approaches to the diagnosis and treatment of dry eye disease: vol 3

ContributorsSteve Arshinoff MDShachar Tauber, MDRichard Maharaj OD

CSOClinicalSurgicalOphthalmology&

VOLUME 3

Approaches tothe Diagnosis ofDry Eye Diseasefrom the ophthalmic andoptometric perspectives

Applications and UsageThe authors and publisher have exerted every effort to ensure that the application and use of all medical drugs, devicesand procedures mentioned in this publication are in accord with current recommendations and practices. However, in viewof ongoing research, changes in regulations, and the constant flow of information relating to optometry and ophthalmol-ogy, the reader is cautioned to consult the package insert of any product for the approved indications and dosage recom-mendations, as well as for any changes, warnings or precautions prior to usage.

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Contributors

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

Richard Maharaj, OD, FAAO completed his Doctor of Optometry degree at theUniversity of Waterloo School of Optometry in 2003, and Fellowship of the AmericanAcademy of Optometry in 2012. Dr. Maharaj is lead optometrist at Humber RiverRegional 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 theretina. He is a clinical adjunct associate for the University of Waterloo College ofOptometry. He is a published respected national speaker in eye education on diseases anddiagnostics of cornea, retina, and meibomian gland dysfunction. His primary research isin non-surgical treatments of the eyelid and periocular glands. He is an active member ofthe Ontario Association of Optometrists, Canadian Association of Optometrists,American Academy of Optometrists and the College of Optometrists of Ontario.

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

Contents

Treating and Managing Dry Eye .....................................................................................................................5Shachar Tauber, MDMuch 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 roleof mucin, through to the interaction between the surface and the tear film. From anepidemiological 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 ...........................................................................9Steve A. Arshinoff, MD, FRCSCCurrent treatment approaches for dry eye can be classified as anti-inflammatories,produces providing aqueous replacement, and evaporation reducing agents. The studyof 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 hyaluronicacid and glycerol. This results in prolonged residence time on the cornea and increasedlubrication, thereby improving the blink process in patients with dry eye.

Blink Mechanics: Viscoadaptive Technologyfor the Ocular Surface ....................................................................................................................................16Richard Maharaj, OD, FAAOThe increasing prevalence of dry eye highlights the importance of the early identificationand treatment of such patients. According to worldwide studies over the past decade, theprevalence 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 dryeye metric: A hyperosmolar tear film is an indication of an inflammatory environment.Compromised blink mechanics such as incomplete or dysfunctional blinking are a keycomponent in meibomian gland dysfunction and dry eye disease.

Advancing the Diagnostic Use of Tear Osmolarityin Primary Eye Care: Part 1 ..........................................................................................................................22Richard Maharaj, OD, FAAOThe intrinsic and extrinsic risk factors associated with ocular surface diseases, as wellas tear film osmolarity — and its role in optometric care are — are key elements in thediagnosis and treatment of dry eye disease. The goal of a stable tear film is based onthe perfect interaction between the lipid, mucus and aqueous layers delivered by themeibomian 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 exam-ination of tear chemistry will play an increasingly major role in the diagnosis andtreatment of dry eye disease and in the future of eye care.

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

Treating and Managing Dry Eye— Tauber 5

Treating and Managing Dry EyeShachar Tauber, MD

ABSTRACTMuch has been learned about the tear film (and its impact on dry eye) overthe years, from the discovery of its multi-level properties,1 increased under-standing on the role of mucin,2 through to the interaction between thesurface and the tear film.3 From an epidemiological standpoint, dry eyeprevalence is in the range of between 6% and 14%, although most peoplehave experienced dry eye in one of its many forms.

INTRODUCTIONThis article reviews dry eye, its epidemiology, etiology, prevalence, andtherapeutic options.

TEAR FILM STRUCTUREFor many years, ophthalmology taught that the tear film wascomprised of three distinct layers. What has been found isthat it is actually an indistinct transition where the mucins aredissolved within the aqueous in a gradient (Fig. 1). The lipidlayer is the thinnest of the layers and acts to prevent the evap-oration produced by the meibomian glands. The aqueous layeris the thickest layer, and its role is to transport oxygen,enzymes, proteins, and other matter. The mucin layer is theinnermost layer closest to the cornea, and it serves as a coat-ing for the hydrophobic cornea regulating surface tension; itis produced by goblet cells and is composed of 21 differentmucins.

ETIOLOGYDry eye worsens with age and can be due to numerouscauses. Therefore, it is important to regard dry eye not as adisease but as a multi-factorial disorder; and because of this,treatment has been extremely difficult to develop and beproven as effective. Other than such environmental factors asair-conditioning and cold or dry weather, there are manyother factors including different surgeries and disease entitiesthat can cause dry eye.

Medication-Induced Dry EyeMany patients present to us on multiple medicationsincluding beta-blockers, antihistamines, diuretics, chemo-therapy, and anti-depressants. In fact, more patients on anti-depressants seek refractive surgery, which is an interestingrelationship worthy of further investigation.

GlycocalyxThe glycocalyx is where the mucin attaches to the cornealepithelium and this interdigitation is quite important: when itfails, clinical dry eye develops (Fig. 2). The glycocalyx is acotton-candy-like substance that grabs the mucin layerof the tear and allows it to adhere to the microvilli or the surface

Fig. 1 The traditional tear film model compared to the updated tear film model

Fig. 2 Glycocalyx helps mucin adhere to corneal epithelial cells; anydamage to the glycocalyx means mucin deficiency, causing tear filmdestabilization and break up

6 Approaches to the Diagnosis of Dry Eye Disease

epithelium. Thus the ocular surface is made up of stroma matrix and fibroblasts,the epithelial cell membrane, the aqueous, the glycocalyx, and the mucin.

InnervationsInnervations are important as they are the sensory componentgoing from the cornea to the lacrimal nucleus (Fig. 3).If those nerves are interfered with, outgoing messages todifferent parts of the lacrimal system will be affected. This isa problem often encountered in laser in-situ keratomileusis(LASIK), where it interferes with the corneal nerves.

DRY EYE CLASSIFICATIONThe National Eye Institute has classified dry eye into twogeneral categories: tear deficient and evaporative; and withineach main category are subcategories. Under “tear deficient”we find such conditions as Sjögren’s and auto-antibodies, andnon-Sjögren’s and lacrimal deficiency, lacrimal obstruction,and reflex. Under “evaporative” we find the subcategories oildeficient lid-related, contact lenses, and surface changes.

TEAR FILM DEFICIENCIESVarious dry eye disorders can be placed under one of three areas of tear filminsufficiency: lipid, aqueous, and mucin.

Lipid Layer DeficiencyUnder this category we find a diverse group of disorders that lead to changesin meibomian gland secretions, including blepharitis.

Aqueous Layer DeficiencyAs with lipid layer deficiency, there are many disorders that can lead to aqueouslayer insufficiency and dry eye. These include: inflammation, trauma, neuro-logical defects, and congenital absence, among others.

MucinsAgain, 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 CYCLETypically, a patient will present complaining of discomfort,which is actually environmental or contact lens intolerance.This creates surface changes that further worsen the dry eyesymptoms, and begins a downward spiral. If we operate onthese 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 InstabilityThe tear film instability cycle (Fig. 4) begins with surfacedesiccation and leads to a hydrophobic cornea to which themucin is unable to attach. This exposes the epithelial cells toevaporation, resulting in an inflamed cornea. Regardless ofthe original causal factor(s), the cycle remains the same: rearproduction decreases or tear evaporation increases; there is an

Fig. 3 Nerve distribution in a normal eye

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

Treating and Managing Dry Eye— Tauber 7

increase in tear osmolarity and toxin concentrations; and goblet cell densitydecreases and epithelial desquamation increases. This leads to a breakdown ofthe cornea-tear interface and leads to an increase in such inflammatory mediatorsas cytokines and leukotrienes. The last step of this cycle is permanent surfacestem cell, stromal matrix, and neurotrophic damage. Patients are then verysusceptible to infection, inflammation, and ulceration of the cornea. Whenmetaplasia is encountered in the lid margin, it becomes difficult for the ophthal-mologist to separate the concomitant blepharitis and dry eye. Due to theadvanced progression of the disease at this point, there are now overlappingissues with oil release, tear film evaporation, and dry eye exacerbation.

Unprotected SurfaceWhat are the consequences of an unprotected surface? At time zero, when theblink occurs, the tear protects the ocular surface until that tear breaks up. If thetear breaks up prior to the subsequent blink, it results in ocularstaining of the now unprotected surface. When repeated over the course of aday, this can result in 4,000 to 8,000 seconds where the surface is unprotected andcauses 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 betweenblinks (IBI). Simply, if the patient blinks prior to TFBUT, thenthe ratio is >1 and the ocular surface is protected. Conversely, ifthe TFBUT occurs prior to the blink the ratio is <1, and the ocu-lar surface is unprotected.

There is a host of conditions that affect an individual’sblink rate. For example: hormonal changes, mental disorders,menstrual phase, muscular fatigue, drug interactions, computeruse, and talking. It is recommended that clinicians watch theirpatients while taking their history to determine their blink rate.

PREVALENCEThe prevalence of diagnostic dry eye must not be under-estimated; because it is so common, it tends to be ignored.The symptoms can be extremely confusing; patients maypresent with decreased vision, and it is difficult to determinewhether one is dealing with an early cataract, early Fuchs,or indeed an ocular surface issue.

TESTING TOOLSIn addition to observation of TFBUT, there are manydiagnostic tools at our disposal for dry eye evaluation.Multiple dyes will stain the cornea and tear including RoseBengal (which stings significantly), Lissamine Green, andfluorescein staining (frequently used). Fluorophotometry andosmolarity testing are quite complex and have not yet beensufficiently standardized to be used clinically.

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

Fig. 5 The OPI measures TFBUT as related to blink interval to determinewhether the ocular surface has adequate tear film protection

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


look straight ahead. Using a stopwatch, time the seconds until they say they haveocular awareness. One second following ocular awareness equals the sympto-matic tear break up time.

THERAPEUTIC OPTIONSPatient education is tantamount in helping them take a proactive role in thetreatment process. Patients must be taught awareness of TFBUT, dryingmedications (i.e., oral antihistamines and antidepressants), adverse environments(i.e., dry, windy places), and visual tasking (i.e., computer usage, reading).

Artificial TearsThere is a lengthy list of tear substitutes. The optimal artificial tear character-istics have increased dwell time and long-lasting protection. It must haveminimal blurring and lid-caking, offer improved comfort, and it should containnon-irritating preservatives. However, rather than simply managing dry eye byflooding it, future therapy is going to involve treating dry eye via targeting thedifferent tear film layers.

Secretagogues Secretagogues will soon treat production of essential tear components at allthree 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-EvaporativesThis upcoming therapeutic category stimulates lipid secretion to enhance andoptimize the barrier function of the lipid layer. Anti-evaporatives includetopical androgens that regulate the quality and quantity of lipid secretions, aswell as lipid component replacements such as lipocalin, phosphatidylcholine,and castor oil.

Anti-InflammatoriesAnti-inflammatories target the inflammation component of dry eye at thelacrimal gland. It has been demonstrated that reducing the inflammatoryresponse of the dry eye is an effective treatment option; Restasis® is one suchanti-inflammatory that has received FDA approval and is used widely inthe United States. Other anti-inflammatories include low-dose steroids andtetracyclines.

MucomimeticsThe mucomimetics, as the name implies, mimic the functions of naturallyoccurring mucins; by stabilizing the tear film, they actually result in a healthierocular surface. MILCIN™ is one mucomimetic that is on the horizon as atreatment option.

CONCLUSIONTo reach our collective goal of ocular surface protection, we must heal thedamage and reduce inflammation and irritation. This will likely be accomplishedby a line of products rather than one “cure-all”. With the many causes of dry eyeand nearly as many therapeutic approaches, we will certainly be looking atcombination therapy, with different treatments for different ideologies. �

REFERENCES1. Wolf. Normal Physiology of the Ocular Surface. Section 8 Basic and Clinical

Sciences Course, American Academy of Ophthalmology 2002-2003, page 49.2. Holly FJ. Formation and stability of the tear film. Int Ophthalmol Clin 1973; 13(1):

73-96.3. Tseng SC, Tsubota K. Important concepts for treating ocular surface and tear dis-

orders. Am J Ophthalmol 1997; 124: 825-835.

A New Modality for the Treatment of Dry Eye Syndrome — Arshinoff 9

A New Modality for the Treatmentof Dry Eye SyndromeSteve A. Arshinoff, MD, FRCSC

ABSTRACTCurrent treatment approaches for dry eye can be classified as anti-inflammatories, produces providing aqueous replacement, and evaporationreducing agents. The study of rheology is important in understandingviscosity, elasticity and the cohesion/dispersion continuum as it relates tothe properties of ophthalmic solutions. Viscoadaptive artificial tears arecharacterized by high-molecular weight hyaluronic acid and glycerol.This results in prolonged residence time on the cornea and increasedlubrication, thereby improving the blink process in patients with dry eye.

INTRODUCTIONDr. Arshinoff began his presentation by outlining the topics he would bediscussing, specifically: a review of past and current choices for the treatmentof 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 visco-adaptive eye drops.

EVOLUTION OF DRY EYE TREATMENT APPROACHESDr. Arshinoff referenced the 2007 International Dry Eye Workshop at whichCommittee members developed a framework for the definition, classificationand mechanisms of dry eye (Fig. 1).

He noted that dry eye has become somewhat of a “catch-all” term whoseunderpinnings are the result of either excessive tear evaporation or decreasedtear production. Prior to the development of Restasis® (Allergan, Markham,ON), an anti-inflammatory form of artificial tears, pharmaceutical companiesresponded by providing watery artificial tears, replacing water, or by decreasingevaporation. There are currently three types of eye drops available: 1) Anti-inflammatories such as Restasis; 2) Aqueous replacement, such as HypoTears®

(Novartis, Dorval, QC), TheraTears® (Advanced Vision Research, an Akorncompany, Ann Arbor, MI); and 3) Evaporation reducing agents, such asSystane® Gel Drops (Alcon, a Novartis company, Mississauga, ON).

Dr. Arshinoff cited Alcon’s development of successive iterations of Systaneeye drops based on a shift in direction from replacing water to preventingevaporation, a direction that merits further examination. This past decade, forexample, has seen a product evolution from Systane, to Systane Ultra, toSystane Balance, to Systane Gel Drops.

RHEOLOGY: STUDYING FLUID BEHAVIOURDr. Arshinoff presented an explanation of rheology, the science of how fluidsrespond to forces, or the mechanics of fluids, and how it works in the devicesophthalmologists use.

The study of rheology involves concepts relating to viscosity, elasticityand the cohesion/dispersion continuum. He pointed out that rather than astraight line of correlating properties, OVDs possess endless variation of theabove properties, such as viscosity changes under stress (Fig. 2).


Dr. Arshinoff stated that there are four different ways that the viscosityof fluids can respond to forces, the first of which is Newtonian, which meansthat no matter how much force you expose the fluid to, its viscosity remainsthe same (Fig. 2).

Another example is the plastic response curve, from which “plastic”materials derive their name. When exposed to very high forces, plastics arefluid, but when exposed to very low forces, they are solid. Imagine, suggestedDr. Arshinoff, trying to use a plastic OVD in ophthalmic surgery. Thesubstance 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 aredevices called pseudoplastic. In Figure 2, the blue line represents a pseudo-plastic fluid which means that, like a plastic under high forces going througha syringe, it has very low viscosity. However, when sitting in the eye, theviscosity increases — reaching what is called a limiting or a zero-shearviscosity — remaining fluid. The graph levels off and does not go higherthan whatever the zero-shear viscosity is. The corollary is: The only useful vis-cosity number for OVD classification is its zero-shear viscosity, as any otherviscosity value is dependent upon the shear rate at which it wasmeasured, which is often not disclosed by the manufacturer.

The pseudoplasticity graphs in Figure 3 illustrate the different OVDs in com-mon use in North America, although the HPMCs can easily be seen to not be verypseudoplastic. 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 thepale blue line, is dilatant. Dilatant is the opposite of pseudoplastic, meaningthat the more force it is exposed to, the more viscous it becomes. A classicexample of a dilatant fluid is albumin (egg whites).

The Definition & Classification of Dry Eye DiseaseGuidelines 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

Asymptomatic

Dry EyeDisease

EvaporativeDry Eye

other

other

AqueousDeficientDry Eye

Lid-relatedDisease

Other OSD

MGD AnteriorBlepharitis

Allergic conjunctivitisChronic infectiveand non-infectiveKeratoconjunctivitis

ConjunctivitisPost-refractive

Prodromalstates

Non-Dry EyeDisease

Fig. 1 Etiology of dry eye


NEWTONIAN SOLUTIONS IN OPHTHALMIC PRODUCTSExamples of ophthalmic viscous solutions that are almostNewtonian (Table I) are the low pseudoplasticity surgicalophthalmic viscoelastic devices (OVDs), such as i-Cel®

(I-MED Pharma, Montreal, QC), OcuCoat® (Bausch &Lomb, Vaughan, ON) and Cellugel® (Alcon, a Novartiscompany, Mississauga, ON), the two bottom curves in Figure 3.The curves representing these are more or less horizontal,meaning that the viscosity does not change with changingshear rate, except for the very end, where the levels descend.What this indicates is that if you are going to use an HPMCOVD, it is going to behave more or less the same in the eye,irrespective of the ambient shear rate. The surgeon wouldhave to push down very hard on the syringe, exposing it to alot of force, to inject the OVD through a cannula. For this rea-son, HPMC OVDs are packaged with larger cannulas thanother 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 SOLUTIONSNon-Newtonian solutions are used in intraocular surgery, mostof which are pseudoplastic (Fig. 3). Highly pseudoplasticitymeans that they exhibit low viscosity at high shear, high visco-sity at low shear, and possess a limiting or zero-shear viscosity.Examples of this are Healon®, Healon GV® (Abbott MedicalOptics, Markham, ON) and i-Visc.

“VISCOADAPTIVE” ARTIFICIAL TEARS:WHAT IT MEANS AND WHAT IT DOESArtificial tears containing hyaluronic acid — a long enoughchain that behaves like a pseudoplastic material — were firstdeveloped twenty years ago; Hylashield.

Dr. Arshinoff stated that three terms — viscous, elasto-viscous and viscoadaptive — are used to describe the varioustreatments for dry eye. He noted that the term “viscoadaptive”may be confusing to some practitioners, as “viscoadaptive”when used to describe tears, has a different meaning than whenthe same term is used to describe intra-ocular OVDs.

With respect to intraocular surgical OVDs, visco-adaptive signifies thatthe behaviour of the OVD changes from a highly viscous cohesive — like aSuper 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 solidunder high stress.” Both i-Visc Phaco and Healon5, when they are absolutelystationary, can behave like fractureable solids when exposed to highfrequency stresses.

The way you make it behave like a solid is by changing the ambientenvironment inside the anterior chamber. So if you increase your flow rate offluid 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

Table I Ophthalmic viscous Newtonian solutions

• Viscosity constant, independent of shear rate

• Exampleso Low pseudoplasticity Surgical OVDs (~ Newtonian)

- OcuCoat - I-Cel- HPMCs

o Topical artificial tears (± Newtonian) - Hypotears- Tears Naturale- Systane- GenTeal- Refresh- Tears Plus- Celluvisc

Rheometric Patterns of Fluid Behaviour: Viscosity

Fig. 2 Pseudoplasticity curves: rheometric patterns of fluid viscosityresponse to increasing force (shear rate).


rate in the eye and make the OVD behave “like a dispersive,” but not throughthe same mechanism. You can make Healon5 or i-Visc Phaco behave likeextremely viscous “super" Healon GVs under low turbulent conditions, or, byincreasing turbulence in the anterior chamber, they behave as pseudodispersivefractureable solids.

Analysis of rheological behaviour generally looks at typical flow ratesbetween 10 and 45 cc/min. In Figure 4, Viscoat® (Alcon, a Novartis company,Mississauga, ON) behaves as a dispersive throughout thoseflow rate settings; and Healon GV behaves as a cohesiveacross those flow rate settings. However, Healon5 will initiallybehave as a viscous cohesive, but with increasing flow ratesabove 25 cc/min, behaves as a fractureable solid.

COMPOSITION AND BEHAVIOUROF VISCOADAPTIVE ARTIFICIAL TEARSIn artificial tears, “viscoadaptive” refers to an elastoviscoussolution that changes under stress. There are chains ofhyaluronic acid that are not as long as those that would beused in an intraocular OVD. When these chains are exposedto the force of blinking, they are more elastic than they areviscous. When you blink with an elastic in your eye, youblink and it compresses; it does not go anywhere. When youopen your eye, it comes back and stays there, because it is act-ing 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 itbehave differently again under stress, which resulted in glycerol, a smallmolecule, being added. Because the hyaluronic acid absorbs all the water, and

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

Fig. 4 Behaviour changes in ophthalmic viscoadaptive OVDs.


there is no free water in the solution, when compressed, the viscoadaptiveelastoviscous 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 providingbetter tear lubrication.

Dr. Arshinoff noted that it is a different interpretationof viscoadaptivity. i-drop® (I-MED Pharma, Montreal, QC)is the first product of its type on the market, made of high-molecular weight hyaluronic acid and glycerol; it is an elasto-viscous solution of hyaluronic acid. Glycerol is excludedduring blink, thereby lubricating the tears during the blinkingprocess (Figs. 5, 6).

An additional advantage is that every human cell hashyaluronic acid binding sites, so when you take these chainsof hyaluronic acid and put it on your cornea, it adheres to thecorneal surface. Therefore, when blinking it remains fixed: itis stuck to the cornea. Together with the water layer andthe glycerol that moves in and out with blinking, the formularepresents the potential for an improved artificial tears product.

In 2003, the first viscoadaptive eye drop was launched inCanada, followed by Oasis Tears® (Oasis Medical, Glendora,CA) in 2009 — the first viscoadaptive hyaluronan-based eyedrop 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-preservedmultidose viscoadaptive eye drops.

PATIENT BENEFITS OF VISCOADAPTIVE ARTIFICIAL TEARSDr. Arshinoff summarized his presentation by describing the potentialadvantages of i-drop artificial tears. i-drop Pur artificial tears are pseudo-plastic elastoviscous tears, with a second molecule to increase lubrication.They exhibit polymer crowding, so there is no free water. In addition, theyare blink responsive in that they are elastic, so they stay inthe eye. They adhere to the cornea and the blink energyallows them to spread better over the eye. It releases glycerolto increase lubrication and it lasts longer than other drops inthe i-drop family of products. Dr. Arshinoff mentioned that asit launched only one year ago, there is not yet substantial clin-ical experience to report.

The proposed patient benefits are: enhanced protection ofthe cornea; prolonged residence time on the cornea becauseof the binding sites; smoother to blinks; higher degree of patientcomfort; very good corneal hydration; and less tear evaporation,which seems to be the direction in which other companies aremoving in developing their eye drops.

Fig. 5 Dispersive and cohesive properties of non-Newtonian tear solutions.

Non-Newtonian Tear Solutions:Viscoadaptive?

Fig. 6 Viscoadaptive eye drops mode of action.

“Viscoadaptive” Eye Drops

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 actionis referred to as viscoadaptivity.

How Viscoadaptive Eye Drops Worki-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.

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.

GLYCERIN

HA

CROSS SECTION OF THE TEAR FILM

MUCINLAYER

AQUEOUSLAYER

LIPIDLAYER

Two Choices for Long Lasting Relief

VISCOADAPTIVE EYE DROPS

I-MED Pharma 800.463.1008www.osdcare.com

B

Enhanced Corneal Protection

Prolonged Residence Time

Smoother Blinks

Higher Degree of Comfort

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Blink Mechanics: Viscoadaptive Technologyfor the Ocular SurfaceRichard Maharaj, OD, FAAO

ABSTRACTThe increasing prevalence of dry eye highlights the importance of the earlyidentification and treatment of such patients. According to worldwidestudies over the past decade, the prevalence of dry eye ranges from 7 percentup to close to 50 percent, rising to more than 90 percent in Dr. Maharaj’sclinic. Tear osmolarity is an important dry eye metric: A hyperosmolartear film is an indication of an inflammatory environment. Compromisedblink mechanics such as incomplete or dysfunctional blinking are a keycomponent in meibomian gland dysfunction and dry eye disease.

INTRODUCTIONWhile 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 tomoderate dry eye patients. There are two components in the discussionof the mechanics of blinking and viscoadaptive technologies. The first is whatthe eyelid does on a given blink. The second is the microanatomy involved inthe blink at the inner and outer eyelid surface. Dr. Maharaj has observed thata blanket approach to treatment with artificial tears isn’t an effective model ofcare for the multifactorial dry eye patient.

Following the artificial tear evolution and consideration of the chemicalproperties of various artificial tearproducts, industry has moved toward meibo-mian gland driven therapies with specific focus on lipid layer supplementation.

BLINK MECHANICS AND VISCOADAPTIVE DEVICESIn a normal functioning eye, the eyelid closes as the superior eyelid comes downand meets the bottom eyelid, grabs onto the lipid layer and the oil film rises withthe upper lid to coat the tear film. This is clearly shown on video imaging withthe Oculus keratograph 5M and looks very clear under slit lamp. The humanbody has evolved in such a way that this mechanism of action is responsible forachieving 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 SurfaceSociety (TFOS) is the mechanics and metrics of blinking.

Computer vision syndrome is not surprisingly on the rise. A common athome tip for patients involves blinking 20 times every 20 seconds by looking20 feet away or the 20-20-20 rule. When one looks at dry eye and ocularsurface disease, one realizes the role that the blink plays in it. Dr. Maharajstated that understanding blink mechanics makes it easier to understand themechanisms involved in the development of the dry eye.

MECHANICS OF DRY EYE DISEASEDr. Maharaj described rheology, the behavior of fluids in response to appliedforces, which is different from Newtonian physics; fluids respond differentlythan solids. An appreciation of this difference is crucial in reviewing visco-adaptive technology and pseudoelastic viscoadaptive tears.

While dry eye is a chronic condition for which there is no cure, ECPs canmanage it. Dr. Maharaj counsels patients that they can be treated and progressto a point where they are more comfortable, where they may not notice theireyes on any given day or any given week, but by no means is it a cure.

Blink Mechanics: Viscoadaptive Technology for the Ocular Surface — Maharaj 17

According to various worldwide studies over the past decade, the prevalenceof dry eye ranges from 7 percent up to close to 50 percent, depending on thestudy. In Dr. Maharaj’s dry eye clinic, more than 90 percent of patients actuallyexhibit the condition in itself; however, in general eye care practices, dry eye asa condition is second only to cataracts. Pre-identification of the dry eye patientundergoing surgery and pretreatment is far more likely to result in patientshaving a better postoperative experience.

When considering sending a 65-year-old patient to a cataract surgeon forcataract surgery, for instance, preparing the patient’s ocular surface has beenshown to contribute to their postoperative success. Patients that lack preoperativetreatment have a four times greater risk of their dry eye worsening followingsurgery. In the next two to ten years, stated Dr. Maharaj, practitioners will seetheir role in the perioperative arena growing, and rightfully so. Based on currenttrends, he predicted greater discussion and use of triglyceride omega 3s for addedsystemic impact on meibomian gland disease.

Dr. Maharaj discussed osmolarity as a dry eye metric that is important tounderstand in a general setting. Tear osmolarity is a valuable tool, relative tothe Ocular Surface Disease Index (OSDI), corneal staining and Schirmer teartest and has been shown to be more sensitive and more specific than these othermeasures.

When examining the correlation to the severity of the condition, osmo-larity has the strongest correlation. To identify existing dry eye patients in ageneral practice, it is extremely relevant for patients that may not be sympto-matic but are silently suffering. Those are the ones who may, in fact, have ahyperosmolar tear film, which means that they do have a higher component ofsalt and proteins like MMP-9 and other inflammatory cytokines in their tearfilm. If this inflammation is elevated and the patient is not symptomatic, thechronic inflammatory environment will eventually produce symptoms.

BLINK MECHANICS

Under a slit lamp, it is quite common for the lower eyelidto hang slightly lower than the iris, which is very commonand produces infrequent, incomplete blinking. There are,however, some patients who don’t have this characteristic;they have a neat palpebral fissure, but the eyelid stilldoesn’t drop all the way down. In terms of blink mechanics,said Dr. Maharaj, what most patients think happens is thattheir lower eyelid and upper eyelid come together, touchand then move away. However, when one starts toexamine the mechanics of a blink, one sees that this is, infact, the opposite of what occurs (Fig. 1). The lower eyelidmakes very little vertical movement; however, the superioreyelid does most of the travel and there’s actually atorsional component to it. That’s not even taking intoconsideration ethnicity, the thickness of the tear, the innereyelid surface, or the lid wiper itself, the band of tissue thatalso impacts the way eyelids move.

In Dr. Maharaj’s experience, examining the asymmetry between one eyeand the other, one often sees anatomical and morphological changes in themeibomian gland of the eye that has a decreased blink rate and decreasedblink completeness. In patients whose eyelids come together, there is acorrelation with meibomian gland atrophy or truncation: if the eyelids are notcoming completely together, the gland orifice isn’t receiving any negativepressure to draw oil out of it, and if it’s not used, obstruction begins, promptinga cascade of events.

Fig. 1 Mechanics of blinking.


Figure 2 depicts a breakdown of the blinking process,showing a superior component and a torsional componentof the upper eyelid moving mainly up and down andslightly, with a minor rotation. However, the inner eyelidbarely moves vertically; it actually has a nasal movement.This is an extremely complex movement with the forcesbeing applied to the cornea and to the ocular surface,in addition to the forces being applied to the fluid betweenthe eyelid and the cornea.

Dr. Maharaj expressed his opinion that there are somemore effective solutions for dry eye than artificial tears.Regardless of ethnicity or the shape of the eye, there isslight vertical movement on the superior eyelid; thereis nasal and torsional movement of the superior eyelid; theinferior eyelid margin typically makes lateral movements. This produces atype of shearing force. What occurs is that rather than the front surface closing,it is the posterior lid margin that closes. The mucocutaneous junction otherwiseknown as the Line of Marx (LOM) forms a ridge that is not meeting up.There’s no seal of the superior and inferior LOM on lid. A quick test for thisis the light test using a transilluminator. With retroillumination a slight gapbecomes apparent.

Even in those patients who, under a microscope, appear to be blinkingcompletely, they may, in fact, have inadequate lid seal which will exacerbate thecondition. This will lead to increased friction, causing the lid wiper to becomeinflamed. In this case, the posterior lid surface is in direct opposition to the corneawith a thin pre-corneal tear film acting as a buffer between the two surfaces. Theresult is tissue with repetitive microtrauma causing eventual, epitheliopathyand lid inflammation. The meibomian glands are very closely associated to thelid wiper and this is where Meibomian Gland Dysfunction (MGD) can startin some patients. Dr. Maharaj stated that while it is important to distinguishbetween aqueous deficiency and evaporative dry eye, he does not view thesituation as one or the other.

This condition is very much a spectrum disease. At some point, MGD willlead to up-regulation of the lacrimal gland, eventually causing it to becomeinflamed, resulting in aqueous deficiency. All dry eye patients appear at somepoint on this spectrum.

MECHANICS OF DYSFUNCTIONAL BLINKINGIn terms of the MGD cycle, Dr. Maharaj stated that the TFOSDEWS algorithm is extremely complex; therefore, he hasextracted some of the elements he feels are most relevant(Fig. 3). He suggests that practitioners examine the eyelidaperture of the blink first, looking for the lid seal. When theblink becomes dysfunctional, it results in lid wiper micro-trauma due to friction. The resulting symptoms can includeextreme pain, mild to severe contact lens intolerance andvisual instability. This will lead to hyperosmolarity with anup-regulation in MMP-9 (Matrix metallopeptidase 9), saltsand other proteins. Tear hyperosmolarity drives the tearsolutes toward the lid margin and meibomian glands andthus the evaporative and aqueous cycle begins. Thisprocess applies to the vast majority of mild to moderate dryeye patients and is therefore a good starting point in deter-mining the goal of an artificial tear.

Fig. 2 Breakdown of blinking process.

Fig. 3 Components of the TFOS DEWS algorithm.


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

CURRENT DRY EYE TREATMENTSThe goal of therapy is long-term stability, which is a very important part of thetear chemistry — an essential element. As an immunomodulator — a targetedanti-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 leadingcause of dry eye disease around the globe. With this, replacing the lipid layerbecame the utmost priority.

The term “viscoadaptive” was introduced; Dr. Maharaj remarked that itappears to be a confusing term. When doctors refer to the viscosity of asolution, 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 comparedto forces on solids because fluids are very much like air; the forces are moreor 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 tomove like a liquid are very, very high. The three tenets are understandingviscosity, understanding elasticity, and then examining the cohesive anddispersive nature of fluids.

Dr. Maharaj stated that there are four patterns of rheo-metric behavior of fluids (Fig. 4); namely Newtonian,pseudoplastic, plastic and dilatant. In Figure 4 the furtherto the left on the x axis, the lower the shear forces beingapplied; the further to the right, the higher the shear force.The y axis relates to viscosity. The solution can be a liquidwhich will be lower down on the graph or, it can behavelike glass or a fractureable solid which will appear higheron the graph.

NEWTONIAN TEAR SOLUTIONSMany fluids are pseudo-Newtonian; they’re not quiteNewtonian; however, they possess more or less these samecharacteristics. On the other hand, plastics when exposed toa great force can carry liquid-like characteristics.

As shown in Figure 4, fluid-like behaviors or lowviscosity behaviors at a certain force will become moreviscous. The term for this is zero shear rate. Past the zeroshear rate it becomes a fractureable solid. The zero shear rate of a pseudoplasticmaterial is important in surgery (intra-operative surgery is really where it allevolved from) because there has to be a point at which it doesn’t become moreviscous. If it did, it would harden in the anterior chamber making surgery verydifficult. Pseudoplastics have evolved and have been adapted to the ocularsurface specifically because of this fact.

Dr. Maharaj stated that this is particularly important when consideringartificial tears: The eyelid moves around and applies shear forces. Viscous

Rheometric Patterns of Fluid Behavior: Viscosity

Fig. 4 Variations in applied force.


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

NON-NEWTONIAN TEAR SOLUTIONSRegarding blink forces, instead of a tear solution progressing from a cohesivefluid to a hard solid, it actually moves from a cohesive fluid to an elasticmaterial.

In the process of blinking, the eyelid comes down and compresses.It squeezes the material down. One example of this type of fluid is hyaluronicacid (HA). In order to make it a dispersive substance, one can add a short-chain branched molecule that is not bound to the HA that can actuallyseparate from the HA by force. What happens with an artificial tear withHA and a short-chain branched polymer is exposed to blink forces, the HAseparates — 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 willalmost behave like a contact lens — a fractureable solid — in the eye whenthe eyelid closes because it is applying a high amount of shear force. Whenthe eyelid opens, the solution returns to a fluid state. In terms of applying theseforces to an artificial tear, consideration needs to be given to the way theeyelid moves with a HA-based eye drop compared to a Newtonian solutionlike methylcellulose, for example.

In the surgical context, the pseudoplastic curves ofsome of the ophthalmic viscoadaptive devices used inintraocular surgery are shown in Figure 5. The curves varydepending on the device used. Dr. Maharaj noted that someexamples currently used in surgery were actually used toderive hyaluronic-based eye drops. Healon® 5 (sodiumhyaluronate, AMO, Markham, ON) and iVisc® (sodiumhyaluronate, I-Med Pharma, Montreal, QC), for instance,are commonly used. Depending on the shear forcesapplied, the liquid will eventually reach a certain viscosityand not go past that point. Artificial tears such as TearsNaturale® (ocular lubricant, Alcon Canada, Mississauga,ON), Systane® (lubricant eye drops, Alcon Canada,Mississauga, ON), GenTeal® (lubricant eye drops, AlconCanada, Mississauga, ON), all have a very simple linearNewtonian movement on the eye regardless of the eye’sblink mechanics.

FEATURES OF PSEUDOPLASTIC ELASTOVICOUS TEARSThe first Canadian pseudoplastic elastoviscous tear is known as i-drop®

(I-Med Pharma, Montreal, QC). It is distinguished by its high molecularweight sodium hyaluronate combined with a short-chain branchedpolymer, glycerin. The interesting feature of HA is that all the cells in thebody, including those of the cornea, have hyaluronic binding sites. The HA inthe eye drop binds to these binding sites, anchoring the tear onto the ocularsurface. The HA actually combines with the water found in the tears.

It excludes the glycerin which rises to the surface as the eyelid blinks. Theglycerin provides a lubricating surface to the blink, decreasing friction on theocular surface. Once the eyelid reaches down to the bottom, and the eyelidcomes up and the solution returns to its original low viscosity. As a result ofthis process, the residence time is high. The tear mimics all three layers of thetear film simply by virtue of its physical properties.

Intraocular OVD Pseudoplasticity Curves

Fig. 5 Pseudoplastic curves of viscoelastic devices.


Dr. Maharaj uses this approach in his general patients, in order to prolongresidence time, decrease evaporation and create visual stability. A high molecularweight hyaluronic-based drop allows this. From a rheological perspective,pseudoplastic elastoviscous tears, or PETs, produce the desired effect, mimickingnaturally occurring tears.

The problem of decreased blink rate and closure requires that a topical tearincreases the residence time on the eye, which i-drop achieves. This is accom-plished through decreasing friction on the ocular surface with unbound glycerinand stabilization of the tear film via HA. This decreases evaporation and stabilizesthe tear film, providing patients substantially greater comfort.

Dr. Maharaj stated that the last benefit of some of the new drops coming tomarket, i-drop being one of them, is that they are packaged in a multi-dose, non-preserved bottle. He views the lack of preservatives as an important benefit. Thebottle 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 theHylan™ Surgical Shield (Elastoviscous Hylan Surgical Shield, 0.45%) whichsurgeons were using during surgery to coat and protect the ocular surface.

Dr. Maharaj suggested that when addressing the ocular surface, practitionersought to carefully consider the true etiology of the condition and all availablesolutions. With an abundance of products on the market and patients not knowingwhich to choose, Dr. Maharaj suggested that eye care professionals make veryspecific patient recommendations.

It is now known that patients are blinking less frequently and lesscompletely, which Dr. Maharaj noted are facts that need to be addressed whenweighing treatment options for dry eye. He stated that the best way to achieve this isto provide patients the most successful available products, rather than simply tellingthem 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 feelbetter. That’s why I’m being specific.” He takes this approach because if one tellspatients to use any artificial tear, they will. This leaves the decision of choosingthe topical up to the patient. As a health provider is it imperative to educatepatients to make an informed decision.

CONCLUSIONDr. Maharaj concluded his presentation by emphasizing the importance ofproviding patients a specific recommendation to their individual dry eyeproblem. The tear film ought to be addressed as a mechanism, as opposedan element that must be supplemented.


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

ABSTRACTThe intrinsic and extrinsic risk factors associated with ocular surfacediseases, 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. Thegoal of a stable tear film is based on the perfect interaction between the lipid,mucus and aqueous layers delivered by the meibomian glands, the gobletcells, and the lacrimal and accessory glands respectively, as well as theoptimal interface between these layers and the lid mechanics. The examina-tion of tear chemistry will play an increasingly major role in the diagnosisand treatment of dry eye disease and in the future of eye care.

INTRODUCTIONDr. Maharaj began his presentation by stating that during his longstandingpractice he has seen a large number of dry eye patients, specifically dry eyepatients with ocular surface diseases. His point of view is that when anoptometrist 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 primaryeye care arena.

His primary interests are the intrinsic and extrinsic risk factors associatedwith ocular surface diseases and his presentation concentrated on the historyand 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 andaqueous layers delivered by the meibomian glands, the goblet cells, and thelacrimal and accessory glands respectively. The goal of a stable tear film isbased on the perfect interaction between these layers, as wellas the optimal interface between these layers and the lidmechanics (Fig. 1). A large part of this is the sensory motorcomponent of the ocular surfaces. In cases of dry eye or othersurface diseases, typically the patient presents by saying, “I'muncomfortable. I feel gritty, I feel sandy.” They often describesome form of discomfort, prompting the question of theunderlying cause.

Dr. Maharaj stated that he examines this query in termsof three major categories. Pathology is first and foremost.Both pathological and age-related changes conspire to breakdown the ocular surface. The second element is environmentalor external factors and the third being anatomical consider-ations, involving an examination of the blink mechanism. It’snot a perfect vertical movement; in fact, there are torsional,tangential and vertical movements of both the upper andlower eyelid. It’s a very complex series of mechanisms thatadd up to a perfect blink; and in fact, the majority of dry eyesufferers, more than 60% of them, have some form of liddysfunction or blink closure; rather, the lack thereof.

Stable Tear Film Maintenance

Anatomical

Sensory Motor

MeibomianGland

Goblet Cells

Lid Blinking

Lid Closure

LacrimalGland

Aqueous

Lipid

Mucin

StableTearFilm

TearClearance& Spread

↓ Evaporation

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

Advancing the Diagnostic Use of Tear Osmolarity in Primary Eye Care: Part 1 — Maharaj 23

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

ENVIRONMENTAL FACTORSIn terms of external environmental factors, seasonal allergens in the airdefinitely have an impact on dry eye disease. For a dry eye patient who has aless than perfect tear film, allergens may be the tipping point: they mayrepresent the element that shifts a patient from being asymptomatic to symp-tomatic, as a large part of the disease exists in the asymptomatic stage.

Another important aspect is the effect of the office environment on theblinking process. In a large room, patients can undertake preventive measuressuch as artificial tears as they know in advance that their eyes are going to getirritated. Foreign bodies such as microparticulates including make-up, dust,epidermis and devitalized epithelium, are evident in patients’ tear film all thetime. The following question arise: Should we address this? Is it normal? In ahealthy eye with a healthy tear film, that may not be necessary; however, saidDr. 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 representan etiology for which practitioners are, in fact, responsible. Currently,optometrists are using single use and reusable lenses, and are adding differentsolutions and playing with various materials. However, as Dr. Maharaj pointedout, 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 bodyof science behind them, but the fact remains that a foreign body will berecognized by one’s body as foreign, contributing to inflammation andtherefore an immunological response will be triggered. All of the above areextrinsic factors that contribute to patient discomfort.

PATHOLOGICAL AND CHRONOLOGICAL CHANGESDr. Maharaj highlighted the challenge of lid wiper epitheliopathy. He feels thatit is an interesting concept and pathology as, like dry eye, it can start in an asymp-tomatic phase; indeed, in most cases, it does. Staining is one of the bestmethods of early testing to help identify the condition; he suggested it for at-riskpatients (contact lens wearers, tight lids, obvious and non-obvious MGDpatients, etc.). Friction at the lid wiper and ocular surfaces is the key to the dryeye symptomology— and the driving force behind the inflammatory cascadeat the ocular surface.

Currently, practitioners are seeing a departure from the model of threediscrete tear film layers: the mucin, the lipid and the aqueous, with theaqueous making up the bulk of the layers. The literature is reflecting a shiftaway 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 emanatesthrough the layers and is anchored to the epithelium. The question arises,“Does the chemical composition of tears affect dry eye progression and isthis important?” Dr. Maharaj pointed out that there are several componentsthat the industry is examining very closely. Physicians have relied heavily onlab work, including blood testing, and a shift in direction when it comes to tear


chemistry is occurring in much the same way. This is relevant consideringthat eyes are constantly bathed in this solution that's being produced by thebody, so any changes in it make a difference. Inorganic salts in particular— microproteins — contribute heavily to the measurement of tearosmolarity.

Tears contain hormones, which is why, in female patients in theirfifties who are going through menopause, start to see the onset in their dryeye symptomology. It may in fact be related, and the endorphins thatcontribute to the sense of pain are also present.

The lipid layer is the interface between tears and the air, but the mucinlayer is the scaffolding that gives tears their structure. Secretory mucins atthe ocular surface interact with epithelial receptors that, so if there isdysfunction in the corneal epithelium or in those receptors, this may indicatea dysfunction in the scaffolding.

Figure 2 illustrates a parallel between blood plasmaand tears, showing very similar values. Regarding bloodchemistry testing and how relevant it is in overall systemichealth, Dr. Maharaj proposed the question, is the same levelof scrutiny helpful for ocular surface diseases? His responseanswer is that it is indeed.

DRY EYE DISEASE AND OCULAR WELLNESSThe prevalence of dry eye disease has been stated in anumber of different ways, depending on how it is defined inthe various clinical studies. However, Dr. Maharaj postulatedabout a unified way of defining dry eye disease such as isdone with glaucoma or macular degeneration. Is there areliable metric that can be used in the primary care arenathat helps to define it — because if so, he pointed out, thesenumbers might actually fall into slightly more agreement.

Knowing that in optometric practice dry eye disease issecond only to cataracts in terms of prevalence, it's a huge cohort.Dr. Maharaj posed the following questions for consideration: how is itbeing managed? Are practitioners doing anything different than they werefive or ten years ago?

Even with the growing number of options in contact lenses and caresolutions, the dropout rates by contact lens wearers due to discomforthasn't changed when considering all of these advances, a decline in dry eyedisease should be evident. Dr. Maharaj suggested that a key piece of thepuzzle might be missing.

TEAR OSMOLARITY PAST AND PRESENTThe history of tear osmolarity began with the late Jeff Gilbard who was, inDr. Maharaj’s opinion, well ahead of his time. As early as 1978, heproposed that hyperosmolarity is the driving force behind ocular surfacedisease. He published papers on the correlation between high incidences ofeye osmolarity and decreased corneal epithelial glycogen, and conjunctivalgoblet 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, coincidentin patients that had good lacrimal gland function but meibomian glandorifices closure. This was the first time anybody had the suggested thathyperosmolarity was actually a major culprit in dry eye disease. Gilbard'swork was finally recognized and catapulted to its current status.

Chemical Composition of HumanTear & PlasmaTEARS PLASMA

Water 98.2% 94%Solids (total) 1.8% 6%NA+ 142meq/l 137-142meq/lK+ 15-29meq/l 5meq/lCL- 120-135meq/l 102meq/lHCO3- 26meq/l 24.3meq/lCa2+ 2.29mg/100mlGlucose 3-10mg/100ml 80-90mg/100mlTotal protein 0.6-2g/100ml 6.78g/100mlAmino Acids 8g/100mlUrea 0.04mg/100ml 20-40mg/100ml

Dr. Vijay Joshi, MS, MBBS Ophthalmology

Fig. 2 Human tear and plasma share similar chemistry.


DEFINITION AND MEASUREMENT OF OSMOLARITYOsmolarity is the measure of solute concentration. Its unit of measure isosmoles per liter, or in the case of the tear film milliosmoles per liter becausethe value is so very low.

Surprisingly, there are three methods of measuring osmolarity. Thefirst, which does not seems to suit the primary eye care setting, is the freez-ing point depression. When a particular material is frozen — for instance,water — it freezes at 0 degrees. If the solute level or the osmolarity of thatsolution is higher, the freezing point drops and that point of depression,that delta between 0 and the freezing temperature, can be extrapolated toosmolarity.

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 toosmolarity. Again, the mechanism is extremely complex and it doesn't lenditself very well to primary care; however, there are several institutions thatuse vapor pressure to measure osmolarity — not tear osmolarity, as it usesquite a large sample size.

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

OSMOLARITY VERSUS OSMOLALITYAs a differentiation between osmolality, and osmolarity, osmolality refersto the solute concentration per kilogram; it's the solvent measured as asolid as opposed to a liquid. Tear film never solidifies therefore in thisdiscussion, stated Dr. Maharaj, osmolality and osmolarity are synonymous.These two words can be used interchangeably; however, in the literature itis referred to as osmolarity.

In the DEWS (International Dry Eye Workshop) report in 2007, tearosmolarity was actually incorporated as part of the definition of dry eyedisease. The IOP at or above which practitioners should be concerned inglaucoma patients is 21, an extremely important recognized benchmark;it has helped to identify glaucoma patients far earlier — and, inDr. Maharaj’s view, the specificity and sensitivity in optometrypractices have increased as a result of that.

Knowing that the prevalence of dry eye disease is signifi-cantly greater than that of glaucoma, and that there is a metricthat has been included in the definition, it does make sense thatpractitioners can delve into this disease through their patientbase and see if there is preventative action they can take.

Patients who test above 308 milliosmoles per liter do, infact, have the disease. Tear osmolarity is the global markeragreed upon by both ODs and MDs alike, which is a rarity, butin the presence of a measure that is so strong, it begsfurther exploration. It is elevated in the diabetic population andin patients on chronic glaucoma medication who are exposed toBAK on a regular basis. The dry eye disease population isparalleled only by that of diabetes in the United States, withsome 25 million people affected.

At 308 mOSm/L cutoff• Specificity = 88% and Sensitivity = 75%At 315 mOSm/L cutoff• Specificity = 92% and Sensitivity = 73%• PPV 85% - i.e. “The % of time a metric > 308 mOsm/L

will actually be DEDRecall• Sensitivity % of persons who actually have the disease.• Specificity % of persons who do not have the disease.• Positive Predictive Value is the percent of people with a

positive test who have the disease.• Negative Predictive Value is the percent of people with a

negative test who do not have the disease.

Defining the Disease

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


ROLE OF OSMOLARITY IN DRY EYE DISEASEThe 308 mOsms/L figure was derived from a 2010 study by Michael Lemp,published in 2011 (Fig. 3). It postulated and confirmed that above 308mOsms/L, one sees an increase in inflammation and apoptosis, as well as abreakdown in useful homeostasis. However, the question remains, whatcauses dry eye disease hyperosmolarity?

Compared to other markers such as tear break-up time, Schirmer's andthe ocular surface increase index, osmolarity has much greater sensitivity andspecificity. 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 whotest 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 speci-ficity. Furthermore, in the second best measure, ocular surface disease index, inDr. Lemp’s research the agreement still wasn't as high as with osmolarity.

PREVALENCE OF DRY EYE DISEASEDr. Eric Donnenfeld began a prevalence study in 2012, whichwas taken over by Dr. Marguerite McDonald in 2013. It com-prised approximately 9,000 patients sequentially, excludingthose who had been artificial teared within two hours oftesting. Their demographics and history were taken followedby a series of yes or no questions. The patients were thenclassified as either having dry eye disease or having normalor low osmolarity.

Of particular interest, Dr. Maharaj stated, was that forpatients who had normal osmolarity, below 308, the inter-eyedifference was actually quite low at ±6. For patients above308, the inter-eye difference is actually fairly significant, at17±16 (Fig. 4). A similar trend was that the inter-eyedifference above the 308 threshold increases. At the sametime, osmolarity tended to be higher in the more painful eye.Dr. Maharaj noted that these are now regarded as trends tolook for. In patients with dry eye disease, often one eye feelsworse than the other. Furthermore, it's quite possible thatafter measuring their osmolarity, the delta is actually in favourof the eye that is more uncomfortable.

Figure 5 presents rates of symptomatology in hyper-osmolar and normal patients. Fifty percent of those withnormal osmolarity reported three or more dry eye-like symp-toms; therefore, 50% were experiencing some other diseasecausing their symptomology. Close to half of these 9,000 dryeye patients were silently suffering and were only uncoveredby the osmolarity testing, stated Dr. Maharaj.

The salient point is that patients who are symptomaticand have abnormal tear film still need to get run through fordiagnosis. In addition, they need to be examined for cornealhealth, staining and other standard testing for other possiblecontributing factors.

RELATIONSHIP BETWEEN OSMOLARITY AND

MEIBOMIAN GLAND DYSFUNCTIONDr. Anthony Bron et al in the UK have put forth the conceptof a solute gradient of the tear film, using a tear prism model:

Observed Differences in Hyperosmolarity& Normal Participants

McDonald ASCRS 2013- Osmolartiy Prevalence Study (from Donnenfeld)

Fig. 4 Comparing hyperosmolar and normal participants.

=< 308 mOsm/L > 308 mOsm/L

Avg osmolarity 297 +/- 7 323 +/- 17

Inter-eye difference 6 +/- 6 17 +/- 16

Differences in Hyperosmolar & NormalParticipants

McDonald ASCRS 2013- Osmolartiy Prevalence Study (from Donnenfeld)

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

=< 308 mOsm/L > 308 mOsm/L

Overall population 52% 48%

Pts reporting 3 or more 49% 51%DED symptoms

Reporting less than 3 DED 54% 46%symtpoms (Asymptomatic)


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

IMPACT OF DRY EYE ON OPTOMETRIC PRACTICEDr. Maharaj mentioned that the average dry eye patient is female, over age30, is a contact lens wearer, and uses a computer. This demographic alsofits 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 besteered clear of a disease that will induce anxiety, depression, and a wholecascade of events that can be life altering — and his first-hand experiencebears witness to this. Regarding contact lens dropouts, the number in recentyears is 30% in the first year of wear alone, despite advances in contactlens materials and solutions.

DRY EYE DISEASE IN SURGICAL PATIENTSWilliam Trattler, MD did a retrospective study called the PHACOstudy which examined 272 eyes of 136 patients for incidence of DED in asurgical population. Using the ITF, the International Task Force classificationon dry eye, almost 63% of patients had abnormal break-up times;21% had an abnormal Schirmer's score; and almost 77% were positive forcorneal staining, 50% of which had central staining. 87% of the dry eyepatients identified were asymptomatic. This potentially represents a highnumber of patients emerging post-surgery with postoperative dryness. Inmany cases DED is present preoperatively and not adequately managed.

In a small internal study at his clinic in Brampton of approximately100 patients, looking at their ocular surface disease index, and fluoresceinstaining, 23% of post-cataract patients developed dry disease, who werenormal pre-operatively. The literature cites postoperative dry eye pre-valence anywhere from 8% to 52%. In light of these negative surgicaleffects, Dr. Maharaj posed the question, is there room for optometrists todo more to these patients pre-surgically in order to identify them properly?

PREVENTIVE MEASURES FOR DRY EYE DISEASEThe TearLab™ detection test for dry eye disease has been on the marketfor a while. It comprises a detection system, with a simple applicator anddisposal test cards that produce the result number.

In July 2015, i-Pen® was launched by I-MED Pharma as another pointof detection test, again using a simple single, disposable chip. Rather thanbeing housed in a charger, it is a hand-held battery operated device whichis very simple to operate. It gives the reading in less than 5 seconds andpatients are very comfortable during the test procedure.

Dr. Maharaj stated that the modern focus of medical endeavours isprevention. This raises the issue of when to initiate preventative measuresin dry eye disease management like diagnostic testing which may impactearly intervention and treatment, as has already happened in diseases likeglaucoma and macular degeneration, for example.

Dr. Maharaj remarked that surgical patient remains under theoptometrist’s care, and always will be, the optometrist’s patient. His view


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

CONCLUSIONDr. Maharaj concluded his presentation by commenting that the contactlens landscape is rapidly evolving. Google, for instance, is now hoping todevelop a contact lens that measures blood glucose. Additionally, he assertedthat 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 thisand other contact lens advances will impact optometric practice shouldimpact the overall management of the ocular surface as a consequence.He feels strongly that tear chemistry will play an increasingly major role inthe future of eye care, and that what worked five or ten years ago shouldnot, 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 aredoing something wrong.

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

ABSTRACTOsmolarity testing is a critical element in expanding optometrists’ diag-nostic capability around their contact lens practice. Other metrics can beemployed; however, tear osmolarity is an extremely good tool to use sothat patients understand their situation very quickly. In addition, clini-cally, 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 enormousgrowth in the next decade.

INTRODUCTIONDr. Maharaj explained that he would be presenting several cases he hasencountered in his clinic, followed by some of the diagnostic capabilities thatinfluence optometrists’ treatment choices, and how they apply to osmolarity.He stated that in the past four years since osmolarity testing has become widelyavailable, 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 thatit is valued. Dr. Maharaj summarized three key factors that induce dryness,namely, pathological/chronological, external, and anatomical influences.

Case #1A 27-year-old male presented to the clinic. He had been acontact lens wearer for roughly six years and had neverbeen happy with his contact lens comfort. He used AirOptix® (Alcon, Mississauga, ON), a monthly lens modality,along with OPTI-FREE® Replenish® multipurpose solution(Alcon, Mississauga, ON). He noted seasonal allergies inhis medical history. He had had a two-week onset of red,itchy eyes, with the left eye worse than the right. Figure 1depicts the left eye.

The patient had vernal keratoconjunctivitis (VKC)with trantas dots along his limbus, an infiltrative response,and severe discomfort. Treating the histamine responsethat was inducing the VKC was certainly integral tomanaging this patient’s condition. He was started onLotemax® (loteprednol etabonate ophthalmic suspension5%, Bausch & Lomb, Vaughan, ON) QID for two weeks – an aggressiveregimen to optimize response – along with no contact lens wear for those twoweeks. 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; andsecond, Dr. Maharaj stated, he wanted him to be without his contact lenses forthat time in order to be a bit punitive. However, Dr. Maharaj did it with theintention of giving the patient a quick result because he was anticipatingtransitioning him into a healthier contact lens modality. The healthiest lens isno 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 toCanadian statistics, yet it’s a known fact that they are accompanied by feweradverse reactions than reusable lenses.

Fig. 1 Patient with long-term contact lens discomfort (OS).


The question was whether or not to change the patient’s contact lensmodality. The patient had stated that his problem was long-standing andwas 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 whichwere normal; his tear osmolarity was high at 317 mOsm/L OD and334 mOsm/L OS.

Dr. Maharaj highlighted that he spends extensive time counselling hisdry eye patients. He explained to this patient that his tears were very salty(hyperosmolar) and that this was a major contributor of his discomfort. Hetold the patient that he would send a letter to his referring optometrist, withsome recommendations, including discontinuing the contact lens solutionas solution toxicity may have been adding to his hyperosmolarity inaddition to denatured protein on his monthly contact lens surface. Thepatient’s optometrist subsequently switched him to a one-day high watercontent hydrogel material. At one-month follow-up the patient reportedthat he was doing very well and wasn’t experiencing nearly the sameamount of discomfort as previously. At this point he also wasn't using anyadditional artificial tears. A follow-up tear osmolarity test revealed thathe was down to 304 mOsm/L OD / 296 mOsm/L OS. His readings werenot completely in the normal range OD, but he was just sub-threshold;however, compared to his 317/334 measurements, he was now in a muchbetter range. In Dr. Maharaj’s view, what was more important here wasthat the patient understood his situation, which would almost certainlyguarantee that compliance would be improved.

PROMOTING PATIENT COMPLIANCEDr. Maharaj raised the question of what is required to get a patient to becompliant. He suggested that practitioners employ certain clinical practicesand integrate them into their contact lens practice to eliminate the com-moditization of contact lenses. There is a health aspect to contact lens carewhich has not been employed to a great enough extent, the result of whichis that patients feel as though they can go out and order contact lens onlinewithout knowing anything about them.

To address this situation, Dr. Maharaj encourages practitioners to builda diagnostic strategy around their contact lens practice in order to insulatethe practice. He posed the following questions: What is the osmolarity oftheir patient? Are practitioners setting their patients up for success orfailure? And if so, what are they doing to mitigate it? Furthermore, if theyare mitigating it, how are they measuring whether or not clinical choicesare in fact successful? Optometrists may be telling patients that they aregoing to get better by putting them on a one-day lens, but how are theymeasuring that? Other metrics can be employed; however, tear osmolarityis an extremely good tool to use so that patients understand their situationvery quickly. What’s more, clinically it's already been proven from anevidence-based perspective. Practitioners use it to engage their patientsclinically without becoming too technical.

Case #2Dr. Maharaj introduced his second case, that of a 53-year-old Caucasianfemale who had been referred to him by an ophthalmologist who had per-formed LASIK on her in 2007 and had put her on Restasis® (cyclosporineophthalmic solution 5%, Allergan, Markham, ON) nine months prior tothis consultation. She reported using Alrex® (loteprednol), BID or as needed.


Dr. Maharaj employs a symptom questionnaire called the SPEED(Standardized Patient Evaluation of Eye Dryness) score, comprising aseries of questions that produce a score out of 28, where 28 is the worsta patient can possibly feel. Dr. Maharaj uses the SPEED score methodwhen the patient comes in because it provides him a validated symptomscore within just 5 minutes. The SPEED score is very useful and it hasbeen validated by the University of Waterloo. This patient’s score was23 out of a possible 28, so she was feeling quite miserable. Her tearbreakup 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 hadsevere keratopathy.

Dr. Maharaj pointed out that Schirmer testing (no anesthetic), tearosmolarity, lid seal and aperture closure were all likely to be abnormal in sucha 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 thediagnosis down to at least three, if not two differentials. In his view, the testwith the greatest diagnostic value is osmolarity. If it were Schirmer, with lowtear volume, what would be the optimal treatment? If it's an aqueous deficientpatient and they're on Restasis, their aqueous deficiency is being addressed soit would not change your treatment approach. Measuring lid seal and apertureclosure is a very quick test that does not cause pain or take more time, but itdoes not, again, add to the clinical decision.

In Dr. Maharaj’s opinion, osmolarity is the only element that trulyadds to the clinical decision. He uses an Oculus keratograph 5M to measuremeibography in his practice. Meibography is infrared imaging of the anatomyand architecture of the meibomian ductules and acini and itcan be done on both top and bottom lids. This patient hadsignificantly atrophied and truncated meibomian gland archi-tecture which was diagnostic of her meibomian gland dys-function (MGD). She had been on Restasis for nine monthsand had evaporative dry eye that was not being managed.Dr. Maharaj pointed out that osmolarity actually helps practi-tioners to discern this because in a patient with an evaporativecondition, their osmolarity increases. In terms of lid apertureseal, there's a very quick way to measure this in the office,using a transilluminator on the upper eyelid to retroilluminatethe inner eyelid. As shown in Figure 2, on the right-hand side,there is slight leakage of light coming through the upper and lower eyelids, whereas the other eye is perfectly sealed.This is not the same as lagophthalmus. If the lid aperture isnot closing, you can assume that there is not good expression of themeibomian glands on lid closure. These patients will progress and developmeibomian gland stagnation and further obstruction. Unfortunately, thispatient had progressed to this point. Her osmolarity at this stage was352/326 mOsm/L OD and OS, respectively; therefore, her symptoms madea 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 ofinflammation at the ocular surface as a positive or negative outcome. In thiscase, the patient measured negative.

With glaucoma patients, OCT, visual fields, pachymetry and IOP aremeasured. With dry eye patients, we examine tear panel testing or tearchemistry. Dr. Maharaj proceeded to describe three patient scenarios

Fig. 2 Use of transilluminator to measure lid aperture seal.


regarding osmolarity in chemistry testing. The first is a patient withhigh osmolarity and normal MMP-9. These are typically early dry eyepatients who haven't yet begun to develop up-regulation of their MMP-9expression. In that scenario, they may also have a normal MMP-9 if theyare already on anti-inflammatory treatment. In the case of the 53-year-oldwoman, she had already been on Restasis for the previous nine months andher MMP-9 was negative, which stands to reason. Osmolarity had not beenaddressed, though, because she was still an evaporative patient.

A second scenario is a patient with high osmolarity and a positiveMMP-9, indicating ocular surface inflammation. These are patients whotypically have had dry eye for some time and it has beenuntreated or poorly managed, essentially producing twopositives. A third scenario is a patient with normalosmolarity and abnormal MMP-9. These are cases ofless typical dry eye disease which are more likely to be afunction of some other ocular surface dysfunction such asEBMD or conjunctival chalasis. Osmolarity providesperspective on MMP-9, and MMP-9 provides perspectiveon osmolarity. How one uses them together can strengthenone’s diagnosis significantly.

Dr. Maharaj was able to determine that this patient hadevaporative dry eye because her inflammatory mediatorswere already being addressed with Restasis. Figure 3depicts before and after treatment for MGD.

Case #3The next case is of a 39-year-old female who had undergone LASIK sevenyears prior. She presented with repeated intermittent foreign body sensationin her left eye. She had exposure due to a limited lid seal and had usedvarious types of drops, but nothing gave her sustained relief. She did havea maternal family history of Sjögren's and her current medical history waspositive for Raynaud’s disease. Her tear breakup time was certainlyreduced in her left eye, and her osmolarity was 273 mOsm/L in her rightand 296 mOsm/L in her left eye. The difference of 23 mOsm/L betweenher two eyes was clinically significant despite each eye’s osmolarity still inthe subclinical range, under 308 mOsm/L. Her MMP-9 was negative in herright eye, ironically, and was positive in her left eye. In summary, thispatient had a suspect tear osmolarity and a positive MMP-9, so she wasclinically defined as having dry eye. Her tear breakup time was almostinstant; this patient wasn't even closing her eyes. She had high evaporation,along with lid wiper epitheliopathy. Dr. Maharaj explained that lid wiperepitheliopathy occurs when there is increased friction between the lidwiper and the ocular surface. When hydrodynamic lubrication between thetwo surfaces is lost, increased friction results in increased inflammation whichthen leads to epitheliopathy. That area is very close to the meibomian glandtissue, causing further propagation of the lid and gland inflammation.

Dr. Maharaj stated that he decided to focus his therapy on her lidmargin and lid wiper with a procedure called periocular scaling, expressionand neutralization. He has been performing this procedure for the past fewyears and it has been presented in the literature. It is a non-surgical processdone in primary care. Dr. Maharaj also used a non-preserved hyaluronic-based drop instead of Systane® BALANCE (Alcon, Mississauga, ON)which she had been using.

Fig. 3 Before and after treatment for MGD.


Dr. Maharaj began by staining the lid and the line of marks on the lidwiper with lissamine green. He then used a golf spud to debride and scalethe surface, passing over the meibomian gland orifice, as well as the lidwiper and mucocutaneous junction. The process involved removingdevitalized epithelium, squamous epithelium that was devitalized and, ifleft long enough, would actually keratinize. He then expressed, using aMastrota paddle and a cotton-tip applicator. Dr. Maharaj pointed out thateffective meibomian gland expression requires a hard back surface: ifone is expressing with one’s thumb against the globe, it's insufficient and ahard back surface is needed to push against. The neutralization aspectinvolves neutralizing the acidic component of the meibum, which iscomprised of a fatty acid; otherwise, it retains on the ocular surface andcan accelerate devitalization. In patients who have MGD, frothy tearsaccumulate and develop into acidic keratoconjunctival changes.Neutralizing with a basic solution, such as mineral oil, helps in addition tocertain artificial tears with a slightly basic pH. Dr. Maharaj advised toneutralize whatever is being expressed, which also helps to soothe thedebrided surface.

Using this technique, Dr. Maharaj’s retrospective analysisof 53 patients revealed that symptomology was improved byapproximately 62%, on average. Meibomian gland function,therefore secretion levels, increased by 30% by doing this oneprocedure. Figure 4 illustrates before and after results in thepreviously-mentioned 53-year-old patient. A recent study outof the University of Waterloo, by Ngo W, Caffery B, et al in2015 have demonstrated components of this procedure on aSjögren’s cohort of patients demonstrated equally positiveresults. Heated expression such as Lipiflow and alike alsowork extremely well on MGD.

There are various new modalities of care that are targetedtoward the lid surface, the lid wiper, and the meibomian glandorifice and structure that greatly help to accent a missingcomponent of the current treatment options. In Dr. Maharaj’sview, practitioners are accustomed to de facto using drops fordry eye disease, without doing anything to actually restoremeibomian gland function.

The pathway to the meibomian gland orifice can be broken bymedicine by decreasing the inflammation which, in turn, decreasesdevitalization of the epithelium. However, current techniques allow practi-tioners to physically debride the epithelium which will break this cycle andreduce the osmotic gradient. Traditionally, in patients who are at risk orwho already have the condition, he repeats the procedure once every sixmonths. In patients whose secretions are good just by gentle expression, orif 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, forinstance, BlephEx®, or microblepharoexfoliation. BlephEx is great atdealing with anterior blepharitis specifically. It also helps to remove someof the squamous cells. However, when there is extensive keratinization anda blunter instrument is needed to get under the skin to lift it, often timesBlephEx won't achieve this in his experience.

Fig. 4 Before and after results of surgical triad: scaling, expression,neutralization.


Case #4A 77-year-old female from Winnipeg was very specific about her discom-fort which was on her lids and the bottom part of her eye. She had hadcataract surgery about 10 years prior, and had been on Restasis for avery long time, along with Lotemax. In addition, she had been put ondoxycycline to treat her MGD and she was using copious non-preservedand preserved lubricants as well as lid hygiene procedures, with which shewas very vigilant.

Conjunctival staining with lissamine green showed someconjunctival rolls indicating a ‘fat conjunctiva’ indicating lossof Tenon’s fascia; this is known as conjunctival chalasis(Fig. 5). In addition, she had floppy eyelid syndrome with onevery large roll juxtaposed to her inferior eyelid such thatwhenever she blinked, it rolled up and down, abrading hercornea. Clinical testing revealed positive MMP-9 test, tearbreakup was instant as one would expect, and her meibomiangland score was zero because her conjunctiva was actuallycovering the orifice. While all of this was negative, her tearosmolarity was normal.

Technically, said Dr. Maharaj, while this wasn’t consistent with dryeye, if one were to look only at the staining, one would conclude that itwas. However, clinically, it was conjunctival chalasis with a desiccatedcornea due to mechanical abrasion. The patient was on the maximal therapy.The surgical options were conjunctival resection or amniotic membranetransfer. Dr. Maharaj indicated that there are not a lot of surgeons in hisarea who surgically treat these cases, although it has been increasinglyrequested, therefore the interest in it may be rising.

On the pharmacologic side, there weren’t many other options apartfrom Restasis. After consultation with the patient’s family physician, shewas put on human autologous serum (HAS), with an aliquot of 20%solution in 5 mL bottles, BID for three months. Dr. Maharaj suggestedthat it is useful to have a compounding pharmacist on hand in the event thatthis process is needed. In Ontario, compliance of the family physician isneeded to order the appropriate blood work. Autologous serum is plasmawhich contains growth factors, and normalizes the proliferation and migrationof epithelial cells, increases healing rates. There are some adverse reactionsthat can be associated with HAS, but in this particular case, the risks wereacknowledged and the patient did very well.

In terms of quality of life alone, she was excessively happy in spite ofher 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 havingher conjunctival resection done. Cyclosporine is extremely effective atcontrolling inflammation but in some cases, where there is a dense amountof SPK and mechanical trauma, it is not sufficient. The objective in thesecases is to minimize friction while controlling inflammation.

As noted in Cornea in a 2011 paper by Dr. Michael Lemp, osmolarityis the single most defining metric for dry eye. If you are looking at asub-specialty clinic or a sub-specialty environment in which to invest, anoculus keratograph 5M which has a comprehensive dry eye module, and atear osmolarity meter are essential. Additionally, stated Dr. Maharaj, it iscritical to identify the general population coming into your office. The roleof optometrists in managing disease continues to expand to maximizepatient outcomes. Optometrists are, in fact, in charge of prevention as wellas treatment; however, if prevention is maximized, there are better chancesof successfully treating a condition that has not yet been controlled.

Fig. 5 Conjunctival chalasis in a 77-year-old female.


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

CONCLUSIONDr. 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 theASCRS meeting in June 2015 contained a very compelling argument forre-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 saturatedOmega-3 measurement after dosing with a triglyceride versus an ethylester. The triglyceride achieved an 8% blood saturation within 1 month ofthe above dosing, which ethyl ester never achieved up to 3 months later.This level of saturation also decreases cardiac risk in addition to improvingmeibomian gland secretion. As a result, Dr. Maharaj is a proponent of rTGOmega-3s, for example, NutraSea HP and Physician RecommendedNutraceuticals.

On the subject of differences between the liquid and gel capsulatedforms, 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 notfound a difference between liquid and gel caps. In his experience, patientsare able to tolerate the liquid better; therefore, if the objective is patientcompliance, it is the preferred form of the product.

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The intrinsic and extrinsic risk factors associatedwith ocular surface diseases, as well as tear filmosmolarity — and its role in optometric care are— are key elements in the diagnosis and treat-ment of dry eye disease. The goal of a stable tearfilm is based on the perfect interaction betweenthe lipid, mucus and aqueous layers delivered bythe meibomian glands, the goblet cells, and thelacrimal and accessory glands respectively, aswell as the optimal interface between these layersand the lid mechanics. The examination of tearchemistry will play an increasingly major role inthe diagnosis and treatment of dry eye diseaseand in the future of eye care.

Richard Maharaj, OD, FAAO

Approaches to the Diagnosisof Dry Eye Disease

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