DRYEYEDISEASE

participants

Penny Asbell, MD, FACS, MBA: New York New York, USA

Stefano Barabino, MD, PhD: Genoa, ItalyChristophe Baudouin, MD, PhD, FARVO: Paris, France

Eric D. Donnenfeld, MD: New York, New York, USA

Gerd Geerling, MD, PhD: Düsseldorf, Germany

Debra A. Schaumberg, ScD, OD, MPH: Boston, Massachusetts, USA

A supplement to

This medical education activity was developed by MedEdicus LLC

This medical education activity was supported by Pfizer Inc.

JULY/AUGUST 2011

the current understanding of

Insights froma RoundtableDiscussion

The Role of Clinicians in Educating the Public

program chair

Anthony J. Bron, FRCOphth, FMedSci, FARVO: Oxford, UK

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participantsPenny Asbell, MD, FACS, MBAProfessor of OphthalmologyDirector of Cornea and Refractive ServicesDepartment of OphthalmologyMount Sinai School of MedicineNew York, New York, USA

Stefano Barabino, MD, PhDAssociate ProfessorClinica OculisticaDepartment of Neurosciences, Ophthalmology, and GeneticsUniversity of GenoaGenoa, Italy

Christophe Baudouin, MD, PhD, FARVOProfessor of OphthalmologyQuinze-Vingts National Ophthalmology HospitalVision Institute, University of Paris 6Paris, France

Eric D. Donnenfeld, MDClinical Professor of OphthalmologyNew York UniversityNew York, New York, USATrustee of Dartmouth Medical SchoolHanover, New Hampshire, USAChair of Cornea for the American Society of Cataract

and Refractive Surgery (ASCRS)

Gerd Geerling, MD, PhDDepartment of OphthalmologyHeinrich-Heine-UniversityDüsseldorf, Germany

Debra A. Schaumberg, ScD, OD, MPHAssociate Professor of Medicine and OphthalmologyDirector of Ophthalmic EpidemiologyBrigham and Women's HospitalHarvard Medical SchoolBoston, Massachusetts, USA

program chairAnthony J. Bron, FRCOphth, FMedSci, FARVOProfessor Emeritus

Nuffield Laboratory of Ophthalmology

University of Oxford, UK

DRYEYEDISEASEthe current understanding of

Insights froma RoundtableDiscussion

The Role of Clinicians in Educating the Public

Proprietary or commercial disclosures may be found after the references.

The International Dry Eye Workshop (DEWS) was held in2007 and was published in Ocular Surface.1 The report is anevidence-based review of the present state of knowledge ofdry eye disease (DED) and the methods used to evaluate,diagnose, and manage the disorder. In addition, theInternational Meibomian Gland Dysfunction Workshop wascompleted in 2010 and was published on March 2011.2 These2 workshops summarize the findings of current research andidentify future needs for a better understanding of theetiology, pathogenesis, and potential therapy of DED. It istherefore an excellent opportunity to assess the outcomes ofthese workshops, to obtain a global perspective and, at thesame time, to consider the implications for ophthalmologistsin Europe.

A group of renowned experts in anterior segment diseaseconvened to share their insights into the current understandingof the disease and to think about the implications for theirpatients. The highlights of this discussion are presented here.

NEEDSOFCLINICIANS TOUNDERSTANDDRYEYEDISEASEPROFGEERLING: There are 2 primary needs to better understanddry eye disease: First, a need to be aware of the differential diagnosisof DED, as has been reviewed in the Dry Eye Workshop (DEWS)and Meibomian Gland Dysfunction Workshop (MGD). Second, thereis a need for diagnostic tools to differentiate between DED and MGD.Additionally, in Germany, ophthalmologists are looking for specifictherapeutic approaches to DED, such as the use of anti-inflammatoryagents to supplement the use of tear substitutes, which are usedcurrently to restore tear volume.

PROF BRON: Yes, I agree. Tear substitutes can amelioratesymptoms and have some important therapeutic effects, but newertherapies can specifically target the disease process.

PROF BAUDOUIN: In France, the situation is similar to that inGermany. There is typically limited knowledge about thepathophysiology of dry eye. This limited knowledge frustrates manyophthalmologists because they believe that their patients are notgetting symptomatic relief from tear substitutes despite theavailability of a large variety of these agents on the market. Sincethe availability of cyclosporine 5 years ago (not approved in France,but obtainable through hospital pharmacies), there has been anincreasing recognition that inflammation is involved in DED.

PROF BRON: Cyclosporine, incidentally, is not approved in mostcountries in Europe, although it is available in Turkey.

PROFBARABINO: The situation is very similar in Italy. One of themajor problems in my country is that dry eye patients are notreferred to an ocular surface specialist. Instead, they consult theirpharmacist, who gives them artificial tears on nonspecific grounds.Next, they see a general practitioner, who also may not recognizedry eye as a disease. Even when patients do consult a generalophthalmologist, that physician often prescribes artificial tearswithout making a diagnosis of DED or distinguishing it frommeibomian gland dysfunction. Therefore, it is imperative that bothophthalmologists and general practitioners become well informedabout both diseases. Moreover, we need to educate patients aboutDED because they do not really understand the nature of the disease.

PROF ASBELL: There remains an underappreciation of dry eyedisease by both European and US professionals. In the last decade,however, clinicians have had an increased understanding of theprevalence of DED and a growing acceptance of the concept thatDED can negatively affect patient quality of vision as well ascomfort.3-5 This may be less well understood in Europe. There is alsoan economic impact of DED that varies from country to country,which is hard to calculate since many patients are self-diagnosed andself-treated with over-the-counter remedies. A limited survey hasbeen reported in Europe.6 Therefore, there is clearly an opportunityin Europe and in the United States, as well as in other parts of theworld, to raise awareness of the prevalence of DED.

EVOLVINGCONCEPTOFDRYEYEDISEASEPROF BRON: The DEWS report defines dry eye disease as amultifactorial disease of the tears and ocular surface that results insymptoms of discomfort, visual disturbance, tear film instability, andpotential damage to the ocular surface.1 Dry eye disease isaccompanied by increased osmolarity of the tear film andinflammation of the ocular surface. Hyperosmolarity plays a causalrole and is regarded as a gold standard in the diagnosis of DED. Howhas this concept evolved?

PROF SCHAUMBERG: Unlike the previous definition, the newdefinition of dry eye disease recognizes that the symptoms of thedisease could cause both discomfort and visual problems and, thus,the new definition eliminates the disconnect that often existsbetween the symptoms and the appearance of the ocular surface.

PROF ASBELL: The 2007 DEWS report also expanded ourunderstanding of the mechanism of dry eye disease.

PROF BRON: We must remember that patients are focusedprimarily on the resolution of their symptoms and not on ocularsurface signs. Ophthalmologists recognize the prime importance ofsymptoms, but they care about signs too, because these signs reflecteye pathology, which may predict later outcomes.

PROFDONNENFELD: In the past, dry eye disease was consideredan irreversible, inevitable change due to age. Now we know thatinflammation plays a major role in many cases of DED and that anti-inflammatory therapy can both improve the ocular surface andprevent disease progression.

PROF BRON: Initially, there was much resistance to the idea ofinflammation of the ocular surface in dry eye disease becauseclinicians did not see a bright red eye. Instead, they saw subtlehyperemic changes. However, Paiva and Pflugfelder convinced themedical community that treating inflammation could reverse bothpatient symptoms and ocular surface signs.7

PROF BAUDOUIN: I believe that we have not yet convinced theentire ophthalmology community that inflammation is present in dryeye disease.

“We have not yet convinced the entireophthalmology community that inflammationis present in dry eye disease.” — PROFBAUDOUIN

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PROF BARABINO: Understanding inflammation is undoubtedly astep forward in our comprehension of the pathogenesis of dry eyedisease, but the problem of diagnosing inflammation on the ocularsurface remains. There is a great need for simple approachesthat can be used by the general ophthalmologist to quantifyinflammation.

PROF BAUDOUIN: Measuring inflammation remains a difficulttask in clinical practice. Biopsies are invasive and difficult to proposeto patients. Impression cytology appears to be a more appropriateway to assess the ocular surface because it allows for thequantification of squamous metaplasia, goblet cell counts, andidentification of inflammatory cells. Flow cytometry is a biologicaltechnique that quantifies inflammatory markers expressed byconjunctival cells. It has been used in the clinical setting and inmulticenter trials to quantify and monitor inflammation in dry eyedisease.8 Human leucocyte antigen DR (HLA-DR) expression is areliable marker for measuring inflammation in DED. Othertechniques such as RT-PCR or tear cytokine measurements may alsobe used. ELISA (enzyme-linked immunosorbent assay) or multiplexbead analysis have been used successfully for assessing the presenceof inflammatory cytokines or chemokines in the tears in DED.9,10However, tear collection in DED patients remains difficult and therisk of protein dilution by reflex tearing cannot be ruled out.

DRYEYEDISEASETERMINOLOGYPROFBRON: The Delphi report11 provided a consensus approachto symptomatic ocular surface disease and generated a treatmentalgorithm based on the severity of symptoms and signs. Thepanelists were justifiably critical of the term “dry eye disease”because it contradicts the fact that patients may not alwaysexperience actual ‘dryness’ and, in fact, may have increased tearingas one of their symptoms as is the case in evaporative dry eye.Because of these conceptual difficulties, the panel created the term“dysfunctional tear syndrome”. This is a nice general term forsymptomatic ocular surface disease, but it is not an appropriate termto replace “dry eye disease” itself, which is a subset characterizedby tear hyperosmolarity.

PROF BARABINO: I agree. The term “dry eye disease” isincomplete, and yet “dysfunctional tear syndrome” is too complex andis difficult for patients to understand. A term in between the 2 wouldbe of value, perhaps a term that includes the words “ocular surface”.

PROFSCHAUMBERG:My issue with the term “dysfunctional tearsyndrome”, apart from its complexity, is that it points the finger atthe tears, while the ocular surface is what is really affected.

PROFGEERLING: Events in the tears are important, but it is true,as you say, that it is problematic when a terminology is chosen fordry eye disease that relates to the tear film only, rather than to aspecific anatomic structure such as the ocular surface.

PROF BRON: There is still some work to be done to arrive at asimple language that locks together the concept of dryness withincreased saltiness of the tears—thus, incorporating both theaqueous-deficient and the evaporative forms of the disease.

PATHOPHYSIOLOGYOFDRYEYEDISEASEPROF BAUDOUIN: Two major mechanisms have been suggestedfor the pathophysiology of dry eye disease—inflammation andhyperosmolarity. Inflammation can be treated, but cannot be

measured easily; hyperosmolarity, however, can be measured quiteeasily. Sullivan and colleagues have shown that hyperosmolarity is abetter indicator of severity than the Schirmer test, tear breakup time,or staining with dyes.12

PROFBRON: Prof Baudouin, please describe your “vicious circle”concept that is important for the understanding of the self-perpetuation of this disease.

PROF BAUDOUIN: Tear hyperosmolarity increases the disordersof corneal and conjunctival epithelial cells and goblet cells becauseit causes apoptosis. Most likely, the destruction of goblet cells, whichis a hallmark of dry eye disease, is a major contributor to the disease.At the level of the cornea, activation of reflex arcs probablystimulates the ocular surface, further augmenting the neurogenicinflammation. This, in turn, leads to the release of inflammatorycytokines and the subsequent stimulation of inflammatory cells andlymphocytes. All those inflammatory or degenerative phenomena areadditional events that cause further goblet cell destruction and tearfilm instability, resulting in a vicious circle (Figure 1).

PROFASBELL: Laboratory research has shown that conjunctival andcorneal epithelial cells can be stimulated by abnormalities in the tearfilm, making them active participants in the inflammatory process, andnot just bystander tissues that are injured during the course of thedisease. The corneal and conjunctival cells actually produce cytokinesand inflammatory mediators that amplify the process.13-18

PROF BARABINO: Mouse models of dry eye disease have clearlyshown that DED is not simply an inflammatory disease, but that itinvolves the activation of immune cells, especially the antigen-presenting cells of the cornea. The DED mouse model that wasdeveloped in Massachusetts Eye and Ear Infirmary (Boston,Massachusetts, USA) has shown the invasion of the cornea bylymphatic vessels, the migration of antigen-presenting cells to thelymph nodes, and the activation of lymphocytes.19 The activation ofthe lymphocytes is probably the reason DED is a chronic diseaseand it explains the reason behind the effectiveness of cyclosporine,which has activity against lymphocytes, in the treatment of DED.19

MAPK=mitogen-activated protein kinase; MGD=meibomian gland dysfunction;MMP=matrix metalloproteinase proteolytic [enzymes]; NSSDE=non-Sjögrensyndrome-associated dry eye; SSDE=Sjögren syndrome-associated dry eye;TNF=tumor necrosis factor

Figure 1: Pathophysiology of dry eye disease.1 Reprinted with permission fromEthis Communications, Inc.

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ENVIRONMENTAL FACTORSTHAT AFFECTDRYEYEDISEASEPROFSCHAUMBERG: The effect of environmental stimuli on dryeye disease poses a complex issue. Recently, several importantresearch articles have added significantly to our knowledge of therole of environmental stimuli. Patients often complain that readingand computer use exacerbate their DED symptoms. Himebaugh andcolleagues have shown decreased blink rates and more centralbreakup of the tear film during computer use in people with DEDcompared with normal subjects.20

There is also the role of low humidity and its effects on patientswith dry eye disease. For example, a study from Taiwan examinedmore than 3000 people,21 with approximately half the peopleinvestigated working in an indoor environment with moderatehumidity. The study showed that working in this environment wassignificantly associated with a higher prevalence of DED.

Other studies have examined the issue of air travel. One studysurveying 1246 Australian pilots showed a marked associationbetween DED and the flight environment, with 72% of respondentsreporting DED during flight, but only 5% reporting such symptomsat other times.22

Lastly, studies from Asia—specifically Tibet,23 Mongolia,24 andIndia25—suggest that people living at high altitudes (ie, lowhumidity), have a very high prevalence (approximately 50%) of DEDsymptoms.

PROF BARABINO: A significant decrease in tear secretion fromthe lacrimal gland was observed 3 days after placing mice in a low-humidity chamber with a constant airflow, suggesting that lowhumidity stimulates a negative feedback loop.26 One of the possiblereasons for this is that chronic stress of the ocular surface couldinduce irreversible changes in the lacrimal gland, thereby decreasingits tear production.

PROFSCHAUMBERG: Sometimes dry eye disease can be affectedby low humidity alone, but the culprit may also be the actualmovement of air over the ocular surface.

PROF BRON: Certainly, both low humidity and air movementincrease evaporation. It seems that environmental factors such ashumidity, high altitude, and extended viewing of computer monitors,among others, affect people in all professions and in all parts of theworld. It is evident that both the clinicians and the public requiremore education about these aspects of dry eye disease.

EFFECTOFMEDICATIONSONDRYEYEDISEASEPROFBRON: What is the effect on dry eye disease of the internalenvironment created, for instance, by certain medications?

PROFSCHAUMBERG: Medications play a very important role indry eye disease. The Physicians’ Health Study27 and the Beaver DamEye Study28 showed that the use of antidepressants is associated withan increased risk of DED. Other commonly used medicines, such asantihistamines, beta-blockers, and anything with an anticholinergiceffect, are also associated with increased DED symptoms.

CLASSIFICATIONOFDRYEYEDISEASEPROF BRON: I think we are comfortable with the 2 establishedmajor categories of dry eye disease classification.1 First is aqueous-deficient DED. This can be subdivided into Sjögren Syndrome(primary or secondary) and non-Sjögren DED, which includes age-related DED. In this case, lacrimal function is impaired by invasionof the lacrimal gland with inflammatory cells. Lacrimal flow can alsobe reduced by cicatricial obstruction to the lacrimal ducts.

The second major category is evaporative DED. The DEWSreport1 recognized an intrinsic form of DED that was lid-related,including not only meibomian gland dysfunction, but also poor lidcongruity or lid dynamics, a low blink rate, and the toxicity ofsystemic retinoids used in the treatment of acne vulgaris. Anotherform of evaporative DED is that caused by damage to the ocularsurface, due to vitamin A deficiency, topical preservatives, contactlens wear, and allergy (Figure 2).

Another mechanism that may trigger dry eye disease is thefeedback from the ocular surface through the lacrimal functionalunit. When corneal sensation is impaired, a loss of sensory drive tothe lacrimal gland occurs, that may reduce the secretory function ofthe lacrimal gland.29,30 It is important to acknowledge that aqueous-deficient and evaporative DED are not mutually exclusive. They canand do occur in combination; therefore, they can produce complexhybrid states.

VTU=video monitor

Figure 2: Classification of dry eye disease.1 Reprinted with permission fromEthis Communications, Inc.

“It is important to acknowledge that aqueous-deficient and evaporative DRY EYE DISEASEare not mutually exclusive. They can and dooccur in combination; therefore, they canproduce complex hybrid states.” — PROFBRON

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PROF SCHAUMBERG: A pure aqueous-deficient dry eye diseasestate with no evaporative component is probably uncommon.Conversely, meibomian gland dysfunction is very common, withperhaps 45% to 60% or more of people with DED having some suchabnormality.31,32 Most people likely experience a mixed mechanism,at least, in the long term. Dry eye disease may start with lacrimalgland disease and aqueous deficiency, but certainly, in Sjögrenpatients, there is MGD as well.

PROFBRON: As you say, it has been demonstrated in the literaturethat both of these disorders occur in patients with severe Sjögrensyndrome. In my opinion, however, there is less evidence for this inthe population as a whole. However, there is a move towardemphasizing the contribution of evaporative dry eye.

DIAGNOSISOFDRYEYEDISEASEPROF DONNENFELD: To diagnose dry eye disease, the clinicianneeds to start with symptoms of DED and the patient’s history.

Aqueous-deficient DED, in general, tends to worsen throughoutthe day as the aqueous component of the tears evaporates from theocular surface, and causes a general irritation and foreign bodysensations. Patients who have rheumatoid arthritis or who are takingcertain medications, as discussed earlier, are most likely to haveaqueous-deficient DED.

Evaporative DED tends to be worse in the morning, perhapsbecause of the abnormal lipids that have accumulated overnight,causing patients to experience burning. Patients with evaporative DEDoften have systemic skin disorders, such as acne vulgaris or rosacea.

On clinical examination, diagnosis can sometimes be made veryeasily by looking at the lids, because of telangiectasia, erythema,meibomian gland dysfunction with meibomian oil turbidity, andoccluded meibomian glands. Aqueous-deficient DED tends to have aless plentiful tear film. Schirmer scores may be lower than normaland there tends to be interpalpebral staining of the conjunctiva andcornea with lissamine green or fluorescein in the classical DEDdistribution.

Patients who have evaporative DED often have clearly definedMGD, meibomian foam, and an increase in staphylococcalcommensals on the lid margin. In addition to interpalpebral staining,some inferior conjunctival staining may be present and is consistentwith the presence of pathogenic staphylococci.

PROF BRON: If a symptomatic patient has a normal Schirmerscore, extensive MGD, and ocular surface staining, he or she can bereasonably diagnosed as having evaporative dry eye disease. It iswhen the Schirmer score is low and there is evidence of decreasedaqueous production that clinicians must make a value judgment asto whether aqueous-deficient and evaporative dry eye are bothpresent. As we have said, lacrimal deficiency and MGD can occurtogether in the same patient and result in a combined mechanismfor dry eye. However, it is also possible that this hybrid state couldcome about in another way. For instance, if we suppose that there isan evaporative dry eye due to MGD, then, as the severity of thecondition increases and the corneal surface is damaged, we canpostulate that a loss of sensory drive to the lacrimal gland couldreduce the compensatory lacrimal flow and result in an additional,functional aqueous deficiency.33

ETIOLOGIESOFDRYEYEDISEASEPROF DONNENFELD: Aqueous-deficient dry eye disease beginswith abnormalities of the lacrimal gland, which not only reduce theamount of aqueous, but also reduce the associated defense proteinsfound in the tear film. Inflammatory events in the gland can havethis result. Furthermore, low androgen levels can negativelyinfluence aqueous production. Meibomian gland dysfunction, whichis also associated with androgen dysfunction, is responsible forevaporative DED. As discussed earlier, medications such as diureticsand topical ocular medications with preservatives, particularlyartificial tears, can play a very significant role.

PROFBAUDOUIN: Preservatives can be detrimental to the ocularsurface. Benzalkonium chloride (BAK) may cause or aggravate dryeye disease. Short exposure to BAK has been shown to decreasegoblet cell density in humans.34 Long-term exposure to antiglaucomadrugs with preservatives also cause decreased goblet cell density.35Many experimental reports have been published showing the overalltoxicity of BAK to the ocular surface, even at low concentrations,and possible direct proinflammatory properties have beensuggested.36 In addition, as a surface-active detergent, BAK alsodestabilizes the lipid layer of the tear film, increasing evaporativeloss. The result of both mechanisms, namely the mucus and lipidlayer alterations, is a globally impaired tear film with tear instabilityand excessive evaporation.

PROF DONNENFELD: An important etiology for dry eye diseasethat is overlooked often is ocular surgery. A meta-analysis studyexamining the incidence of DED after LASIK (laser-assisted in situkeratomileusis) surgery, found that 20% of LASIK patientsexperienced dryness symptoms that were significantly worse thanthose experienced preoperatively. This indicates that DED symptomsare common complications of ocular surgery.37

PROF BRON: Prof Donnenfeld, does that worsen the risk ofregression after surgery?

PROF DONNENFELD: Yes, there are articles by several authors,including Marguerite McDonald38 and John Hovanesian,39 that haveshown that dry eye disease can affect postoperative results.De Paiva40 and Ursea41 showed that DED was associated withregression, suboptimal outcomes, and low patient satisfaction. Theetiology of this relationship stems from the negative effect of surgicaltrauma, specifically because of the damage to the corneal nervescaused by the incision and photoablation. Damage to these nerves,which are responsible for innervating the cornea, can disrupt thenormal feedback loop from the cornea, which normally drives lacrimaltear production. Recent evidence suggests that topical cyclosporinemay reduce the risk of DED after intraocular lens implantation andLASIK by having a direct effect on corneal nerve repair.42,43

PROFBRON: Prof Donnenfeld, do you think neuropathic input canalso cause pain independent of a dry eye disease mechanism?

PROF DONNENFELD: Yes, I do. In my opinion, it is an etiologythat is sometimes overlooked. Some patients have significantneurogenic pain following surgery without associated cornealstaining. Wilson and colleagues have made a very strong case thatwhat is classified as dry eye disease following LASIK may actually bea neurological disease, which they have termed LASIK-inducedneuroepitheliopathy, or LINE.43,44

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PROF BARABINO: Dry eye disease is also a complication ofcataract surgery. A study presented at the European Association forVision and Eye Research (EVER) showed significant, prolonged tearinstability after cataract surgery. Changes in tear film breakup timewere evident 1 month after surgery and changes in the lipid part ofthe tear film were still seen 2 months after surgery.45

PROF BRON: Do you think this patient population was already atrisk for dry eye disease and was tipped into it by destabilization ofthe ocular surface?

PROF BARABINO: Yes, I do. With these patients, the surgery goesperfectly well and they have excellent postoperative vision, but theycomplain of burning and foreign body sensation. The possible causesfor these postoperative symptomswere attributed to tear film instability.

PROF DONNENFELD: Cyclosporine has been shown tosignificantly improve the quality of vision after cataract surgery.Limbal relaxing incisions probably caused the most significant dryeye disease of all other incisions.42

PROF GEERLING: Dry eye should be viewed as an expectedcomplication of any surgery that disturbs the ocular surface.Heimann and colleagues showed that approximately two-thirds ofpatients who underwent vitreoretinal surgery suffered from DEDsymptoms postoperatively.46

PROFASBELL: One way to think about dry eye disease and ocularsurgery is in terms of the DEWS classification of severity,1 with ascale ranging from 1 to 4. If a patient has a score of 1 preoperatively,he or she is going to have a score of 2 or 3 postoperatively.

PROF BRON: Clinicians generally treat patients based on theseverity of dry eye disease that was judged intuitively. But as you say,both the DEWS and the meibomian gland dysfunction workshopshave attempted to classify the severity of disease. Sullivan andcolleagues studied a large number of subjects, both DED and normalindividuals, looking at the typical tests for DED diagnosis—OcularSurface Disease Index (OSDI), osmolarity, tear breakup time,Schirmer test, corneal and conjunctival stain. The authors obtaineda consensus severity assessment of each of those tests and thennormalized the data, mapping those gradings to a single scale, toproduce a composite score for each patient.12

PROF SCHAUMBERG: Dr. Sullivan used a weighted average ofmultiple tests to arrive at an overall score. A difficulty with such anapproach is that some patients have very severe symptoms, butminimal ocular surface signs. Using this method, clinicians wouldprobably underestimate the severity of the symptoms.

Before we leave the topic of etiology, I would like to point outthat contact lenses can be another exacerbating factor for dry eyedisease. Patients may be fairly well compensated in terms of ocularsurface homeostasis without contact lenses, but putting a contactlens on the eye disrupts the system enough to cause the DEDsymptoms. More than 50% of people who discontinue contact lensesdo so because of DED symptoms.47

PREVALENCEOFDRYEYEDISEASEPROFSCHAUMBERG: There are a large number of studies of theprevalence of dry eye disease across the globe, including the UnitedStates,27,48 Australia,49 Canada,50 Europe,51 and Asia.52 We havelearned from the prevalence studies that DED symptoms are verycommon, with DED ranging from 3% to 15% in patients aged 50years and older, which is the age of populations examined in most ofthese studies.51 The study in Spain reported a prevalence of 11% or12%. Asian studies generally show a higher prevalence,approximately double that reported in either the United States,Australia, or Europe.

PROF BRON: How does the prevalence of meibomian glanddysfunction relate to the prevalence of dry eye disease?

PROF SCHAUMBERG: There have been fewer studies looking atmeibomian gland dysfunction, but in my opinion, the trends aresimilar, with higher levels of MGD in the Asian populations comparedwith the Caucasian populations.

EMERGINGDIAGNOSTICTECHNIQUESPROF ASBELL: Minimally invasive diagnostic methods are thefuture of dry eye disease diagnosis. First, we need to be able todiagnose DED, differentiate it from other types of external diseases,and then to classify the DED subtypes. Second, we would like tobetter classify disease severity because the current severity gradingis difficult to put into practice. Third, we need tests that can quantifychanges on the ocular surface and tear film that result fromtreatment.

Some of the interesting new diagnostic areas include theevaluation of tear osmolarity,12 examining tears with opticalcoherence tomography (OCT), measuring tear height and tearvolume, and looking at the contents of the tears both by proteomicsand by measuring inflammatory cytokines.

Another exciting possibility is the use of impression cytologycombined with flow cytometry, to examine specific inflammatorybiomarkers. This approach was pioneered by Prof Baudouin.8

I think the next diagnostic area that has gained momentum latelyis the improved evaluation of the eyelids and meibomian glanddysfunction and, specifically, the recognition of how lid disease andmeibum alterations contribute to changes in the tear film and theocular surface. There is certainly a high level of interest amongophthalmologists in obtaining better biomarkers and more objective

“Dry eye should be viewed as an expectedcomplication of any surgery that disturbs theocular surface.” — PROFGEERLING “We have learned from the prevalence studies that

DRY EYE DISEASE symptoms are very common,with DED ranging from 3% to 15% in patientsaged 50 years and older.” — PROF SCHAUMBERG

“Minimally invasive diagnostic methods are thefuture of dry eye disease diagnosis.”

— PROF ASBELL

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metrics to help in the diagnosis of DED. Currently, scientists fromEurope and Singapore are collaborating to explore such techniquesin other human disease models. Their work may lead tobreakthroughs and a better understanding of DED.

PROFBRON: I was especially interested in the study by Beuermanand colleagues in which it was found that the level of 2 tear proteins,calgranulin A and B, correlated with the severity of meibomian glanddysfunction and a range of ocular surface symptoms.53

PROF BARABINO: With respect to the use of lissamine green orrose bengal as a diagnostic tool for dry eye disease, it has to bepointed out that both vital stains are available in Europe, but theiruse is limited to some ocular surface specialists. In fact, there isevidence that ophthalmologists in Italy use lissamine green less than10% of the time. Lissamine green is very important because, as doesrose bengal, it can quantify both corneal and conjunctival damage,but without the discomfort induced by rose bengal’s intrinsic toxicityor the phototoxicity induced by ultra-violet exposure.

PROF BRON: This is an important point because lissamine greenis hardly used in the United Kingdom, and rose bengal is unavailable.In the past, clinicians used rose bengal routinely, but when it waswithdrawn from the market and lissamine green became available,clinicians did not switch to lissamine green; and so, a real diagnosticopportunity has been lost. It seems that residents in training hesitatebefore using lissamine green because it is unfamiliar to them orbecause it might stain the lids if not used properly. As a result, theseclinicians are failing to examine the ocular surface directly.

PROFDONNENFELD: A study by Sullivan and colleagues on tearosmolarity and dry eye disease severity showed that the secondhighest correlation with DED severity was conjunctival staining,followed by corneal staining.12 Therefore, if a tear osmolarity sensoris not available, in my opinion, conjunctival staining is the secondmost useful way to diagnose DED.

PROFASBELL: The other point to emphasize is that when examiningthe eye, clinicians often ignore the lid, the meibomian gland orifices,and the quality of expressed meibum, thereby missing an importantpart of the examination in patients with ocular surface disease.

MANAGEMENTOFDRYEYEDISEASEPROF GEERLING: There is extensive variation across nations inthe management of dry eye disease, in no small part due todifferences in the availability of certain drugs. The majority ofpatients, regardless of disease subtype, are treated first withlubricants because these are widely available.

There is a huge need in the early stages, however, for additionalnonpharmacologic management. This includes instructing patientsabout etiologies; use of lid hygiene and lid warming (eg, inmeibomian gland dysfunction-associated dry eye); and avoidance ofrisk factors or exacerbating conditions such as certain medications,

low-humidity environments, and specific head positions duringcomputer use.54 However, these nonpharmacologic treatments havepoor compliance among patients. Other measures, such as anti-inflammatory medication, are generally more accepted by patients.

Surgical measures, such as punctal plugging in aqueous-deficientdry eye and systemic tetracycline derivatives, which are thought tobe effective in patients with MGD, are limited to the severe form ofthe disease. These treatments, even if available, are frequentlyunderused.

PROFBRON: Some experts have suggested using a short course oftopical steroids prior to inserting punctal plugs in patients withmoderate or severe aqueous-deficient dry eye disease.55 Therationale is that punctal plugs may not only conserve the tears, butmay also conserve inflammatory mediators. Thus, the steroids canbe useful initially to damp down the inflammation, and possiblyincrease the effectiveness of the plugs.

Prof Asbell, do you use a severity-specific protocol for managementof DED?

PROF ASBELL: I often direct my treatment according to thepatient's symptoms because that is the key reason for the patientseeking treatment. If the patient is satisfied with what is being done,I continue using that treatment. If the patient is not satisfied, Iexplore other treatments.

With respect to the various artificial tear preparations, I look atthe differences among them. I do not think all of them work well foreverybody. For mild disease, I generally start out with a multiusebottle, since it is cost-effective and convenient. I tend to choosepreparations that are available without BAK because that preservativeis particularly toxic to the ocular surface. If the response is notsatisfactory, I move to unit-dose artificial tears. I reserve topicalcyclosporine for those patients who have severe findings.

Recently, I have also been prescribing a low-dose nonpreservedsteroid (dexamethasone, 0.01%), which is available in the UnitedStates only through a compounding pharmacy—a pharmacy that willprepare, on request, specific eye drop formulations that are notcommercially available. This very-low-dose steroid medication doesnot appear to induce elevated intraocular pressure, a side effect weoften find with higher-dose steroids. Yet, it can be effective for manypatients with inflammatory ocular surface disease.

Another treatment option approved by the US Food and DrugAdministration is a hydroxypropyl cellulose ophthalmic insert, whichis a tear pellet that is placed in the lower lid cul-de-sac. The pelletmelts with the patient's own tears, providing lubrication over aperiod of time. These lubricants can be a little thick and sometimesinterfere with vision. Therefore, I suggest placing the pellet at nightto provide lubrication overnight and possibly even provide someearly morning comfort.

PROFBAUDOUIN:We also have the tear pellets in France. MainlySjögren syndrome patients, who instill many, many eye drops eachday, use these pellets.

PROFBRON: When do you offer conserving spectacles?

PROF ASBELL: The idea of using conserving spectacles todecrease evaporation is appealing. However, these spectacles arenot easy to get for my patients in New York.

“There is extensive variation across nations inthe management of dry eye disease, in no smallpart due to differences in the availability ofcertain drugs.” — PROFGEERLING

PROF BRON: In the United Kingdom, one can get commercialconserving spectacles, or the optometry departments will make them.They are very helpful if the patient can accept them cosmetically.

PROF BAUDOUIN: Conserving spectacles are not available inFrance. With respect to management, ophthalmologists areconvinced that preservatives are toxic for the ocular surface,especially in dry eye disease, so they worry about preservatives inartificial tears. Ocular surface specialists will frequently use anti-inflammatory eye drops. Additionally, in France, there ispreservative-free steroid and topical cyclosporine. Hospitalpharmacists can prepare cyclosporine, or commercial cyclosporinecan be imported with a specific authorization. We also use systemicdoxycycline, which is particularly prescribed in meibomian glanddysfunction and rosacea patients. In such patients, topicalazithromycin, recently introduced in France, is under investigation.

PROF BRON: As mentioned earlier, commercial topicalcyclosporine is not available in the European Union, but people doformulate it for treatment of dry eye disease. Erythromycin andazithromycin have been of interest as systemic or topical treatmentsof meibomian gland dysfunction in younger patients.

PROF GEERLING: Metronidazole topical gel, 0.75%, is availablefor topical treatment of inflammatory changes associated withrosacea in Germany, the United Kingdom, and the United States. Ithas been used successfully for evaporative dry eye disease,meibomian gland dysfunction, and blepharitis.56 We often initiatetreatments simultaneously simply because patients have beensuffering for so long and want rapid relief. Punctal plugging iseffective in patients with a zero Schirmer score. I choose not to usea topical steroid unless there is obvious inflammation, because myexpectation is that the frequent instillation of artificial tears maydilute any inflammatory markers on the surface. In addition, patientsprefer not to apply too many eye drops.

PROF DONNENFELD: In our practice, we are strong believers ofthe use of combination immunomodulation. By adding acorticosteroid to cyclosporine, you obtain a more rapid effect andalleviate the burning and irritation that is sometimes associated withcyclosporine therapy.57 However, we recognize the possibility of long-term side effects with topical corticosteroids and limit their use to 1month, during acute exacerbations of dry eye disease. With respectto tear preparations, we start with 1, which is transiently preserved,that is to say, a preservative that inactivates on exposure to light orto the tear film. We also believe that patients who have hyperosmolartear films benefit from a hypo-osmotic tear formulation.

To bring up a new topic, we also advocate oral nutritionalsupplements. Wojtowicz and colleagues reported a dramaticimprovement in Schirmer scores in patients taking omega-3supplementation.58

PROF ASBELL: There has been great interest by both cliniciansand patients in the use of nutritional supplements to treat dry eyedisease. Most suggest an increase in dietary intake of omega-3 fattyacids to reduce inflammation associated with DED. Though there issome experimental data supporting the use of essential fatty acidsfor heart disease and rheumatoid arthritis, the evidence for treatmentof DED is limited at this time, and even contradictory.59

PROF BARABINO: Inflammation certainly plays a pivotal role indry eye disease pathogenesis and, therefore, we need to focussimultaneously on tear replacement and anti-inflammatory therapy.I do not think we need to eliminate inflammation, but we need tomodulate it by using soft steroids or using other commercialcorticosteroids in diluted formulations or at reduced dosage. Weneed to be dynamic in our approach and adjust anti-inflammatorytherapy according to changes in ocular surface conditions with time.For example, in some of my patients I control inflammation by usingsteroids twice a week, which has a positive effect on ocular surfaceinflammation and may help tear substitutes to adhere to ocularsurface epithelia. At the same time, at this dosage, the well-knownnegative effects of steroids can be limited. Most Italianophthalmologists do not feel comfortable prescribing chroniccorticosteroid therapy, but if it is used cautiously, it may bebeneficial.60,61 Regarding the use of systemic omega-3 fatty acids, Itotally agree with Prof Donnenfeld, that in most cases they are veryhelpful in improving patients’ symptoms, as my group haddemonstrated some years ago.62

PROF BRON: Steroids are potentially risky in dry eye diseasebecause the ocular surface is already damaged, possibly enhancingtheir entry into the eye. Newer steroidal agents, such as soft steroidsand glucocorticoid receptor agonists, are becoming commerciallyavailable. They are interesting agents because of their favorablesafety profiles. However, if patients are prescribed steroid therapy,how can a clinician make sure that patients do not use themindiscriminately?

PROFGEERLING: I prescribe only 1 bottle, which ensures that thepatient runs out of supply within a month. Furthermore, I reexamineand reevaluate my patients at 6 weeks, including assessment ofintraocular pressure.

There are many other modalities for the off-label medicaltreatment of dry eye disease, including systemic tetracyclines,acetylcysteine, and even retinoic acid for secondary surface changessuch as keratinisation, but some of these agents are difficult toobtain. Another medication that is even more challenging to obtainis a form of nutrient tear substitute. We produce these autologousserum drops to add nutrients to the tear film. Patients often benefitimmensely, but supplying this blood-derived medication on apermanent basis requires the distributor to have a specific license forthe product. Currently, only 4 universities in Germany have thislicense, so it is nearly always unavailable unless a patient happens tolive near one of these institutions. I believe that this is the samesituation throughout the continent.

“In our practice, we are strong believersof the use of combination immunomodulation.By adding a corticosteroid to cyclosporine, youobtain a more rapid effect and alleviate theburning and irritation that is sometimesassociated with cyclosporine therapy.”

— PROFDONNENFELD

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PROF BAUDOUIN: I treat severe dry eye disease the same way,including the occasional use of autologous serum.

PROFBARABINO:We also use autologous serum in very specificcases in Italy, but in my opinion, in the more severe cases, the use ofa combination of steroids and cyclosporine is the best approach.

PROF BRON: Autologous serum is also used in the UnitedKingdom, to a limited extent.

PHYSICIANS’ UNDERSTANDINGOFDRYEYEDISEASEPROFGEERLING: General physicians misunderstand the conceptof dry eye disease, and think that it is primarily an aqueousdeficiency.

PROFBRON:Also, some physicians trivialize dry eye disease. Evenophthalmologists often do not always give it enough weight, perhapsbecause detailed information about DED has not been emphasizedin our education and early practice.63

PROFGEERLING: Education is needed to emphasize the effect ofthe severe form of the disease on individual patients. Buchholz andcolleagues showed that the quality of life of patients with severe dryeye disease was similar to that for patients with severe angina, renaldialysis, or disabling hip fracture.64

PROFSCHAUMBERG: In the United States, multiple events tookplace to convince physicians of the seriousness of dry eye disease.First, large epidemiological studies demonstrated that DED is indeedvery prevalent. Additionally, awareness of the inflammatorymechanism has helped patients and clinicians to understand DED asa disease and not just a normal part of aging.

With only one prevalence study conducted and published in Europe,it might be helpful if there were some additional European data thatcould be covered in the popular press and used to educate patients.

PROF BRON: I think that is an important message. I do not reallyknow why Europe is lagging behind in this area. It may be related tolack of funding for such studies.

PROFBAUDOUIN: I have organized many meetings in France. Allthe meetings that dealt with ocular surface disease, dry eye disease,or allergic disease were well attended because ophthalmologistswant to better understand these conditions so they can better treattheir patients. There is undoubtedly a great desire within theophthalmological community to improve their knowledge andefficiency in the management of ocular surface diseases.

PROF BARABINO: Ophthalmologists are increasingly interestedin the treatment of dry eye disease. This year we have launched anonline course on ocular surface disease with the intention ofreaching more than 1000 ophthalmologists in Italy each year. Westrongly believe that education is the most important way to improveour knowledge of DED treatment. We are hoping that in the future,our course can be translated to make it available to other Europeancountries and to encourage the participation of other Europeanocular surface experts. We are also producing a document for theItalian government to increase the understanding of DED as animportant chronic disease. We could possibly collaborate with othercountries to do this throughout Europe.

PROFBRON: In summary, dry eye disease is prevalent all over theworld and has many causes. It adversely affects ocular comfort,vision, and quality of life. The DEWS report broadened the definitionof DED and confirmed its major forms as aqueous-deficient andevaporative dry eye. The recently published meibomian glanddysfunction workshop report emphasized the importance ofevaporative dry eye, of which the most common cause is MGD.

The presence of MGD is sometimes overlooked, but it can bereadily diagnosed by routine lid inspection and meibum expression.Our discussion highlighted the causal role of tear hyperosmolarity inDED and the importance of ocular surface inflammation.Inflammation is an important therapeutic target. There is a need toidentify inflammatory biomarkers to aid diagnosis, and to monitorseverity and the response to treatment. One of the consequences ofsurface inflammation is epithelial damage and increased tear filminstability, causing a vicious circle that amplifies and perpetuates thedisease. An avoidable contributor to this vicious circle is the frequentuse of preserved eye drops.

Many other aspects of dry eye disease were discussed, morethan can be summarized here, but an important conclusionof the roundtable was that ophthalmologists can do a betterjob to promote a clearer understanding of dry eye disease,among themselves, other physicians, and members of thepublic. It is our hope that this report will provide someimpetus to this intent.

“We strongly believe that education is the mostimportant way to improve our knowledge of dryeye disease treatment.” — PROFBARABINO

financial disclosuresThe authors have made the following disclosures: Prof Asbell received an honorarium fromPfizer for participation in this project; she has other relevant financial relationships asfollows: consultancy–Addition, Alcon, Aton Pharma, Bausch + Lomb, Candeo Clinical/Science Communications, Inspire, Johnson & Johnson, Merck, Otsuka, Pfizer, Santen,Vindico Medical Education, Vistakon; grant/research funding to institution– Alcon, AtonPharma, Bausch + Lomb, Inspire, Martin and Toni Sosnoff New Works Fund, NationalInstitutes of Health, Pfizer, Research to Prevent Blindness. Prof Barabino received anhonorarium from Pfizer for participation in this project; he has no other disclosures tomake. Prof Baudouin received an honorarium from Pfizer for participation in this project;he has other relevant financial relationships as follows: consultancy–Alcon, Allergan, MSD,Pfizer, Santen Pharmaceutical. Prof Bron received an honorarium from Pfizer forparticipation in this project; he has other relevant financial relationships as follows:consultancy–Acucela, Actelion Pharmaceuticals, Alcon, Alto Pharma, AOPharma, Bausch +Lomb, Clinact, F2G Discovery, Novagali Pharma, Novaliq, Otsuka, Pfizer, Takeda,OcuSense/TearLab; stock– OcuSense/TearLab. Prof Donnenfeld received an honorariumfrom Pfizer for participation in this project; he has other relevant financial relationships asfollows: consultancy–Alcon, Allergan, Bausch + Lomb, Inspire/Merck, Pfizer. Prof Geerlingreceived an honorarium from Pfizer for participation in this project; he has other relevant

financial relationships as follows: board membership–Alcon, Allergan, Bausch + Lomb,Pfizer; expert testimony–Santen, Voisin Consult; speakers bureau– Bausch + Lomb;manuscript preparation– Alcon. Prof Schaumberg received an honorarium from Pfizer forparticipation in this project; she has other relevant financial relationships as follows: boardmembership–SARcode, Mimetogen; consultancy–Alcon, Allergan, Bausch + Lomb, CelticPharma, Eleven Biotherapeutics, Inspire/Merck; grants to institution–Pfizer; developmentof educational presentations–Allergan; stock–Tearlab, Mimetogen.

correspondenceAnthony J Bron, FRCOphth, c/o MedEdicus, 73 Redding Road, PO Box 839, Georgetown,CT 06829, USA. email: ctornallyay@mededicus.com.

grant supportThis medical education activity is supported through an educational grant from Pfizer Inc.

The views and opinions expressed in this educational activity are those of the authorsand do not necessarily represent the views of MedEdicus LLC, Pfizer Inc, or EuroTimes.Please refer to the official prescribing information for each product for discussion ofapproved indications, contraindications, and warnings.

©2011 MedEdicus LLC. All rights reserved.

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