for tear supplementation. One of his maxims with any product in the realm of dry eye disease treatment is that practitioners should recommend what they sell and sell what they recommend. If optometrists are recommending a product but aren’t selling it, they’re encouraging the concept of patients going elsewhere for what they need and what has been recommended to them. It’s essential to get the staff on board, and to find products that are unique and above the average grade. He recommends first, selling items that patients can’t find in other practices; and second, creating more loyalty to one’s practice so that patients aren’t simply seeking out the lowest-cost products at big box stores. The practitioner’s responsibility is not to be cost sensitive to patients, but to provide them the best recommendations, whether it’s an artificial tear, a heat compress mask, a progressive lens, or a contact lens. In his view, optometry is far too conservative in terms of what the patient can and can’t spend. They need to be provided options, but should always be given the best one first.

There is a plethora of artificial tears (Table II), Dr. Avinashi noted that his view of artificial tears has greatly changed over the last few years. Most patients, roughly 80%, have evaporative dry eye disease, therefore, optometrists should be recommending lipid-based artificial tears. These patients are often consulting with their GPs and pharmacists for recommendations, and they’re using such products as Tears Naturale® 2 (Alcon, Mississauga, ON) and GenTeal® (Novartis, Dorval, QC). Dr. Avinashi regards these as antiquated given that there has been such an evolution in artificial tears and newer, more advanced products are available. When a patient consults with an optometrist, they may not even mention that they have dry eyes, yet they use a small amount of artificial tears. He advises that practitioners take the time to find out what patients are using because sometimes they become complacent about their drops. They aren’t even aware of which product it is and if it’s appropriate for their situation. Inform them that a customized drop is what they need, more than anything else. Sodium Hyaluronate Dr. Avinashi is a proponent of preservative-free artificial tears. For aqueous deficient dry eyes for which he doesn’t wish to use a lipid-based agent, he opined that if a practitioner isn’t prescribing a product containing sodium hyaluronate, they’re underserving their patient population. In the European market, said Dr. Avinashi, if someone took a poll of every artificial tear that was being offered, 70% of these would contain sodium hyaluronate. A few years ago in Canada, there were only one or two products; now there are perhaps eight, and in the next year or two there are going to be a lot more in the pipeline. Sodium hyaluronate is a polymer that is found in the body’s synovial joints, aqueous humor, many collagen cells, and in the corneal tissue, as well. It’s a natural lubricant and the reason it’s so effective is that it has

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viscoelastic properties with hypo-osmolar stability. Sodium hyaluronate increases corneal surface binding which is extremely beneficial to a dry eye patient. It enhances tear film stability, corneal wettability and corneal epithelial healing. Various studies have shown that it actually promotes corneal epithelialization, and in turn decreases the overall toxic environment of the ocular surface. It’s also has a positive effect on lid wiper epitheliopathy, a condition which a lot of optometrists don’t diagnose or manage. There are numerous preservative-free hyaluronate sodium products on the market, including those from I-MED Pharma, as well as HYLO™ (CandorVision, Montreal, QC) and others coming down the product pipeline. In addition, there are an increasing number of dermatology products incorporating it for its ability to create a more youthful appearance to the skin as the result of epithelial tissue healing. Hot Compresses Dr. Avinashi stated that hot compresses are another type of treatment that is not being properly managed by the profession. Whether acute or mildly chronic MGD, optometrists are telling patients about hot compress treatment, but aren’t going to the extent of educating patients regarding their proper application. Several studies have alluded to hot compresses as having some clinical effect on the meibomian glands. However, first, the compresses have to reach a certain temperature − between 41° and 43° Celsius; and second, they must be applied at that temperature for a minimum of 5-10 minutes. The Bruder® moist heat mask (Bruder Healthcare Company, Alpharetta, GA) and the dry heat TheraPearl® mask, distributed by Bausch + Lomb in Canada, are two masks Dr. Avinashi uses. He favors the Bruder version because it contains a moisture bead component, and provides enhanced comfort and durability. An additional consideration is that a moisture release hot mask will provide the meibomian glands increased heat. Lid Hygiene To ensure good lid hygiene, stated Dr. Avinashi, there are a variety of products available, such as i-Lid ‘n Lash™ (I-MED Pharma, Montreal, QC) which has sodium hyaluronate embedded in it. Patients with chronic eczema and irritation find this product very soothing to their skin.

CHRONIC DRY EYE DISEASE Dr. Avinashi is of the opinion that for chronic dry eye disease, optometrists shouldn’t be reticent to prescribe steroids, cyclosporine and anti-inflammatory prescription drops in order to properly manage and treat ocular surface disease. He feels that current treatment exists on a very

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superficial palliative level of care, rather than concentrating on long-term treatment that addresses the progression of the condition. Current short-term management of moderate to severe dry eye disease involves a steroid, whether it’s ketone- or ester-based. He prefers Lotemax® (loteprednol etabonate ophthalmic suspension, Bausch + Lomb, Vaughan, ON) not only because it has a high safety profile, but also because it has recently been launched in gel form in Canada, in a formula that contains 70% less BAK. This translates to substantially less stinging, extensive corneal interface time and improved results. In fact, the gel form of Lotemax has become the gold standard in the U.S. All of Dr. Avinashi’s patients are currently using the gel form; he uses the ointment only in certain cases. The duration of steroid use depends on the patient’s history, however, generally prescribes it q.i.d. for two weeks. Naturally, follow-ups are necessary to monitor IOP changes. He recommends Restasis® (cyclosporine ophthalmic emulsion 0.05%, Allergan, Unionville, ON) for long-term treatment. Studies have proven that practitioners don’t have to wait until a patient’s dry eye disease is at Stage 3 or a severe state to use Restasis, he said. Several studies have demonstrated that the patients who benefit most from a long-term anti-inflammatory such as cyclosporine are actually chronic mild and moderate cases. Essential Fatty Acids Dr. Avinashi explained that when he recommends omega-3 fatty acids, it’s critical to educate patients as to why he’s doing so, also noting the difference between properly formuated omega-3s and the generic forms. The 2014 Canadian Guidelines, as well as the U.S. Guidelines, are now recommending an omega-3 even in mild patients; they should be one of optometrists’ first lines of treatment. Especially in Vancouver, where there is strong interest in managing conditions more naturally, this is an important management modality to consider before prescribing any therapeutics. He always recommends omega-3s with a triglyceride base versus an ethyl ester base. Many omega-3 products have various ratios of EPA to DHA, but a high ratio of EPA to DHA 3:1 or 4:1 is needed to better target the ocular surface. GLA is a derivative of the fatty chain of omega-6, which may be counterproductive; however, in the proper ration with EPA/DHA it has been shown to have significant antiinflammatory properties effective in the inflammatory cycle of dry eye disease. This is also outlined in the Canadian Dry Eye Guidelines. The effective dose is typically 2,000 mg per day, and they should be taken with a meal for higher absorption. Several studies have outlined that it can take upwards of two months for any omega-3 to have a proper clinical effect.


MGD patients. He finds that it has some limited effectiveness for his MGD patients, but not nearly enough to rationalize spending $200 per treatment. Other new therapies on the market and in the product pipeline include those by Oculeve (San Francisco, CA), as well as Intense Pulse Light (IPL) treatment which works on the exterior of the dermis. It uses heat and intense light to act on meibomian gland atrophy. The initial results Dr. Avinashi has heard are that it’s extremely effective.

CONCLUSION Dr. Avinashi concluded his talk by presenting several key points for building a dry eye practice:

Fig. 2 Scleral contact lenses have been proven effective in severe dry eye disease.

Punctal Occlusion Dr. Avinashi feels that this technique has a role to play in dry eye disease management, but that it’s not as widely used in optometric circles. Ten or fifteen years ago, punctal plugs were routinely used whereas now practitioners use it at the end of the treatment process. When a plug is inserted it maintains the inflammatory mediators on the tear film which simply propagates the disease cycle. Scleral Lenses Dr. Avinashi began using scleral lenses two years ago because there were some patients in whom no matter what the treatment, the ocular surface symptomatology was still quite severe (Fig. 2). In patients with severe dry eye disease mini scleral lens have been proven successful. LipiFlow The debate concerning LipiFlow® (TearScience, Morrisville, NC), thermal pulsating treatment for the meibomian glands, isn’t about whether or not it works clinically, but rather, the duration of its efficacy and whether or not it is an end solution. In Dr. Avinashi’s view, the fee is high, at $1,500 per eye or per treatment, and is a prohibitive factor to many patients. Blephex The Blephex® concept is based on microblepharoexfoliation. It removes the biofilm plaque that builds up on lid orifices. While Dr. Avinashi thinks that it has a large part to play in optometric practice, he reserves it for his chronic anterior blepharitis patients, not necessarily his

Number one: Make a commitment to do so. For example, when using the slit lamp, make an active effort to look at things beyond simply the cornea and eyelids. Number two: Create protocols for treatment. Describe it in writing which always makes it official and, more importantly, involve and educate the staff. Treatment of dry eye is a constantly evolving technology. Whether it’s progressive lenses, contact lenses or therapeutics, if the staff isn’t being educated and updated, they’re not on board with the practitioner’s efforts and it’s difficult to build a practice without employee involvement. Number three: Refer to the National Dry Eye Disease Guidelines for Canadian Optometrists (CJO, Vol. 76, Suppl. 1, 2014), an excellent piece of literature that comprises everything concerning dry eye disease and provides a template for developing a dry eye disease practice. Number four: With the latest advancements in diagnostic testing such as the i-Pen from I-MED Pharma, focus on delivering customized therapeutics, and have in hand their osmolarity readings and tear breakup times. So when they return in six-months, or for their postoperative follow-up, or after treatment with cyclosporine, a comparison can be made. While these tests provide good information, practitioners should still customize a patient’s treatment and explain to them why this particular drop, lid wipe or hot mask is being recommended. Provide them information founded on science-based evidence that supports the treatment plan. Number five: Dr. Avinashi is a strong advocate of properly informing and educating patients. In his practice, if he admits someone to his dry eye clinic, he spends the time required to dialogue with them. If this isn’t being done, they’re not going to be compliant with the treatment plan being proposed. Number six: Don’t be afraid to aggressively treat inflammation in particular and Dry Eye Disease in general. ❏

Principles of Dry Eye Disease: Diagnosis, Treatment and Management — Avinashi

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Ce cours a été approuvé pour 1 crédit UFC de catégorie A en santé oculaire par l’Ordre des optométristes du Québec. Veuillez répondre à ce questionnaire et le soumettre pour notation avant le 31 mars 2018. Afin d’obtenir un crédit UFC de catégorie A, veuillez suivre les étapes suivantes : • Remplissez la section d’identification et répondez aux dix questions à choix multiple dans ce formulaire de demande de crédit UFC. • Faites un chèque de 25,00 $ à l’ordre de Mediconcept. • Postez votre formulaire de demande de crédit UFC ainsi que votre chèque à : CROQ, 3484, boul. des Sources, bureau 518, Dollard-des-Ormeaux, Québec H9B 1Z9. Si vous obtenez une note de 50 % ou plus, un certificat de crédit UFC approuvé par l’Ordre des optométristes du Québec vous sera envoyé pour vos dossiers.

CLIQUEZ ICI POUR IMPRIMER CE TEST DE CRÉDIT UFC ET L’ARTICLE Prénom :____________________________ Nom :______________________________________ Adresse :_______________________________________________________________________ Numéro

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QUESTIONNAIRE Principles of Dry Eye Disease: Diagnosis, Treatment and Management Pavan Avinashi, OD 1. ❑ ❑ ❑ ❑

According to the literature, what is the incidence of ocular surface disease in the general population? 10% to 70% 15% to 60% 25% to 50% 30% to 80%

2. ❑ ❑ ❑ ❑

One study showed that tear instability can constitute up to ______ percent of visual variability? 5 10 20 25

3. ❑ ❑ ❑ ❑

All of the following statements about Dry Eye Disease (DED) are true, EXCEPT: Osmolarity has a greater sensitivity and specificity than other diagnostic tests It’s progressive in some cases Lotemax® (loteprednol etabonate) has a high safety profile Level of alcohol consumption plays a role

Clinical & Refractive Optometry Quebec 1:5, 2016


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4. ❑ ❑ ❑ ❑

What percentage of diabetics have some level of ocular surface disease as reported in the literature? 23% to 43% 38% to 50% 49% to 52% 54% to 60%

5. ❑ ❑ ❑ ❑

What is the high normal level of tear film osmolarity? 300 mOsm/L 302 mOsm/L 303 mOsm/L 305 mOsm/L

6. ❑ ❑ ❑ ❑

All of the following can have an impact on DED, EXCEPT: Environment Smoking Diet Genetics

7. ❑ ❑ ❑ ❑

What percentage of artificial tears contain sodium hyaluronate? 50% 60% 70% 80%

8. ❑ ❑ ❑ ❑

What is the appropriate ratio of EPS/DHA to GLA in omega-3 supplements? 1:1 or 2:1 2:1 or 3:1 3:1 or 4:1 4:1 or 5:1

9. ❑ ❑ ❑ ❑

All of the following are recommended treatments for DED, EXCEPT: Long-term steroids Hot compresses Cyclosporine Preservative-free artificial tears

10. ❑ ❑ ❑ ❑

Approximately what percentage of patients have evaporative DED? 65% 70% 75% 80%

Principles of Dry Eye Disease: Diagnosis, Treatment and Management — Avinashi

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Clinical & Refractive Optometry Quebec is pleased to present this continuing education (CE) article by Dr. Richard Maharaj, Clinical Director, eyeLABS, Brampton, ON. This article has been approved for 1 Category A, UFC credit in Ocular Health by the Ordre des Optométristes du Québec. In order to obtain your credit, please refer to page 188 for complete instructions.

Tear Dysfunction and Osmolarity: Tales from the Trenches Richard Maharaj, OD, FAAO

INTRODUCTION Dr. Maharaj began his presentation by stating that he would be discussing new treatment options for dry eye, also referred to as tear dysfunction, comprising three areas: 1) Clinical approaches to diagnostics in terms of the ocular surface in tear dysfunction; 2) Several case studies revolving around treatment options; and 3) How to apply tear osmolarity testing in the primary eye care arena. He noted that he feels the concept of osmolarity is going to be gaining momentum with new diagnostics coming onto the market and may even differentiate how we traditionally have looked at tear film osmolarity. On the anatomical side, he reviewed that tears are made up of three layers, the aqueous, mucin and lipid, all coming from the lacrimal glands goblet cells and meibomian glands, respectively. There is also a sensory motor component where the eyelids start to play a role. In the way patients blink and the way their eyelids close, the aperture seal is extremely important. The combination of neurosensory and anatomical components is really the crux of a healthy ocular surface and a stable tear film.

TEAR OSMOLARITY AND THE INFLAMMATION CASCADE Dr. Maharaj stated that the basic concept is whether a patient has an isotonic, hypertonic or hyperosmolar tear film; in other words, a salty or non-salty tear (Fig. 1). Most practitioners have experience with Muro 128® (sodium chloride hypertonicity ophthalmic ointment, 5%, Bausch + Lomb, Vaughan, ON) which is a hypertonic solution that draws water out in order to dehydrate the tissue

R. Maharaj — Clinic Director, eyeLABS, Brampton, ON; Staff Optometrist, Humber River Regional Hospital - York/Finch Eye Associates, Toronto, ON; Clinical Adjunct Associate, University of Waterloo, School of Optometry, Waterloo, ON Correspondence to: Dr. Richard Maharaj, 7900 Hurontario, Suite 406, Brampton, ON L6Y 0P6; E-mail: rmaharaj@eyelabs.ca This article has been peer-reviewed.

180 Clinical & Refractive Optometry Quebec 1:5, 2016

it’s in contact with, for example, to treat corneal edema. If the patient’s eyes are being bathed in a hypertonic solution, the water will be drawn out of the tissue leaving it in a dehydrated state. What ends up happening as a result of the dehydration is a type of insult that starts the inflammatory process, with epithelial breakdown and an inflammatory cascade. It is therefore crucial to properly identify hyperosmolar patients early on because many times, hyperosmolarity precedes dry eye symptoms. Dr. Maharaj stated that there are various components to dry eye, namely anatomical impact, environmental impact and age-related changes. Any dysfunction in these areas will result in insult to the ocular surface. On the physiological side, there is activation of inflammation, as well as an immune response involving the T-cells. Restasis® (cyclosporine ophthalmic emulsion 0.05%, Allergan, Unionville, ON) which, Dr. Maharaj noted, targets the T-cell pathway, working on immunomodulation. The question is, at what point do optometrists address the inflammatory cascade equation as the primary eye care doctors? How can they enter this equation a bit earlier? With any disease, whether it is glaucoma, meibomian dysfunction or diabetic eye disease, for example, early intervention or risk reduction has always led to better prognosis. All of the factors mentioned above contribute to friction, which is actually what brings a patient to optometry offices. No patient comes for a consultation and says, “I feel wonderful, my eyes feel like butter and I think I have dry eye.” Until they feel it, until there is insult that they can actually describe, they’re not going to say anything. This leads to the issue of diagnostic criteria: How can practitioners identify risk factors for this friction? When considering the chronology of tear dysfunction, osmolarity tends to be an early indicator. Patients don’t start to feel anything until well after osmolarity has begun to peak and then their symptoms start to worsen. Longterm unmanaged hyperosmolarity can contribute to neuroinflammation which will inevitably lead to corneal hypoesthesia. Subsequently, the patient feels better as if to say, “It’s magic, I’m cured.” The question is not what the practitioner has done but what has the patient done? The natural history of untreated hyperosmolarity has led them to neuropathy and hypoesthesia, and in some cases dysesthesia, referred to as pain without stain by Dr. Perry Rosenthal of the Boston Eye Pain Foundation. The objective is to avoid them arriving at this point through


Concept of Hyperosmolarity Isotonic

Hypertonic

(no net exchange of water)

(net loss of water from ocular cells)

Tear Film

Tear Film

H2O

H2O

Surface of the eye

Surface of the eye

H2O

H2O Epithelial cells

Fig. 2 Reducing surface friction: Identifying the cause of friction is essential. electrolytes

Epithelial cells

electrolytes

Fig. 1 Tear hyperosmolarity triggers an inflammatory cascade.

Table I Role of the tear film 7 major functions of the tear film 1. Maintains hydration of the eye 2. Lubricates the ocular surface 3. Nourishes the cornea 4. Cleanses the ocular surface 5. Defends against bacterial invasion 6. Buffers the pH of the ocular surface 7. Refracts light for visual clarity

early intervention; and on this point, measuring osmolarity is the key. Figure 2 depicts a patient with damaged corneas or bilateral epitheliopathy, before and after treatment, who is planning on having cataract surgery. Identifying the source of friction requires an understanding of the tear film function, including seven major points listed in Table I, some of which the patient highlighted. The main objective is to maintain hydration. Second is to lubricate the ocular surface as lubrication leads to decreased friction which translates to less inflammation. The tear film is antibacterial as well. Finally, and again this is where patients may become symptomatic, the tear film actually helps the visual pathways so it transmits and refracts light. If a patient has a transient visual complaint, it’s important not to dismiss the tear film as a culprit in the differential diagnosis. A healthy tear film contains a complicated cascade of chemicals, including cytokines, proteins, mucin-related factors, and potassium, to name a few. Dr. Maharaj stated that it’s possible in the future there may be panel testing for these constituents because the tear film is actually very similar to blood in terms of the constituents. This panel testing is only as useful as existing targeted therapies to treat the specific components of a dysfunctional tear film. In comparison to blood, the water content of the human tear is similar and, in fact, the osmolarity overall is quite similar. If there is a wealth of information in the vascular

system, that same wealth of information resides in the tear film as well. For example, Google has already designed a contact lens that will measure a patient’s fasting glucose levels. Industry is looking at different ways to do this through the tear film because it’s more accessible than blood. Dr. Maharaj highlighted that it’s critical to understand that there are similarities and therefore, very likely, there are some answers that lie in the tears that may not have already been thought of. Regarding the proportion of dry eye patients in the average practice, some studies show that it has the highest prevalence of the major eye disease categories in general practices; because of this high prevalence, it makes sense to identify these patients and help them in a more meaningful way than we are currently. Dr. Maharaj remarked that early in his training and career, the treatment of mild corneal fluorescein staining would be one of a bag of various artificial tears, and the practitioner would advise the patient to use them as needed. That was, and perhaps still is in some cases, acceptable patient management. The report from the International Dry Eye Workshop (DEWS) in 2007 did an excellent job at raising awareness in both the academic circuit and in general in the eye care world, on the etiology and classification of dry eye. There are evaporative patients who are affected primarily by environmental factors, lid inflammation and surface anomalies; and there are aqueous deficient patients. Years ago it was thought that the majority of dry eye disease (DED) patients were aqueous deficient and treatment involved artificial tearing every single patient. The followup to the Dry Eye Workshop was the International Workshop on Meibomian Gland Dysfunction (MGD) in 2011 sponsored by the Tear Film & Ocular Surface Society (TFOS). The summary of that entire meeting pointed to MGD being perhaps one of the leading causes of dry eye around the world; we know now that evaporative and aqueous causes may not exist in mutually exclusive pools. In fact, noted Dr. Maharaj, they likely exist together on a spectrum, however, with aqueous patients specifically, it’s important to think about these various categories. The

Tear Dysfunction and Osmolarity: Tales from the Trenches — Maharaj 181


Fig. 3 A 52-year-old Asian female with moderate dry eye.

Sjögren’s cases, which probably represent an underdiagnosed population just because historical testing has demonstrated poor specificity and sensitivity for diagnosis. There is now a blood smear test available in the United States called Sjö which may help to increase identification of these patients. Additionally, there are medically induced cases resulting from certain medications such as antidepressants and antihistamines, among others. All of these categories affect aqueous production.

MEASURING OSMOLARITY For the purpose of tear film metric, osmolality and osmolarity are synonymous. Osmolality refers to measures in a solid state, while osmolarity is in a liquid state. It’s the concentration of osmoles or moles of a solute per liter of a solution. There are three main measuring methods, one of which is familiar to most practitioners. Freezing point depression uses the temperature at which a solution freezes below its normal temperature that can be calculated to an osmolarity value. It does require a rather large sample (0.2 µL) and it is not something that is amenable to a clinical setting. It is, however, a very accurate way of measuring osmolarity and is commonly used in academic settings. The converse to that is vapor pressure, the temperature above which a solution will vaporize. The difference between the temperature at which it vaporizes is calculated into an osmolarity value. The sample size required, 5 µL, sounds small, however, it is actually an extremely large sample for the average tear film of 7 µL. Collecting that amount is actually nearly impossible. The electrical impedance model is employed in glucose measuring systems, with which all optometrists are familiar. It measures the electrical impedance of a solution which is proportionate to solute concentration. TearLabTM

182 Clinical & Refractive Optometry Quebec 1:5, 2016

(San Diego, CA), for instance, uses this process. Tears have an ionic content and will alter its conductivity which is then calculated to yield an osmolarity value. Tear osmolarity actually came into the dry eye conversation in the 1970s. The late Jeff Gilbard, MD, an ophthalmologist, discussed and wrote extensively on osmolarity at that time. In the late 1980s, he wrote a paper on how it related to MGD, which was well ahead of his time. The paper discussed the relationship between osmolarity and meibomian gland obstruction, and it wasn’t until the 2011 MGD Workshop (TFOS) that there was actually a consensus about that relationship. In 2007 at the DEWS workshop, tear osmolarity was finally incorporated into the clinical definition of DED. It is a very strong indicator so it has the higher positive predictive value when compared to other metrics such as tear breakup, Schirmer, staining and tear meniscus height according to Lemp et al, 2009. Dr. Maharaj highlighted that one of his educational objectives for practitioners is to have a common language with which to speak intraprofessionally. Osmolarity is a concept that is agreed upon in both ophthalmology and optometry, so it’s an effective bridge when discussing patients.

CASE STUDIES Case #1 Dr. Maharaj presented several cases from his clinical practice, some of which are still in progress. The first is a 52-year-old Asian female who had had LASIK surgery two years prior (Fig. 3). She reported to the clinic with moderate symptoms. Dr. Maharaj quantifies his patients’ symptoms using the SPEEDTM (Standard Patient Evaluation of Eye Dryness score, TearScience, Morrisville, NC). It’s a very quick questionnaire that takes his technician five


Fig. 4 A case of progressive dry eye with meibomian gland atrophy.

minutes to complete and it provides a validated number from a measure of 28. This patient had a score of 16. Symptom scores are very helpful in the identification and management of patients’ symptoms because they provide the patient and practitioner a measurement to quantify their condition. This patient’s symptoms were consistent with moderate dry eye. Shortly after her LASIK she was put on Restasis OU b.i.d., so she had been on it for roughly one-and-a-half years. Dr. Maharaj noted that it typically takes a minimum of three months to appreciate clinical improvement. She was previously a monthly contact lens wearer who disliked wearing her lenses, which was part of her motivation for LASIK. Dr. Maharaj uses an Oculus Keratograph® 5M (Arlington, WA) for meibography, an infrared lighting system that examines the meibomian glands. In this case, it showed gland truncation, which signals gland atrophy measured on a Heiko Pult scale. It also showed the meibomian gland ductules were dilated, which is a sign of obstruction that can lead to meibomian gland atrophy. This is very telling of progressive evaporative dry eye. The patient presented with significant gland atrophy in both eyes, more so in the right than the left. Her osmolarity was 315 mOsm/L in the right eye and 327 mOsm/L in her left (Fig. 4). Additionally, Dr. Maharaj uses an MMP-9 indicator which measures the concentration of an inflammatory marker in the tear film and provides a positive or a negative result, similar to a home pregnancy test. Testing positive for MMP-9 generally signifies surface inflammation. MMP — matrix metalloproteinase — are proteolytic enzymes in the tear film that are produced by surface epithelium when under duress. This patient was MMP-9 negative (InflammaDry®, RPS Inc., Sarasota, FL) which would lead to the conclusion that she doesn’t have inflammation on her

ocular surface, despite her having a hyperosmolar tear film. Dr. Maharaj subsequently consulted with the patient’s optometrist who had done a tear analysis prior to her having LASIK. Her pre-LASIK osmolarity was 299 and 301; for reference, generally a number of 300 mOSm/L or below is considered “normal.” Even before the patient had LASIK, she was on the borderline between normal and mild dry eye. Now that she wasn’t wearing contacts anymore and her eyes were essentially naked to the air, she was becoming symptomatic. Then two years later, her osmolarity had increased. But why was her MMP-9 negative? Dr. Maharaj diagnosed the patient with untreated CLIDE, contact lens induced dry eye, even though she was a post-LASIK patient. Her tear breakup time at this particular visit was markedly reduced in both right and left. MGYLS is a meibomian gland yielding liquid secretion score, a standardized way to measure gland function by diagnostic expression to uncover glands secreting fluid. Dr. Maharaj measured 15 in a row, 5 nasal, 5 central and 5 temporal. This patient had MGYLS of 3 in her right eye and 1 in her left, and they were severely inspissated. She had evaporative dry eye which was exacerbated by her incomplete blinking which is very common in this population. At home she was diligent about using warm compresses with a microwavable heat mask. Dr. Maharaj explained that he tends to be conservative in his treatment, but in this case it was obvious that the patient needed more help than simply a hot compress at home. He used LipiFlow® (TearScience, Morrisville, NC) thermal pulsation which consists of in-clinic vectored heat therapy applied to the posterior gland surface combined with pulsatile pressure. It does a very good job of clearing out all the meibom and aims to leave behind a patent meibomian gland with which the patient can function. Dr. Maharaj then stopped administration of preservative tears and replaced them with i-drop® Pur Gel (I-MED

Tear Dysfunction and Osmolarity: Tales from the Trenches — Maharaj 183


Normal mOsm/L + irritation complaint Epithelial basement membrane dystrophy (EBMD) Conjunctival chalasis Demodex blepharitis Non-obvious meibomian gland dysfunction (MGD) Contact lens/solution toxicity Lagophthalmos

Tear Prism Solute Gradient

Hyperosmolar Meibomian gland dysfunction (MGD) Contact lens induced dry eye (CLIDE) Androgen deficiency Peri-surgical Sjögren’s syndrome

Low volume high solute

High volume low solute

+ + +++ +++ ++

Solute gradient towards low solute

++ + + ++ + + + + ++ + + ++ + +

Osmotic pressure

Table II Analysis of dry eye patient symptoms in consideration of osmolarity.

This is why normal mOsm/L with symptoms should not be assumed to resolve with cyclosporine A alone.

Fig. 5 Proposed pathway for measuring tear prism solute gradient.

Pharma, Montreal, QC), a non-preserved hyaluronic acid derivative which works very well in such cases. After one month, the patient’s SPEED score was reduced from 16 to 4. At this point she reported feeling “normal.” The take-home from this is that there was some information gathered preoperatively that was missed. When looking at her history and taking the reference mark of her osmolarity into account, suddenly the picture became a lot clearer. She could have been identified earlier and actually been pre-treated for her ocular surface disease, in which case, Dr. Maharaj opined, she would have done better. Dr. Maharaj questioned whether optometrists are doing enough for their contact lens patients and “insulating their contact lens practice.” He stated that the contact lens industry in general and the impact of competing forces are concerning to some practitioners in terms of possibly losing market share to retail environments with greater buying power. Dr. Maharaj has a differing point of view, namely that practitioners actually have an opportunity to really improve their contact lens healthcare. By identifying patients who are at risk for developing CLIDE, practitioners can build a care model around that to ensure that their contact lens patients are diagnostically screened, using a healthy product contact lens modality. Perhaps a reusable contact lens wasn’t the best idea for this patient; maybe she should have been on a one-day lens. He posed the question, “Can tear osmolarity help increase compliance; to get the patient who is paying two hundred dollars for a year’s supply of a monthly lens and stretching it to a two month lens, to understand why a one-day lens may be more suitable?” He feels that it’s very possible and suggested that a contact lens practice is a dry eye practice that can be enhanced for prevention of ocular surface related conditions. In 2011, Dr. Michael Lemp published a paper in Cornea that established the hallmark of what is now known as the defining number, with 308 mOsm/L as the cutoff point between normal and clinical dry eye disease. In his study of 146 patients, he showed that specificity of

184 Clinical & Refractive Optometry Quebec 1:5, 2016

tear osmolarity testing climbs when the osmolarity increases higher than 308. He also demonstrated that tear osmolarity (tOsm) as a measure had a very high positive predictive value, for people who have the disease. If a patient’s osmolarity is 327, there is a 95% chance the patient has dry eye disease. Dr. Lemp compared osmolarity to Schirmer, tear breakup time and Ocular Surface Disease Index. Osmolarity was the strongest predictor of DED among all measures. Marguerite McDonald, an ophthalmologist in the U.S., presented her work at 2013 ASCRS, examining the prevalence of dry eye in a large sequential cohort. They put patients through a very simple assessment including, demographic, history, and a yes or no series of questions, and then cross-referenced that against osmolarity. The study population was n=9,067. What they found was that of the patients were actually reporting dry eye symptoms, half did not meet the clinical criteria of 308 mOsm/L for dry eye, which is a very interesting finding. What is equally intriguing, said Dr. Maharaj, in fact more troubling, is that almost 50% of patients who were considered asymptomatic by the definition of the study, were hyperosmolar. These were patients who had a hyperosmolar tear film but were not reporting any significant symptoms. These are silent sufferers who are eventually going to develop this condition and are slipping through the cracks of treatment. These are LASIK and premium cataract patients who are possibly remaining underdiagnosed and this is where Dr. Maharaj feels practitioners can improve in identifying that patient base. The question is why do these patients have three or more symptoms if their osmolarity is “normal”? Table II explains this. A patient can have discomfort on the ocular surface without having a hyperosmolar tear film, depending on the stage of the condition. There is an entire host of conditions with which patients may in fact exhibit normal


Table III Tear osmolarity and MMP-9 categorization of OSD (Maharaj Ocular Surface Classification Model). Category 1

Category 2

Category 3

Category 4

Tear Osmolarity

Normal

High

High

Normal

MMP-9

Negative

Negative

Positive

Positive

Diagnostic Status

Non-DED

Early DED or on current MMP-9 targeted therapy Treat other aspects of tear dysfunction (MGD)

Moderate to severe DED

Postoperative CCh, EBMD, other etiology (diagnostically may not be tear dysfunction)

Fig. 6 A 69-year-old female patient, one-month post-surgery.

osmolarity. These include epithelial basement membrane disorders, conjunctival chalasis and non-obvious MGD. What is important to understand is that osmolarity isn’t there to classify the patient having one condition or the other, it’s actually meant to signal a practitioner to look more closely into the true etiology of the patient’s discontent.

MEIBOMIAN GLAND DYSFUNCTION One of the questions frequently asked of Dr. Maharaj is, “How does this tie in to meibomian gland dysfunction (MGD)? What do osmolarity and tear film have to do with the glands?” Dr. Anthony Bron in the UK published a paper that described the solute gradient (Fig. 5). Within the tear prism, there is a high concentration at the apex of the tear film and a very dilute concentration at the base; therefore, there is osmotic pressure being applied to the surface of the lid. The osmotic gradient actually forces solutes to the epithelial surface, contributing to the inflammatory process and eventual apoptosis. The epithelial cells, the meibomian gland surface, the orifice and then therefore the glands posterior to them, are being subjected to

insult, namely, inflammation and injury. This gradient is another reason to measure and ensure that osmolarity is being identified. The use of MMP-9 measures complements the use of osmolarity measurement similar to using both OCT and the visual field in a glaucoma patient. He stated that there are four possible scenarios, as shown in Table III. Category 1: The patient shows normal osmolarity and negative MMP-9, in which case they are considered normal. They don’t have or at least don’t meet existing clinical diagnostic criteria at this point to be considered having DED. Category 2: The patient may be hyperosmolar, but have a negative MMP-9. Recalling the case study previously outlined, the patient was on Restasis and it has been demonstrated in several papers that the drug inhibits the presence of MMP-9 on the surface. Therefore, generally speaking, this combination of findings is going to indicate either a patient who has early dry eye disease or a condition that is being pharmacologically managed. Category 3: The patient has a hyperosmolar tear film and has a positive MMP-9 measure. This patient most likely has moderate to severe dry eye and may require more

Tear Dysfunction and Osmolarity: Tales from the Trenches — Maharaj 185


pharmacological attention to control the inflammation. Category 4: Osmolarity is normal, however, the patient has a positive MMP-9. Dr. Maharaj pointed out that these four categories can help guide practitioners in their diagnosis and treatment of dry eye. The demographic of a dry eye patient is more consistent with being female than male and over the age of 50, who also tend to be decision-makers in their families. This profile represents the target for an optometrist’s primary care practice, and is certainly in a demographic that should be identified well in advance. In addition, in terms of pre- and post-surgical care, it’s vital to see these patients before they have surgery. It’s crucial to manage their osmolarity and tear dysfunction, or at least identify it and mitigate their risk of postoperative dryness, as demonstrated in the case below. Case #2 A 69-year-old female, one-month post cataract surgery OD, was referred to Dr. Maharaj by her eye surgeon. Her left eye was yet to be done and the difference in ocular surface staining is clear (Fig. 6). In fact, Dr. Maharaj saw this patient preoperatively after being referred initially for preoperative ocular surface optimization. He was asked to pre-treat her dry OS cornea preoperatively. The patient opted to have only one eye pre-treated. At this time OS was scheduled for surgery prior to OD, which eventually was changed. At this second presentation, OD showed that tear and ocular surface metrics were extremely poor. In addition, the patient had blink dysfunction — she wasn’t having full aperture closure due to floppy eyelid syndrome (FES) — and her tear breakup time was low. In terms of osmolarity and MMP-9, though, she was negative on MMP-9 and she did present with a hyperosmolar tear film 331 mOsm/L and 301 mOsm/L OD and OS, respectively. As a result, she fell into Category 2 (Table III). Did the patient have early dry eye disease or was she an MMP-9 targeted therapy? The fact that she was on postoperative Lotemax® (loteprednol etabonate 0.5% ophthalmic suspension, Bausch + Lomb, Vaughan, ON) which downregulates and decreases MMP-9 at the surface, it explains her negative MMP-9 result. Naturally, the patient was very uncomfortable with a severely compromised cornea and multiple sources of friction. Dr. Maharaj used a bandage contact lens (senofilcon A, Johnson & Johnson Vision Care, Markham, ON) which, he said, works very well for these cases. He also prescribed non-preserved hyaluronate and had the patient return for a follow-up. The purpose of the bandage contact lens was to decrease friction because the patient’s lid wiper was rubbing against her cornea and abrading it repeatedly, every time she blinked. He also continued her on loteprednol b.i.d. for another two weeks. In addition, he used his “triad treatment” which is a non-surgical meibomian gland treatment, which consists of eye lid scaling, meibomian gland expression and tear film neutralization with a basic mineral oil solution.

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The patient responded well to the combination of anti-inflammation with meibomian gland optimization via the triad treatment in follow-up care. Physiologically, the improvement in both signs and symptoms happens by managing the obstructive component to her MGD. The obstruction leads to a build-up of biofilm at the lid margin, which contributes to the inflammatory state at the surface. Gland clearance and removal of devitalized epithelium reduce the chemical burden of the surface and allow for more efficient epithelial repair. MMP-9 metrics were misleading in this case because her post-surgical topical regimen included loteprednol 0.5%. This case led into a review of William Trattler’s PHACO study (Prospective Health Assessment of Cataract Patients Ocular Surface Study) which was a prospective multi-centre observational pilot study of 143 patients scheduled to undergo cataract surgery. Key findings of the study suggested that the prevalence of DED signs is more common than frequently reported, with as much as 76.8% of patients testing positive for fluorescein corneal staining of which 50% had significant central staining. Dr. Maharaj opined that with the changing landscape of “premium” cataract and refractive surgery, it’s becoming more and more necessary to optimize the ocular surface. Failing to do so may impact the quality of surgical outcomes and therefore confidence in predicting refractive outcomes. He briefly discussed the study by Alice Epitropoulos, MD et al, in which pre-surgical patients with hyperosmolarity had a statistically significant greater variability in average K readings which impacted IOL power difference by more than 0.5 D. Of note, this difference was not observed when the same patients were grouped by self-reported dry eye, which highlights the value of tOsm as a significant preoperative measure. In a broader sense it further stands to reason that the ocular surface or the peri-surgical patient truly requires primary eye care by optometrists because the complications related to postoperative dry eye will inevitably fall into the hands of optometry long term. Case #3 Dr. Maharaj discussed a 27-year-old female patient, 2 months post-LASIK, who had chronic eye pain and peri-ocular discomfort as her chief complaint. She was a previous compliant contact lens wearer who did not report discomfort prior to surgery. She was prescribed Restasis b.i.d. OU by her surgeon, in addition to non-preserved hyaluronate q3-4h and larci-lube q.h.s. She was also using lid wipes for ocular hygiene. Despite having maximal symptom scores (SPEED=28), her pain was disproportionate to her clinical findings as noted on the incoming referral, as well as during presentation to the dry eye clinic. Oxford staining was <1 OD and OS, TBUT 6s OD, 7s OS, and tOsm 289 and 285 mOsm/L OD and OS, respectively. MMP-9 was negative and tear volume was normal. When referencing Dr. Maharaj’s categorization of


ocular surface disease by MMP-9 and tOsm, this patient falls into Category 1 – Non-DED. An increasing diagnostic entity that both parallels and intersects with DED is neuropathic pain. These cases can be particularly frustrating and often get lumped together by clinicians as the “crazy patient” who cannot seem to be pleased. However, Dr. Maharaj noted, it’s in fact a real entity, but due to diagnostic limitations can only be confirmed by exclusion and careful examination of clinical history and presentation. Managing neuropathic pain can be treated by managing the cyclo-oxygenase (COX) pathways (1 and 2) via COX inhibition, by use of human autologous serum (ranging in 20% to 40% concentrations), and some evidence has pointed to amniotic tissue transfer having some impact on nerve repair. Amniotic tissue in both cryopreserved and dehydrated options has demonstrated efficacy anecdotally with rapid reduction in pain with healing corneas, with cryopreserved possibly having superior impact on nerve repair. Although this list isn’t exhaustive, it represents a cursory review of current literature on pharmacological options for this group of patients. On discussion with the patient and her surgeon, she was initially managed with topical NSAID Prolensa® (bromfenac 0.07%, Bausch + Lomb, Vaughan, ON) q.d. for 1 month with the option of human autologous serum vs. amnion membrane transfer to be considered after 1 month. At the time of this lecture, the patient had sought out ocular surface reconstruction by a U.S. surgeon in addition to meibomian gland intraductal probing and was currently receiving that care. This prompted a short discussion on another commonly dry eye masquerader known as conjunctival chalasis, which is noted by conjunctival redundancy due to loss of Tenon’s fascia causing displaced tear fluid from the ocular surface and mechanical rubbing. Again, in review of Dr. Maharaj’s categorization, these patients may likely fall into Category 4. Case #4 A 63-year-old female presented to the dry eye clinic with a large OS central corneal abrasion. What made the treatment of this case more complicated was that the patient had previously arranged same day travel to Calgary. Although it was her first visit to the clinic, the patient noted a long history of recurrent corneal erosions (RCE) occurring almost monthly. Dr. Maharaj noted that the diagnostic difficulty of this case was low, however he highlighted that the long-term treatment would become more relevant as an educational tool. She was fitted with a bandage contact lens (senofilcon A, Johnson & Johnson Vision Care, Markham, ON) and started on topical Vigamox® (moxifloxacin hydrochloride 0.5%, Alcon, Mississauga, ON) t.i.d., and Muro 128. Arrangements were made for her to follow up with a colleague in Calgary the next day so as not to disrupt her travel. She responded well to therapy and the bandage lens was removed in Calgary 3 days later, with complete visual recovery.

At her two-week follow up back at the dry eye clinic, she received a full ocular surface work-up due to her frequency of RCEs. InflammaDry testing showed positive for MMP-9 which, along with clinical history, resulted in this patient being put on a two-month course of oral doxycycline 50 mg, in addition to loteprednol 0.5% b.i.d. in the affected OS. She was also started on non-preserved 0.3% hyaluronate (i-drop® Pur Gel, I-MED Pharma, Montreal, QC) for the duration. The choice of this combination was based on multiple studies relating MMP-9 inhibition to reduced RCE episodes. Dr. Maharaj reviewed the literature demonstrating oral doxycycline’s efficacy at reducing MMP-9 activity in corneal epithelial cultures, in addition to the benefits of low dose (20 mg) doxycycline when compared to anti-infective doses (200 mg b.i.d.). Whenever prescribing this combination however, patients should always be warned of the potential gastrointestinal discomfort and UV skin sensitivity when taking oral doxycycline, and this medicine should be avoided in patients who are pregnant, nursing or under the age of 13. Finally, Dr. Maharaj concluded the presentation by reviewing the osmolarity systems, with TearLab being one of the devices currently available for clinical use. He also introduced the i-Pen® osmolarity meter (I-MED Pharma, Montreal, QC) which was launched in June 2016. Dr. Maharaj remarked that he has been betatesting the system since July of 2015 and has been involved in some clinical studies using the i-Pen in a DED prevalence study that is yet to be completed. He reminded the audience of his disclosures, particularly his consultancy with the manufacturer, but he is not financially benefiting from this product.

SUMMARY Tear osmolarity represents the single-most defining metric of DED and based on current literature can uncover up to 50% of silent dry eye sufferers in primary eye care practices. Optometry’s role in contact lens care and peri-surgical care is growing rapidly, therefore Dr. Maharaj reminded the audience to identify these patients early and pre-treat surgical cases so as to optimize outcomes. Lastly, tear chemistry represents one of the most interesting areas of DED from both a diagnostic and therapeutic perspective. Using the Maharaj Ocular Surface Classification Model (Table III) as outlined in the cases discussed, the combination of tear osmolarity and MMP-9 may provide clinicians with a tear panel to better classify patients and therefore improve targeted treatment outcomes. He finished by articulating his passion for this area of care and emphasized that optometry’s growing role in managing anterior segment diseases will only grow, so keeping abreast of current literature and treatment options is vital to the growth of the profession. ❏

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QUESTIONNAIRE Tear Dysfunction and Osmolarity: Tales from the Trenches Richard Maharaj, OD, FAAO 1. ❑ ❑ ❑ ❑

Which of the following conditions has the highest prevalence of the major eye disease categories in general practices? Diplopia Blepharitis Open-angle glaucoma Dry eye

2. ❑ ❑ ❑ ❑

At what level of tear osmolarity will a patient be suspected of having dry eye disease? 290 mOsm/L or more 300 mOsm/L or more 305 mOsm/L or more 310 mOsm/L or more

3. ❑ ❑ ❑ ❑

All of the following statements accurately describe the patient in Case #1, EXCEPT: She had a SPEED score of 14 Her symptoms were consistent with moderate dry eye She was previously a monthly contact lens wearer She had previously had LASIK surgery

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❑ ❑ ❑ ❑

According to the literature, approximately ______ percent of patients who were considered asymptomatic were hyperosmolar? 30 40 50 60

5. ❑ ❑ ❑ ❑

All of the following statements accurately describe the patient in Case #2, EXCEPT: She had blink dysfunction Her tear breakup time was normal She was negative on MMP-9 She had hyperosmolar tear film

6. ❑ ❑ ❑ ❑

According to William Trattler’s PHACO study, approximately what percentage of patients tested positive for fluorescein corneal staining? 50% 58% 67% 77%

7. ❑ ❑ ❑ ❑

The following statement regarding the patient in Case #3 is TRUE: Her chief complaint was peri-ocular discomfort Her SPEED score was 26 Her MMP-9 was positive Her tear volume was low

8. ❑ ❑ ❑ ❑

All of the following statements accurately describe the patient in Case #4, EXCEPT: At her initial presentation to the clinic, she showed no history of corneal erosions At her initial presentation to the clinic, she was fitted with a senofilcon A bandage contact lens At her two-week follow-up at the dry eye clinic, she showed positive for MMP-9 At her two-week follow-up at the dry eye clinic, she was prescribed oral doxycycline 50 mg

9. ❑ ❑ ❑ ❑

All of the following are components of dry eye, EXCEPT: Anatomical impact Genetic impact Environmental impact Age-related changes

10. ❑ ❑ ❑ ❑

All of the following statements about MMP-9 are true, EXCEPT: A patient can show normal osmolarity and negative MMP-9, in which case they are considered normal A patient may be hyperosmolar, but have a negative MMP-9 Hyperosmolar patients treated with cyclosporine will have a positive MMP-9 Lotemax® (loteprednol etabonate) down-regulates and decreases MMP-9 at the surface

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4.

Tear Dysfunction and Osmolarity: Tales from the Trenches — Maharaj 189


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Clinical & Refractive Optometry Quebec is pleased to present this continuing education (CE) article by Dr. Bernard Hurley, Assistant Professor, University of Ottawa Eye Institute, Ottawa ON. This article has been approved for 1 Category A, UFC credit in Ocular Health by the Ordre des Optométristes du Québec. In order to obtain your credit, please refer to page 198 for complete instructions.

AREDS2 Controversies and Facts: Delving Deeper into our Knowledge on Eye Health Bernard Hurley, MD

INTRODUCTION Dr. Hurley described the objectives of his presentation: To recognize the impact age-related macular degeneration (AMD) has on Canadians; identify the risk factors associated with AMD; discuss the impact and limitations of the AREDS and AREDS2 studies; recognize the role of ocular vitamin supplementation in the management of patients; understand the status and limitations of pharmacogenetic testing today; and, finally, apply some of these to patients in everyday practice.

IMPACT OF AREDS2 ON AGE-RELATED MACULAR DEGENERATION He began by discussing the scope and effects of macular degeneration, a neurodegenerative condition at the center of the retina. It takes away patients ability to read, to recognize and see their family, to drive, and to live an independent lifestyle; and it's a disease that has a huge impact on society. Ophthalmologists are seeing an overwhelming number of older patients; because of the genetic makeup of the patient population, AMD is a very common condition in Canada that is having huge impacts. Thankfully now, there are treatments available. Beyond the impact on the patient themselves, however, this condition has a huge impact on the families as well. Dr. Hurley mentioned that he sees this frequently in his clinic. Patients coming in month after month to get their treatments for wet macular degeneration, which involves family having to take time off work and find time to drive mom or dad there. People are losing their independence. I have many patients who come in, they've been the driver for their spouse for many years and now they're not able to B. Hurley — Assistant Professor, Department of Ophthalmology and Residency Program Director, University of Ottawa Eye Institute, Ottawa, ON Correspondence to: Dr. Bernard Hurley, University of Ottawa Eye Institute The Ottawa Hospital, General Campus, 501 Smyth Road, Box 307 Ottawa, Ontario K1H 8L6; E-mail: bhurley@toh.ca This article has been peer-reviewed.

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drive; their spouse is so dependent on them to get them from place to place and now they're both dependent on other family members. So it greatly affects family dynamics. It has a huge impact on other conditions, as well. Depression is becoming much more common, in addition to falls and hip fractures; and people who lose their vision don’t live as long as those who see well. There are several studies on this. Dr. Hurley mentioned his colleague in Ottawa, Ralph Buhrmann, who had studied the impact of visual acuity on life expectancy. There are over a million people in Canada with macular degeneration today. More Canadians now live with AMD than breast cancer, prostate cancer, Parkinson's disease, and Alzheimer's disease combined.

RISK FACTORS Naturally, the most significant risk factor for AMD is age and that can’t be changed. Nor can other risk factors such as family history and ethnicity. There are however, a few things that can be controlled. Smoking and risk factors for cardiovascular disease are, in fact, more important than any vitamins or pills, or extra things patients can do. Getting a patient to stop smoking, can have more of an effect on their risk of macular degeneration than anything else. Dr. Hurley stated that advising patients to stop smoking should be part of ophthalmologists’ clinical interactions (not just to help their AMD but to improve overall health as well). Other risk factors are blood pressure control, healthy diet and staying physically active. All of these have been shown to be very helpful for macular degenerations and, of course, the patient's overall health. Often patients want a pill or medication to help them with their disease, but the basic principle is that keeping the patient healthy keeps their eyes healthy.

STAGES OF MACULAR DEGENERATION The stages of macular degeneration are important. The AREDS studies set up categories 1 through 4 (Fig. 1). In category 1, there are just a few small drusen. In category 2, there are what they call some intermediate size drusens, between 63 and 124 microns. People always ask how they arrived at the number of 124 microns to define the size of a large versus an intermediate drusen, and it actually


Stages of AMD: AREDS Categories • AREDS Category 1 (No DMLA) Fewer than 5 small (<63 µm) drusen • AREDS Category 2 (Early DMLA) Multiple small drusen or some intermediate size (63-124 µm) drusen in 1 or both eyes

Category 1

• AREDS Category 3 (Intermediate DMLA) Extensive intermediate sized drusen in both eyes, more than one large (>125 µm) druse, or geographic atrophy that did not involve the center of the macula

at baseline. Dr. Hurley noted that this is important and is often lost on people because they think that studies have shown that supplements will help everybody with AMD; however, they do not. The studies have only shown vitamin supplementation help people who progress at a more rapid rate, in category 3 or 4 on the AREDS rating scale. If a patient had either the large soft drusen or had already lost vision in one eye, the chances of progressing to further vision loss were much greater. Those are the people that had a sufficient rate of progression that a treatment effect was shown in the AREDS studies. This is a very important point.

Category 2

FINANCIAL BURDEN OF AMD

Category 3

• AREDS Category 4 (Advanced DMLA) Central geograpgic atrophy or neovascularization causing vision loss in one eye Category 4

Fig. 1 AREDS staging of AMD.

makes sense. The width of the retinal vessels as they cross the optic nerve shows what 125 microns look at in the eye. To understand how big a drusen is, compare it to the size of the blood vessels and that helps differentiate the large versus the intermediate drusen. Category 3 signifies intermediate AMD and category 4, advanced AMD; category 3 has the larger drusen and in category 4, the patient has already suffered vision loss in one of their eyes. They will have either central geographic atrophy or a choroidal neovascular membrane that's already reduced the vision in one of their two eyes. Dr. Hurley explained that these categories are important because they serve to define the rate at which patient’s AMD will progress. In category 1 or category 2, with very minor changes in the back of the eye, the chances that the patient will progress over 5, 7 or 10 years is extremely low. Those patients are very safe; practitioners can encourage them, explain that they have perhaps a couple of drusen, a couple of gray spots in the back of their eyes, but their probability of losing vision to macular degeneration is extremely low. It’s so low, in fact, that studies couldn't show any treatment effect for patients in these categories who have low likelihood of progression

Vision loss secondary to AMD represents a huge cost in Canada. There's the cost of optometrist and ophthalmology visits, the direct health care costs, all of the related injections, the cost of the medications, the emergency visits all of which amount to an enormous expense. However, there are indirect costs beyond this. These include the loss in productivity, the fact family and friends have to be taken out of their jobs to accompany patients, the transportation to get people to their appointments once they suffer vision loss. Dr. Hurley expressed his enthusiasm that there are, in fact, ways to save money, as described in the optometry white paper that was published in Ontario. It’s a pivotal document providing evidence that there are significant savings – up to $13 million – that can be realized if people are started on ocular vitamins. The paper also proposed a lot of other ways to save money in eye care and Dr. Hurley highlighted that he is a big proponent of reducing cost. The document stipulates that when people have eye problems they should see their optometrist instead of going to the emergency room, along with many other ways of achieving savings that can be realized in macular degeneration.

AREDS TRIALS Regarding the AREDS1 and AREDS2 trials, the first AREDS trial was being done just as Dr. Hurley entered his professional training in ophthalmology. It was of course a landmark study, a huge effort put forth by major funding organizations in the U.S. With the original AREDS trial, at the time, people thought that practitioners could supplement patients with vitamins, specifically, antioxidants and other components that would help break down oxygen free radicals within the eye. That was being proposed, but there were a lot of people with strong resistance against it. Several of the authors of the original AREDS study really felt that there was no proof these supplements were doing anything and that practitioners could be wasting patients’ money. Some who participated thought that the hypothesis of the benefits of vitamins

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Original AREDS AMD Randomization Placebo N=903

Participants received:

Antioxidant N=945

Randomized AMD Participants (Category 2, 3, 4 AMD) N=3640

Vitamin C (500 mg) Vitamin E (400 IU) Beta carotene (15 mg)

Participants received:

Zinc N=904

Zinc oxide (80 mg) Cupric oxide (2 mg)

Antioxidant + Zinc N=888

Mean follow-up = 6.3 years Fig. 2 Neither lutein nor zeaxanthin were readily available for manufacturing in a research (oral) formulation. The original AREDS study included a true placebo group.

would be disproved and that the study would show that taking certain supplements wasn’t helpful at all. As is common knowledge, it became quite the opposite. The objective of the trial was to examine if high-dose vitamin C, vitamin E, beta carotene and zinc slow the progression of AMD and AMD-associated vision loss. They knew at that time that the macular keratinoids such as beta carotene and others were important, but at the time of AREDS1, beta carotene was the only one that was really available as a supplement. Lutein and zeaxanthin weren't yet available in the commercial form that could be easily given to patients. So they looked at the antioxidants, vitamins, beta carotene and zinc, and they asked the question: The data suggest that these are beneficial, however, do they actually delay the progression of AMD and vision loss? They randomized nearly 4,000 people into four groups; the placebo group received the water pill, antioxidants, vitamin C, vitamin E and beta carotene; the zinc group – of course one can't give zinc alone or the person

192 Clinical & Refractive Optometry Quebec 1:5, 2016

will become anemic so copper has to be added to it. Finally, there was the group that received both the antioxidants and the zinc (Fig. 2). The mean follow-up at the time was 6.3 years but, of course, there has been longer data since the initial publications. The take home message from the AREDS trial, for patients who were lucky enough to be randomized to the group that received the zinc and the antioxidants, was that their risk of progression of vision loss was reduced provided they had AREDS category 3 or 4 in macular degeneration. The greatest driving factor was the zinc, so those with the antioxidants did slightly better; those with the zinc did a lot better; the patients with the zinc and the antioxidants were better off still. The number that is always quoted is 25% relative risk reduction in the group that received both the antioxidants and the zinc. That was the key table message; 19% reduced risk for vision loss in those patients, however, the primary take home message is the delayed development by about 25% of advanced AMD.


AREDS2 Study Design Primary Randomization:

Randomized participants

AREDS with Lutein and Zeaxanthin, DHA + EPA, or Both

N=4203; Mean age = 73 years

Lutein and Zeaxanthin 1044

Control 1012

Secondary Randomization

Variations of the AREDS Formula 3036

AREDS with no ß-Carotene with low-dose Zinc, or Both

AREDS 659

DHA and EPA 1068

Lutein/ Zeaxanthin + DHA/EPA 1079

AREDS minus ß-Carotene 863

AREDS + Low Zinc 689

AREDS minus ß-Carotene + Low Zinc 825

Fig. 3 AREDS2 study design comprised 16 groups of subjects.

ROLE OF OMEGA-3 FATTY ACIDS Within that study, said Dr. Hurley, and at the time there was some suggestion that even more than this could be accomplished. The omega-3 fatty acids were really being touted at that time to be beneficial for the eye in terms of dry eye, ocular inflammation, cataract and AMD, as well. So people began to look at it as a nested cohort study within the original AREDS data and there was certainly some strong evidence there that if omega-3 fatty acids were added these patients could be helped. If they were taking in their diet more of the omega-3 fatty acids, their risk of going on to develop choroidal neovascularization or central geographic atrophy was less. The question was: Could the results be even greater if these patients were given the omega-3 fatty acids? This was a cohort study meaning that it wasn't set up to prove a hypothesis; the researchers didn't randomize and

didn't try to control other variables; it was simply looking at the data afterwards. There certainly was a suggestion that it would be beneficial and most people jumped on the bandwagon, including Dr. Hurley. I thought it would be great to give people something else that would help even more. One has to understand the limitations of cohort studies like this. Was it the omega-3 fatty acids that were driving the initial benefit or was it something else? People who ate a lot of fish and took in their omega-3 fatty acids, were they just healthier in general? Were they exercising more? Were they less likely to be doing something that was harmful? Was it not the omega-3 but something else associated that was actually causing the benefit? The researchers went on to set up the AREDS2 trial to look at the effect of the omega-3 fatty acids, but to also look

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at lutein and zeaxanthin because both of them were now commercially available and were proposed to provide more benefit for the eye as well. In addition, there was the issue of beta carotene which is associated with higher risks of lung cancer in smokers. It was considered medically unsound to supplement somebody who was a smoker or a recent ex-smoker with beta carotene because it could increase their risk of lung cancer at the expense of trying to protect their eyes. As a result, they were looking at whether or not they could eliminate that risky component of the original AREDS formula. Zinc was also an issue; in Canada, it was very controversial because of reports that it was causing GI upset, that it was having an effect on the genitourinary tract. The question was whether or not there was too much zinc, and was it making the AREDS supplements less tolerable to patients? Could the amount of zinc therefore be reduced? The researchers wanted to look at all the elements: lutein, zeaxanthin, the omega-3 fatty acids, the effect of eliminating the beta carotene to make the formulation safer, and also, reducing the zinc dose. They hypothesized that if lutein, zeaxanthin and the omega-3 fatty acids could be added, patients would get more bang for their buck and one could further reduce the rate of progression in macular degeneration.

AREDS2 TRIAL Similar to the first AREDS trial, in AREDS2, approximately 4,000 people participated. It was a very well-run study with close follow-up over many years. It was a complicated double randomized design (Fig. 3). The first randomization decided whether or not they would get the lutein and zeaxanthin or the omega-3 fatty acids. Then there was the group that received both, as well as the control group. Dr. Hurley pointed out that at this time, it had already been proven that AREDS1 was overwhelmingly beneficial to the patients so one couldn't withhold the standard of care. Therefore, they all had to get AREDS1 supplements to participate in the study. So everybody got the AREDS1 formulation, therefore, the control group was actually AREDS1 supplements. The second randomization was, which variant of the AREDS1 supplement did a subject receive? All of the groups were secondary randomized. One either got the standard AREDS formulation or the AREDS without the beta carotene; or one got the AREDS with the low zinc; or the AREDS without the beta carotene and the low zinc. This amounted to sixteen different groups of patients within the study. So there was a lot of analysis to be done and the analysis surprised some of the researchers, including Dr. Hurley, because they were really looking for additional benefit being conferred from the omega-3 fatty acids. However, the raw data indicates that the people who were

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given just the omega-3 fatty acids did half a percent worse than those who were getting the original AREDS formulation. So if one added omega-3 fatty acids, lutein and zeaxanthin, there wasn’t as much benefit as with only the lutein and zeaxanthin. It looked like the additional conferred benefit in the second AREDS trial was from the lutein and zeaxanthin. For the group that was lucky enough to be randomized into the group that received the lutein and zeaxanthin, that further reduced their risk by an additional 10%, on top of the benefits from the first AREDS study. The risk reduction was better for those with lower dietary intake of lutein and zeaxanthin. With the lutein and zeaxanthin, without the beta carotene, again, patients did better than if they had all three macular keratinoids. So lutein and zeaxanthin as a replacement for the beta carotene conferred additional benefit, and it was better if patients didn't get the beta carotene at all. There have been some suggestions that one of the limitations of this study is that they took a group of well-nourished, highly motivated, educated people that were interested in staying in a clinical trial for the next ten years and were very concerned about their health. There is debate surrounding the notion that they don't truly represent the general population seen in practitioners’ clinics. They may not be as well-nourished, they may be eating at McDonald's more often than is desirable, they may not be as physically active, and may not be as compliant. As a result, there are suggestions that if a person’s diet is poor, this is even more beneficial. But again, those are just suggestions that have been raised and one can't read into it too much based on the hard fact that the only number that can be quoted is that an additional 10% benefit is conferred if the lutein and zeaxanthin are added. Dr. Hurley related that the researchers were surprised that the omega-3 fatty acids didn't provide the benefit they had been expecting, but he doesn’t tell any of his patients who are taking omega-3 fatty acids to stop them. There was no harm in taking them but they just couldn't say, “You've got to take them now for your wet macular degeneration or for your macular degeneration.” They now could only say, “This doesn't seem to help your macular degeneration but there are other studies that suggest that they're helpful from a neurological standpoint, a cardiovascular standpoint, and with other eye conditions such as inflammation and dry eye.” Practitioners just can't suggest that people take them to specifically address their concern of vision loss due to AMD.

SAFETY PROFILE Dr. Hurley stated that there were no safety concerns raised by either of the AREDS studies. He mentioned that he always highlights the take home message that in the AREDS studies, if a person was lucky enough to be randomized to the group that was actually getting treatment as opposed to the placebo group, their overall mortality was better. People on the AREDS supplements lived longer than their cohorts according to the first and second studies.


VITAMIN AND MINERAL SUPPLEMENTS Regarding beta carotene, Dr. Hurley noted that it can be safely removed from the regimen, ending the controversy revolving around putting people at risk for lung cancer by giving it to them. If it’s replaced with lutein and zeaxanthin, it produces a better outcome. In terms of smoking, with Canada’s current aging population, they came from a generation where smoking was much more common. Sadly, it's starting to become more common again among youth. Based on the AREDS studies that became the standard of care in North America, the new formulation can be used safely regardless of the patient's smoking status. The National Institutes of Health (NIH) came out with the strong recommendation to use AREDS2 supplements and the American Academy of Ophthalmology supported it. Their position papers tell practitioners more about how to manage these patients beyond just vitamin supplements, but evidence level 1 states to use AREDS supplements for intermediate category 3 and advanced category 4 AREDS, so it has the highest level of evidence associated with it. The same information was contained in the Canadian guidelines based on an expert consensus from Canadian practitioners about not only dry but wet macular degeneration, as well. However, regarding the dry form, again, the highest level of evidence supports the use of ocular vitamin supplementation for patients in category 3 or category 4. Dr. Hurley addressed the following question: To whom should vitamins be recommended? The current AREDS2 supplements are vitamin E, vitamin C and copper. Not all AREDS-labelled vitamins follow the AREDS recommendations, this is something to be aware of. There are older supplements, other versions of this on the market today, but if one wants to have the latest evidence, one has to check and ensure that they follow AREDS2. The issue with the zinc was that they wanted to reduce it to see if that would help with some of the side effects and perhaps ensure patient compliance, but the studies didn't show any difference in side effects from 80 mg compared to 25 mg, and didn't show any difference in outcome. It wasn't overly powered so the final result was that since there was no difference, practitioners have to rely on the AREDS1 data. It’s important to recall that zinc drove the overwhelming treatment benefit in AREDS1. According to Dr. Hurley, the key question is: If a practitioner is recommending ocular vitamin supplementation, has the patient been diagnosed with macular degeneration? Dr. Hurley frequently has patients who come to his clinic with their grandmother, grandfather, mother or father who have macular degeneration. An ocular vitamin is suggested, so everybody in the room thinks that it’s a good thing to do, that they should take it, as well. Dr. Hurley underscored that the supplements are of proven benefit only if people have

moderate or advanced AMD, supplements have not be shown to modify progression in early AMD nor have they been shown to halt the onset of AMD An important point to consider, said Dr. Hurley, is do the product’s ingredients match the AREDS formulas? There are still older formulations on the market today that don't follow the AREDS supplementation. Also, consider whether or not the patient has comorbidities. Polypharmacy is a major issue in our society today. Our elderly patients are taking a lot of medicine, and it's difficult and confusing for them. Some of them have advanced cancers; some of them are coming from nursing homes and practitioners have to take the patient in front of them into account. Spend time with that patient to consider what’s best for them. If they’re already terminal, if they're undergoing chemotherapy, the last thing they want is more medicine and more pills, so take that into account with the very sick and elderly patients. Their anticipated life expectancy comes into account when dealing with glaucoma and other medications as well. When dealing with sick and frail people, try to simplify the amount of medication they take. They may have medication fatigue and get confused with how many medicines they’re taking. If more medication is being added, do it with some caution with the very elderly on multiple medications. Get them to talk to their primary care physicians; also, their pharmacist can be extremely helpful in terms of preparing blister packs. Make the overall care of the patient the first consideration. There's talk that some patients have tried one vitamin supplement and they don't like it. Remember that there's more than one supplement available on the market today and sometimes if patients haven't tolerated one, it may be easier for them to take a different pill. In addition, the size of the tablet and other considerations may be important to the patient. Some are easier to take and are easier for the patient to maintain compliance with. There's a suggestion that the soft gels are perceived as the ones that are easier to swallow and easier to take from a patient's standpoint.

PHARMACOGENETIC TESTING HIERARCHY OF EVIDENCE

AND THE

Dr. Hurley posed the question: Can practitioners further refine what they’re giving patients to make it even better for them? This is the area of prognostic and pharmacogenetic testing. There was some excellent research done several years ago showing that the genetic makeup of the patient can predict how they might respond to ocular vitamin supplementation. This was specific to two genes, complement factor H and the age-related macular degeneration sensitivity 2 gene - CFH and ARMS2. Based on the patient's genetic makeup with respect to those two genes, can treatment be improved and tailored to make it more specific to the patient? This concept of pharmacogenetic modification is a big issue in medicine today, most notably in cancers such as ocular cancer and melanoma.

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Table I Pharmacogenetic selection of nutritional supplements. Review of 2013 Awh CC et al Study Results • Over an average of 10.1 years, patients with 1 or 2 CFH risk alleles derived maximum benefit from antioxidants alone (without zinc) • Patients with AMD sensitivity 2 (ARMS2) risk alleles derive maximum benefit from zinc-containing formulations, with a deleterious response to antioxidants • Patients homozygous for CFH and ARMS2 risk alleles derived no benefit from any category of AREDS treatment Conclusion Patients with moderate AMD (category 3 in 1 eye and categories 1–4 in the other eye) could benefit from pharmacogenetic selection of nutritional supplements, potentially leading to improved outcomes through genotype-directed therapy. Awh CC, Lane AM, Hawken S, et al. CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology. 2013; 120: 2317–2323.

The genes are tested to predict the patient's response. It’s done in other cancers as well, especially in breast cancer, so there is some significant backing to this in medicine today. Some very good papers were written about this in 2013 and 2015. Sadly, Dr. Hurley stated, like many things in medicine, it has become an area of controversy and there are now papers that refute some of the initial findings by Carl Awh, by Emily Chew and others. It’s now known that macular degeneration is a multifactorial genetic disease; there are many things that contribute to it, similar to most forms of glaucoma and many other eye conditions. Many genes put a person at risk for macular degeneration. There's no current test to test all of the known ones, but there is one available that will test for two of them, complement factor H and the ARMS2 gene. Carl Awh's paper came out showing that treatment response can be optimized based on complement factor H and ARMS2 genes (Table I). The researchers looked at the patients within the first AREDS trial who had peripheral blood samples available. They could subtype them according to their genetic makeup and then see how each of these subgroups did within the treatment categories. They found that if a patient was at the lowest risk − negative for those two genes – the risk for developing macular degeneration was lower, less than one; lowest if the patient took the antioxidants; and not as good if the patient took the zinc. If they were two alleles positive, so homozygous for complement factor H, there was a much higher risk, no matter what they took. The risk was well over 1 in every one of these supplements. However, there was a better result with the antioxidants, again, than if they received the zinc. Also, if they were heterozygous for CFH and for ARMS2, the zinc seemed to be what was

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providing the greatest benefit as opposed to the antioxidants. Furthermore, if there was double positivity for both of them, every one of the treatment groups crossed unity, so one couldn't really say that any of the vitamins were really helping the patients. Based on this, they concluded that patients with category 3 or category 4 AREDS could benefit from a selection of their nutrients based on their genetic makeup, which is a very interesting proposition. While it was like the original cohort study that looked at the omega-3 fatty acids, this was a cohort study as opposed to a randomized control study. There were sample size issues: Looking at people who had no complement factor H markers and were double positive for ARMS2, for example, there were only 10 such patients in the study and then they're broken down into the four treatment groups. This provides only 2 or 3 patients per treatment group which really opens it up to the effect of chance. When there are so few people, if there is one patient who does poorly or really well for other reasons, that's really going to overdrive the results, and people have raised that as an issue. This was a retrospective subgroup analysis and one can break down and cut up data in many different ways. For example, consider presenting the data by the day of the week that the patient was born. One can keep cutting and sub-cutting data, producing some very spurious results that find if you were born on a Thursday or Friday, you did much worse than if you were born on a Monday, Tuesday or Wednesday. Obviously, there's no scientific merit for that. The fact that it was a Caucasian cohort doesn't bother Dr. Hurley because there were many confounders, and it was based on the original AREDS data. There was a response from the people who were very strong proponents of the AREDS data as being the gospel and they added some additional patients that they had access to with genetic markers. In Emily Chew's report, they could not replicate the original findings of Carl Awh. As a result, their final take home message was that complement factor H and ARMS2 loci didn't alter the benefits from the AREDS supplements across the board. The Awh group came back out with their next publication which analyzed the data as well. They predicted the probability of improvement and found that this did support their original findings, so patients with moderate AMD could benefit from pharmacogenetics. This controversy has led to editorials in some of the major publications in ophthalmology, with some people saying that their data doesn't correctly adjust for the multiple statistical testing and it's a post hoc analysis as well; therefore, those editorials couldn't support the use of pharmacogenetic testing. Emily Chew's article, as well, said that genetic testing is currently not recommended for determining the appropriateness of the AREDS formulation and that practitioners should rely on the original AREDS studies.


In terms of whether or not to test, Dr. Hurley noted that physicians have to remember which type of evidence they're looking at in order to make the best, most informed decision for their patients. He looks at some of the guidelines, for example, those of the American Academy of Ophthalmology, which state that routine genetic testing for complex disorders like AMD and glaucoma should not be done until there is solid data that the patient's response to treatment can actually be modified and better data exists that supports its use. The Canadian expert consensus panel’s paper which also states that further data is needed and practitioners should rely on the highest level of evidence available, the double-blind, placebo-controlled AREDS clinical trials.

CASE STUDIES Dr. Hurley presented several cases relating to whether or not patients should receive ocular vitamins. The first case was of a 58-year-old female of African descent with no AMD currently on ocular examination and no family or background history of the condition. She is not a candidate for vitamin supplements. If there is no AMD to start with, there is no treatment benefit and the rate of progression is too low. In addition, this patient enjoys excellent quality of life, including running long distance marathons and weight training. I didn't write this, I wish I had patients like this in my practice but that's phenomenal, right? Concerning the issue of this patient’s genetics, they’re at risk for polypoidal choroidal vasculopathy, not macular degeneration. This case is an example of a different disease than macular degeneration that presents in Canadians of African descent. The second case was of a 54-year-old male, professional looking, with multiple 125 micron drusen in one eye diagnosed earlier. He is a former smoker with no family history of AMD. The drusens are large, so he's

AREDS category 3. He is a patient for whom ocular vitamin supplementation is absolutely recognized and recommended by the clinical trial. He would benefit from it according to the best evidence at hand. In the third case, a 71-year-old Caucasian female with wet AMD in one eye was receiving injections every month. Her other eye is category 2, but that doesn't matter – she is category 4 based on the vision loss in one eye. She has a neovascular membrane in one eye, and these are the patients who would benefit the most from AREDS supplementation. Much more interesting to Dr. Hurley is the patient with bilateral wet AMD who is already receiving injections in both eyes. Should they take ocular vitamin supplementations? His thought is that it's already wet in both eyes, so what would the treatment be trying to prevent? However, the massive benefit of anti-VEGF medication is known, be it Lucentis® (ranibizumab injection, Roche Canada, Mississauga, ON), Avastin® (bevacizumab, Roche Canada) or Eylea® (aflibercept, Bayer). It allows people to keep driving, for instance, but they're still losing vision due to the underlying background dry degeneration that's progressing at the same time. In many patients, their neovascular membranes have regressed, but the central geographic atrophy is still progressing. They’re going blind slowly, so he continues to do everything he can to help them. So even though they're bilaterally wet, he still puts them on the AREDS supplements.

CONCLUSION With AREDS1 and AREDS2, said Dr. Hurley, it looks like AREDS2 helps define how much practitioners can reduce patients' risk of progression. Physicians’ ultimate goal is to prevent somebody who is seeing well but is at high risk of a neovascular scar, for example, from progressing to geographic atrophy. ❏


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QUESTIONNAIRE AREDS2 Controversies and Facts: Delving Deeper into our Knowledge on Eye Health Bernard Hurley, MD 1. ❑ ❑ ❑ ❑

All of the following are risk factors for AMD, EXCEPT: Age Reduced visual acuity Diet Ethnicity

2. ❑ ❑ ❑ ❑

All of the following statements about AMD are true, EXCEPT: Studies have shown no treatment effect in patients with low likelihood of progression at baseline In patients with category 2 AREDS, the likelihood of progression is low Vitamin supplementation is effective in all cases Patients with large, soft drusen are more likely to progress

3.

In AREDS1, what was the relative risk reduction in the group that received both the antioxidents and the zinc? 25% 30% 35% 40%

❑ ❑ ❑ ❑

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4. ❑ ❑ ❑ ❑

In AREDS2, what percentage represented the additional benefit when lutein and zeaxanthin were added to the formulation? 5% 10% 20% 25%

5. ❑ ❑ ❑ ❑

All of the following statements about the AREDS trials are true, EXCEPT: No safety concerns were raised Patients on the AREDS supplements had improved overall mortality In AREDS2, patients taking beta carotene, lutein and zeaxanthin had better results In AREDS2, the risk reduction was better for patients with lower dietary intake of lutein and zeaxanthin

6. ❑ ❑ ❑ ❑

All of the following statements about vitamin and mineral supplementation are true, EXCEPT: The AREDS2 formulation can be used safely regardless of the patient’s smoking status There was no difference in side effects between the 80 mg and 25 mg doses The overwhelming treatment benefit in AREDS1 was conferred by zinc Patients with AMD who are heavy smokers should not be prescribed the AREDS2 regimen

7. ❑

All of the following statements are true, EXCEPT: According to the paper by Dr. Awh et al, treatment response can be optimized based on complement factor H and ARMS2 genes Many genes put a person at risk for macular degeneration Only patients with category 4 AREDS can benefit from a selection of their nutrients based on their genetic makeup In category 4 AREDS, the patient has already suffered vision loss in one of their eyes

❑ ❑ ❑ 8. ❑ ❑ ❑ ❑

All of the following statements are true, EXCEPT: The patient in Case #1 was a candidate for vitamin supplements based on her ethnicity The patient in Case #3 was categorized as category 4 AREDS If a patient has one eye in category 2 AREDS and the other in category 4, they are considered category 4 If AMD is not present, there is no benefit in ocular vitamins

9. ❑ ❑ ❑ ❑

Which of the following statements is TRUE? Patients with category 2 AREDS and a family history of AMD may benefit from zinc supplementation Patients with category 1 AREDS and a family history of AMD may benefit from zinc supplementation Patients with extensive intermediate sized drusen in both eyes may benefit from the AREDS regimen Patients with multiple small drusen in both eyes may benefit from the AREDS regimen

10. All of the following statements about the study by Dr. Awh et al are true, EXCEPT: ❑ Patients homozygous for CFH and ARMS2 risk alleles had an excellent response to AREDS treatment ❑ Over an average of 10.1 years, patients with 1 or 2 CFH risk alleles derived maximum benefit from antioxidants alone (without zinc) ❑ Patients with AMD sensitivity 2 (ARMS2) risk alleles derive maximum benefit from zinc-containing formulations, with a deleterious response to antioxidants ❑ Patients homozygous for CFH and ARMS2 risk alleles derived no benefit from any category of AREDS treatment

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Clinical & Refractive Optometry Quebec is pleased to present this continuing education (CE) article by Dr. Paul M. Karpecki, Kentucky Eye Institute, Lexington, KY. This article has been approved for 1 Category A, UFC credit in Ocular Health by the Ordre des Optométristes du Québec. In order to obtain your credit, please refer to page 209 for complete instructions.

Diagnosis and Treatment of Ocular Surface Conditions: Focus on Allergy Paul M. Karpecki, OD, FAAO

INTRODUCTION Dr. Karpecki began his presentation by noting that he established his first dry eye clinic in 1997 and in the first ten years of ocular surface disease, there wasn’t a lot to teach about dry eye disease as we were learning as we went along. In addition, there wasn't much practitioners could do for success. In fact, he noted, his success rate was probably less than fifty percent. In a survey conducted before he joined Kentucky Eye Institute, approximately 96% to 98% of patients said they were satisfied or very satisfied with their treatment results. Dr. Karpecki mentioned that in the last six or seven years, great strides have been made in the management of the ocular effects of dry eye disease and allergies.

THE CURRENT OCULAR ALLERGY LANDSCAPE When an allergy is seasonal, it's an acute condition; however, in patients with perennial allergies, dry eye and blepharitis, it’s typically chronic. As a result, said Dr. Karpecki, practitioners have to be able to teach them that this is progressive and will typically last for the rest of their life. In addition to chronic, acute, perennial and GPC forms of allergy, the sight-threatening forms, vernal and atopic keratoconjunctivitis, which are not very common, occur at a rate of about 3-5 cases per year in his clinic. Seasonal allergies are by far responsible for the largest proportion of allergies. Fluctuations in weather are particularly hard on allergy sufferers. In fact, what makes it tougher is that patients get a bolus of pollen in the spring depending on the allergen, then relatively little for a few months and then they often get another bolus of allergens in the fall. This pattern makes it difficult on allergy suffers to perform P.M. Karpecki — Director of Corneal Services and the Advanced OSD Clinic, Kentucky Eye Institute, Lexington, KY Correspondence to: Dr. Paul M. Karpecki, Kentucky Eye Institute, 601 Perimeter Drive, Suite 100, Lexington, KY 40517; E-mail: paul@karpecki.com This article has been peer-reviewed

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at their optimum at all times and can affect everything from sleeping to reading and concentration. Environmental allergens, such as grass pollen in summer and ragweed in the fall, are common causes, as well as animal dander and dust mites which are more perennial. Cat dander holds on to the conjunctiva or skin; ragweed resembles burrs and can stick to clothing and even ocular structures; and grass pollen is so small that it can stay in the cul de sac before it’s washed away. This also raises a key clinical pearl when managing allergies: Don't forget to tell patients to wash the allergen away using preservative-free artificial tears. Practitioners often think of artificial tears for dry eye, but they play a key role in allergy because it’s important to dilute all of these elements that are adhering to the conjunctival surface. Perennial Allergy Animal dander is one of the most common forms of perennial allergy, but the biggest cause is dust mites. They’re impossible to get rid of so, unfortunately, if a person is allergic to dust mites, they can’t truly clean a home any more than we do today because these mites are only 10 to 24 microns in size. Furthermore, said Dr. Karpecki, it's not the dust mites themselves that people react to; it's actually their droppings, their waste pellets: they eliminate approximately 10 to 20 a day. One gram of dust equates to about 240,000 dust mite droppings. It has been said that after five years, without a pillow cover, 50% of the weight of one’s pillow is actually dust mite droppings. In terms of the clinical presentation, it’s typically a bilateral condition resulting in a glossy or thematic appearance with mild injection. A unilateral form of type 1 hypersensitivity is contact dermatitis, for instance, a reaction to nail polish. This involves the eyelids more than the eye, and typically it's unilateral as contact dermatitis can affect the conjunctiva, skin and neck. Contact dermatitis is best treated with topical corticosteroids. Dr. Karpecki highlighted that in North America optometry treats allergic conjunctivitis more than any other medical specialty. Symptoms of burning, tearing, redness, itching, photophobia, and grittiness all imitate dry eye disease, making the differential between allergic conjunctivitis and dry eye disease difficult at times. One key differential is that allergic conjunctivitis is associated with rhinitis and dry eye disease is not.


Looking forward, there are some interesting technologies emerging, including those by TearLab (San Diego, CA), which is working on their next innovation. They measure osmolarity right now, but they're working on IgE and inflammatory markers, among other things that may create a multi-chip format allowing us to differentiate the presence of various ocular diseases before we even see the patient. Within a year one would actually sample the tears and know how much allergy is present, compared to dry eye inflammation and even specific inflammatory markers that may dictate the optimal treatment. This currently exists in cardiology with panels of tests, as they’re referred to. These tests aren’t currently available in eye care, therefore, practitioners have to be the ones who differentiate it. Itching, the hallmark symptom of allergies, could be caused by dry eye disease or blepharitis such as demodex blepharitis. When a patient presents at the office and says, “My eyes itch,” a good differentiating question is, “Do you feel better after you rub them?” If so, typically it’s more of a histamine involvement. An additional question relates to the location of the allergy. Allergic conjunctivitis is located on the conjunctiva or in the canthal region. If it’s in the eyelids or eyelid margins, demodex or staphylococcal blepharitis plays a role. A patient recently stated to Dr. Karpecki that her eyes were itchy, but on further questioning was identified as particularly around her lashes. The diagnosis was demodex blepharitis, so he proceeded with Cliradex® (4-Terpineol, Bright Optical, Toronto, ON) treatment on her eyelids. The condition cleared up completely and her itching was resolved. In this case, it wasn't allergies, even though allergy is the first thought when one hears the term itching.

ALLERGY SYMPTOMS AND DIFFERENTIATORS Dr. Karpecki noted that an optometrist can quickly recognize a person with allergies due to a glossy-looking eye. It's not beet red as with most bacterial conjunctivitis and there's no discharge. In allergic conjunctivitis, a tearing or mucin discharge is present. One can sometimes see papillae, especially in the lower fornix area, and possible eyelid swelling; however, the key is the chemotic look of the conjunctiva. These types of differentiating signs and symptoms are crucial to treatment. The other differential is viral forms which not only need to be differentiated from allergic conjunctivitis but also bacterial conjunctivitis. Dr. Karpecki pointed out that when looking for discharge, it’s vital to look at the tear lake or lower tear meniscus. Debris in the tear film is also discharge and can help differentiate a bacterial conjunctivitis. Patients will report that when they woke up their eyes were matted shut and a yellow substance on their lashes was visible; this is more typical in bacterial conjunctivitis.

In viral conditions a watery discharge is more common. These patients tend to have an eye that may not be as red although in some forms such as epidemic keratoconjunctivitis (EKC) it can be. One differentiating factor is preauricular lymphadenopathy, which is why it's always important to check by actually rubbing the preauricular area to try and find a pea-sized nodule. What’s more, in viral forms, it starts in one eye and then spreads to the other, whereas with allergies it is a bilateral presentation immediately. Naturally, mentioned Dr. Karpecki, if patients have had it for more than a week and it’s something like EKC, there may be subepithelial infiltrates which are a help in finding the differential, but the goal is to try and pick up on that sooner than later. If the viral form is detected early, it can often be managed early.

DIAGNOSTIC TOOLS There are a number of diagnostic steps to take, and point of care diagnostics are now available. Rapid Pathogen Screening in Florida makes the AdenoPlus® test. A former colleague and coworker of Dr. Karpecki’s asked for a consult with a case he suspected might be preseptal cellulitis. This patient had one of the most severe cases of conjunctivitis Dr. Karpecki had seen. The patient was extremely chemotic and red, and he determined that it was a case of EKC. He had an AdenoPlus which indicated positive for adenovirus. Some of the worst-looking conjunctivitis cases are EKC, so that's a good way to differentiate it from allergy as well.

TREATMENT OPTIONS FOR EKC The other advantage with EKC in Canada is that there are good treatment options we don’t have in the United States. In the U.S., Zirgan® (ganciclovir ophthalmic gel, Bausch + Lomb, Rochester, NY) has been shown to decrease the course of EKC from about 18 days to roughly 5 days. Another option is Betadine® (povidone iodine, Purdue Pharma, Stamford, CT) and although it’s available in the States in bottle form, Canada has the preservative-free Minims® (povidone iodine 5%, Bausch + Lomb, Vaughan, ON). The dosage is three drops after having put Alcaine® (proparacaine hydrochloride ophthalmic solution 0.5%, Alcon, Mississauga, ON) or Minims Tetracaine (tetracaine hydrochloride 0.5%, Bausch + Lomb, Vaughan, ON) in the eyes, followed by an NSAID drop. Have the patient close their eyes, roll them around for about a full minute, and then use balanced saline to rinse it out completely. Dr. Karpecki stated that it will eradicate the virus immediately. Patients won't typically get subepithelial infiltrates; they'll achieve great results and they'll be grateful, although not immediately as the eye is very uncomfortable for about 24 hours. For this reason, steroid drops q.i.d. for 4 days should also be recommended.

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Fig. 1 Various phases of the allergic conjunctivitis cascade.

Seasonal Allergies With seasonal allergies, it's important to truly understand the mechanisms. What occurs is a cascade of allergic conjunctivitis (Fig. 1). The early stage is characterized by antigens in the tears, a major histocompatibility complex that involves T-cells, plasma cells and an antigen presenting cell in the conjunctiva. The first time an allergen presents, IgE forms on the mast cell. On the second presentation a cross binding occurs between the two IgE on the cell. When this happens, the entire mast cell becomes destabilized and all of the content including histamine is released. In the early stages there is an immediate response which is primarily made up of histamine, heparin, chymase and tryptase (Fig. 2). The person presenting at this stage will complain of itching, sometimes severe. There are two treatment choices, a steroid or an antihistamine combination – and despite what most of my residents answer (steroids for severe itching), the correct answer is an antihistamine combination drop. In the early stages of the allergic conjunctivitis, the main element causing itching

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is histamine and nothing stops itching as effectively as an antihistamine. Pataday® (olopatadine hydrochloride ophthalmic solution, Alcon, Mississauga, ON), Patanol® (olopatadine hydrochloride ophthalmic solution, Alcon, Mississauga, ON) or Bepreve® (bepotastine besilate ophthalmic solution, Bausch + Lomb, Vaughan, ON) in Canada are possible options, in addition to Zaditor® (ketotifen fumarate, Alcon, Mississauga, ON). In the early stages, they’re more effective than a steroid for itching symptoms, even if the condition is severe. If the condition is allowed to progress, the allergic cycle gets to a level called synthesis, which typically doesn't take a long time. This may occur at 48, 72 or even 12 hours in some cases, depending on the severity. At that point, leukotrienes, prostaglandins, cytokines and platelet activating factor (PAF), which are inflammatory components, are present and the most effective treatment at this stage is a topical corticosteroid. Patients will manifest more injection or redness, chemosis and overall inflammatory signs. Dr. Karpecki


Fig. 2 The early phase response occurs in allergic conjunctivitis.

stated that differentiating treatment based on the pathophysiology makes sense given the two treatment options (steroids and antihistamines). The patient’s signs are a key element, most notably the redness and chemosis which may also be considered symptoms. Patients often mention this because they feel self-conscious about how they look. A steroid would be a better choice when the signs are comparable to the symptoms. In fact, with Pataday, and Bepreve, neither of these have a US FDA indication for clinical signs of redness. However, Alrex® (loteprednol etabonate ophthalmic suspension 0.2%, Bausch + Lomb, Vaughan, ON) has an indication for signs and symptoms. The general rule would be: when there are more symptoms of itching than signs, use an antihistamine; when the signs (redness, chemosis, etc.) have caught up, the appropriate choice is a steroid. Sometimes both are appropriate to achieve good control of both elements. In the late phase, the condition is virtually completely inflammatory, however, and therefore corticosteroids may well be the better treatment option (Fig. 3).

There are studies showing that antihistamines are faster-acting against itch than steroids but there are others indicating that steroids have greater efficacy against clinical signs than any antihistamine by far. Antihistamines won't control the chemosis or redness to the level that a steroid will. It is quite a significant disease though, said Dr. Karpecki, and optometrists have become somewhat complacent about it because in North America optometry prescribes more allergy medications than any other discipline. We have to be reminded of the significant morbidity associated with allergic disease. Of the patients who have seasonal allergies, 70% said their reading is greatly affected to the point that it affects work. Driving is affected, which obviously is quite significant. Concentration has been shown to be diminished. Even difficulty sleeping is among the many functions affected by this disease. Therefore, it’s essential to counsel patients, explaining the need for treatment and setting the right expectations about it being a chronic disease in the case of perennial allergies. If their problem is seasonal, it

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Fig. 3 Late-phase reactions occur only in more severe allergic states and represent a cellular response to prolonged allergic challenge in conditions such as vernal keratoconjunctivitis.

will most likely return. In fact, Dr. Karpecki schedules his patients for their follow-up according to their seasonality. If he knows they have spring allergies, he typically sees them in March or April in order to try to alleviate their symptoms. These patients should be educated about how to minimize problems in their environment. The website www.pollen.com indicates the level of pollen in a given city. During “red” days, these patients should be more cautious. For example, if they are avid runners, they ought to run on the treadmill that day. They should keep their car windows up and avoid the outdoors for a short period of time. They should also be advised to wash their linens more frequently than they normally would and to keep the speed of the ceiling fan to a lower level or turn it off. From a palliative perspective, at level 1, a cold compress can have a tremendous impact on chemosis, whether it's a cloth, an icepack or a commercial cool compress over the closed eyes.

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Giant Papillary Conjunctivitis Dr. Karpecki discussed giant papillary conjunctivitis (GPC) which has seen a surge related to silicone hydrogel lenses. It’s much more difficult to treat than it was 20 years ago. It’s still GPC; it just appears to take longer to manifest and is a little more resilient to treatment. GPC is one of the four allergic eye diseases and is defined as large papillae on the upper tarsal plate and is easy to identify not because of itching, but rather, decreased contact lens wearing time and the presence of mucin discharge. Switching patients from silicone hydrogel contact lenses to a non-silicone hydrogel lens is recommended. However, even after six months of treatment, the papillae may still be visible, but the patient may not be symptomatic. What the practitioner should actually be treating is the hyperemic papillae. If the papillae are red, there is too much inflammation. After treatment, if there is a normal pink tarsal plate, even if a few papillae remain, that's acceptable, as long as they're not hyperemic. Dr. Karpecki explained that it’s a matter of active versus


Fig. 4 Vernal shield ulcers are indicative of an eosinophilic reaction.

non-active states. If it's active, hyperemia, and usually a fairly large level of papillae, will be present. It’s important to flip eyelids on patients fairly regularly in order to gauge its presence, especially in people who have worn silicone hydrogel lenses for more than three years. Sometimes the symptoms are related to makeup, however, most of the time it's a contact lens issue. Refractive surgery may be a treatment option, stated Dr. Karpecki. While patients don't want to be out of their contact lenses, if the practitioner can get them to stop their wear for at least a week during treatment, that's more effective. During that week, they should be put on Lotemax® (loteprednol etabonate ophthalmic suspension, Bausch + Lomb, Vaughan, ON) q.i.d. then tapered to b.i.d. before and after contact lens insertion and removal. Even though studies have shown that there has never been an infection complication related to loteprednol and contact lens wear during GPC treatment, there is one study by Dr. Jimmy Bartlett on GPC using Lotemax and it showed incredible effectiveness, more than any other previous steroid has shown, perhaps because it's much more lipophilic. Dr. Bartlett’s study showed that the incidence of significant IOP rise, i.e., 10 mmHg or more increase from baseline, was 8%, rather than the traditional 1% or 2% reported in all the other studies. When it’s put on a lens it becomes a depot and the same complication rate of IOP results as with the older ketone steroids is evident. As a result, he prefers not to put any topical corticosteroid on a contact lens, if possible. Once the patient is back in a lens, reduce the treatment to twice a day, before and after lens wear, continuing for approximately four to six weeks if pressures are normal. Regarding Lotemax gel form, it's still 0.5% concentration, with less preservative; it doesn’t have to be shaken, and there is the advantage of moisturizing agents.

It’s expected to show the same effect, but there has not yet been a study confirming this. An important component of treatment success is hygiene and patient compliance. There is a need for patients to learn to replace their lenses on a regular basis. In most of the patients experiencing problems, they extended the use time, they topped up their solution, or there was some other form of non-compliance. Vernal Keratoconjunctivitis Vernal keratoconjunctivitis (VKC) is a warm weather condition and Dr. Karpecki sees roughly eight to ten cases in the course of a summer. It typically occurs in male children between the ages of roughly 4 and 16 and manifests with very large cobblestone papillae on the upper tarsal plate. The key to diagnosis, because 17% of cases have this, is to note an area of elevation at the limbus. If a child presents with allergic conjunctivitis, the practitioner should look very carefully at the limbus 360 degrees. If there is any elevation, even if it's just one clock hour, that's a diagnosis of VKC. The elevation signifies Horner-Tranta’s dots which are eosinophilic accumulations at the limbus. Dr. Karpecki highlighted that VKC is sight-threatening and can lead to what's called a shield ulcer (Fig. 4). The former thinking was that the papillae rubbing on the surface caused these ulcers. Actually, it's something called basic major protein that is released in the inflammatory cascade or immunology. The limbal accumulations are eosinophils so they release the major basic protein and will cause the epithelium to slough, leading to a shield ulcer; these can scar if they're not treated. Management of the condition includes an antibiotic, antihistamines and low grade anti-inflammatories which might get it controlled over time. One of the best treatments for vernal shield ulcers is a cyclosporine (Restasis®, Allergan, Unionville, ON) twice a day, or even four times a day. Following this, lubricate the eye and use an antihistamine combination, all of which work even better than steroids in cases of VKC.

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Dr. Karpecki addressed the issue of why Restasis works immediately in VKC when in dry eye it takes so long to take effect. The precise answer isn’t known, but it relates to the physiology – the type of cells that are present, and a different mechanism of action. It’s thought that for some reason cyclosporine inhibits major basic protein more than other therapeutics or some key receptor in the inflammatory cascade. The reason why it doesn't work as quickly in dry eye patients is that it primarily affects migrating T-cells, which can take some time to be fully affected. In dry eye, one has to wait for those cells to die off; it takes roughly 90 days for a T-cell to run its normal apoptotic cycle. However, in the case of shield ulcers, major basic protein can be suppressed right away with cyclosporine and other non-approved options such as tacrolimus. Dr. Karpecki emphasized that VKC requires very aggressive treatment. Steroids are essential until the point of a shield ulcer, dosed at every two hours for about the first week, plus the antihistamine, olopatadine, bepotastine, or ketotifen. Systemic antihistamines are an option, even though they dry the eyes. Children don't have as much dry eye, so oral antihistamines should not be a problem. Aspirin has been shown to help children, but the studies on this have been inconclusive. Children should be instructed to avoid eye rubbing as this exacerbates the problem. Another sight-threatening allergic eye disease seen occasionally is atopic keratoconjunctivitis (AKC). It more commonly affects men ages 30 to 50, and the hallmark of atopic keratoconjunctivitis, which is the fourth form of the type I hypersensitivity conditions. Contact dermatitis is a type IV hypersensitivity, the delayed response type of allergies. The key signs of AKC are eczema and neovascularization or pannus on the cornea; classic presentations not seen in any other allergy form. Roughly nine out of ten of these patients have asthma, but 95% have eczema somewhere, often around the eyes, with conjunctivalization in the severe form. Often it's just slight neovascularizational encroachment, especially in a non-contact lens wearer. Typically, these patients can't wear their lenses and they have typical symptoms of burning and itching, therefore, it sounds like allergies; it goes into remission, then there are exacerbation episodes. To treat the eczema, Dr. Karpecki suggests a triamcinolone cream, 0.1% which is a kenalog steroid, or Lotemax ointment if there is concern of the patient getting the cream in their eyes. As these patients have dry eyes, neovascularization is a concern. If that's present, prescribe heavy corticosteroids, every two hours until it can be reversed. Lotemax gel every two hours would be ideal because of its safety profile, however, if it's very severe, Pred Forte® (prednisolone acetate, Allergan, Unionville, ON) works well. A Japanese study showed that Lotemax gel was equivalent to branded Pred Forte. In severe cases such as uveitis and AKC, one can start with Pred Forte and then use Lotemax longer term, but they

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are very comparable now that the gel formulation has come out. Therapy needs to be adjusted on a two-week basis; typically, dosing is every couple of hours for a week or two, then q.i.d. for a week or two. Dr. Karpecki prefers loteprednol because this regimen involves long-term use of steroids. He would rather use the safest agent, but if it's not producing a response, Pred Forte is required. Again, eye rubbing is a concern in this group; and this could be why there's a high incidence of keratoconus in these patients. Regarding comorbidities, for example, in patients with dry eye and rhinitis, Dr. Karpecki recommends avoiding oral antihistamine treatments, which is contrary to current teaching: These patients’ primary complaint revolves around their eyes and their systemic condition can be treated at a later point.

PHARMACOLOGIC AND NON-PHARMACOLOGIC TREATMENT OPTIONS The Role of Oral Antihistamines Regarding oral antihistamines, Dr. Karpecki cited a study by Dr. Osler that came out of Harvard University, showing the effect if a person used Claritin® (loratadine, Bayer, Mississauga, ON) which is actually not one of the most drying antihistamines, taken once a day for four days. It resulted in a drop in tear volume of 34% which is significant – and most of our patients don’t use oral antihistamines for just four days – most use it for a month or the entire allergy season. Imagine the effects on the tear film of Benadryl® (diphenhydramine hydrochloride, Johnson & Johnson, Markham, ON) which has potent antimuscarinic receptor activity. He tells his residents to take their patients off oral antihistamines if they're willing to do so because an antihistamine drop is not going to dry their eyes and is also going to get through their sinuses, throat and non-ocular tissues. This was shown in research involving a drug available in the U.S. called bepotastine which showed statistically significant improvement in the secondary markers, namely, nasal congestion, rhinitis, itchy palate, and itchy throat. The only exception to prescribing an oral antihistamine at the onset of treatment would be allergic sinusitis where a patient presents with pain around their eyes involving the sinus cavities and no signs of infectious sinusitis. If allergic sinusitis is diagnosed, Claritin-D®, Allegra-D® (fexofenadine hydrochloride; pseudoephedrine hydrochloride, Sanofi Canada, Laval, QC) and Zyrtec-D® (cetirizine HCl 5 mg/ pseudoephedrine HCl 120 mg, Johnson & Johnson, Markham, ON) all make sense because a decongestant is needed. But if it's just for allergies and it's the non-decongestant form, Dr. Karpecki would try to avoid it at the early stages of allergic conjunctivitis. Patients think that it’s helping their eyes, however, it's actually drying them by at least 34% after just four days, at once-daily dosing.


Decongestants For the treatment of allergies, decongestants such as Visine-A® (naphazoline, Johnson & Johnson, Markham, ON) or Naphcon-A® (naphazoline, Alcon, Mississauga, ON) are not recommended for three reasons. First, they contain significant amounts of BAK, usually about double what is found in good artificial tears. They represent a significant amount of toxicity potential based on just the preservative. Second, they cause constriction of blood vessels. The reason they're dilated to begin with is they're trying to heal something, so by constricting them, their disease isn’t being helped. A much better choice is a steroid where vascular permeability is maintained. Third, and this is commonly known, decongestants and vasoconstrictors cause rebound hyperemia. Once a patient is on it, they’re “addicted” because the moment they’re off the medication there is a rebound effect that may be even worse than when they started these medications. In fact, if someone comes into the office, a diagnosis of allergic conjunctivitis is made and they say, “I've been using Visine for the last six months,” I wouldn’t recommend immediate discontinuation because their eyes are going to become more injected and they will question the practitioner’s abilities. The best way to get them off of the decongestant/vasoconstrictor is to taper them. Start them on a steroid such as loteprednol q.i.d. for two weeks, then b.i.d. Allow them to use the Visine no more than the steroid such as four times a day for a week, then taper down each week because by then the steroids will have the ocular surface under control. Therefore, said Dr. Karpecki, it’s best just to avoid them in the first place but, unfortunately, if they've already chosen an overthe-counter (OTC) vasoconstrictor, it’s best to switch medication to a corticosteroid and taper them off the vasoconstrictor agent. If a patient has to use an OTC medication, Dr. Karpecki prefers combination agents over vasoconstrictors as his key treatment, including ketotifen, Alaway® (Bausch + Lomb, Rochester, NY) and Zaditor® (Alcon, Fort Worth, TX). There is alcaftadine in the U.S., and in Canada and the U.S., olopatadine and bepotastine are available. Bepotastine is probably the best treatment for severe itch that he has ever seen, but it’s advisable to disguise its taste. Although bepotastine is a very good product, it’s perhaps better reserved for moderate to severe itching. However, it works about as well as olopatadine for mild and moderate allergic conjunctivitis. Ester Steroids and Other Treatments Dr. Karpecki shared that he favors ester steroids, a safer version and yet still very potent for ocular surface conditions such as allergic conjunctivitis. Because there are enzymes known as esterase in the body, it can break down ester steroids. In the case of ketone steroids, there is no enzyme to break down the metabolites that can now attach to the IOP receptors or create a Schiff base on the

crystalline lens, which can lead to cataract development. In fact, there has never been a reported cataract on loteprednol, even after over approximately 40 million scripts. There is still a risk of IOP rise: About 2% of patients on loteprednol have a 10 mm or more increase in pressure so it doesn't mean that it can be prescribed without monitoring IOP. As he noted, he still doesn’t write any refills the first time he writes a prescription for steroids. Dr. Karpecki uses either the on-label option of 0.2% loteprednol (Alrex) in most cases of allergic conjunctivitis or in severe cases, 0.5% (Lotemax). The Lotemax gel has some unique properties; it's still 0.5% concentration but the gel provides more advantages such as significantly less BAK, along with better moisturizers and a longerlasting effect due to the vehicle. Additionally, it doesn’t need to be shaken, which is extremely important as most patients don't shake suspension steroids the required 30 times for true re-suspension. For this reason, drops that don’t need to be shaken are a huge advantage for patients. It can be administered every couple of hours for the first few days in severe forms involving significant chemosis or injection. Patients can’t take it forever; their pressure will still need to be monitored, but it’s extremely effective against the signs that are present in allergic conjunctivitis. Alrex is a 0.2% concentration indicated for temporary short-term relief of signs and symptoms. Dr. Karpecki typically tells patients that a couple of months is good as maximum therapy duration. If they have a lot of itching, he adds the antihistamine component. Dr. Karpecki mentioned that he avoids oral antihistamines, even though the majority of patients think that all antihistamines help relieve their itchy eyes. The frequently used options are oral Claritin, Allegra and Zyrtec. If the eyes are dry and the patient has allergies, the allergen remains. He would therefore avoid these, except in cases of sinus congestion where the decongestant is the key. Regarding pseudoephedrine, which is the common decongestant in most of these oral antihistamine/ decongestant medications, physicians must be cautious in patients with known hypertension as it has been shown to cause a hypotensive state. Dr. Karpecki also pointed out that the newer forms may not be as sedating as the older oral allergy medications, however, they're still very drying to the ocular surface. If a medication like Claritin-D is needed because a patient has sinusitis, simply increase the use of artificial tears. There was an article or research paper published a while ago that discussed anticholinergics and over-thecounter drugs in relation to dementia, and Benadryl is one of those. A recent study reported that anticholinergics like Benadryl are contraindicated because they cause effects in patients with dementia. In terms of mild conditions where patients self-treat, a study showed that over 80% of people will try something over-the-counter before they come into an optometrist's office. Practitioners then have to educate patients about

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vasoconstrictors and how to get off of them, as well as the risks of using them long term because typically that’s a common OTC selection. Dr. Karpecki noted that if there is significant systemic involvement, with rhinitis, itchy throat, cough, or sinus congestion, he would use a topical medication. The use of loteprednol is substantiated in clinical studies. However, if oral administration is the chosen route, Benadryl is an effective choice provided the patient has no risk of dementia, administered before the patient goes to bed. Inhalers such as Dristan® (oxymetazoline, Pfizer, Montreal, QC) or Otrivin® (xylometazoline, Novartis, Dorval, QC) are available in Canada and provide the desired effect where it’s wanted, without going through the drying effects of taking a pill. Regarding long-term corticosteroids, one must bear in mind that cataracts can result, in addition to the low risk of IOP rise, not at the level of drops, but still a risk to consider. Non-Pharmacologic Treatments Dr. Karpecki stated that he favors non-preserved artificial tears because patients with allergies are already atopic; therefore, the less preservatives, the less chance of a reaction. In the early phase or if itching is their chief or only complaint, he prescribes an antihistamine/mast cell stabilizer. If they're saying, “It’s just the itching, it's unbearable, it's incapacitating,” that requires an antihistamine combination agent if it is severe. In terms of non-pharmacologic therapies, mucolytic agents are suitable for severe cases; likewise in severe allergic signs, select Lotemax instead of Alrex. There are many options for preservative-free artificial tears that will work. Dr. Karpecki opined that Canada has some of the best products available, such as HYLO™ (CandorVision, Montreal, QC) and especially for allergic conjunctivitis, HYLO Dual, (CandorVision, Montreal, QC)). In advanced cases, his patients are very appreciative of its effects. Refresh Optic Fusion™ (Allergan, Unionville, ON) is another good product containing hyaluronic acid. On the lipid side, there are Liposic® (Bausch + Lomb, Vaughan, ON), Refresh Optive® Advanced (Allergan, Unionville, ON), Refresh® Ultra (Allergan, Unionville, ON), and Systane® Balance (Alcon, Mississauga, ON). Mast cell stabilizers can be used alone, however, they won’t affect the histamine or relieve the itch, so one might as well use a combination. Equally, Dr. Karpecki doesn’t like to use NSAIDs alone. Looking at the arachidonic acid pathway of inflammation, there are two pathways, the cyclo-oxygenase pathway and the lipoxygenase pathway. NSAIDs only block prostaglandin formation of the cyclooxygenase pathway, not the entire leukotriene pathway, whereas steroids block both pathways. The same occurs with a mast cell stabilizer alone, as it would be preferable to have antihistamine and mast cell stabilization.

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CONCLUSION Dr. Karpecki concluded his presentation by reviewing several clinical pearls. The first of these is to educate patients about the importance of avoiding eye rubbing. If a patient rubs their eyes and feels better for a moment, that's usually a sign of allergies. He advises them to avoid this tendency because they’re going to mechanically degranulate the mast cells and make the condition worse over the long term. Second, refrigerate eye drops. Sometimes, the first time a person will ever put drops in their eyes is when they have allergies and so they're missing their eye, and they can't tell if it went in or not. By refrigerating them, they can tell if it's in the eye, plus it provides a soothing, cool compress effect. Next, tell patients to keep ceiling fan speeds lower; change their lenses more often, place protective covers on pillows, shower before sleeping; avoid being outdoors during the peak season; and keep house and car windows closed, if possible. In terms of medications, be aware of the side effects of some of the oral antihistamines. Most of these patients are going to present on an oral antihistamine, but may not even list it on their medication intake form because it is OTC; educate them about the potential side effects of these agents. Furthermore, when treating with topical corticosteroids, be sure to check their intraocular pressures in three to four weeks. Write zero refills the first time, just to be on the safe side. That way, they have to come back in three or four weeks to get another prescription. Dose these b.i.d. with a contact lens wearer, as previously discussed, with GPC. Get them out of their lens when they’re on Lotemax q.i.d., but then put them in a new lens and use the drops before and after lens wear. With regard to prescribing Patanol versus Pataday, Dr. Karpecki typically starts with Pataday as he feels it offers better efficacy, with slightly higher concentration. However, if the patient says, “I'm having to use this much more than once a day” when they return, and there are many who do, this often means that they either need a steroid or are better served with a b.i.d. antihistamine/mast cell stabilizer agent. If they're on a steroid and they're still saying that, he’ll prescribe Patanol where they can justifiably use it a couple of times a day and achieve slightly better results. A preferred solution is adding in a steroid if there is more clinical sign involvement. Dr. Karpecki’s rationale is that many times, patients will say, “The itching is fine, but I'm using it more often because I can't get this redness controlled.” That would be an indication for adding a topical corticosteroid. Concerning the issue of when to remove contact lenses in patients with seasonal allergies, the answer may be in the upper eyelids. Evert the upper eyelid and if it's hyperemic, the contact lens is contributing to their symptoms and it does need to be taken out for a while. If the eyelid looks normal, simply advise the patient to use drops before and after contact lens wear, along with preservative-free hydrogen peroxide solutions. In addition, instruct patients to hydrate their lenses regularly throughout their wear. ❏


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DIRECTIVES POUR UN CRÉDIT UFC DE CATÉGORIE A Ce cours a été approuvé pour 1 crédit UFC de catégorie A en santé oculaire par l’Ordre des optométristes du Québec. Veuillez répondre à ce questionnaire et le soumettre pour notation avant le 31 mars 2018. Afin d’obtenir un crédit UFC de catégorie A, veuillez suivre les étapes suivantes : • Remplissez la section d’identification et répondez aux dix questions à choix multiple dans ce formulaire de demande de crédit UFC. • Faites un chèque de 25,00 $ à l’ordre de Mediconcept. • Postez votre formulaire de demande de crédit UFC ainsi que votre chèque à : CROQ, 3484, boul. des Sources, bureau 518, Dollard-des-Ormeaux, Québec H9B 1Z9. Si vous obtenez une note de 50 % ou plus, un certificat de crédit UFC approuvé par l’Ordre des optométristes du Québec vous sera envoyé pour vos dossiers.

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QUESTIONNAIRE Diagnosis and Treatment of Ocular Surface Conditions: Focus on Allergy Paul M. Karpecki, OD, FAAO

1. ❑ ❑ ❑ ❑

Which of the following types of allergy is most common? Perennial Chronic Giant papillary conjunctivitis Seasonal

2. ❑ ❑ ❑ ❑

All of the following statements about perennial allergy are true, EXCEPT: Contact dermatitis involves the eyelids more than the eye Typically it’s unilateral In North America, optometry treats allergic conjunctivitis more than any other medical specialty Contact dermatitis is best treated with topical corticosteroids

3. ❑ ❑ ❑ ❑

All of the following are possible signs of allergic conjunctivitis, EXCEPT: Glossy-looking eye Papillae Deep red coloration Eyelid swelling

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4. ❑ ❑ ❑ ❑

Which of the following is NOT characteristic of viral forms of allergy? Watery discharge Preauricular lymphadenopathy It begins unilaterally, then spreads to the other eye It begins bilaterally

5. ❑ ❑ ❑ ❑

All of the following statements about seasonal allergies are true, EXCEPT: Steroids have been shown to be faster-acting than antihistamines against itch When the signs are comparable to the symptoms, corticosteroids are the preferred treatment Overall inflammatory signs are typical Chemosis may be present

6. ❑ ❑ ❑ ❑

What percentage of patients with seasonal allergies reported that their reading was greatly affected? 50% 70% 80% 85%

7. ❑ ❑ ❑ ❑

In Dr. Osler’s Harvard University study concerning seasonal allergies, Claritin® resulted in what percentage of decrease in tear volume? 22% 34% 44% 56%

8. ❑ ❑ ❑ ❑

Giant papillary conjunctivitis (GPC) is characterized by all of the following, EXCEPT: Large papillae on the upper tarsal plate Mucin discharge Ocular swelling Decreased contact lens wearing time

9. ❑ ❑ ❑ ❑

In Dr. Bartlett’s study on GPC, Lotemax resulted in what percentage of IOP increase from baseline? 5% 6% 7% 8%

10. ❑ ❑ ❑ ❑

Which of the following describes the profile of a patient with vernal keratoconjunctivitis (VKC) Male children between the ages of roughly 4 and 16 Female children between the ages of roughly 4 and 16 Male children between the ages of roughly 5 and 17 Female children between the ages of roughly 5 and 10

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Pr

Indications and clinical use: LOTEMAX® Ointment (loteprednol etabonate ophthalmic ointment 0.5% w/w) is indicated for the treatment of post-operative inflammation n pain following cataract surgery. and • (The safety and efficacy of LOTEMAX® have inot been studied in pediatric patients (<18 years of age) and 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. s Relevant warnings and precautions: • LOTEMAX® Ointment is indicated for short-term treatment only (up to 14 days). If LOTEMAX® Ointment 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. • Should not be used in pregnant or lactating women unless the benefit to the mother clearly outweighs the risk to the infant/child.

8VDJH FOLQLTXH /¶LQQRFXLWp HW O¶HI¿FDFLWp G¶$/5(;MD n’ont pas été étudiées chez les enfants (< 18 ans) ou chez les personnes âgées (> 65 ans) et ce médicament ne doit pas être utilisé chez ces populations. Contre-indications : ,QIHFWLRQ RFXODLUH VRXSoRQQpH RX FRQ¿UPpH maladies virales de la cornée et de la conjonctive, y compris la kératite épithéliale à Herpes simplex (kératite dendritique), la vaccine et la varicelle; infection oculaire non traitée; infection mycobactérienne de l’œil et maladies fongiques des structures oculaires; • Hypersensibilité à ALREXMD ou à l’un des ingrédients retrouvés dans la préparation ou les composantes du contenant ou à d’autres corticostéroïdes. Mises en garde et précautions les plus LPSRUWDQWHV • ALREXMD est destiné à un usage ophtalmique uniquement. Il est indiqué pour un traitement à court terme uniquement (jusqu’à 14 jours). Si ALREXMD est utilisé pendant 10 jours ou plus, une surveillance étroite de la pression intraoculaire (PIO) s’impose. • L’utilisation prolongée de corticostéroïdes peut entraîner la formation d’une cataracte et/ou l’apparition du glaucome. ALREXMD ne doit pas être utilisé en cas de glaucome ou de PIO élevée à moins d’absolue nécessité, dans quel cas une surveillance ophtalmologique étroite doit être exercée. • Il doit être utilisé avec prudence chez les personnes portant des lentilles cornéennes souples. • Il ne doit pas être utilisé chez les femmes enceintes à moins que les bienfaits pour la mère ne l’emportent clairement sur les risques pour le fœtus.

For more information: Please consult the Product Monograph at http://www.bausch.ca/Portals/87/Files/ Monograph/Pharma/Lotemax-MonographConsumer-English.pdf for complete dosing instructions, warnings, precautions, adverse events and patient selection criteria. The Product Monograph is also available by calling 1-888-459-5000.

3RXU GHV SOXV DPSOHV UHQVHLJQHPHQWV Veuillez consulter la monographie du produit à l’adresse http://www.bausch.ca/Portals/59/ Files/Monograph/Pharma/FR/Alrex-PM-F.pdf pour obtenir des renseignements complets sur les directives posologiques, les mises en garde, les précautions, les effets indésirables et les critères de sélection des patients. On peut également se procurer la monographie du produit en composant le 1-888-459-5000.

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

Bausch & Lomb Canada Inc., Vaughan (Ontario) L4K 4B4 © Valeant Canada LP ®/MD désigne la marque de commerce de Bausch & Lomb Incorporated


Consultez les renseignements supplémentaires sur l’innocuité à la page 212


Introducing LOTEMAX Ointment ®

Demonstrated efficacy to reduce incidence of post-operative inflammation and pain following cataract surgery compared to placebo at day 8.1† In two pivotal studies†, LOTEMAX® had a significantly higher incidence of complete clearing of anterior chamber cells and flare‡, and elimination of pain. In Study A, complete clearing of post-operative inflammation was achieved in 24% of subjects treated with LOTEMAX® vs. 14% treated with the vehicle (48 vs. 27 individuals; P )0.0082), and 78% of subjects in the LOTEMAX® group were pain-free vs. 45% in the vehicle group (156 vs. 90 individuals; P 0.0001).

To order please contact Bausch + Lomb Customer Service at 1-800-686-7720 (English) or 1-800-686-0002 (French). Wholesale Order Numbers:

In Study B, 32% in the LOTEMAX® group vs. 11% in the vehicle group (64 vs. 23 individuals; P 0.0001) had complete clearing of post-operative inflammation, and 73% of subjects treated with LOTEMAX® were pain-free vs. 41% treated with the vehicle (149 vs. 83 individuals; P 0.0001).1

McKesson Order Number

Kohl & Frisch

69848

149463

THE FIRST AND ONLY PRESERVATIVE-FREE, MONOTHERAPY OCULAR STEROID OINTMENT2* LOTEMAX® (loteprednol etabonate ophthalmic ointment 0.5% w w//w) is indicated ind for the treatment of post-operative inflammation and pain following cataract surgery. Refer to the page in the bottom right icon for additional safety information and for a web link to the Product Monograph discussing: • Contraindications in patients with suspected or confirmed infections of the eye or hypersensitivity to LOTEMAX X® or any ingredient in the formulation or containerr, or to other corticosteroids; • Use in pregnant or nursing women, pediatric and geriatric patients; • Relevant warnings and precautions regarding potential complications with prolonged use, IOP monitoring, and contact lens wearers; • Conditions of clinical use, adverse reactions, drug interactions and dosing instructions. * Comparative clinical significance has not been established. In two phase 3, randomized, d, multicenterr,, double-masked, parallel-group, 4-week, trials, clinical safety and efficacy evaluations of LO LOTEMAX X® ointment (loteprednol etabonate ophthalmic ointment) 0.5% vs. vehicle (mineral oil and white petrolatum) were evaluated for the treatment of inflammation and pain following cataract surgery (N = 805).1 Post-operative inflammation was judged by complete resolution of anterior chamber cells and flare at post-operative day 8. P-values were determined etermined using both the P Pear earson chi-squared test (primary outcome) and the Cochran Mantel-Haenszel test (controlling for site). ‡ Cell count 0 and no flare. †

References: 1. LOTEMAX X® Product Monograph, Bausch and Lomb Inc., February 27, 2014. 2. Bausch and Lomb, Data on File. Medical Letter tterr, August 15, 2014. Pr

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

Seeadditional additional safety safety information See informationon onpage page000 212


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