Approaches to the Diagnosis and Treatment of Dry Eye Disease: Vol 3 by MediConcept

VOLUME 3

Approaches to the Diagnosis of Dry Eye Disease from the optometric and ophthalmic perspectives

Contributors Richard Maharaj OD Steve Arshinoff MD Shachar Tauber MD

CRO

Clinical & Refractive Optometry

Applications and Usage The authors and publisher have exerted every effort to ensure that the application and use of all medical drugs, devices and procedures mentioned in this publication are in accord with current recommendations and practices. However, in view of ongoing research, changes in regulations, and the constant flow of information relating to optometry and ophthalmology, the reader is cautioned to consult the package insert of any product for the approved indications and dosage recommendations, as well as for any changes, warnings or precautions prior to usage. All Rights Reserved No part of this publication may be translated into any other language, reproduced, or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without prior written permission from the publisher. Prepared, printed and published online by: Mediconcept Inc. 3484 Sources Blvd. Suite 518 Dollard-des-Ormeaux, Quebec H9B 1Z9 Canada Copyright ÂŠ 2016 Mediconcept Inc.

Contributors Richard Maharaj, OD, FAAO completed his Doctor of Optometry degree at the University of Waterloo School of Optometry in 2003, and Fellowship of the American Academy of Optometry in 2012. Dr. Maharaj is lead optometrist at Humber River Regional Hospital – York/Finch Eye Associates – an intergrated medical eye clinic. Dr. Richard Maharaj has a special interest in dry eye disease, glaucoma and disease of the retina. He is a clinical adjunct associate for the University of Waterloo College of Optometry. He is a published respected national speaker in eye education on diseases and diagnostics of cornea, retina, and meibomian gland dysfunction. His primary research is in non-surgical treatments of the eyelid and periocular glands. He is an active member of the Ontario Association of Optometrists, Canadian Association of Optometrists, American Academy of Optometrists and the College of Optometrists of Ontario.

Steve Arshinoff, MD, FRCSC received his medical degree at Baylor College of Medicine in Houston, Texas, and then attended the University of Toronto for his residency in ophthalmology. He has been in private ophthalmic group practice in Toronto, Canada, at York Finch Eye Associates and Humber River Regional Hospital, since 1980. He has academic appointments at the University of Toronto and McMaster University. Dr. Arshinoff’s areas of special interest in ophthalmology are primarily cataract and refractive surgery. He is the author of over 240 peer-reviewed publications and has lectured all over the world on techniques of cataract and refractive surgery. He maintains an ongoing research commitment. Dr. Arshinoff has particular interest in simultaneous bilateral cataract surgery (SBCS), antibiotic prophylaxis for intraocular surgery and ophthalmic viscosurgical devices (viscoelastics).

Shachar Tauber, MD serves as the Director of Ophthalmic Research and Consultant in Cornea and Refractive Surgery at the Mercy Clinic Eye Specialists – Ophthalmology – Surgery Center in Springfield, Missouri. From 1996-2004 he has been an Assistant Professor of Ophthalmology, Director of Cornea and Refractive Surgery at the Yale University School of Medicine Department of Ophthalmology and Visual Sciences. He is actively involved in refractive surgery and cornea research with particular interest in wavefront guided lasers, lamellar corneal surgery, corneal wound healing, infectious corneal diseases and keratoprosthesis. He serves on the editorial board of Cataract and Refractive Surgery Today, Review of Refractive Surgery and the Video Journal of Ophthalmology. He has been a visiting professor at the University of Tennessee and the University of Vermont as well as Tamil Nadu Dr., MGR Medical University in Chennai India.

Contents Treating and Managing Dry Eye .....................................................................................................................5 Shachar Tauber, MD Much has been learned about the tear film (and its impact on dry eye) over the years, from the discovery of its multi-level properties, increased understanding on the role of mucin, through to the interaction between the surface and the tear film. From an epidemiological standpoint, dry eye prevalence is in the range of between 6% and 14%, although most people have experienced dry eye in one of its many forms.

A New Modality for the Treatment of Dry Eye Syndrome ...........................................................................9 Steve A. Arshinoff, MD, FRCSC Current treatment approaches for dry eye can be classified as anti-inflammatories, produces providing aqueous replacement, and evaporation reducing agents. The study of rheology is important in understanding viscosity, elasticity and the cohesion/ dispersion continuum as it relates to the properties of ophthalmic solutions. Viscoadaptive artificial tears are characterized by high-molecular weight hyaluronic acid and glycerol. This results in prolonged residence time on the cornea and increased lubrication, thereby improving the blink process in patients with dry eye.

Blink Mechanics: Viscoadaptive Technology for the Ocular Surface ....................................................................................................................................16 Richard Maharaj, OD, FAAO The increasing prevalence of dry eye highlights the importance of the early identification and treatment of such patients. According to worldwide studies over the past decade, the prevalence of dry eye ranges from 7 percent up to close to 50 percent, rising to more than 90 percent in Dr. Maharaj’s clinic. Tear osmolarity is an important dry eye metric: A hyperosmolar tear film is an indication of an inflammatory environment. Compromised blink mechanics such as incomplete or dysfunctional blinking are a key component in meibomian gland dysfunction and dry eye disease.

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 1 ..........................................................................................................................22 Richard Maharaj, OD, FAAO The intrinsic and extrinsic risk factors associated with ocular surface diseases, as well as tear film osmolarity — and its role in optometric care are — are key elements in the diagnosis and treatment of dry eye disease. The goal of a stable tear film is based on the perfect interaction between the lipid, mucus and aqueous layers delivered by the meibomian glands, the goblet cells, and the lacrimal and accessory glands respectively, as well as the optimal interface between these layers and the lid mechanics. The examination of tear chemistry will play an increasingly major role in the diagnosis and treatment of dry eye disease and in the future of eye care.

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 2 ..........................................................................................................................30 Richard Maharaj, OD, FAAO Osmolarity testing is a critical element in expanding optometrists’ diagnostic capability around their contact lens practice. Other metrics can be employed; however, tear osmolarity is an extremely good tool to use so that patients understand their situation very quickly. In addition, clinically, it has already been proven from an evidence-based perspective. Tear osmolarity is the only element that truly adds to the clinical decision. Tear chemistry and dry eye management are areas that will see enormous growth in the next decade.

Treating and Managing Dry Eye Shachar Tauber, MD

ABSTRACT Much has been learned about the tear film (and its impact on dry eye) over the years, from the discovery of its multi-level properties,1 increased understanding on the role of mucin,2 through to the interaction between the surface and the tear film.3 From an epidemiological standpoint, dry eye prevalence is in the range of between 6% and 14%, although most people have experienced dry eye in one of its many forms.

INTRODUCTION This article reviews dry eye, its epidemiology, etiology, prevalence, and therapeutic options.

TEAR FILM STRUCTURE For many years, ophthalmology taught that the tear film was comprised of three distinct layers. What has been found is that it is actually an indistinct transition where the mucins are dissolved within the aqueous in a gradient (Fig. 1). The lipid layer is the thinnest of the layers and acts to prevent the evaporation produced by the meibomian glands. The aqueous layer is the thickest layer, and its role is to transport oxygen, enzymes, proteins, and other matter. The mucin layer is the innermost layer closest to the cornea, and it serves as a coating for the hydrophobic cornea regulating surface tension; it is produced by goblet cells and is composed of 21 different mucins.

ETIOLOGY Dry eye worsens with age and can be due to numerous causes. Therefore, it is important to regard dry eye not as a Fig. 1 The traditional tear film model compared to the updated tear film model disease but as a multi-factorial disorder; and because of this, treatment has been extremely difficult to develop and be proven as effective. Other than such environmental factors as air-conditioning and cold or dry weather, there are many other factors including different surgeries and disease entities that can cause dry eye. Medication-Induced Dry Eye Many patients present to us on multiple medications including beta-blockers, antihistamines, diuretics, chemotherapy, and anti-depressants. In fact, more patients on antidepressants seek refractive surgery, which is an interesting relationship worthy of further investigation. Glycocalyx The glycocalyx is where the mucin attaches to the corneal epithelium and this interdigitation is quite important: when it fails, clinical dry eye develops (Fig. 2). The glycocalyx is a cotton-candy-like substance that grabs the mucin layer of the tear and allows it to adhere to the microvilli or the surface

Fig. 2 Glycocalyx helps mucin adhere to corneal epithelial cells; any damage to the glycocalyx means mucin deficiency, causing tear film destabilization and break up

Treating and Managing Dry Eyeâ&#x20AC;&#x201D; Tauber

epithelium. Thus the ocular surface is made up of stroma matrix and fibroblasts, the epithelial cell membrane, the aqueous, the glycocalyx, and the mucin. Innervations Innervations are important as they are the sensory component going from the cornea to the lacrimal nucleus (Fig. 3). If those nerves are interfered with, outgoing messages to different parts of the lacrimal system will be affected. This is a problem often encountered in laser in-situ keratomileusis (LASIK), where it interferes with the corneal nerves.

DRY EYE CLASSIFICATION The National Eye Institute has classified dry eye into two general categories: tear deficient and evaporative; and within each main category are subcategories. Under “tear deficient” we find such conditions as Sjögren’s and auto-antibodies, and non-Sjögren’s and lacrimal deficiency, lacrimal obstruction, and reflex. Under “evaporative” we find the subcategories oil Fig. 3 Nerve distribution in a normal eye deficient lid-related, contact lenses, and surface changes.

TEAR FILM DEFICIENCIES Various dry eye disorders can be placed under one of three areas of tear film insufficiency: lipid, aqueous, and mucin. Lipid Layer Deficiency Under this category we find a diverse group of disorders that lead to changes in meibomian gland secretions, including blepharitis. Aqueous Layer Deficiency As with lipid layer deficiency, there are many disorders that can lead to aqueous layer insufficiency and dry eye. These include: inflammation, trauma, neurological defects, and congenital absence, among others. Mucins Again, there are many potential causes of disruption to this tear film layer, including: Stevens-Johnson syndrome, pemphigoid, vitamin A deficiecy, trachoma, and radiation-induced issues.

DRY EYE CYCLE Typically, a patient will present complaining of discomfort, which is actually environmental or contact lens intolerance. This creates surface changes that further worsen the dry eye symptoms, and begins a downward spiral. If we operate on these people, there is a risk of wound healing issues, infection, and chronic inflammation, whether performing LASIK, cataract surgery, transplant surgery, or glaucoma surgery. Therefore, treating the dry eye prior to surgery is indicated. Tear Film Instability The tear film instability cycle (Fig. 4) begins with surface desiccation and leads to a hydrophobic cornea to which the mucin is unable to attach. This exposes the epithelial cells to evaporation, resulting in an inflamed cornea. Regardless of the original causal factor(s), the cycle remains the same: rear production decreases or tear evaporation increases; there is an

Approaches to the Diagnosis of Dry Eye Disease

Fig. 4 The process of tear film destabilization and the resulting corneal cell damage

increase in tear osmolarity and toxin concentrations; and goblet cell density decreases and epithelial desquamation increases. This leads to a breakdown of the cornea-tear interface and leads to an increase in such inflammatory mediators as cytokines and leukotrienes. The last step of this cycle is permanent surface stem cell, stromal matrix, and neurotrophic damage. Patients are then very susceptible to infection, inflammation, and ulceration of the cornea. When metaplasia is encountered in the lid margin, it becomes difficult for the ophthalmologist to separate the concomitant blepharitis and dry eye. Due to the advanced progression of the disease at this point, there are now overlapping issues with oil release, tear film evaporation, and dry eye exacerbation. Unprotected Surface What are the consequences of an unprotected surface? At time zero, when the blink occurs, the tear protects the ocular surface until that tear breaks up. If the tear breaks up prior to the subsequent blink, it results in ocular staining of the now unprotected surface. When repeated over the course of a day, this can result in 4,000 to 8,000 seconds where the surface is unprotected and causes epithelial desiccation.

OCULAR PROTECTION INDEX (OPI) The OPI (Fig. 5) measures the tear film break up time (TFBUT). We then divide that time by the interval between blinks (IBI). Simply, if the patient blinks prior to TFBUT, then the ratio is >1 and the ocular surface is protected. Conversely, if the TFBUT occurs prior to the blink the ratio is <1, and the ocular surface is unprotected. There is a host of conditions that affect an individual’s blink rate. For example: hormonal changes, mental disorders, menstrual phase, muscular fatigue, drug interactions, computer use, and talking. It is recommended that clinicians watch their patients while taking their history to determine their blink rate.

PREVALENCE The prevalence of diagnostic dry eye must not be underestimated; because it is so common, it tends to be ignored. Fig. 5 The OPI measures TFBUT as related to blink interval to determine The symptoms can be extremely confusing; patients may whether the ocular surface has adequate tear film protection present with decreased vision, and it is difficult to determine whether one is dealing with an early cataract, early Fuchs, or indeed an ocular surface issue.

TESTING TOOLS In addition to observation of TFBUT, there are many diagnostic tools at our disposal for dry eye evaluation. Multiple dyes will stain the cornea and tear including Rose Bengal (which stings significantly), Lissamine Green, and fluorescein staining (frequently used). Fluorophotometry and osmolarity testing are quite complex and have not yet been sufficiently standardized to be used clinically.

TFBUT TFBUT is diagnostically helpful, but must also be standardized. Improved tear-film evaluation techniques include using ≤ 5µl of sodium fluorescein and Wratten filters for optimal imaging. Figure 6 shows one such tear-film evaluation in action. Another method to evaluate TFBUT is to ask patients to blink twice and

Fig. 6 An evaluation (in seconds) of tear film break up elapsed time

Treating and Managing Dry Eye— Tauber

look straight ahead. Using a stopwatch, time the seconds until they say they have ocular awareness. One second following ocular awareness equals the symptomatic tear break up time.

THERAPEUTIC OPTIONS Patient education is tantamount in helping them take a proactive role in the treatment process. Patients must be taught awareness of TFBUT, drying medications (i.e., oral antihistamines and antidepressants), adverse environments (i.e., dry, windy places), and visual tasking (i.e., computer usage, reading). Artificial Tears There is a lengthy list of tear substitutes. The optimal artificial tear characteristics have increased dwell time and long-lasting protection. It must have minimal blurring and lid-caking, offer improved comfort, and it should contain non-irritating preservatives. However, rather than simply managing dry eye by flooding it, future therapy is going to involve treating dry eye via targeting the different tear film layers. Secretagogues Secretagogues will soon treat production of essential tear components at all three levels: there is the 15(S)-HETE that stimulates mucin production, as well as the INS-365 that stimulates all three tear-film layers. Anti-Evaporatives This upcoming therapeutic category stimulates lipid secretion to enhance and optimize the barrier function of the lipid layer. Anti-evaporatives include topical androgens that regulate the quality and quantity of lipid secretions, as well as lipid component replacements such as lipocalin, phosphatidylcholine, and castor oil. Anti-Inflammatories Anti-inflammatories target the inflammation component of dry eye at the lacrimal gland. It has been demonstrated that reducing the inflammatory response of the dry eye is an effective treatment option; Restasis® is one such anti-inflammatory that has received FDA approval and is used widely in the United States. Other anti-inflammatories include low-dose steroids and tetracyclines. Mucomimetics The mucomimetics, as the name implies, mimic the functions of naturally occurring mucins; by stabilizing the tear film, they actually result in a healthier ocular surface. MILCIN™ is one mucomimetic that is on the horizon as a treatment option.

CONCLUSION To reach our collective goal of ocular surface protection, we must heal the damage and reduce inflammation and irritation. This will likely be accomplished by a line of products rather than one “cure-all”. With the many causes of dry eye and nearly as many therapeutic approaches, we will certainly be looking at combination therapy, with different treatments for different ideologies. ❏

REFERENCES 1. 2. 3.

Wolf. Normal Physiology of the Ocular Surface. Section 8 Basic and Clinical Sciences Course, American Academy of Ophthalmology 2002-2003, page 49. Holly FJ. Formation and stability of the tear film. Int Ophthalmol Clin 1973; 13(1): 73-96. Tseng SC, Tsubota K. Important concepts for treating ocular surface and tear disorders. Am J Ophthalmol 1997; 124: 825-835.

Approaches to the Diagnosis of Dry Eye Disease

A New Modality for the Treatment of Dry Eye Syndrome Steve A. Arshinoff, MD, FRCSC

ABSTRACT Current treatment approaches for dry eye can be classified as antiinflammatories, produces providing aqueous replacement, and evaporation reducing agents. The study of rheology is important in understanding viscosity, elasticity and the cohesion/dispersion continuum as it relates to the properties of ophthalmic solutions. Viscoadaptive artificial tears are characterized by high-molecular weight hyaluronic acid and glycerol. This results in prolonged residence time on the cornea and increased lubrication, thereby improving the blink process in patients with dry eye.

INTRODUCTION Dr. Arshinoff began his presentation by outlining the topics he would be discussing, specifically: a review of past and current choices for the treatment of dry eye; the variety of treatment modalities available for dry eye syndrome; rheology; intraocular aophthalmic visco-surgical device (OVD) properties; and their comparison to the unique composition and behaviour of viscoadaptive eye drops.

EVOLUTION OF DRY EYE TREATMENT APPROACHES Dr. Arshinoff referenced the 2007 International Dry Eye Workshop at which Committee members developed a framework for the definition, classification and mechanisms of dry eye (Fig. 1). He noted that dry eye has become somewhat of a “catch-all” term whose underpinnings are the result of either excessive tear evaporation or decreased tear production. Prior to the development of Restasis® (Allergan, Markham, ON), an anti-inflammatory form of artificial tears, pharmaceutical companies responded by providing watery artificial tears, replacing water, or by decreasing evaporation. There are currently three types of eye drops available: 1) Antiinflammatories such as Restasis; 2) Aqueous replacement, such as HypoTears® (Novartis, Dorval, QC), TheraTears® (Advanced Vision Research, an Akorn company, Ann Arbor, MI); and 3) Evaporation reducing agents, such as Systane® Gel Drops (Alcon, a Novartis company, Mississauga, ON). Dr. Arshinoff cited Alcon’s development of successive iterations of Systane eye drops based on a shift in direction from replacing water to preventing evaporation, a direction that merits further examination. This past decade, for example, has seen a product evolution from Systane, to Systane Ultra, to Systane Balance, to Systane Gel Drops.

RHEOLOGY: STUDYING FLUID BEHAVIOUR Dr. Arshinoff presented an explanation of rheology, the science of how fluids respond to forces, or the mechanics of fluids, and how it works in the devices ophthalmologists use. The study of rheology involves concepts relating to viscosity, elasticity and the cohesion/dispersion continuum. He pointed out that rather than a straight line of correlating properties, OVDs possess endless variation of the above properties, such as viscosity changes under stress (Fig. 2).

A New Modality for the Treatment of Dry Eye Syndrome — Arshinoff

The Definition & Classification of Dry Eye Disease Guidelines from the 2007 International Dry Eye Workshop Michael A. Lemp, MD and Gary N. Foulks, MD, FACS Major Etiological Causes of Dry Eye Ocular Surface Disease Symptomatic Prodromal states Asymptomatic NonDry Eye Disease

Dry Eye Disease

Aqueous Deficient Dry Eye

Lid-related Disease

Evaporative Dry Eye other

MGD

Anterior Blepharitis other

Fig. 1 Etiology of dry eye

Dr. Arshinoff stated that there are four different ways that the viscosity of fluids can respond to forces, the first of which is Newtonian, which means that no matter how much force you expose the fluid to, its viscosity remains the same (Fig. 2). Another example is the plastic response curve, from which “plastic” materials derive their name. When exposed to very high forces, plastics are fluid, but when exposed to very low forces, they are solid. Imagine, suggested Dr. Arshinoff, trying to use a plastic OVD in ophthalmic surgery. The substance is injected into the eye as a liquid, but once at rest, it turns solid, which would make surgery difficult. As a result, what is used instead are devices called pseudoplastic. In Figure 2, the blue line represents a pseudoplastic fluid which means that, like a plastic under high forces going through a syringe, it has very low viscosity. However, when sitting in the eye, the viscosity increases — reaching what is called a limiting or a zero-shear viscosity — remaining fluid. The graph levels off and does not go higher than whatever the zero-shear viscosity is. The corollary is: The only useful viscosity number for OVD classification is its zero-shear viscosity, as any other viscosity value is dependent upon the shear rate at which it was measured, which is often not disclosed by the manufacturer. The pseudoplasticity graphs in Figure 3 illustrate the different OVDs in common use in North America, although the HPMCs can easily be seen to not be very pseudoplastic. Note that the top red line depicts i-Visc® Phaco (I-MED Pharma, Montreal, QC) as “almost plastic.” Returning to Figure 2, the fourth fluid behaviour type, represented by the pale blue line, is dilatant. Dilatant is the opposite of pseudoplastic, meaning that the more force it is exposed to, the more viscous it becomes. A classic example of a dilatant fluid is albumin (egg whites).

Approaches to the Diagnosis of Dry Eye Disease

Other OSD Allergic conjunctivitis Chronic infective and non-infective Keratoconjunctivitis Conjunctivitis Post-refractive

NEWTONIAN SOLUTIONS IN OPHTHALMIC PRODUCTS

Table I Ophthalmic viscous Newtonian solutions

Examples of ophthalmic viscous solutions that are almost • Viscosity constant, independent of shear rate Newtonian (Table I) are the low pseudoplasticity surgical • Examples ophthalmic viscoelastic devices (OVDs), such as i-Cel® o Low pseudoplasticity Surgical OVDs (~ Newtonian) ® (I-MED Pharma, Montreal, QC), OcuCoat (Bausch & - OcuCoat Lomb, Vaughan, ON) and Cellugel® (Alcon, a Novartis - I-Cel company, Mississauga, ON), the two bottom curves in Figure 3. - HPMCs The curves representing these are more or less horizontal, o Topical artificial tears (± Newtonian) meaning that the viscosity does not change with changing - Hypotears shear rate, except for the very end, where the levels descend. - Tears Naturale What this indicates is that if you are going to use an HPMC - Systane OVD, it is going to behave more or less the same in the eye, - GenTeal irrespective of the ambient shear rate. The surgeon would - Refresh have to push down very hard on the syringe, exposing it to a - Tears Plus lot of force, to inject the OVD through a cannula. For this rea- Celluvisc son, HPMC OVDs are packaged with larger cannulas than other OVDs. In terms of artificial tears, examples that are more or less Newtonian include: HypoTears, Tears Naturale, Systane, GenTeal® (Alcon, a Novartis company, Mississauga, ON), and Refresh® (Allergan, Markham, ON).

NON-NEWTONIAN SOLUTIONS Non-Newtonian solutions are used in intraocular surgery, most of which are pseudoplastic (Fig. 3). Highly pseudoplasticity means that they exhibit low viscosity at high shear, high viscosity at low shear, and possess a limiting or zero-shear viscosity. Examples of this are Healon®, Healon GV® (Abbott Medical Optics, Markham, ON) and i-Visc.

Rheometric Patterns of Fluid Behaviour: Viscosity

“VISCOADAPTIVE” ARTIFICIAL TEARS: WHAT IT MEANS AND WHAT IT DOES Artificial tears containing hyaluronic acid — a long enough chain that behaves like a pseudoplastic material — were first developed twenty years ago; Hylashield. Dr. Arshinoff stated that three terms — viscous, elastoviscous and viscoadaptive — are used to describe the various Fig. 2 Pseudoplasticity curves: rheometric patterns of fluid viscosity treatments for dry eye. He noted that the term “viscoadaptive” response to increasing force (shear rate). may be confusing to some practitioners, as “viscoadaptive” when used to describe tears, has a different meaning than when the same term is used to describe intra-ocular OVDs. With respect to intraocular surgical OVDs, visco-adaptive signifies that the behaviour of the OVD changes from a highly viscous cohesive — like a Super Healon or Super Healon GV — to a pseudodispersive. However, Dr. Arshinoff pointed out, pseudodispersive is not the same as dispersive, hence thedifferent term: pseudodispersive means “fractureable solid under high stress.” Both i-Visc Phaco and Healon5, when they are absolutely stationary, can behave like fractureable solids when exposed to high frequency stresses. The way you make it behave like a solid is by changing the ambient environment inside the anterior chamber. So if you increase your flow rate of fluid in the anterior chamber, you are exposing the OVD to turbulence. The very viscous OVD will behave like a solid and will fracture like a solid. The term viscoadaptive was designed to mean that we can change our flow

A New Modality for the Treatment of Dry Eye Syndrome — Arshinoff

Fig. 3 Pseudoplasticity curves of intraocular OVDs in common use in North America.

rate in the eye and make the OVD behave “like a dispersive,” but not through the same mechanism. You can make Healon5 or i-Visc Phaco behave like extremely viscous “super" Healon GVs under low turbulent conditions, or, by increasing turbulence in the anterior chamber, they behave as pseudodispersive fractureable solids. Analysis of rheological behaviour generally looks at typical flow rates between 10 and 45 cc/min. In Figure 4, Viscoat® (Alcon, a Novartis company, Mississauga, ON) behaves as a dispersive throughout those flow rate settings; and Healon GV behaves as a cohesive across those flow rate settings. However, Healon5 will initially behave as a viscous cohesive, but with increasing flow rates above 25 cc/min, behaves as a fractureable solid.

COMPOSITION AND BEHAVIOUR VISCOADAPTIVE ARTIFICIAL TEARS

In artificial tears, “viscoadaptive” refers to an elastoviscous solution that changes under stress. There are chains of hyaluronic acid that are not as long as those that would be used in an intraocular OVD. When these chains are exposed to the force of blinking, they are more elastic than they are viscous. When you blink with an elastic in your eye, you Fig. 4 Behaviour changes in ophthalmic viscoadaptive OVDs. blink and it compresses; it does not go anywhere. When you open your eye, it comes back and stays there, because it is acting like a spring. This was the first concept in developing a viscoadaptive tear. The second concept is to add something to the tear which will make it behave differently again under stress, which resulted in glycerol, a small molecule, being added. Because the hyaluronic acid absorbs all the water, and

Approaches to the Diagnosis of Dry Eye Disease

there is no free water in the solution, when compressed, the viscoadaptive elastoviscous artificial tear solution excludes the glycerol from its structure, liberating it to the surface. As a result, as soon as you blink with these tears, the glycerol comes to the surface, reinforcing your lipid layer and providing better tear lubrication. Dr. Arshinoff noted that it is a different interpretation Non-Newtonian Tear Solutions: of viscoadaptivity. i-drop® (I-MED Pharma, Montreal, QC) is the first product of its type on the market, made of highViscoadaptive? molecular weight hyaluronic acid and glycerol; it is an elastoviscous solution of hyaluronic acid. Glycerol is excluded during blink, thereby lubricating the tears during the blinking process (Figs. 5, 6). An additional advantage is that every human cell has hyaluronic acid binding sites, so when you take these chains of hyaluronic acid and put it on your cornea, it adheres to the corneal surface. Therefore, when blinking it remains fixed: it is stuck to the cornea. Together with the water layer and the glycerol that moves in and out with blinking, the formula represents the potential for an improved artificial tears product. In 2003, the first viscoadaptive eye drop was launched in Fig. 5 Dispersive and cohesive properties of non-Newtonian tear solutions. Canada, followed by Oasis Tears® (Oasis Medical, Glendora, CA) in 2009 — the first viscoadaptive hyaluronan-based eye drop launch in the United States. In 2013, i-drop Pur and i-drop Pur Gel (I-MED Pharma, Montreal, QC) were approved as the first non-preserved multidose viscoadaptive eye drops.

PATIENT BENEFITS OF VISCOADAPTIVE ARTIFICIAL TEARS Dr. Arshinoff summarized his presentation by describing the potential advantages of i-drop artificial tears. i-drop Pur artificial tears are pseudoplastic elastoviscous tears, with a second molecule to increase lubrication. They exhibit polymer crowding, so there is no free water. In addition, they are blink responsive in that they are elastic, so they stay in the eye. They adhere to the cornea and the blink energy “Viscoadaptive” Eye Drops allows them to spread better over the eye. It releases glycerol to increase lubrication and it lasts longer than other drops in the i-drop family of products. Dr. Arshinoff mentioned that as it launched only one year ago, there is not yet substantial clinical experience to report. The proposed patient benefits are: enhanced protection of the cornea; prolonged residence time on the cornea because of the binding sites; smoother to blinks; higher degree of patient comfort; very good corneal hydration; and less tear evaporation, which seems to be the direction in which other companies are Fig. 6 Viscoadaptive eye drops mode of action. moving in developing their eye drops.

A New Modality for the Treatment of Dry Eye Syndrome — Arshinoff

How Viscoadaptive Eye Drops Work i-drop ® Pur and i-drop ® Pur GEL are the world’s first and only, viscoadaptive, multi-dose, preservative-free, eye drops. They are both combinations of viscoadaptive sodium hyaluronate (HA) and glycerine molecules; and they are available in two different concentrations of HA for use with varying degrees of dry eye disease. i-drop® Pur contains 0.18% viscoadaptive HA and is indicated for use with mild to moderate dry eye disease as well as with contact lenses. i-drop® Pur GEL contains 0.3% viscoadaptive HA and is indicated for use with moderate to severe dry eye disease.

LIPID LAYER

GLYCERIN HA

AQUEOUS LAYER

MUCIN LAYER

CROSS SECTION OF THE TEAR FILM

Both formulations of i-drop® contain long chained HA molecules that trap and hold glycerin and any available free water in a soluble suspension on the surface of the cornea. With each blink, the eyelids exert a physical force on the tear film pushing the glycerin and water out of suspension. This action enables the glycerin to reinforce the lipid layer, the water to hydrate the aqueous layer, and the HA to supplement the mucin layer. Then, as the eyelids relax and re-open, the glycerin and water return to suspension and they are ready for the next blink. This pseudoplastic elastoviscous action is referred to as viscoadaptivity.

Viscoadaptive eye drops enhance the three natural layers of the tear film and are remarkably comfortable and long lasting for the patient. It is also why i-drop® Pur and i-drop® Pur GEL are highly effective at hydrating and lubricating the cornea while reducing tear film evaporation, which are generally recognized as being the principle factors required to improve the symptoms associated with dry eye disease.

Two Choices for Long Lasting Relief i-drop®, the world’s first and only viscoadaptive, multi-dose, preservative-free, eye drop is now available in two concentrations. i-drop® Pur for treating mild to moderate dry eye disease, and i-drop® Pur GEL for treating moderate to severe dry eye disease.

VISCOADAPTIVE EYE DROPS s Enhanced Corneal Protection s Prolonged Residence Time s Smoother Blinks s Higher Degree of Comfort s Excellent Corneal Hydration s Reduced Tear Film Evaporation

i-drop® Pur GEL 0.3% viscoadaptive HA Provides immediate, long lasting relief for moderate to severe dry eye disease i-drop® Pur 0.18% viscoadaptive HA Provides immediate, long lasting relief for mild to moderate dry eye disease indicated for use with contact lenses

I-MED Pharma

800.463.1008 www.osdcare.com www .osdca are.com

Blink Mechanics: Viscoadaptive Technology for the Ocular Surface Richard Maharaj, OD, FAAO

ABSTRACT The increasing prevalence of dry eye highlights the importance of the early identification and treatment of such patients. According to worldwide studies over the past decade, the prevalence of dry eye ranges from 7 percent up to close to 50 percent, rising to more than 90 percent in Dr. Maharaj’s clinic. Tear osmolarity is an important dry eye metric: A hyperosmolar tear film is an indication of an inflammatory environment. Compromised blink mechanics such as incomplete or dysfunctional blinking are a key component in meibomian gland dysfunction and dry eye disease.

INTRODUCTION While the body of Dr. Maharaj’s work is in Meibomian Gland Dysfunction, he noted that this presentation topic was focused on blink metrics in mild to moderate dry eye patients. There are two components in the discussion of the mechanics of blinking and viscoadaptive technologies. The first is what the eyelid does on a given blink. The second is the microanatomy involved in the blink at the inner and outer eyelid surface. Dr. Maharaj has observed that a blanket approach to treatment with artificial tears isn’t an effective model of care for the multifactorial dry eye patient. Following the artificial tear evolution and consideration of the chemical properties of various artificial tearproducts, industry has moved toward meibomian gland driven therapies with specific focus on lipid layer supplementation.

BLINK MECHANICS AND VISCOADAPTIVE DEVICES In a normal functioning eye, the eyelid closes as the superior eyelid comes down and meets the bottom eyelid, grabs onto the lipid layer and the oil film rises with the upper lid to coat the tear film. This is clearly shown on video imaging with the Oculus keratograph 5M and looks very clear under slit lamp. The human body has evolved in such a way that this mechanism of action is responsible for achieving comfort, and in fact can be the source of discomfort, said Dr. Maharaj. He noted that one of the current focuses of the Tear Film & Ocular Surface Society (TFOS) is the mechanics and metrics of blinking. Computer vision syndrome is not surprisingly on the rise. A common at home tip for patients involves blinking 20 times every 20 seconds by looking 20 feet away or the 20-20-20 rule. When one looks at dry eye and ocular surface disease, one realizes the role that the blink plays in it. Dr. Maharaj stated that understanding blink mechanics makes it easier to understand the mechanisms involved in the development of the dry eye.

MECHANICS OF DRY EYE DISEASE Dr. Maharaj described rheology, the behavior of fluids in response to applied forces, which is different from Newtonian physics; fluids respond differently than solids. An appreciation of this difference is crucial in reviewing viscoadaptive technology and pseudoelastic viscoadaptive tears. While dry eye is a chronic condition for which there is no cure, ECPs can manage it. Dr. Maharaj counsels patients that they can be treated and progress to a point where they are more comfortable, where they may not notice their eyes on any given day or any given week, but by no means is it a cure.

Approaches to the Diagnosis of Dry Eye Disease

According to various worldwide studies over the past decade, the prevalence of dry eye ranges from 7 percent up to close to 50 percent, depending on the study. In Dr. Maharaj’s dry eye clinic, more than 90 percent of patients actually exhibit the condition in itself; however, in general eye care practices, dry eye as a condition is second only to cataracts. Pre-identification of the dry eye patient undergoing surgery and pretreatment is far more likely to result in patients having a better postoperative experience. When considering sending a 65-year-old patient to a cataract surgeon for cataract surgery, for instance, preparing the patient’s ocular surface has been shown to contribute to their postoperative success. Patients that lack preoperative treatment have a four times greater risk of their dry eye worsening following surgery. In the next two to ten years, stated Dr. Maharaj, practitioners will see their role in the perioperative arena growing, and rightfully so. Based on current trends, he predicted greater discussion and use of triglyceride omega 3s for added systemic impact on meibomian gland disease. Dr. Maharaj discussed osmolarity as a dry eye metric that is important to understand in a general setting. Tear osmolarity is a valuable tool, relative to the Ocular Surface Disease Index (OSDI), corneal staining and Schirmer tear test and has been shown to be more sensitive and more specific than these other measures. When examining the correlation to the severity of the condition, osmolarity has the strongest correlation. To identify existing dry eye patients in a general practice, it is extremely relevant for patients that may not be symptomatic but are silently suffering. Those are the ones who may, in fact, have a hyperosmolar tear film, which means that they do have a higher component of salt and proteins like MMP-9 and other inflammatory cytokines in their tear film. If this inflammation is elevated and the patient is not symptomatic, the chronic inflammatory environment will eventually produce symptoms.

BLINK MECHANICS Under a slit lamp, it is quite common for the lower eyelid to hang slightly lower than the iris, which is very common and produces infrequent, incomplete blinking. There are, however, some patients who don’t have this characteristic; they have a neat palpebral fissure, but the eyelid still doesn’t drop all the way down. In terms of blink mechanics, said Dr. Maharaj, what most patients think happens is that their lower eyelid and upper eyelid come together, touch and then move away. However, when one starts to examine the mechanics of a blink, one sees that this is, in fact, the opposite of what occurs (Fig. 1). The lower eyelid makes very little vertical movement; however, the superior eyelid does most of the travel and there’s actually a torsional component to it. That’s not even taking into consideration ethnicity, the thickness of the tear, the inner Fig. 1 Mechanics of blinking. eyelid surface, or the lid wiper itself, the band of tissue that also impacts the way eyelids move. In Dr. Maharaj’s experience, examining the asymmetry between one eye and the other, one often sees anatomical and morphological changes in the meibomian gland of the eye that has a decreased blink rate and decreased blink completeness. In patients whose eyelids come together, there is a correlation with meibomian gland atrophy or truncation: if the eyelids are not coming completely together, the gland orifice isn’t receiving any negative pressure to draw oil out of it, and if it’s not used, obstruction begins, prompting a cascade of events.

Blink Mechanics: Viscoadaptive Technology for the Ocular Surface — Maharaj

Figure 2 depicts a breakdown of the blinking process, showing a superior component and a torsional component of the upper eyelid moving mainly up and down and slightly, with a minor rotation. However, the inner eyelid barely moves vertically; it actually has a nasal movement. This is an extremely complex movement with the forces being applied to the cornea and to the ocular surface, in addition to the forces being applied to the fluid between the eyelid and the cornea. Dr. Maharaj expressed his opinion that there are some more effective solutions for dry eye than artificial tears. Regardless of ethnicity or the shape of the eye, there is Fig. 2 Breakdown of blinking process. slight vertical movement on the superior eyelid; there is nasal and torsional movement of the superior eyelid; the inferior eyelid margin typically makes lateral movements. This produces a type of shearing force. What occurs is that rather than the front surface closing, it is the posterior lid margin that closes. The mucocutaneous junction otherwise known as the Line of Marx (LOM) forms a ridge that is not meeting up. Thereâ&#x20AC;&#x2122;s no seal of the superior and inferior LOM on lid. A quick test for this is the light test using a transilluminator. With retroillumination a slight gap becomes apparent. Even in those patients who, under a microscope, appear to be blinking completely, they may, in fact, have inadequate lid seal which will exacerbate the condition. This will lead to increased friction, causing the lid wiper to become inflamed. In this case, the posterior lid surface is in direct opposition to the cornea with a thin pre-corneal tear film acting as a buffer between the two surfaces. The result is tissue with repetitive microtrauma causing eventual, epitheliopathy and lid inflammation. The meibomian glands are very closely associated to the lid wiper and this is where Meibomian Gland Dysfunction (MGD) can start in some patients. Dr. Maharaj stated that while it is important to distinguish between aqueous deficiency and evaporative dry eye, he does not view the situation as one or the other. This condition is very much a spectrum disease. At some point, MGD will lead to up-regulation of the lacrimal gland, eventually causing it to become inflamed, resulting in aqueous deficiency. All dry eye patients appear at some point on this spectrum.

MECHANICS OF DYSFUNCTIONAL BLINKING In terms of the MGD cycle, Dr. Maharaj stated that the TFOS DEWS algorithm is extremely complex; therefore, he has extracted some of the elements he feels are most relevant (Fig. 3). He suggests that practitioners examine the eyelid aperture of the blink first, looking for the lid seal. When the blink becomes dysfunctional, it results in lid wiper microtrauma due to friction. The resulting symptoms can include extreme pain, mild to severe contact lens intolerance and visual instability. This will lead to hyperosmolarity with an up-regulation in MMP-9 (Matrix metallopeptidase 9), salts and other proteins. Tear hyperosmolarity drives the tear solutes toward the lid margin and meibomian glands and thus the evaporative and aqueous cycle begins. This process applies to the vast majority of mild to moderate dry eye patients and is therefore a good starting point in determining the goal of an artificial tear.

Approaches to the Diagnosis of Dry Eye Disease

Fig. 3 Components of the TFOS DEWS algorithm.

Looking at the problems created by that cycle, the first thing that occurs is decreased blink rate and poor closure. Therefore, said Dr. Maharaj, the goal in tear film therapeutics should be aimed at increased residence time on the cornea with minimal effect on vision stability. Examining the attributes of a topical treatment that allows it to last longer on the eye is essential. For instance, how it interacts with the eyelid surfaces with the shearing forces previously discussed, and whether or not it stabilizes the tear film.

CURRENT DRY EYE TREATMENTS The goal of therapy is long-term stability, which is a very important part of the tear chemistry — an essential element. As an immunomodulator — a targeted anti-inflammatory therapy — Restasis® (cyclosporine ophthalmic emulsion, Allergan Canada, Markham, ON), is extremely effective, noted Dr. Maharaj, at addressing aqueous deficient dry eye. At the 2011 MGD workshop, MGD became defined as perhaps the leading cause of dry eye disease around the globe. With this, replacing the lipid layer became the utmost priority. The term “viscoadaptive” was introduced; Dr. Maharaj remarked that it appears to be a confusing term. When doctors refer to the viscosity of a solution, they know what it means in terms of thicker or thinner. Intraoperatively, it has a different meaning than viscoadaptive on the external eye. In rheology, the study of forces on fluids is very different when compared to forces on solids because fluids are very much like air; the forces are more or less Newtonian. One can pass one’s hands through it without resistance. However, with a fluid like glass, the forces that need to be applied to get it to move like a liquid are very, very high. The three tenets are understanding viscosity, understanding elasticity, and then examining the cohesive and dispersive nature of fluids. Dr. Maharaj stated that there are four patterns of rheoRheometric Patterns of Fluid Behavior: Viscosity metric behavior of fluids (Fig. 4); namely Newtonian, pseudoplastic, plastic and dilatant. In Figure 4 the further to the left on the x axis, the lower the shear forces being applied; the further to the right, the higher the shear force. The y axis relates to viscosity. The solution can be a liquid which will be lower down on the graph or, it can behave like glass or a fractureable solid which will appear higher on the graph.

NEWTONIAN TEAR SOLUTIONS Many fluids are pseudo-Newtonian; they’re not quite Newtonian; however, they possess more or less these same characteristics. On the other hand, plastics when exposed to a great force can carry liquid-like characteristics. Fig. 4 Variations in applied force. As shown in Figure 4, fluid-like behaviors or low viscosity behaviors at a certain force will become more viscous. The term for this is zero shear rate. Past the zero shear rate it becomes a fractureable solid. The zero shear rate of a pseudoplastic material is important in surgery (intra-operative surgery is really where it all evolved from) because there has to be a point at which it doesn’t become more viscous. If it did, it would harden in the anterior chamber making surgery very difficult. Pseudoplastics have evolved and have been adapted to the ocular surface specifically because of this fact. Dr. Maharaj stated that this is particularly important when considering artificial tears: The eyelid moves around and applies shear forces. Viscous

Blink Mechanics: Viscoadaptive Technology for the Ocular Surface — Maharaj

solutions that still have Newtonian-like behavior with long and short branched polymers behave in more or less a Newtonian fashion. Pseudoplastic or viscoadaptive solutions will behave differently to the various moments in a blink.

NON-NEWTONIAN TEAR SOLUTIONS Regarding blink forces, instead of a tear solution progressing from a cohesive fluid to a hard solid, it actually moves from a cohesive fluid to an elastic material. In the process of blinking, the eyelid comes down and compresses. It squeezes the material down. One example of this type of fluid is hyaluronic acid (HA). In order to make it a dispersive substance, one can add a shortchain branched molecule that is not bound to the HA that can actually separate from the HA by force. What happens with an artificial tear with HA and a short-chain branched polymer is exposed to blink forces, the HA separates — it binds with the water found in the aqueous component of tears — and it excludes the short branched polymer present. A hyaluronate and glycerin solution during the blinking process will almost behave like a contact lens — a fractureable solid — in the eye when the eyelid closes because it is applying a high amount of shear force. When the eyelid opens, the solution returns to a fluid state. In terms of applying these forces to an artificial tear, consideration needs to be given to the way the eyelid moves with a HA-based eye drop compared to a Newtonian solution like methylcellulose, for example. In the surgical context, the pseudoplastic curves of some of the ophthalmic viscoadaptive devices used in Intraocular OVD Pseudoplasticity intraocular surgery are shown in Figure 5. The curves vary depending on the device used. Dr. Maharaj noted that some examples currently used in surgery were actually used to derive hyaluronic-based eye drops. Healon® 5 (sodium hyaluronate, AMO, Markham, ON) and iVisc® (sodium hyaluronate, I-Med Pharma, Montreal, QC), for instance, are commonly used. Depending on the shear forces applied, the liquid will eventually reach a certain viscosity and not go past that point. Artificial tears such as Tears Naturale® (ocular lubricant, Alcon Canada, Mississauga, ON), Systane® (lubricant eye drops, Alcon Canada, Mississauga, ON), GenTeal® (lubricant eye drops, Alcon Canada, Mississauga, ON), all have a very simple linear Newtonian movement on the eye regardless of the eye’s Fig. 5 Pseudoplastic curves of viscoelastic devices. blink mechanics.

FEATURES OF PSEUDOPLASTIC ELASTOVICOUS TEARS The first Canadian pseudoplastic elastoviscous tear is known as i-drop® (I-Med Pharma, Montreal, QC). It is distinguished by its high molecular weight sodium hyaluronate combined with a short-chain branched polymer, glycerin. The interesting feature of HA is that all the cells in the body, including those of the cornea, have hyaluronic binding sites. The HA in the eye drop binds to these binding sites, anchoring the tear onto the ocular surface. The HA actually combines with the water found in the tears. It excludes the glycerin which rises to the surface as the eyelid blinks. The glycerin provides a lubricating surface to the blink, decreasing friction on the ocular surface. Once the eyelid reaches down to the bottom, and the eyelid comes up and the solution returns to its original low viscosity. As a result of this process, the residence time is high. The tear mimics all three layers of the tear film simply by virtue of its physical properties.

Approaches to the Diagnosis of Dry Eye Disease

Curves

Dr. Maharaj uses this approach in his general patients, in order to prolong residence time, decrease evaporation and create visual stability. A high molecular weight hyaluronic-based drop allows this. From a rheological perspective, pseudoplastic elastoviscous tears, or PETs, produce the desired effect, mimicking naturally occurring tears. The problem of decreased blink rate and closure requires that a topical tear increases the residence time on the eye, which i-drop achieves. This is accomplished through decreasing friction on the ocular surface with unbound glycerin and stabilization of the tear film via HA. This decreases evaporation and stabilizes the tear film, providing patients substantially greater comfort. Dr. Maharaj stated that the last benefit of some of the new drops coming to market, i-drop being one of them, is that they are packaged in a multi-dose, nonpreserved bottle. He views the lack of preservatives as an important benefit. The bottle form may make it more convenient for patients. The first clinical study of hyaluronan eye drops was undertaken in 1982. At the time, HA was found to have a much longer residence time. This led to the Hylan™ Surgical Shield (Elastoviscous Hylan Surgical Shield, 0.45%) which surgeons were using during surgery to coat and protect the ocular surface. Dr. Maharaj suggested that when addressing the ocular surface, practitioners ought to carefully consider the true etiology of the condition and all available solutions. With an abundance of products on the market and patients not knowing which to choose, Dr. Maharaj suggested that eye care professionals make very specific patient recommendations. It is now known that patients are blinking less frequently and less completely, which Dr. Maharaj noted are facts that need to be addressed when weighing treatment options for dry eye. He stated that the best way to achieve this is to provide patients the most successful available products, rather than simply telling them to modify their blink behavior and to use the nearest artificial tear. In Dr. Maharaj’s Dry Eye Clinic, a very discrete and direct protocol is used. He instructs his patients, “Follow my specific instructions or you won’t feel better. That’s why I’m being specific.” He takes this approach because if one tells patients to use any artificial tear, they will. This leaves the decision of choosing the topical up to the patient. As a health provider is it imperative to educate patients to make an informed decision.

CONCLUSION Dr. Maharaj concluded his presentation by emphasizing the importance of providing patients a specific recommendation to their individual dry eye problem. The tear film ought to be addressed as a mechanism, as opposed an element that must be supplemented.

Blink Mechanics: Viscoadaptive Technology for the Ocular Surface — Maharaj

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 1 Richard Maharaj, OD, FAAO

ABSTRACT The intrinsic and extrinsic risk factors associated with ocular surface diseases, as well as tear film osmolarity — and its role in optometric care are — are key elements in the diagnosis and treatment of dry eye disease. The goal of a stable tear film is based on the perfect interaction between the lipid, mucus and aqueous layers delivered by the meibomian glands, the goblet cells, and the lacrimal and accessory glands respectively, as well as the optimal interface between these layers and the lid mechanics. The examination of tear chemistry will play an increasingly major role in the diagnosis and treatment of dry eye disease and in the future of eye care.

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

SUGGESTING AN ALTERNATIVE TEAR FILM MODEL Dr. Maharaj described the various layers of the tear film: the lipid, mucus and aqueous layers delivered by the meibomian glands, the goblet cells, and the lacrimal and accessory glands respectively. The goal of a stable tear film is based on the perfect interaction between these layers, as well as the optimal interface between these layers and the lid mechanics (Fig. 1). A large part of this is the sensory motor component of the ocular surfaces. In cases of dry eye or other Lacrimal surface diseases, typically the patient presents by saying, “I'm Gland Aqueous uncomfortable. I feel gritty, I feel sandy.” They often describe Meibomian Lipid Anatomical some form of discomfort, prompting the question of the Gland Mucin underlying cause. Goblet Cells Dr. Maharaj stated that he examines this query in terms Stable of three major categories. Pathology is first and foremost. Tear Film Both pathological and age-related changes conspire to break Lid Blinking Tear down the ocular surface. The second element is environmental Clearance Sensory Motor & Spread or external factors and the third being anatomical considerLid Closure ↓ Evaporation ations, involving an examination of the blink mechanism. It’s not a perfect vertical movement; in fact, there are torsional, tangential and vertical movements of both the upper and Fig. 1 Proper interaction between tear film layers is vital to a stable tear film. lower eyelid. It’s a very complex series of mechanisms that add up to a perfect blink; and in fact, the majority of dry eye sufferers, more than 60% of them, have some form of lid dysfunction or blink closure; rather, the lack thereof.

Stable Tear Film Maintenance

Approaches to the Diagnosis of Dry Eye Disease

What may be defined as lagophthalmos in some cases may not, in fact, be so obvious. What’s more, these microanatomical changes at the level of the blink have a huge impact. Depending on the ethnicity of the patient and their age, and with various activities, these movements can change. Dr. Maharaj underscored the fact that optometrists tell their patients about the 20/20/20 rule, trying to drive home the message that the anatomy of the blink matters.

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

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

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 1 — Maharaj

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

Chemical Composition of Human Tear & Plasma

DRY EYE DISEASE AND OCULAR WELLNESS

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

TEARS

PLASMA

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

94% 6% 137-142meq/l 5meq/l 102meq/l 24.3meq/l

The prevalence of dry eye disease has been stated in a number of different ways, depending on how it is defined in 80-90mg/100ml the various clinical studies. However, Dr. Maharaj postulated 6.78g/100ml about a unified way of defining dry eye disease such as is done with glaucoma or macular degeneration. Is there a 20-40mg/100ml reliable metric that can be used in the primary care arena that helps to define it — because if so, he pointed out, these Fig. 2 Human tear and plasma share similar chemistry. numbers might actually fall into slightly more agreement. Knowing that in optometric practice dry eye disease is second only to cataracts in terms of prevalence, it's a huge cohort. Dr. Maharaj posed the following questions for consideration: how is it being managed? Are practitioners doing anything different than they were five or ten years ago? Even with the growing number of options in contact lenses and care solutions, the dropout rates by contact lens wearers due to discomfort hasn't changed when considering all of these advances, a decline in dry eye disease should be evident. Dr. Maharaj suggested that a key piece of the puzzle might be missing.

Dr. Vijay Joshi, MS, MBBS Ophthalmology

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

Approaches to the Diagnosis of Dry Eye Disease

DEFINITION AND MEASUREMENT OF OSMOLARITY Osmolarity is the measure of solute concentration. Its unit of measure is osmoles per liter, or in the case of the tear film milliosmoles per liter because the value is so very low. Surprisingly, there are three methods of measuring osmolarity. The first, which does not seems to suit the primary eye care setting, is the freezing point depression. When a particular material is frozen — for instance, water — it freezes at 0 degrees. If the solute level or the osmolarity of that solution is higher, the freezing point drops and that point of depression, that delta between 0 and the freezing temperature, can be extrapolated to osmolarity. The sample requires 0.2 uL so it's still rather large but it can be done, and it is used in lab testing, stated Dr. Maharaj. The converse is also true. The second method — vapor pressure — can also be tested to correlate to osmolarity. Again, the mechanism is extremely complex and it doesn't lend itself very well to primary care; however, there are several institutions that use vapor pressure to measure osmolarity — not tear osmolarity, as it uses quite a large sample size. The third method is commonly recognized and used: electrical impedance. The conductivity of the fluid is changed and it is proportional to the osmolarity or concentration of the solution. It actually requires a very small sample of approximately 50 nL, which is perfect because only a small amount of tears is available, about 17 uL. It has been available through TearLabTM testing for some time.

OSMOLARITY VERSUS OSMOLALITY As a differentiation between osmolality, and osmolarity, osmolality refers to the solute concentration per kilogram; it's the solvent measured as a solid as opposed to a liquid. Tear film never solidifies therefore in this discussion, stated Dr. Maharaj, osmolality and osmolarity are synonymous. These two words can be used interchangeably; however, in the literature it is referred to as osmolarity. In the DEWS (International Dry Eye Workshop) report in 2007, tear osmolarity was actually incorporated as part of the definition of dry eye disease. The IOP at or above which practitioners should be concerned in glaucoma patients is 21, an extremely important recognized benchmark; it has helped to identify glaucoma patients far earlier — and, in Dr. Maharaj’s view, the specificity and sensitivity in optometry practices have increased as a result of that. Knowing that the prevalence of dry eye disease is signifiAt 308 mOSm/L cutoff cantly greater than that of glaucoma, and that there is a metric • Specificity = 88% and Sensitivity = 75% that has been included in the definition, it does make sense that At 315 mOSm/L cutoff practitioners can delve into this disease through their patient • Specificity = 92% and Sensitivity = 73% base and see if there is preventative action they can take. • PPV 85% - i.e. “The % of time a metric > 308 mOsm/L Patients who test above 308 milliosmoles per liter do, in will actually be DED fact, have the disease. Tear osmolarity is the global marker Recall agreed upon by both ODs and MDs alike, which is a rarity, but • Sensitivity % of persons who actually have the disease. in the presence of a measure that is so strong, it begs • Specificity % of persons who do not have the disease. • Positive Predictive Value is the percent of people with a further exploration. It is elevated in the diabetic population and positive test who have the disease. in patients on chronic glaucoma medication who are exposed to • Negative Predictive Value is the percent of people with a BAK on a regular basis. The dry eye disease population is negative test who do not have the disease. paralleled only by that of diabetes in the United States, with some 25 million people affected. Fig. 3 Using sensitivity and specificity to define dry eye disease.

Defining the Disease

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 1 — Maharaj

ROLE OF OSMOLARITY IN DRY EYE DISEASE The 308 mOsms/L figure was derived from a 2010 study by Michael Lemp, published in 2011 (Fig. 3). It postulated and confirmed that above 308 mOsms/L, one sees an increase in inflammation and apoptosis, as well as a breakdown in useful homeostasis. However, the question remains, what causes dry eye disease hyperosmolarity? Compared to other markers such as tear break-up time, Schirmer's and the ocular surface increase index, osmolarity has much greater sensitivity and specificity. In Dr. Lemp’s paper, above the cutoff of 308, sensitivity was at 70% and specificity was at 88%. Specificity indicates that the number of patients who test negative is high; therefore, if it's good at determining who doesn't have it, it's good at determining who does have it. As osmolarity increases, so does specificity. Furthermore, in the second best measure, ocular surface disease index, in Dr. Lemp’s research the agreement still wasn't as high as with osmolarity.

PREVALENCE OF DRY EYE DISEASE

Observed Differences in Hyperosmolarity & Normal Participants

Dr. Eric Donnenfeld began a prevalence study in 2012, which was taken over by Dr. Marguerite McDonald in 2013. It comprised approximately 9,000 patients sequentially, excluding those who had been artificial teared within two hours of testing. Their demographics and history were taken followed =< 308 mOsm/L > 308 mOsm/L by a series of yes or no questions. The patients were then classified as either having dry eye disease or having normal or low osmolarity. Avg osmolarity 297 +/- 7 323 +/- 17 Of particular interest, Dr. Maharaj stated, was that for patients who had normal osmolarity, below 308, the inter-eye Inter-eye difference 6 +/- 6 17 +/- 16 difference was actually quite low at ±6. For patients above 308, the inter-eye difference is actually fairly significant, at 17±16 (Fig. 4). A similar trend was that the inter-eye McDonald ASCRS 2013- Osmolartiy Prevalence Study (from Donnenfeld) difference above the 308 threshold increases. At the same Fig. 4 Comparing hyperosmolar and normal participants. time, osmolarity tended to be higher in the more painful eye. Dr. Maharaj noted that these are now regarded as trends to look for. In patients with dry eye disease, often one eye feels worse than the other. Furthermore, it's quite possible that after measuring their osmolarity, the delta is actually in favour of the eye that is more uncomfortable. Figure 5 presents rates of symptomatology in hyperosmolar and normal patients. Fifty percent of those with normal osmolarity reported three or more dry eye-like symptoms; therefore, 50% were experiencing some other disease causing their symptomology. Close to half of these 9,000 dry =< 308 mOsm/L > 308 mOsm/L eye patients were silently suffering and were only uncovered by the osmolarity testing, stated Dr. Maharaj. Overall population 52% 48% The salient point is that patients who are symptomatic and have abnormal tear film still need to get run through for Pts reporting 3 or more 49% 51% diagnosis. In addition, they need to be examined for corneal DED symptoms health, staining and other standard testing for other possible Reporting less than 3 DED 54% 46% contributing factors.

Differences in Hyperosmolar & Normal Participants

symtpoms (Asymptomatic)

RELATIONSHIP BETWEEN OSMOLARITY AND MEIBOMIAN GLAND DYSFUNCTION Dr. Anthony Bron et al in the UK have put forth the concept of a solute gradient of the tear film, using a tear prism model:

Approaches to the Diagnosis of Dry Eye Disease

McDonald ASCRS 2013- Osmolartiy Prevalence Study (from Donnenfeld)

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

it has a thick base and a thin apex, with solute concentration in osmolarity highest at the apex and lower at the base. As a result, there is a driving force from tear film to the lid margin and therefore the meibomian gland orifice (MGO) forcing solutes towards the lid margin and into the MGO. This may in fact be a key mechanism in the genesis of MGD demonstrating its origin in hyperosmolar environments.

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

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

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

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 1 — Maharaj

is that ODs are “lending” the person to ophthalmology to perform a surgical medical procedure — and that patient will return to the OD. The chances are, he stated, that if there are any complications, it will flow through the optometrist’s office, and it is incumbent upon ODs to manage the situation.

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

Approaches to the Diagnosis of Dry Eye Disease

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Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 2 Richard Maharaj, OD, FAAO

ABSTRACT Osmolarity testing is a critical element in expanding optometrists’ diagnostic capability around their contact lens practice. Other metrics can be employed; however, tear osmolarity is an extremely good tool to use so that patients understand their situation very quickly. In addition, clinically, it has already been proven from an evidence-based perspective. Tear osmolarity is the only element that truly adds to the clinical decision. Tear chemistry and dry eye management are areas that will see enormous growth in the next decade.

INTRODUCTION Dr. Maharaj explained that he would be presenting several cases he has encountered in his clinic, followed by some of the diagnostic capabilities that influence optometrists’ treatment choices, and how they apply to osmolarity. He stated that in the past four years since osmolarity testing has become widely available, there has been little in terms of guidance regarding how to use it, which may have resulted in practitioners not actually using it to the extent that it is valued. Dr. Maharaj summarized three key factors that induce dryness, namely, pathological/chronological, external, and anatomical influences. Case #1 A 27-year-old male presented to the clinic. He had been a contact lens wearer for roughly six years and had never been happy with his contact lens comfort. He used Air Optix® (Alcon, Mississauga, ON), a monthly lens modality, along with OPTI-FREE® Replenish® multipurpose solution (Alcon, Mississauga, ON). He noted seasonal allergies in his medical history. He had had a two-week onset of red, itchy eyes, with the left eye worse than the right. Figure 1 depicts the left eye. The patient had vernal keratoconjunctivitis (VKC) with trantas dots along his limbus, an infiltrative response, and severe discomfort. Treating the histamine response that was inducing the VKC was certainly integral to Fig. 1 Patient with long-term contact lens discomfort (OS). managing this patient’s condition. He was started on Lotemax® (loteprednol etabonate ophthalmic suspension 5%, Bausch & Lomb, Vaughan, ON) QID for two weeks – an aggressive regimen to optimize response – along with no contact lens wear for those two weeks. This was done for two reasons: first, because he was highly reactive; he was in a reusable lens, and was also non-compliant with his cleaning; and second, Dr. Maharaj stated, he wanted him to be without his contact lenses for that time in order to be a bit punitive. However, Dr. Maharaj did it with the intention of giving the patient a quick result because he was anticipating transitioning him into a healthier contact lens modality. The healthiest lens is no lens; the second healthiest lens really is a one-day lens. Fewer than 20% of contact lens patients are wearing one-day contact lenses according to Canadian statistics, yet it’s a known fact that they are accompanied by fewer adverse reactions than reusable lenses.

Approaches to the Diagnosis of Dry Eye Disease

The question was whether or not to change the patient’s contact lens modality. The patient had stated that his problem was long-standing and was actually reporting symptoms of contact lens induced dry eye (CLIDE). After the VKC resolved, Dr. Maharaj took some clinical measurements, specifically, tear breakup, corneal and lid wiper staining, none of which were normal; his tear osmolarity was high at 317 mOsm/L OD and 334 mOsm/L OS. Dr. Maharaj highlighted that he spends extensive time counselling his dry eye patients. He explained to this patient that his tears were very salty (hyperosmolar) and that this was a major contributor of his discomfort. He told the patient that he would send a letter to his referring optometrist, with some recommendations, including discontinuing the contact lens solution as solution toxicity may have been adding to his hyperosmolarity in addition to denatured protein on his monthly contact lens surface. The patient’s optometrist subsequently switched him to a one-day high water content hydrogel material. At one-month follow-up the patient reported that he was doing very well and wasn’t experiencing nearly the same amount of discomfort as previously. At this point he also wasn't using any additional artificial tears. A follow-up tear osmolarity test revealed that he was down to 304 mOsm/L OD / 296 mOsm/L OS. His readings were not completely in the normal range OD, but he was just sub-threshold; however, compared to his 317/334 measurements, he was now in a much better range. In Dr. Maharaj’s view, what was more important here was that the patient understood his situation, which would almost certainly guarantee that compliance would be improved.

PROMOTING PATIENT COMPLIANCE Dr. Maharaj raised the question of what is required to get a patient to be compliant. He suggested that practitioners employ certain clinical practices and integrate them into their contact lens practice to eliminate the commoditization of contact lenses. There is a health aspect to contact lens care which has not been employed to a great enough extent, the result of which is that patients feel as though they can go out and order contact lens online without knowing anything about them. To address this situation, Dr. Maharaj encourages practitioners to build a diagnostic strategy around their contact lens practice in order to insulate the practice. He posed the following questions: What is the osmolarity of their patient? Are practitioners setting their patients up for success or failure? And if so, what are they doing to mitigate it? Furthermore, if they are mitigating it, how are they measuring whether or not clinical choices are in fact successful? Optometrists may be telling patients that they are going to get better by putting them on a one-day lens, but how are they measuring that? Other metrics can be employed; however, tear osmolarity is an extremely good tool to use so that patients understand their situation very quickly. What’s more, clinically it's already been proven from an evidence-based perspective. Practitioners use it to engage their patients clinically without becoming too technical. Case #2 Dr. Maharaj introduced his second case, that of a 53-year-old Caucasian female who had been referred to him by an ophthalmologist who had performed LASIK on her in 2007 and had put her on Restasis® (cyclosporine ophthalmic solution 5%, Allergan, Markham, ON) nine months prior to this consultation. She reported using Alrex® (loteprednol), BID or as needed.

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 2 — Maharaj

Dr. Maharaj employs a symptom questionnaire called the SPEED (Standardized Patient Evaluation of Eye Dryness) score, comprising a series of questions that produce a score out of 28, where 28 is the worst a patient can possibly feel. Dr. Maharaj uses the SPEED score method when the patient comes in because it provides him a validated symptom score within just 5 minutes. The SPEED score is very useful and it has been validated by the University of Waterloo. This patient’s score was 23 out of a possible 28, so she was feeling quite miserable. Her tear breakup time was 5s OD and 4s OS, which wasn’t alarming clinically. Although she was on some form of therapy for her dry eye, she still had severe keratopathy. Dr. Maharaj pointed out that Schirmer testing (no anesthetic), tear osmolarity, lid seal and aperture closure were all likely to be abnormal in such a case. He tells his interns that after they've spoken to the patient the first time, they should already have a working diagnosis, and have narrowed the diagnosis down to at least three, if not two differentials. In his view, the test with the greatest diagnostic value is osmolarity. If it were Schirmer, with low tear volume, what would be the optimal treatment? If it's an aqueous deficient patient and they're on Restasis, their aqueous deficiency is being addressed so it would not change your treatment approach. Measuring lid seal and aperture closure is a very quick test that does not cause pain or take more time, but it does not, again, add to the clinical decision. In Dr. Maharaj’s opinion, osmolarity is the only element that truly adds to the clinical decision. He uses an Oculus keratograph 5M to measure meibography in his practice. Meibography is infrared imaging of the anatomy and architecture of the meibomian ductules and acini and it can be done on both top and bottom lids. This patient had significantly atrophied and truncated meibomian gland architecture which was diagnostic of her meibomian gland dysfunction (MGD). She had been on Restasis for nine months and had evaporative dry eye that was not being managed. Dr. Maharaj pointed out that osmolarity actually helps practitioners to discern this because in a patient with an evaporative condition, their osmolarity increases. In terms of lid aperture seal, there's a very quick way to measure this in the office, using a transilluminator on the upper eyelid to retroilluminate the inner eyelid. As shown in Figure 2, on the right-hand side, there is slight leakage of light coming through the upper Fig. 2 Use of transilluminator to measure lid aperture seal. and lower eyelids, whereas the other eye is perfectly sealed. This is not the same as lagophthalmus. If the lid aperture is not closing, you can assume that there is not good expression of the meibomian glands on lid closure. These patients will progress and develop meibomian gland stagnation and further obstruction. Unfortunately, this patient had progressed to this point. Her osmolarity at this stage was 352/326 mOsm/L OD and OS, respectively; therefore, her symptoms made a lot of sense. In tear chemistry, MMP-9 is an inflammatory marker. InflammaDry® is a point of detection test that can be used to measure the amount of inflammation at the ocular surface as a positive or negative outcome. In this case, the patient measured negative. With glaucoma patients, OCT, visual fields, pachymetry and IOP are measured. With dry eye patients, we examine tear panel testing or tear chemistry. Dr. Maharaj proceeded to describe three patient scenarios

Approaches to the Diagnosis of Dry Eye Disease

regarding osmolarity in chemistry testing. The first is a patient with high osmolarity and normal MMP-9. These are typically early dry eye patients who haven't yet begun to develop up-regulation of their MMP-9 expression. In that scenario, they may also have a normal MMP-9 if they are already on anti-inflammatory treatment. In the case of the 53-year-old woman, she had already been on Restasis for the previous nine months and her MMP-9 was negative, which stands to reason. Osmolarity had not been addressed, though, because she was still an evaporative patient. A second scenario is a patient with high osmolarity and a positive MMP-9, indicating ocular surface inflammation. These are patients who typically have had dry eye for some time and it has been untreated or poorly managed, essentially producing two positives. A third scenario is a patient with normal osmolarity and abnormal MMP-9. These are cases of less typical dry eye disease which are more likely to be a function of some other ocular surface dysfunction such as EBMD or conjunctival chalasis. Osmolarity provides perspective on MMP-9, and MMP-9 provides perspective on osmolarity. How one uses them together can strengthen one’s diagnosis significantly. Dr. Maharaj was able to determine that this patient had evaporative dry eye because her inflammatory mediators were already being addressed with Restasis. Figure 3 Fig. 3 Before and after treatment for MGD. depicts before and after treatment for MGD.

Case #3 The next case is of a 39-year-old female who had undergone LASIK seven years prior. She presented with repeated intermittent foreign body sensation in her left eye. She had exposure due to a limited lid seal and had used various types of drops, but nothing gave her sustained relief. She did have a maternal family history of Sjögren's and her current medical history was positive for Raynaud’s disease. Her tear breakup time was certainly reduced in her left eye, and her osmolarity was 273 mOsm/L in her right and 296 mOsm/L in her left eye. The difference of 23 mOsm/L between her two eyes was clinically significant despite each eye’s osmolarity still in the subclinical range, under 308 mOsm/L. Her MMP-9 was negative in her right eye, ironically, and was positive in her left eye. In summary, this patient had a suspect tear osmolarity and a positive MMP-9, so she was clinically defined as having dry eye. Her tear breakup time was almost instant; this patient wasn't even closing her eyes. She had high evaporation, along with lid wiper epitheliopathy. Dr. Maharaj explained that lid wiper epitheliopathy occurs when there is increased friction between the lid wiper and the ocular surface. When hydrodynamic lubrication between the two surfaces is lost, increased friction results in increased inflammation which then leads to epitheliopathy. That area is very close to the meibomian gland tissue, causing further propagation of the lid and gland inflammation. Dr. Maharaj stated that he decided to focus his therapy on her lid margin and lid wiper with a procedure called periocular scaling, expression and neutralization. He has been performing this procedure for the past few years and it has been presented in the literature. It is a non-surgical process done in primary care. Dr. Maharaj also used a non-preserved hyaluronicbased drop instead of Systane® BALANCE (Alcon, Mississauga, ON) which she had been using.

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 2 — Maharaj

Dr. Maharaj began by staining the lid and the line of marks on the lid wiper with lissamine green. He then used a golf spud to debride and scale the surface, passing over the meibomian gland orifice, as well as the lid wiper and mucocutaneous junction. The process involved removing devitalized epithelium, squamous epithelium that was devitalized and, if left long enough, would actually keratinize. He then expressed, using a Mastrota paddle and a cotton-tip applicator. Dr. Maharaj pointed out that effective meibomian gland expression requires a hard back surface: if one is expressing with one’s thumb against the globe, it's insufficient and a hard back surface is needed to push against. The neutralization aspect involves neutralizing the acidic component of the meibum, which is comprised of a fatty acid; otherwise, it retains on the ocular surface and can accelerate devitalization. In patients who have MGD, frothy tears accumulate and develop into acidic keratoconjunctival changes. Neutralizing with a basic solution, such as mineral oil, helps in addition to certain artificial tears with a slightly basic pH. Dr. Maharaj advised to neutralize whatever is being expressed, which also helps to soothe the debrided surface. Using this technique, Dr. Maharaj’s retrospective analysis of 53 patients revealed that symptomology was improved by approximately 62%, on average. Meibomian gland function, therefore secretion levels, increased by 30% by doing this one procedure. Figure 4 illustrates before and after results in the previously-mentioned 53-year-old patient. A recent study out of the University of Waterloo, by Ngo W, Caffery B, et al in 2015 have demonstrated components of this procedure on a Sjögren’s cohort of patients demonstrated equally positive results. Heated expression such as Lipiflow and alike also work extremely well on MGD. There are various new modalities of care that are targeted toward the lid surface, the lid wiper, and the meibomian gland Fig. 4 Before and after results of surgical triad: scaling, expression, orifice and structure that greatly help to accent a missing neutralization. component of the current treatment options. In Dr. Maharaj’s view, practitioners are accustomed to de facto using drops for dry eye disease, without doing anything to actually restore meibomian gland function. The pathway to the meibomian gland orifice can be broken by medicine by decreasing the inflammation which, in turn, decreases devitalization of the epithelium. However, current techniques allow practitioners to physically debride the epithelium which will break this cycle and reduce the osmotic gradient. Traditionally, in patients who are at risk or who already have the condition, he repeats the procedure once every six months. In patients whose secretions are good just by gentle expression, or if he stains and sees nothing there, he won’t perform the procedure. Naturally, if there is no tissue to debride or scale, there's nothing to do; however, by and large, this has not been Dr. Maharaj’s experience. There are other tools that clinicians use for a similar purpose, for instance, BlephEx®, or microblepharoexfoliation. BlephEx is great at dealing with anterior blepharitis specifically. It also helps to remove some of the squamous cells. However, when there is extensive keratinization and a blunter instrument is needed to get under the skin to lift it, often times BlephEx won't achieve this in his experience.

Approaches to the Diagnosis of Dry Eye Disease

Case #4 A 77-year-old female from Winnipeg was very specific about her discomfort which was on her lids and the bottom part of her eye. She had had cataract surgery about 10 years prior, and had been on Restasis for a very long time, along with Lotemax. In addition, she had been put on doxycycline to treat her MGD and she was using copious non-preserved and preserved lubricants as well as lid hygiene procedures, with which she was very vigilant. Conjunctival staining with lissamine green showed some conjunctival rolls indicating a ‘fat conjunctiva’ indicating loss of Tenon’s fascia; this is known as conjunctival chalasis (Fig. 5). In addition, she had floppy eyelid syndrome with one very large roll juxtaposed to her inferior eyelid such that whenever she blinked, it rolled up and down, abrading her cornea. Clinical testing revealed positive MMP-9 test, tear Fig. 5 Conjunctival chalasis in a 77-year-old female. breakup was instant as one would expect, and her meibomian gland score was zero because her conjunctiva was actually covering the orifice. While all of this was negative, her tear osmolarity was normal. Technically, said Dr. Maharaj, while this wasn’t consistent with dry eye, if one were to look only at the staining, one would conclude that it was. However, clinically, it was conjunctival chalasis with a desiccated cornea due to mechanical abrasion. The patient was on the maximal therapy. The surgical options were conjunctival resection or amniotic membrane transfer. Dr. Maharaj indicated that there are not a lot of surgeons in his area who surgically treat these cases, although it has been increasingly requested, therefore the interest in it may be rising. On the pharmacologic side, there weren’t many other options apart from Restasis. After consultation with the patient’s family physician, she was put on human autologous serum (HAS), with an aliquot of 20% solution in 5 mL bottles, BID for three months. Dr. Maharaj suggested that it is useful to have a compounding pharmacist on hand in the event that this process is needed. In Ontario, compliance of the family physician is needed to order the appropriate blood work. Autologous serum is plasma which contains growth factors, and normalizes the proliferation and migration of epithelial cells, increases healing rates. There are some adverse reactions that can be associated with HAS, but in this particular case, the risks were acknowledged and the patient did very well. In terms of quality of life alone, she was excessively happy in spite of her loose conjunctiva. She was on a non-preserved hyaluronic-based drop, as well as high-dose Omega-3s, and she was closer in line to having her conjunctival resection done. Cyclosporine is extremely effective at controlling inflammation but in some cases, where there is a dense amount of SPK and mechanical trauma, it is not sufficient. The objective in these cases is to minimize friction while controlling inflammation. As noted in Cornea in a 2011 paper by Dr. Michael Lemp, osmolarity is the single most defining metric for dry eye. If you are looking at a sub-specialty clinic or a sub-specialty environment in which to invest, an oculus keratograph 5M which has a comprehensive dry eye module, and a tear osmolarity meter are essential. Additionally, stated Dr. Maharaj, it is critical to identify the general population coming into your office. The role of optometrists in managing disease continues to expand to maximize patient outcomes. Optometrists are, in fact, in charge of prevention as well as treatment; however, if prevention is maximized, there are better chances of successfully treating a condition that has not yet been controlled.

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 2 — Maharaj

Dr. Maharaj opined that tear chemistry – tear panel testing – is an area that will see enormous growth in the next decade. He advocated adding advanced dry eye management to optometrists’ practice. He endorses tear osmolarity testing, whose devices are currently manufactured by two companies. One of these is I-Med Pharma (Montreal, QC) which produces the I-Pen®, a product that will most likely be coming to market in the next few months. It is extremely easy to use, and the cost prohibition that used to be a factor has now been eliminated.

CONCLUSION Dr. Maharaj concluded his presentation with a discussion of Omega-3s, raising the issue of the ethyl ester form versus triglycerides. A poster by Dr. Eric Donnenfeld and his group published at the ASCRS meeting in June 2015 contained a very compelling argument for re-esterified triglyceride (rTG) Omega-3 in a three month course at 2.48 g. Another study examined the Omega-3 index – a red blood cell saturated Omega-3 measurement after dosing with a triglyceride versus an ethyl ester. The triglyceride achieved an 8% blood saturation within 1 month of the above dosing, which ethyl ester never achieved up to 3 months later. This level of saturation also decreases cardiac risk in addition to improving meibomian gland secretion. As a result, Dr. Maharaj is a proponent of rTG Omega-3s, for example, NutraSea HP and Physician Recommended Nutraceuticals. On the subject of differences between the liquid and gel capsulated forms, Dr. Maharaj noted that he prefers liquid where it is available; however, the vast majority of products are produced in gelcap form. He stated that he performs Omega index testing in his office and has not found a difference between liquid and gel caps. In his experience, patients are able to tolerate the liquid better; therefore, if the objective is patient compliance, it is the preferred form of the product.

Approaches to the Diagnosis of Dry Eye Disease

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Approaches to the Diagnosis of Dry Eye Disease The intrinsic and extrinsic risk factors associated with ocular surface diseases, as well as tear film osmolarity â&#x20AC;&#x201D; and its role in optometric care are â&#x20AC;&#x201D; are key elements in the diagnosis and treatment of dry eye disease. The goal of a stable tear film is based on the perfect interaction between the lipid, mucus and aqueous layers delivered by the meibomian glands, the goblet cells, and the lacrimal and accessory glands respectively, as well as the optimal interface between these layers and the lid mechanics. The examination of tear chemistry will play an increasingly major role in the diagnosis and treatment of dry eye disease and in the future of eye care. Richard Maharaj, OD, FAAO

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