cme supplement to: current opinion in ophthalmology professionals/continuing...2003/07/17 · carl...

Volume 28 • Supplement 1 • January 2017 www.co-ophthalmology.com

IMPA

CT FA

CTOR

*

2.968

Current Opinion inCurrent Opinion in

OphthalmologyOphthalmology

CME Supplement to:

Dysfunctional Tear Syndrome: Dry Eye Disease and Associated Tear Film Disorders - New Strategies for

Diagnosis and Treatment

Co-chairs: Mark S. Milner, MD, Kenneth A. Beckman, MD, and Jodi I. Luchs, MD, on Behalf of the Cornea, External Disease, and Refractive Society (CEDARS) Dysfunctional Tear Syndrome Panel

Jointly provided by New York Eye and Ear Infi rmary of Mount Sinai and MedEdicus LLC

Original Release: January 16, 2017Last Review: November 12, 2016Expiration: January 31, 2018

This continuing medical education activity is supported through unrestricted educational grants from Alcon ; Allergan, Inc; Bausch & Lomb Incorporated; Blythe; Oasis; Rapid Pathogen Screening, Inc; Santen Pharmaceutical Co, Ltd; Shire; TearLab Corporation; and TearScience.

EDITORIAL BOARDMark S Blumenkranz

Stanford University School of Medicine, USA

Roy S ChuckMontefi ore Medical Center, USA

Thomas A CiullaIndiana University, USA

Borja F CorcosteguiInstitute de Microvvugia Ocular, Spain

Emmett T Cunningham JrCalifornia Pacifi c Medical Center and Stanford University School of Medicine, USA

David R GuyerNew York University of Medicine, USA

Edward A JaegerWills Eye Hospital, USA

Glenn J JaffeDuke University Eye Center, USA

Arthur SM LimGleneagles Hospital, Singapore

Maureen G MaguireScheie Eye Institute, USA

Timothy G MurrayBascom Palmer Eye Institute, USA

Carmen A Pullafi toUniversity of Southern California School of Medicine, USA

Christopher RapuanoWills Eye Hospital, USA

Carl D RegilloWills Eye Hospital, USA

Gisele A SoubraneClinique Ophthalmologique Universitaire, France

William S TasmanWills Eye Hospital, USA

Nicholas J VolpeNorthwestern University Feinberg School of Medicine, USA

George WilliamsBeaumont Eye Institute, USA

2017 CONTENTSJANUARYCataract surgery and lens implantation

Edited by Natalie A Afshari, University of California, San Diego, California, USA

MARCHGlaucoma

Edited by Donald L Budenz, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

MAYRetinal, vitreous and macular disorders

Edited by Brandon G Busbee, Tennessee Retina, Tennessee, USA and John W Kitchens, Retina Associates of Kentucky, Lexington, USA

Translational research Edited by Jason Hsu, Mid Atlantic Retina, USA and Sunir J Garg, Mid Atlantic Retina, USA

JULYRefractive surgery

Edited by Jimmy K Lee, Montefi ore Medical Centre, New York, USACorneal and external disorders

Edited by Shahzad I Mian, University of Michigan, USA

SEPTEMBEROcular genetics

Edited by Alex Levin, Wills Eye Hospital, Philadelphia, USAPediatrics and strabismus

Edited by J Mark Engel, University Children's Eye Center, New Jersey, USA

Oculoplastic and orbital surgeryEdited by Richard C Allen, University of Iowa Hospitals and Clinics, Iowa, USA

NOVEMBERNeuro-ophthalmology

Edited by Dean M Cestari, Massachusetts Eye and Ear Infi rmary, Harvard Medical School, Boston, USA

Ocular manifestations of systemic diseaseEdited by Russell W Read, University of Alabama at Birmingham, USA

Editor-in-Chief Allen C Ho, Wills Eye Institute and Thomas Jefferson University, Philadelphia, Pennsylvania, USA

Literature Scanners P. Shah, D. Heath, T. Leong, K.M. Nyunt

*2015 Journal Citation Reports® (Thomson Reuters, 2016)


OphthalmologyOphthalmology CURRENTOPINION

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OphthalmologyOphthalmology CURRENTOPINION

1 Dysfunctional tear syndrome: dry eye disease and associated tear fi lm disorders – new strategies for diagnosis and treatmentMark S. Milner, Kenneth A. Beckman, Jodi I. Luchs, Quentin B. Allen, Richard M. Awdeh, John Berdahl, Thomas S. Boland, Carlos Buznego, Joseph P. Gira, Damien F. Goldberg, David Goldman, Raj K. Goyal, Mitchell A. Jackson, James Katz, Terry Kim, Parag A. Majmudar, Ranjan P. Malhotra, Marguerite B. McDonald, Rajesh K. Rajpal, Tal Raviv, Sheri Rowen, Neda Shamie, Jonathan D. Solomon, Karl Stonecipher, Shachar Tauber, William Trattler,Keith A. Walter, George O. Waring IV, Robert J. Weinstock, William F. Wiley, and Elizabeth Yeu

TABLE OF CONTENT

Volume 28 • Supplement 1 • January 2017


OphthalmologyOphthalmology CURRENTOPINIONOpen access article is available online.

CME SUPPLEMENT

LEARNING METHOD AND MEDIUM

highest accreditation status awarded by the ACCME.

AMA CREDIT

This educational activity consists of a supplement and fifteen (15)study questions. The participant should, in order, read the learn-ing objectives contained at the beginning of this supplement,read the supplement, answer all questions in the post test, andcomplete the Activity Evaluation/Credit Request form. To receivecredit for this activity, please follow the instructions provided onthe post test and Activity Evaluation/Credit Request form. Thiseducational activity should take a maximum of 3.0 hours tocomplete.

CONTENT SOURCE

This continuing medical education (CME) activity captures con-tent from a series of meetings and web conferences conducted bythe Cornea, External Disease, and Refractive Society Dysfunc-tional Tear Syndrome Panel in 2014 and 2015.

ACTIVITY DESCRIPTION

The management of dysfunctional tear syndrome (DTS) hastraditionally followed established guidelines based on diseaseseverity. In recent years, however, there have been clinical advan-ces that might allow refinement of the management of DTS basedon a differential diagnosis of DTS subtypes. New diagnostic testsand treatments are now available to help inform decisions for DTSsubtypes. New diagnostic techniques can be applied to the differ-ential diagnosis of DTS in individual patients. Likewise, newtreatment modalities can be incorporated into managementplans to improve outcomes in patients with different DTS sub-types. The purpose of this activity is to update clinicians on newdevelopments in diagnosis, treatment for patients with DTS, andthe application of newer diagnostic tests and treatments forindividual patients with DTS.

TARGET AUDIENCE

This activity is intended for ophthalmologists and other eye careprofessionals.

LEARNING OBJECTIVES

Upon completion of this activity, learners will be better able to:

�

Cu

DO

10

Outline the potential roles of new diagnostic tests for DTS

�

Discuss recent developments in treatments for DTS

�
Apply available evidence on diagnostic techniques and
clinical assessment tools for the differential diagnosis ofDTS subtypes

�
Design management plans for patients using treatment modal-ities that address the underlying disease mechanisms ofDTS subtypes
ACCREDITATION STATEMENT

This activity has been planned and implemented in accordancewith the accreditation requirements and policies of the Accred-itation Council for Continuing Medical Education (ACCME)through the joint providership of New York Eye and EarInfirmary of Mount Sinai and MedEdicus LLC. TheNew York Eye and Ear Infirmary of Mount Sinai isaccredited by the ACCME to provide continuing medicaleducation for physicians.

rr Opin Ophthalmol 2017, 28 (Suppl 1):1–47

I:10.1097/ICU.0000000000000355

40-8738 Copyright � 2017 MedEdicus LLC. All rights reserved.

In July 2013, the Accreditation Council for Continu-ing Medical Education (ACCME) awarded New YorkEye and Ear Infirmary of Mount Sinai ‘‘Accreditationwith Commendation,’’ for six years as a provider ofcontinuing medical education for physicians, the

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This continuing medical education activity is supported throughunrestricted educational grants from Alcon; Allergan; Bausch &Lomb Incorporated; Blythe; Oasis; Rapid Pathogen Screening, Inc;Santen Pharmaceutical Co, Ltd; Shire; TearLab Corporation; andTearScience.

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It is the policy of New York Eye and Ear Infirmary of MountSinai that the faculty and anyone in a position to control activitycontent disclose any real or apparent conflicts of interest relating tothe topics of this educational activity, and also disclose discussionsof unlabeled/unapproved uses of drugs or devices during theirpresentation(s). New York Eye and Ear Infirmary of MountSinai has established policies in place that will identify and resolveall conflicts of interest prior to this educational activity.

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The contributing physicians listed at the end of this monographattested to the following:

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that the relationships/affiliations noted will not bias or oth-erwise influence their involvement in this activity;
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that practice recommendations given relevant to the compa-nies with whom they have relationships/affiliations will besupported by the best available evidence or, absent evidence,will be consistentwith generallyacceptedmedicalpractice; and
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Full disclosure of faculty/planners and their commercialrelationships, if any, can be found at the end of the manuscriptbefore the references.

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New Strategies for Diagnosis and Treatment of DTS

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CME SUPPLEMENT

CURRENTOPINION Dysfunctional tear syndrome: dry eye disease andassociated tear film disorders – new strategiesfor diagnosis and treatment

aYale University School of Medicine, NedComprehensive Eye Care of Central OYork, gFlorida Vision Institute, Jupiter, hBiVance Thompson Vision, Sioux Falls, SlOphthalmologyConsultants, St. Louis, MBeach Gardens, Florida, pRush UniversLake Villa, tMidwest Center for Sight, DeIllinois, wWashington University DepartmYork, NewYork, yTulaneUniversity Schoofor Ocular Surface Excellence of NewMedical Center, Washington, DC, ccNEyeCenters of Newport Beach, NewporggKeck School ofMedicine, University ofLaser Eye Centers, Greensboro, NorthllStorm Eye Institute and Magill Vision CnnUniversity of South Florida, Tampa, oo

Brecksville, Ohio, and qqEastern Virgini

Correspondence to Mark S. Milner, MD248 6365; fax: +1 203 230 1520; e-�Mark S. Milner, Kenneth A. Beckman,

This is an open access article distributereproduction in any medium, providedDOI:10.1097/01.icu.0000512373.817

1040-8738 Copyright � 2017 MedE

a,b,� c,d,� e,f,�
Mark S. Milner , Kenneth A. Beckman , Jodi I. Luchs ,Quentin B. Alleng, Richard M. Awdehh, John Berdahli, Thomas S. Bolandj,k,Carlos Buznegoh, Joseph P. Giral, Damien F. Goldbergm,n, David Goldmano,Raj K. Goyalp,q, Mitchell A. Jacksonr,s, James Katzt, Terry Kimu,Parag A. Majmudarp,v, Ranjan P. Malhotraw, Marguerite B. McDonaldx,y,z,aa,Rajesh K. Rajpalbb, Tal Ravivcc, Sheri Rowendd,ee, Neda Shamieff,gg,Jonathan D. Solomonhh, Karl Stonecipher ii, Shachar Tauberjj,William Trattlerh, Keith A. Walterkk, George O. Waring IVll,mm,Robert J. Weinstocknn,oo, William F. Wileypp, and Elizabeth Yeuqq
Dysfunctional tear syndrome (DTS) is a common and complex condition affecting the ocular surface. Thehealth and normal functioning of the ocular surface is dependent on a stable and sufficient tear film.Clinician awareness of conditions affecting the ocular surface has increased in recent years because ofexpanded research and the publication of diagnosis and treatment guidelines pertaining to disordersresulting in DTS, including the Delphi panel treatment recommendations for DTS (2006), theInternational Dry Eye Workshop (DEWS) (2007), the Meibomian Gland Dysfunction (MGD) Workshop(2011), and the updated Preferred Practice Pattern guidelines from the American Academy ofOphthalmology pertaining to dry eye and blepharitis (2013). Since the publication of the existingguidelines, new diagnostic techniques and treatment options that provide an opportunity for bettermanagement of patients have become available. Clinicians are now able to access a wealth ofinformation that can help them obtain a differential diagnosis and treatment approach for patientspresenting with DTS. This review provides a practical and directed approach to the diagnosis andtreatment of patients with DTS, emphasizing treatment that is tailored to the specific disease subtype aswell as the severity of the condition.

w Haven, bThe Eye Center of Southern Connecticut, Hamden, Connecticut, cOhio State University, Columbus,hio,Westerville, Ohio, eHofstra Northwell School of Medicine, Hempstead, fSouth Shore Eye Care,Wantagh, Newascom Palmer Eye Institute, Florida International University, and Center for Excellence in Eye Care, Miami, Florida,outh Dakota, jNortheastern Eye Institute, Scranton, kCommonwealth Medical College, Scranton, Pennsylvania,issouri, mJules Stein Eye Institute, Los Angeles, nWolstan &Goldberg Eye Associates,Torrance, California, oPalm

ity Medical Center, Chicago, qChicago Eye Specialists, rUniversity of Chicago Hospitals, Chicago, sJacksoneye,s Plaines, Illinois, uDuke EyeCenter, Durham, North Carolina, vChicagoCorneaConsultants, Ltd, Hoffman Estates,ent of Ophthalmology and Ophthalmology Associates, St. Louis, Missouri, xNYU Langone Medical Center, Newl ofMedicine, NewOrleans, Louisiana, zOphthalmicConsultants of Long Island, Lynbrook, NewYork, aaTheCenterJersey, Woodland Park, New Jersey, bbGeorgetown University Medical Center, George Washington Universityew York Eye and Ear Infirmary of Mount Sinai and Eye Center of New York, New York, New York, ddNVisiont Beach, California, eeUniversity of Maryland, Baltimore, Maryland, ffAdvanced Vision Care, Century City, California,SouthernCalifornia, Los Angeles, hhBowie Vision Institute, Bowie, Maryland, iiUniversity of NorthCarolina and TLCCarolina, jjMercy Eye Specialists, Springfield, Missouri, kkWake Forest University,Winston-Salem, North Carolina,enter, Medical University of South Carolina, Charleston, mmClemson University, Mt. Pleasant, South Carolina,The Eye Institute of West Florida, Largo, Florida, ppCleveland Eye Clinic, Clear Choice Custom LASIK Center,a Medical School and Virginia Eye Consultants, Norfolk, Virginia, USA

, FACS,The Eye Center of Southern Connecticut, 2880Old Dixwell Ave, Hamden, CT 06518, USA. Tel: +1 203mail: [email protected]

and Jodi I. Luchs are co-chairs.

d under the Creative Commons Attribution License 4.0 (CCBY),which permits unrestricted use, distribution, andthe original work is properly cited.49.b7

dicus LLC. All rights reserved. www.co-ophthalmology.com

mailto:[email protected]


INTRODUCTION

Management of dysfunctional tear syndrome [1](DTS) is often a source of frustration for eye careprofessionals and patients. Several factors createchallenges in the diagnosis and management ofDTS. These include the lack of correlation betweensigns and symptoms [2,3], overlap among symp-toms of different DTS subtypes (Fig. 1) [2], complexetiology, poorly understood pathophysiology ofDTS-associated conditions, historically limitedrange of diagnostic tests, limited number of US Foodand Drug Administration-approved treatmentoptions, and the potential progressive nature ofthe condition. Poor patient compliance withfollow-up visits also contributes significantly tothe difficulties encountered when treating patientswith DTS.

Clinician awareness of conditions affecting theocular surface has increased in recent years becauseof new clinical research and the publication of diag-nostic and treatment guidelines for disorders result-ing in DTS. These guidelines include the Delphi

Ble

ph

aritis/M

GD

(

Evap

orati

ve an

d None

vaporative)

Exposure-Rela

ted

DTS

Aqueous Deficiency

Goblet Cell Deficiency

Mucin Deficiency

OverlappingSymptoms of DTS:

Ocular DiscomfortDryness

Burning/StingingGrittiness/Foreign Body Sensation

PhotophobiaBlurred/Fluctuating Vision

FIGURE 1. Overlap of symptoms in dysfunctional tearsyndrome (DTS) subtypes. There is a substantial overlap inthe patient-reported symptoms of the types of DTS. Patientswith subtypes of aqueous deficiency, blepharitis/meibomiangland dysfunction (MGD) – evaporative and nonevaporative– goblet cell deficiency/mucin deficiency, and exposure-related forms of DTS, including exposure keratopathy, mayreport symptoms of ocular discomfort, dryness, burning/stinging, grittiness or a foreign body sensation,photophobia, and blurred/fluctuating vision. Clinicalevaluation with a battery of assessments and diagnostictechniques are needed for a differential diagnosis.

4 www.co-ophthalmology.com

panel treatment recommendations for DTS (2006)[1], the International Dry Eye WorkShop (DEWS)(2007) [4], the International Workshop on Meibo-mian Gland Dysfunction (MGD) (2011) [5], and theupdated Preferred Practice Pattern guidelines fromthe American Academy of Ophthalmology pertain-ing to dry eye and blepharitis (2013) [6,7]. Theseguidelines generally recommend treatment basedon the severity of the condition for the subtypesof DTS. New diagnostic methods and pharmacologictreatments that can be used to further informseverity-based decisions to help better manageDTS and associated masquerading conditions havesince become available.

To combine the latest evidence-basedapproaches for diagnosis and management ofDTS with existing guideline-based approaches,we convened a specialty panel with experts fromthe Cornea, External Disease, and RefractiveSociety (CEDARS), hereafter referred to as theDTS Panel, to provide a clinical approach to usingthe latest diagnostic tools and guidelines to directtreatment that is tailored to the specific diseasesubtype(s). The evidence for a comprehensiverange of diagnostic methods, including recentlydeveloped techniques, and a comprehensivereview of established and new treatment modal-ities for managing DTS and its subtypes is reviewedherein. Case studies are included to demonstratehow the new approaches can be applied to specificclinical scenarios.

DIAGNOSIS-BASED INDIVIDUALIZEDTREATMENT APPROACH

The primary goal of the DTS Panel was to provide anapproach for improved outcomes in the treatmentof patients with DTS through differential diagnosisand directed treatment. Toward this end, we startedby defining DTS as a disorder of the tear film inquality and/or quantity, which is caused by a rangeof etiologies and involves abnormalities in one ormore components of the tear film, resulting in aconstellation of signs and symptoms affecting theocular surface. Any alteration in the quantity and/orquality of the tear film can result in DTS, a chroniccondition with multiple subtypes that include dryeye disease (DED) and associated tear film disorders.It has been shown that without proper diagnosisand management, DTS can result in profound degra-dation in quality of life and visual function-basedactivities (i.e., reading, driving, and computer use),the extent of which correlates with the severity ofthe condition [8]. Additionally, DTS can negativelyaffect surgical outcomes, such as those of cataractand refractive surgical procedures [9,10]. The


Dysfunctional Tear Syndrome Milner et al.

overlap and frequent comorbidity of DED andother conditions affecting the quantity or qualityof the tear film require careful examination ofpatients with DTS. Achieving a differential diagnosisand classification into specific disease-state sub-types allows a directed, individualized treatmentapproach.

Four main subtype classifications used by theDTS Panel approach are as follows: first, aqueousdeficiency; second, blepharitis/MGD (evaporativeand nonevaporative); third, goblet cell deficiency/mucin deficiency; and fourth, exposure-relatedDTS (Fig. 2). Following the clinical assessment andevaluation of a patient with DTS, each patient canbe classified into one or more of the disease-statesubtypes (the presence of multiple subtypes withina patient is common). Identifying and treatingother conditions or ‘DTS co-conspirators’ thatmay masquerade as or contribute to the signs andsymptoms of DTS are equally important.

This approach can be used with new and currentpatients reporting DTS symptoms (e.g., ocular dry-ness, discomfort, burning/stinging, and grittiness/foreign body sensation), patients reporting a fluctu-ation in vision or other nonspecific visual obscura-tions, referred patients with a history of dry eye orblepharitis, and patients who are being evaluated forlaser vision correction or cataract surgery, particu-larly those who may use multifocal or other pre-mium intraocular lenses.

Published information supporting the use ofnew diagnostic tests, recently approved therapies,

FIGURE 2. Flow chart of the DTS Panel clinical approach. A difapproach through examination of patients via a series of clinicaldysfunctional tear syndrome (DTS) are classified to one or more omeibomian gland dysfunction, goblet cell deficiency/mucin deficidetermined on the basis of the specific DTS subtype(s) identified,


and the potential role of novel or investigationaltherapies for patients with DTS was evaluated on atiered basis, ranging from level I through level III,depending on the rigor of the study design, withlevel I denoting evidence from a randomized con-trolled clinical trial (or equivalent), level II indicat-ing evidence from a controlled study that was notrandomized or involved a cohort-based study at oneor more centers, and level III indicating case studies,published meeting abstracts, or expert opinions.The DTS Panel compiled the published literature(i.e., reports of clinical trials, case reports, and meet-ing presentations) and presented the informationfor a review discussion at panel working meetings,which used voting to achieve a consensus. Thestudies cited were deemed the most relevant tothe individual topic.

Step 1: patient history

Table 1 summarizes the types of information thatshould be collected from a patient with potentialDTS. Recording a thorough medical and ocularhistory, including surgical history, provides theinitial context for evaluating the patient. Currentand past use of systemic and ocular medicationsis also important to capture at this stage. Past orcurrent therapy for conditions such as DED, blephar-itis, and any allergies, even treatments that wereregarded as ‘failures’, should be noted and queried.The timing, frequency, and severity of the chiefcomplaints or symptoms reported by the patient also

ferential diagnosis is achieved through the DTS Panel clinicalassessments and diagnostic techniques. Patients withf the four DTS subtypes: aqueous deficiency, blepharitis/ency, and exposure-related DTS. Treatment options arethus allowing for a directed treatment approach.

www.co-ophthalmology.com 5

Table 1. Patient history

mportant information to collect from patients with potentialTS

edical history

cular history, including surgical history and contact lens use

ystemic medications

cular medications

llergies

hief complaints or current symptoms

rior and current therapy for treatment of DTS

TS, dysfunctional tear syndrome.


ID

M

O

S

O

A

C

P

D

offer initial insight into the classification of the DTSsubtype(s).

Step 2: preliminary assessments

A technician or other member of the office staff mayperform the initial assessment of a patient withpotential DTS; however, in some practices, the clini-cian may conduct this part of the evaluation. Table 2lists the preliminary assessments recommended bythe authors at this point. Consistency in the con-duct of each of the assessments among staff mem-bers is critical because the results of the diagnostictests at the initial visit will serve as the baseline forcomparison with follow-up visits. Patients with DTSoften report blurred vision or intermittent distor-tion of vision [11]. As such, evaluation of thepatient’s visual acuity, with and without his orher current corrective glasses or lenses, and anassessment of any refraction necessary to achievebest-corrected visual acuity is an important portionof the preliminary assessment. In addition to assess-ment of visual acuity, patients should be queriedregarding the nature and frequency of any reports of

Table 2. Preliminary assessments performed by thetechnician or clinician

Clinical assessments and diagnostic measures used as part ofthe preliminary examination

Visual acuity (with and without glasses/lenses)

Refraction evaluation – best-corrected visual acuity

Administer a questionnaire (e.g., OSDI and SPEED)

Tear osmolaritya – must be conducted before disturbing the eye

Assess inflammatory markers present in the tear film (MMP-9)a

Schirmer test with and/or without anesthesia (clinician preference)

MMP-9, matrix metalloproteinase-9; OSDI, Ocular Surface Disease Index;SPEED, Standard Patient Evaluation of Eye Dryness.aIf available.


fluctuation in vision. Once the visual acuity andrefraction assessments are complete, the patientmay be assessed using a questionnaire.

Prior to conducting any additional assessmentsinvolving contact with the ocular surface, tear filmosmolarity can be evaluated if the necessary equip-ment is available [12–15]. Following this evaluation,the relative level of ocular inflammation (commonamong all subtypes of DTS), as measured by quanti-fying the level of inflammatory mediator markers,such as matrix metalloproteinase (MMP)-9, in thetear film can be assessed if the laboratory equipmentor diagnostic device is available [16–18]. Finally,the patient’s relative tear volume and secretionshould be measured via a Schirmer strip test [15].Depending on the patient’s response to contactwith the ocular surface as part of the preliminaryassessments, some of the assessments may needto be conducted at a follow-up visit if significantreflex tearing is observed. The ‘Diagnostics andclinical assessments’ section presents additionaldetailed information pertaining to the descriptionand interpretation of the diagnostic tests describedpreviously.

Step 3: primary assessments

The physician or lead clinician generally conductsthe primary assessments and tests used in the diag-nosis of DTS. Table 3 presents a summary descrip-tion of the following primary assessments anddiagnostic procedures that are recommended at thisstage:

(1)
Conduct a thorough review of the patient’smedical, ocular, and surgical history as well asthe nature and frequency of past and currentmedication use, including any changes thathave been noted since a prior visit.
(2)
Discuss the patient’s responses to the question-naire or other instrument to help clarify therelative frequency and timing (diurnal pattern)of DTS-related symptoms and any effect on dailyactivities, such as reading, driving, or computeruse. During the review of the patient’s medicalinformation and discussion of questionnaireresponses, behaviors that may contribute toocular irritation, such as mucus fishing, maybe observed. The responses to the questionnairemay provide insight regarding the severity levelof the DTS as well.
(3)
Conduct an external examination of thepatient’s skin, adnexa, and eyelids to provideadditional insight toward a differential diagno-sis. Express the meibomian glands for each eye-lid. Emphasis on the eyelid margin, lashes, and

Table 3. Primary assessments and diagnostic proceduresperformed by the clinician

Clinical assessments and diagnostic measures used by theclinician

Review of patient’s medical and ocular history, including responsesto questionnaire

Review of past/current medication use

External examination: particular emphasis on the lid, lid closure,and blinking (complete and incomplete)

Slit-lamp examination

Lids and lashes (lids should be everted)

Anterior segment – ocular surface

Tear meniscus

Instill fluorescein dye; observe staining pattern on cornea andTBUT

Instill lissamine green and/or rose bengal; observe stainingpattern on the conjunctiva and cornea

Evaluation and expression of meibomian glands

TBUT, tear break-up time.


1040

lid closure is important to note any anatomicdefects, malposition of the tissue, partial orincomplete blinking, debris, and alteration ofthe meibum or inflammation of the orifices ofthe meibomian glands (Fig. 2).

(4)
Conduct a slit-lamp examination to detectabnormalities that are essential in determininga differential diagnosis of DTS. The eyelids,including features of the anterior and posteriorlid margin, and lashes, should be examinedcarefully. Additionally, the upper lids shouldbe everted to allow direct visualization of thetarsal conjunctiva. Observe structures of theanterior segment, noting the relative severityof any discernible inflammation or other abnor-malities associated with ocular structures. Therelative height of the inferior tear meniscusshould also be evaluated at this step of theexamination. Practitioners may note a normalor decreased tear meniscus during a standardexamination; a tear meniscus height of less than0.3 mm is considered abnormal [15]; however,in the experience of the authors, clinicians mayoften estimate the tear meniscus and make asubjective determination about whether itis decreased.
(5)
Instill fluorescein dye (2–5 ml of 1 or 2%sodium fluorescein or a commercially availablefluorescein preparation) via micropipette, adevice designed to precisely deliver a smallamount of liquid, or through the applicationof physiological saline-moistened fluoresceinstrips to the ocular surface for visualization ofthe tear film and any damage to the corneal
-8738 Copyright � 2017 MedEdicus LLC. All rights reserved.

epithelium when viewed through the slit-lampwith cobalt blue light and the addition of aWratten (yellow) filter, if available. Waitingapproximately 2 min following the applicationof the dye to the ocular surface may enhancethe visible staining pattern [6]. In generalclinical practice, specialty devices, such as amicropipette and slit-lamp filter, may not beavailable. Ocular surface staining may still beobserved through the application of dye via afluorescein strip or a commercially availablefluorescein preparation and direct illuminationwith the slit-lamp. The severity and location/pattern of corneal fluorescein staining shouldbe carefully noted.

(6)
Assess the tear break-up time (TBUT) during thispart of the examination by measuring the timebetween the patient’s last blink and the appear-ance of the first patch of discontinuity in thetear film. Replicating the test two to three timesper eye will provide a more reliable result todetermine whether the patient has a rapidTBUT (

Table 4. Additional assessments and diagnosticprocedures

Clinical assessments and diagnostic measures that provideadditional information that may be helpful in determining adifferential diagnosis

Corneal sensation

Corneal topography

Tear film imaging

Evaluation of the tear film lipid layer

OCT: evaluation of the tear meniscus

Functional tear analysis light scatter

Imaging of the meibomian glands

Serum antibody biomarkers and/or other serological tests

Cultures from the ocular surface or associated tissue

OCT, optical coherence tomography.


corneal sensation (normal, decreased, or none)may be determined through the use of a cottonswab, tip of a tissue, nonwaxed dental floss, or asimilar substitute.

In conjunction with the patient’s medicalhistory and clinical findings, serologic testing pro-vides insight or confirmation of a diagnosis ofsystemic conditions, such as Sjögren syndrome,through the presence of autoantibody biomarkers.Cultures and samples from the ocular surface oradnexa can be sent for laboratory analysis or test-ing onsite to investigate the presence of patho-genic organisms or elevated markers for otherocular conditions [e.g., immunoglobulin E (IgE)and lactoferrin]. The ‘Diagnostics and clinicalassessments’ section presents additional detailedinformation pertaining to the description andinterpretation of the diagnostic tests describedpreviously.

Step 5: differential diagnosis

Dysfunction of the tear film is a common con-dition that causes patients to seek ophthalmiccare. ‘Dry eye’ is a term used to discuss a lack oftear production; however, the term is often used torefer to any tear disorder. Dry eye, a commoncause of DTS, is currently estimated to affect2–14.4% of the US population [22]. Extensiveresearch has been conducted in the area of DEDover the past several decades. The definition ofDED has evolved based on understanding of thepathogenesis of the condition. The DEWS 2007report [4] defined dry eye as ‘a multifactorial dis-ease of the tears and ocular surface that results insymptoms of discomfort, visual disturbance, andtear film instability with potential damage to the


ocular surface; it is accompanied by increasedosmolarity of the tear film and inflammation ofthe ocular surface’.

The prevalence of blepharitis/MGD (evapora-tive and nonevaporative), another common causeof DTS that frequently alters the functionality of thetear film, has also been difficult to accurately deter-mine. The results of recent surveys conductedamong ophthalmologists and optometrists indicatethat blepharitis has been observed in 37–47% ofpatients [23]. Additionally, a recent assessment ofpatients preparing to undergo cataract surgery indi-cated that 59% of patients were diagnosed withblepharitis [24]. MGD is a common cause of excessevaporation of the tear film, resulting in dry eye.Analysis of the frequency of distribution of dry eyesubtypes indicates that MGD is one of the mostcommon underlying conditions, with signs ofMGD present in 86% of a mixed patient populationwith dry eye [25].

To achieve the primary goal of the DTS Panelof using a diagnosis-based approach to improvepatient outcomes, all the evidence from thepatient’s medical history information, reportedsymptoms and effect on daily activities, clinicalassessments, and diagnostics must be evaluated.A patient diagnosed with DTS can be classifiedwith one or more of the four main disease-statesubtypes described subsequently. Table 5 describesthe primary characteristics and clinical findingsthat will aid in the identification of the DTSsubtype(s) present in a particular patient.Additionally, it is important to recognize and treatany DTS co-conspirator conditions that may bemasquerading as DTS or exacerbating a patient’ssigns and symptoms.

Aqueous deficiency

Aqueous tear deficiency is primarily identified as avolumetric condition. Aqueous-deficient dry eye(ADDE) is one of the primary subtypes of DED,as recognized by the etiologic classificationssystem presented in the DEWS report [4]. Aqueousdeficiency is characterized by a reduction in thesecretions from the lacrimal gland (main and acces-sory glands) that form the basis of the bulk aqueouscomponent of the tear film. The reduction in theaqueous secretions may be due to dysfunctionor destruction of the lacrimal gland or a scarring/blockage of the lacrimal gland ductules, whichprohibits the aqueous secretions from reachingthe ocular surface, generally resulting in a reducedtear lake and elevated tear film osmolarity, orinflammation [26–28]. Because of the regulatoryneuronal control of tear secretion, neurogenicinflammation – associated with injury, surgery,


Table 5. Differential diagnosis

Primary characteristics that may be observed for each of the main subtypes of DTS

Aqueous tear deficiencyBlepharitis/MGD (evaporative ornonevaporative)

Goblet cell deficiency/mucindeficiency

Exposure-relatedDTS

Decreased Schirmer score(


the nature or quality of meibum may result in arapid TBUT, exposing the ocular surface to desic-cating stress [36–38].

The outermost component of the tear film, thelipid layer, plays a critical role in the stability of thetear film. Alterations in the posterior lid margin,including the development of prominent bloodvessels or telangiectasia, thickened or turbidsecretions of the meibomian glands, and pluggedgland orifices, are primary characteristics of MGD[7,39]. Changes in the tear film lipids or meibomianglands observed through interferometry and mei-bography can also provide valuable insight into thedifferential diagnosis of blepharitis/MGD. A focusedexamination of the anterior and posterior portionsof the lid margin and manual expression of meibo-mian glands are important components for diagnos-ing blepharitis/MGD [7]. Although EDE associatedwith MGD is a common condition [25], theblepharitis/MGD subtype of the DTS Panel approachincludes both evaporative and nonevaporativemanifestations of the condition.

Goblet cell deficiency/mucin deficiency

Patients with goblet cell loss suffer from a sub-sequent reduction in mucin production. Attachedmucin glycoproteins at the cell surface and solublemucins interact with the aqueous componentto affect the surface tension of the tear film andimprove the spreading of tears across the ocularsurface. Goblet cell loss and/or mucin deficiencyaffects the stability of the tear film. Although arapid TBUT (


misdiagnosis because of the underlying condition.Other diseases that affect the ocular surface andtear film, such as allergic conjunctivitis, frequentlycoexist in patients with DTS and contribute tothe signs and symptoms. All identified DTS co-conspirators should be addressed as part of apatient’s treatment regimen. Treatment of theseother ocular conditions is outside the scope of thismonograph and should be managed accordingto the clinician’s preferred treatment options.The ‘Diagnostics and clinical assessments’ sectionpresents further discussion and detailed informa-tion pertaining to the description and interpret-ation of the diagnostic tests that are used to obtaina differential diagnosis.

Step 6: treatment options

Once a differential diagnosis has been attained,including identification of all subtypes of DTSand/or DTS co-conspirators that may be present,a directed treatment regimen should be imple-mented to address the patient’s condition.Table 6 summarizes the treatment options recom-mended by the DTS Panel for the four mainsubtypes of DTS. First-line therapy, second-linetherapy, and interventional procedures are pre-sented for each subtype of DTS, as appropriate.Inflammation and a reduced quantity or qualityof the tear film is central to the various subtypesof DTS. As such, some of the recommendedtreatment options are included for multiplecategories.

Artificial tears, gels, ointments, and inserts areused to replenish the tear film. Tears can be con-served via punctal plugs, cautery, and moisturechamber eyewear. Alterations in environmentalconditions may benefit patients with DTS throughincreases in relative humidity. Adjustments in lidhygiene, warm compresses, and massage may alsobe necessary for patients with blepharitis/MGD.Anti-inflammatory and immunomodulatory agentoptions include cyclosporine, lifitegrast, steroids,and nutritional supplements, such as omega-3fatty acids. In addition to the conventional treat-ments for DTS, innovative treatment options,including compounded formulations of agents,are also available.

The overall severity of a patient’s DTS is animportant factor that affects the sequence and fre-quency of the treatment regimen. The particularsequence for first-line therapy, second-line therapy,and interventional procedures is a decision best leftto the individual clinician according to the patient’smedical history, prior treatment, and severity of thecurrent disease state. The ‘Treatment options for


dysfunctional tear syndrome’ section presents adetailed discussion of each of the treatment optionsfor the subtypes of DTS.

Step 7: follow-up

Patient follow-up via regular clinic visits is anessential part of successful treatment of DTS.The fluctuations that occur in patient symptoms,signs, and diagnostic test results require the clini-cian to observe the patient over a period and totailor treatment on the basis of response totherapy and changes from baseline values.Observed trends in inflammatory markers or tearfilm osmolarity provide a quantitative assessmentof the progress of treatment from both the clini-cian and patient perspectives. The chronic natureof DTS and the frequent lack of correlation ofclinical signs and patient symptoms emphasizethe importance of monitoring a patient over timeand making adjustments to the treatment plan,as necessary.

DIAGNOSTICS AND CLINICALASSESSMENTS

A wide range of clinical assessments and diagnosticmeasures can be employed in the diagnosis ofDTS. No single assessment or diagnostic procedureis sufficient for a differential diagnosis of DTS [6].Identification of the specific subtypes of DTSis essential to determine a directed treatmentapproach. A thorough review of the patient’smedical history, including past and current DTSsymptoms and treatment, provides the contextfor interpretation of the current examination anddiagnostic test results. This section presents thediagnostic tools that can be used to identify sub-types of DTS. Equipment access at each clinic andthe preferences of each clinician differ and willinfluence the chosen diagnostic methods.

Questionnaires

Patient-reported symptoms and the effects of DTS ondaily activities can provide important informationpertaining to the disease-state subtype and theseverity of the condition. Although the clinicallyobserved signs and patient-reported symptoms ofDTS do not often correlate, addressing patient dis-comfort or functional limitations due to symptoms isa significant factor in determining the treatmentapproach. Validated questionnaire instrumentsdesigned with ranked scoring systems allow forquantification of patient responses and an overallestimate of the severity of their discomfort and the


Table 6. Recommended treatment options for the DTS Panel clinical approach

Treatmentoption

Aqueous teardeficiency

Blepharitis/meibomian glanddysfunction (evaporative ornonevaporative)

Goblet cell deficiency/mucin deficiency Exposure-related DTS

First linea Tear supplements andlubricants (i.e.,drops, gels,ointments, sprays,and lubricatinginserts)

Tear supplements and lubricants(i.e., drops, gels, ointments,sprays, and lubricating inserts)

Tear supplements andlubricants (i.e., drops, gels,ointments, sprays, andlubricating inserts)

Tear supplements andlubricants (i.e.,drops, gels,ointments, sprays,and lubricatinginserts)

Nutritional supplements Lid hygiene and lid scrubs (i.e.,cleansers, warm compresses,and massage)

Topical cyclosporine Taping of the eyelid

Topical cyclosporine Nutritional supplements Topical lifitegrast Moisture chambereyewear

Topical lifitegrast Topical cyclosporine Vitamin A ointment – retinoicacid (compounded)

Topical steroids Topical lifitegrast Moisture chamber eyewear

Topical secretagogues Topical erythromycin/bacitracin Topical secretagogues

Moisture chambereyewear

Topical azithromycin

Topical steroids or antibiotic/steroids

Second linea Oral secretagogues Oral doxycycline/tetracycline Scleral lenses Scleral lenses

Topical hormones(compounded)

Tea tree oil

Autologous serum(compounded)

Topical metronidazole ointment ordrops (compounded)

Albumin (compounded) Topical doxycycline(compounded)

Bandage contactlenses/scleral lenses

Topical clindamycin(compounded)

Topical dapsone(compounded)

Topical dehydroepiandrosterone(compounded)

Topical tacrolimus(compounded)

Topical dapsone (compounded)

Topical N-acetylcysteine Topical N-acetylcysteine

Proceduresa Punctal plugs In-office thermal pulsation and/orlid massage

Eyelid surgery (i.e.,correction of lidmalposition andtarsorrhaphy)

Cautery occlusion Debridement of the lid margin

Amniotic membranetransplantation

Intense pulsed light

Meibomian gland probing

Refer to the main text for the description, level of evidence, and approved indications, as appropriate. DTS, dysfunctional tear syndrome.aThe order of treatment in each category is left to the clinical judgment of the clinician and to the preference of the patient.


effect on visual function [4]. Patient responses toindividual questions contribute to the overall scorein the assessment and may also help direct the diag-nosis of the particular DTS subtype.

A variety of questionnaires to evaluate the symp-toms of dry eye have been developed [4]. Question-naires such as the Ocular Surface Disease Index(OSDI) [54] and the Standard Patient Evaluationof Eye Dryness [55] are commonly used in standard


clinical practice to assess patient symptoms and inclinical trial research to screen potential individualsor to evaluate the effect of treatment on individual-reported symptoms and visual function [54].

Slit-lamp examination

Detection of abnormalities affecting the eyelid,anterior and posterior lid margins, conjunctiva,



and cornea observed during the slit-lamp examin-ation offers insight toward a differential diagnosisof DTS subtypes and identification of DTS co-conspirators that may exacerbate a patient’s DTScondition [6]. During the initial portion of theslit-lamp examination, the following should beobserved in detail:

(1)

FIGU

meibblepObsaltersecre� 19

1040

Tear film meniscus (tear lake) and any debris orfoam that may be present in the tear film

(2)
Lashes for any abnormalities (i.e., loss, misdir-ection, sleeves, scurf, and collarettes)
(3)
Anterior and posterior lid margins, notingthe characterization of the vasculature andany abnormalities in the meibomian glandorifices
(4)
Nature of the meibomian gland secretions –grade 0–3 scale: 0 ¼ clear/normal; 1 ¼ cloudy;2 ¼ cloudy particulate fluid; and 3 ¼ inspissated(like toothpaste) [5] (Fig. 3)
(5)

Appearance of the puncta

(6)
Any anomalies of the conjunctiva and cornea
(i.e., hyperemia, mucus strands, scarring, andepithelial erosions) [5]

Each abnormality may be ranked as mild,moderate, severe, or according to some other sys-tem to allow for a baseline comparison at follow-up visits.

Once the initial examination is complete, dye isintroduced on the ocular surface to further evaluatethe tear film and corneal/conjunctival tissue. Instil-lation of liquid sodium fluorescein or application offluorescein dye via moistened strips to the ocular

RE 3. Meibomian gland orifices and expression of theomian glands. Image from a patient with posteriorharitis/meibomian gland dysfunction (MGD).truction of the orifices of the meibomian glands andations in the meibum, leading to turbid, thickenedtions, can occur in patients with blepharitis/MGD.94 American Academy of Ophthalmology.

-8738 Copyright � 2017 MedEdicus LLC. All rights reserved.

surface allows for visualization of the tear film andintegrity of the corneal and conjunctival epithelium(Fig. 4). Fluorescein dye will penetrate tissue wherethe epithelial intracellular junctions have beendisrupted (i.e., cells that are dead or absent). Thestability of the tear film can be observed via the slitlamp with a cobalt blue filter following applicationof fluorescein. To evaluate the stability of the tearfilm, the TBUT test is usually conducted before anyother drops or anesthetic are applied. The patientis instructed to blink a few times, and the timeinterval between blinking and disruption of the tearfilm is measured several times for each eye (averag-ing the time for each eye). A rapid TBUT (

Table 7. DTS Panel approach ocular surface fluorescein staining patternsa,b

Severe

keratoconjunctivitis

sicca

Severe blepharitisChemical injurySevere medication

toxicityContact lens-related

keratitis due tohypoxia, solutiontoxicity (i.e., H2O2),and cracked contactlens

Infectious keratitisNeurotrophic keratitisUltraviolet exposure

keratitis/arc weldingkeratitis

TrichiasisFilamentary keratitisConjunctival concretions

Moderate

keratoconjunctivitis

sicca

BlepharitisChemical injury

(hairspraykeratopathy)

Ultraviolet exposurekeratitis/arc weldingkeratitis

Medication toxicityContact lens-related

keratitisInfectious keratitisThyroid eye disease/

exposure keratopathyNeurotrophic keratitisTrichiasis

Blepharitis

Exposure keratopathy

(thyroid eye disease,lagophthalmos,inferior lidlagophthalmos,scleral show,ectropion, partial orincomplete blink,andconjunctivochalasis)

Keratoconjunctivitissicca (less likely, butpossible)

Chemical injuryEntropionTrichiasisMedication toxicityInfectious keratitis

(right eye)

Medication toxicity

Keratoconjunctivitis sicca(less likely, butpossible)

BlepharitisEntropionTrichiasisInfectious keratitisExposure keratopathy

(thyroid eye disease,lagophthalmos,inferior lidlagophthalmos/scleralshow, ectropion, andpartial or incompleteblink)

Contact lens-related

keratitis (especiallylikely in a rigid gaspermeable contactlens wearer)

Keratoconjunctivitissicca

BlepharitisChemical injury

(hairspray toxicity)Ultraviolet exposure


Medication toxicityInfectious keratitisExposure keratopathy

(thyroid eye disease,trichiasis, pterygium,pinguecula, andband keratopathy)

Superior limbic keratitis

Foreign body under lid

BlepharitisFloppy lid syndromeConjunctival concretionsVernal

keratoconjunctivitisInfectious keratitisSuperior entropionAtopic

keratoconjunctivitisTrichiasis

aConditions listed in bold are considered more likely and/or high on the differential list.bCharacteristic corneal staining patterns indicative of particular conditions affecting the ocular surface may be observed following application offluorescein dye.


bengal may be uncomfortable when applied to theocular surface) (Fig. 6), are recommended to beapplied to the ocular surface once the fluoresceinevaluation is complete. Vital stains assist in the

FIGURE 5. Staining of the conjunctiva with lissamine green.Image from a patient with aqueous deficiency. Vital dyes,such as lissamine green, may be used to visualize debris inthe tear film and regions of the conjunctiva that are deficientin mucin. Moderate-to-severe lissamine green staining of thetemporal aspect of the conjunctiva is shown. Image courtesyof Elizabeth Yeu, MD.


visualization of debris in the tear film and areas ofthe ocular surface that do not have a mucus coating(i.e., cells that are ‘unhealthy or abnormal’)[20,21,56]. Table 8 presents corneal/conjunctivallissamine green/rose bengal staining patternscharacteristically associated with a range of ocular

FIGURE 6. Staining of the conjunctiva with rose bengal.Image from a patient with aqueous deficiency. Rosebengal may be used to highlight areas of the conjunctivathat are abnormal or unhealthy in patients withdysfunctional tear syndrome (DTS). Moderate staining ofthe conjunctiva is shown with a classic pattern forkeratoconjunctivitis sicca. � 1994 American Academy ofOphthalmology.


Table 8. DTS Panel approach ocular surface lissamine green/rose bengal staining patternsa,b

Mild presentation of:Keratoconjunctivitis

sicca (classic pattern)BlepharitisChemical injury

(hairspray keratopathy)Ultraviolet exposure


Medication toxicity

Moderate presentation of:Keratoconjunctivitis

sicca (classic pattern)BlepharitisChemical injury

(hairspray keratopathy)Ultraviolet exposure

keratitis/arcwelding keratitis

Medication toxicity

Severe presentation withfilaments (noted in green)of:Keratoconjunctivitis

sicca (classic pattern)BlepharitisChemical injury (hairspray

keratopathy)Ultraviolet exposure


Medication toxicity

Mucus fishingsyndrome

Chemical injuryMedication toxicityInferior ectropionEntropionTrichiasisConjunctivochalasis

Superior limbickeratoconjunctivitis

Foreign body under lidAtopic

keratoconjunctivitisFloppy lid syndromeConjunctival concretionsVernal

keratoconjunctivitisInfectious keratitisSuperior entropion

aConditions listed in bold are considered more likely and/or high on the differential list.bCharacteristic conjunctival staining patterns indicative of particular conditions affecting the ocular surface may be observed following application of lissaminegreen or rose bengal dye.


conditions. It is important to note that mild fluor-escein staining may be present even in normal eyes[6]. Also, diagnostic procedures, such as theSchirmer test, may result in mild staining withfluorescein, rose bengal, or lissamine green in theregion where the test strip was placed.

Scoring systems for ocular surface staininghave been developed in an effort to standardizepatient assessments for clinical practice andresearch. Adoption of a scoring system is notnecessary for use of the DTS Panel approach toarrive at an accurate diagnosis; however, cliniciansmay find the use of a scoring system (e.g., NationalEye Institute scale or Oxford scheme) helpful inmonitoring a patient’s response to treatment[30,57,58].

FIGURE 7. Schirmer strip test. Illustration of apatient undergoing Schirmer strip testing. Abnormalities inthe production of the aqueous component of the tear filmmay be diagnosed using Schirmer strip testing. TheSchirmer strip is placed in the inferior cul-de-sac near thelateral canthus.

Schirmer test

The Schirmer test is a diagnostic method for eval-uating aqueous tear production [19,59]. Cliniciansuse several variations of this procedure. Topicalanesthesia may or may not be used during theprocedure, and, in keeping with clinician prefer-ence, the procedure may include nasal stimulationto induce reflex tearing. The use of topical anes-thesia prior to the assessment allows for themeasurement of basal tear secretion, as comparedwith basal plus reflex tearing from the nonanes-thetized version of the test. To perform the test, anarrow strip of filter paper (Schirmer strip) isplaced in the inferior cul-de-sac near the lateralcanthus (Fig. 7). Excess fluid in the fornix shouldbe dried prior to insertion of the test strip. The


length of the test strip that is wetted after 5 min ismeasured in millimeters. A Schirmer test score ofless than 10 mm after 5 min is generally consideredabnormal [6,15].

The phenol red thread test is an alternativemethod to evaluate tear volume. The thread isplaced in the inferior cul-de-sac toward the lateralcanthus [3]. The length of the thread wetted (indi-cated by a color change) in 15 s is measured andrecorded. A length of less than 10 mm of the threadafter 15 s is considered abnormal.

Although the Schirmer test is frequently used inthe diagnosis of various subtypes of dry eye, the



results of the test are often variable [60]. Singleabnormal test results may not be considered suffi-cient for a diagnosis. As with other diagnostic pro-cedures used to assess patients with potential DTS,the observation of trends indicating consistentlyabnormal findings are beneficial in determining adifferential diagnosis [6,15].

Members of the DTS Panel recommend the useof the Schirmer test as part of the battery of diag-nostic assessments. Panel members use the test onboth anesthetized and nonanesthetized patients.Both methods of employing the tests are correctand provide insight into the patient’s aqueous tearproduction capacity. Additionally, a Schirmer testassessment should be considered for patients withDTS prior to punctal plug insertion to decrease therisk of secondary epiphora.

Tear film osmolarityOsmolarity is a measurement of the concentrationof dissolved solutes in a solution. In terms of thetear film, osmolarity is generally expressed in unitsof milliosmoles per liter. Hyperosmolarity of thetear film is a recognized and validated marker ofdry eye [13]. Hyperosmolarity of the tear filmoccurs through decreased flow of the bulk aqueouscomponent of the tear film from the lacrimalgland and/or through increased evaporation andinstability of the tear film. Increased osmolarity ofthe tear film stimulates the release of inflamma-tory cytokines, enhances the rate of cell apoptosis,and results in a decrease in the number of gobletcells [12,13].

Patients with a normal tear film typically havea stable tear film osmolarity. A higher degree offluctuation in tear film osmolarity is observed inpatients with DTS. Fluctuations occur bothbetween measurements taken from the same eyeand measurements concurrently taken betweenthe eyes of a patient. The inherent fluctuationsin tear film osmolarity of patients with DTS canbe a point of confusion for clinicians unless theinstability of the tear film is recognized as a hallmarkof DED. A point-of-care test for the measurement ofthe osmolarity of the tear film of patients suspectedof having DTS is available [14]. In general, an elev-ated tear film osmolarity correlates with DTS. Thenormal tear film osmolarity in patients withoutDTS ranges from 270 to 308 mOsm/l (mean of302 mOsm/l). A threshold of 308 mOsm/l has beenfound to be indicative of early/mild dry eye, whereasa tear film osmolarity of 316 mOsm/l or higher iscorrelated with moderate-to-severe dry eye. Meantear film osmolarity values of patients with mild-to-moderate dry eye are 315 mOsm/l, whereas those


of patients with severe dry eye have been found to be336 mOsm/l. Based on the stability of the tear film inthe eyes of normal patients, a difference in the tearfilm osmolarity of more than 8 mOsm/l betweenthe eyes is suggestive of ocular surface instabilityand indicative of DED [12–14]. In addition tothe specific tear osmolarity values associatedwith the severity of DED listed previously, cliniciansmay also find it useful to generally categorizethe assessed severity level using ranges of upto 300 mOsm/l for normal, 300–320 mOsm/l formild, 320–340 mOsm/l for moderate, and above340 mOsm/l for severe DED [61].

Evaluation of tear film osmolarity should be con-ducted prior to disturbance of the eye to obtainaccurate results because any disturbance to the ocularsurface may stimulate reflex tearing, which canfalsely lower the osmolarity reading [62]. Althoughan elevated measurement of tear film osmolarityis a strong indicator of DTS, the presence of anelevated osmolarity reading may not correlate witha patient’s symptoms or other clinical signs [62]because of the nature of the disease and fluctuationsobserved in these patients. Trends observedthrough multiple osmolarity assessments arebeneficial to increase the sensitivity and specificityof the diagnosis of individual patients. If used, tearfilm osmolarity should be assessed at the initialevaluation of a patient with DTS and at follow-upvisits to establish a baseline and quantify thepatient’s response to treatment as the tear filmstabilizes. The tear film osmolarity assessment hasbeen demonstrated to have an 88% specificity and78% sensitivity for mild/moderate dry eye and a95% sensitivity for severe dry eye [6,13,14].Despite these results, some studies question theaccuracy of the tear film osmolarity assessmentand have shown variability in the osmolaritymeasurements, with a lack of strong correlationswith other signs and symptoms of DED [63–66].Bunya et al. [63] suggest that tear film osmolaritytesting has feasibility in the clinical setting andinduces less discomfort than the Schirmer test. Onthe basis of their experience, members of the DTSPanel have found the assessment of tear osmolar-ity helpful for diagnosing DTS when used incombination with other clinical assessmentsand procedures.

Inflammatory markers in the tear film

Inflammation is a common factor across the sub-types of DTS. The inflammatory cascade respon-sible for producing inflammation on the ocularsurface in DTS offers the opportunity to correlatemeasurements of inflammatory biomarkers with



the severity of the disease. The levels of inflam-matory mediators, including cytokines, chemo-kines, and enzymes, involved in tissueremodeling may be assessed in the tear film.Recent research has evaluated a member of theMMP family, MMP-9, an enzyme produced bycorneal epithelial cells, as a biomarker for dryeye [16,17]. The MMP family of enzymes playsan important role in wound healing and inflam-mation through the ability to degrade collagen.Elevated levels of MMP-9 have been observed inthe tears of patients with dry eye [67].

The normal range of MMP-9 in the tears ofpatients ranges from 3 to 40 ng/ml. In contrast,the MMP-9 levels in the tears of patients withmoderate-to-severe DTS can exceed 40 ng/ml. Apoint-of-care test for the measurement of the con-centration of MMP-9 in the tear film of patientssuspected of DTS is available [18,67]. Because of arequirement for MMP-9 levels to be greater than40 ng/ml to provide a positive assessment usingthe point-of-care diagnostic, the use of MMP-9 asa diagnostic measure may be valid only for patientswith more severe forms of DTS [68].

Corneal sensation

The cornea, one of the most highly innervatedtissues in the body, is susceptible to alterations insensitivity because of damage or injury. Irritationor injury to the ocular surface due to hyperosmo-larity or inflammation triggers the reflex arc tostimulate the lacrimal gland secretions. Changesin the sensitivity of the cornea have been observedin patients with chronic conditions such as DTS.Sensitivity may be increased during the earlystages of the disease, whereas a reduction in cor-neal sensitivity is associated with disease pro-gression [19,69,70].

Instruments to precisely quantify corneal sen-sitivity, such as the Cochet–Bonnet esthesiometer,are available and used in basic research or clinicaltrial settings [71]. In general clinical practice,access to esthesiometers may be limited; con-sequently, qualitative methods can be employedto assess changes in a patient’s corneal sensitivity.Basic scoring systems may be developed throughthe use of simple tests for sensation, in which acotton swab, unwaxed dental floss, or the tip of atissue is gently applied to the ocular surface. In theauthors’ clinical experience, grading scales,including numeric scales (0–4, ranging from nosensation to normal sensation exhibited via areflex to pull away) or descriptive scales (normal,decreased, or none), may be used to characterizecorneal sensation.


Lacrimal gland secretion biomarkers

The secretions of the lacrimal gland that form thebulk of the aqueous component of the tear filmcontain a range of proteins, including enzymesand immunoglobulins, electrolytes, and other fac-tors involved in maintaining the health of theocular surface. Assessments of the protein com-ponents of lacrimal secretions have found alteredlevels in the tear film of patients with diseasesaffecting the ocular surface, which allows theseproteins to be used as biomarkers [72,73].

Lactoferrin, a molecule belonging to the trans-ferrin class of proteins, is one of the most abundantprotein components of the healthy tear film.Through the sequestration of iron, lactoferrin actsas an antimicrobial agent and plays a role in theimmunologic and anti-inflammatory properties ofthe tear film. The concentration and absoluteprotein levels of lactoferrin in the tear film havebeen observed to be reduced in patients withaqueous-deficient dry eye [74]. A point-of-care testfor the measurement of the concentration of lacto-ferrin in the tear film of patients suspected of havingDTS is available. Lactoferrin levels below 0.9 mg/mlsuggest the patient has ADDE, with the severity ofthe disease correlating with lower levels of thebiomarker [72,73].

The immunoglobulin family of proteins playsan essential role in the functioning of the immunesystem. IgE proteins, antibodies specific forparticular allergens, are found in the tear film ofpatients with ocular allergic conditions. Exposureto allergen particles results in binding of IgE andinteraction with mast cells in the conjunctiva,initiating the inflammatory response of the aller-gic cascade [75,76]. A commercially availablepoint-of-care test designed to evaluate the levelof IgE in tear samples with IgE levels at least80 ng/ml suggests a diagnosis of allergic conjunc-tivitis, with the level of IgE present in the tearfilm correlating with the severity of the allergiccondition [53].

Optical coherence tomography

OCT is a noninvasive technique that uses lightwaves to construct a three-dimensional, high-resolution, cross-sectional image of biologic tissuesor fluids. OCT devices capable of evaluating theanterior segment offer the opportunity to quantifyaspects of the tear film. The precise height, volume,and cross-sectional area of the tear meniscus can bemeasured. Figure 8 presents a representative OCTimage showing the cross-sectional area of a normaltear meniscus [77]. In addition to a comparison ofthe tear meniscus characteristics to the mean


FIGURE 8. Evaluation of the tear film meniscus with opticalcoherence tomography (OCT). Image of the cross-sectionalarea of the tear film meniscus with OCT. Evaluation of thetear film with a high-resolution OCT allows for thecharacteristics of the tear film to be quantified. The area ofthe inferior meniscus was calculated to be 0.05 mm2 in thispatient, which was within the normal range [77]. Imagecourtesy of Elizabeth Yeu, MD.


values of patients with DTS versus those withoutDTS, OCT offers a means to monitor a patient’sresponse to treatment options. Improvements inthe tear meniscus following the installation ofpunctal plugs or other therapy for DTS allow theclinician to provide quantitative feedback topatients [78,79]. Recent advances include the auto-mation of analysis of the tear meniscus height overmultiple image scans, which potentially increasethe accuracy of the measurement compared with asingle scan [80].

Interferometry and meibography

Interferometry is a noninvasive technique thatcan be used to measure the thickness of the tearfilm through the use of the principle of opticalinterference or the interaction of light waves.Colored images of the superficial layer of the tearfilm, the lipid layer, can be generated and eval-uated to assess the thickness across the ocularsurface [15,81].

Diagnostic devices are commercially available,allowing for the visualization and assessment of apatient’s tear film lipids [82,83]. A reduction inthe thickness of the lipid component of thetear film (

FIGURE 9. Visualization of the meibomian glands, tear film lipid layer, and partial blinking. Image of a patient withmeibomian gland dysfunction (MGD) and exposure-related dysfunctional tear syndrome (DTS). Diagnostic systems designedfor visualization of the meibomian gland (meibography) are also capable of providing an analysis of the thickness of the tearfilm lipid layer and an assessment of partial blinking. Note a decrease in lipid layer thickness of 46 nm in the right eye and43 nm in the left eye; increased partial blinking OU; and meibomian gland truncation OD greater than OS. Image courtesyof Mark Milner, MD.


Multiple treatment options are presented foreach subtype of DTS. Although the emphasis of thisapproach is to direct treatment on the basis of thespecific disease-state subtype(s) for each patient, therelative severity of a patient’s condition is also animportant consideration in the sequence and/orcombination of therapies applied in any treatmentregimen.

Table 6 categorizes the treatment optionsin groups recommended for first-line therapy,second-line therapy, and interventional pro-cedures. It is important to keep in mind, however,that each patient is unique, and the decisionregarding which treatment option(s) to use is bestleft to the individual clinician. Treatment optionsfor each DTS subtype are presented on the basisof treatment category rather than the order inTable 6.

Patient education regarding early diagnosis,risk factors, treatment options, and prognosis ofDTS is considered a part of the first-line treatmentplan for all subtypes of DTS. All patients maybenefit from efforts to mitigate the severity


and effect of DTS symptoms on quality of lifethrough potential adjustments to their behavior,daily activities, and exposure to environmentalstressors.

Aqueous deficiency treatment options

Tear supplements and lubricants

Tear supplements and topical lubricants are avail-able in a range of options for the treatment of ocularsymptoms associated with DTS. Artificial tears serveto lubricate the ocular surface and remove debris,supplement-deficient components of the tear film,dilute a hyperosmolar tear film, and reduce elevatedlevels of proinflammatory mediators [4,5,88–91].The current array of tear supplements and lubricantsare distinguished by their formulation differences,which include variations inviscosity, electrolytes,pH, osmolarity, and the presence/type of a preser-vative [4].

Artificial tears are considered as first-line therapyfor tear deficiency and other types of DTS because of



availability, their noninvasive nature, and a generallyminimal side-effect profile [6]. Clinical studies inves-tigating the efficacy of various formulations of tearsupplements have been conducted, including com-parative studies to evaluate the differential effectson patient symptoms and clinical signs of DTS[92]. The use of preserved tear supplements is appro-priate for many patients with mild tear deficiency torelieve the symptoms of DTS, as needed. However,because of the potential for disruption of the tearfilm and toxicity to the corneal epithelium, theauthors recommend that patients with moderate-to-severe tear deficiency requiring the use of artificialtears more than four times per day use preservative-free formulations. The potential for ocular toxicityhas been well characterized for benzalkoniumchloride. Newer preservative agents may still poten-tially damage the corneal epithelium [92–95]. Pres-ervative-free artificial tear supplements may be usedliberally, as needed.

Lubricating inserts

Hydroxypropyl cellulose ophthalmic inserts aresterile, water soluble, and slow-release lubricantsthat are placed in the inferior cul-de-sac. Hydrox-ypropyl cellulose ophthalmic inserts are indicatedfor patients with moderate-to-severe dry eye.Because the formulation is preservative free, itmay help patients who are not able or willingto use artificial tears on a frequent basis [96,97].Published clinical evidence of efficacy (level II)has reported a significant improvement in teardeficiency symptoms and OSDI scores with once-daily use of hydroxypropyl cellulose ophthalmicinserts [98,99]. Transient blurred vision was themost common adverse event reported that wasassociated with use of the hydroxypropyl celluloseophthalmic inserts [97,98].

Nutritional supplements

Essential fatty acids, including omega-3 andomega-6 fatty acids, must be obtained throughdietary consumption. Omega-3 and omega-6 fattyacids are required for the normal function of humancellular metabolism. Dietary intake of essential fattyacids may play a role in the risk for developingsubtypes of DTS. A diet that has a higher ratio ofomega-6 fatty acids (a precursor for proinflamma-tory mediators) is associated with an increased riskof dry eye. Conversely, a diet that has a high ratio ofomega-3 fatty acids is associated with a reducedchance of developing dry eye [100].

Evidence from clinical investigations involv-ing dietary supplements, primarily omega-3 fattyacids, generally supports that intake is associatedwith an improvement in the symptoms of tear


deficiency. Recent meta-analyses of randomized,placebo-controlled studies (level I) indicated thatsignificant improvements in TBUT and Schirmertest scores were associated with daily dietary intakeof omega-3 fatty acids (eicosapentaenoic acid anddocosahexaenoic acid) [101]. Significant improve-ments in individual-reported symptoms (OSDIassessment) and objective evaluations of cornealsmoothness were observed in a clinical evaluationof long-term consumption (6 months) of nutri-tional supplements containing gamma-linolenicacid and omega-3 fatty acids by patients withmoderate-to-severe dry eye compared with inges-tion of a placebo (level I). The study reported thatno ocular adverse events were attributed to thenutritional supplement or to the placebo; sim-ilarly, no significant systemic adverse events werenoted in either treatment group [102]. Omega-3fatty acid supplements are available from a rangeof sources and formulations [101]. Clinical inves-tigation regarding the recommended dosage andformulation of these supplements is ongoing.

Topical cyclosporine

Inflammation associated with the ocular surface andsecretory components of the lacrimal system isbelieved to be a core feature of the pathogenesisof dry eye. Changes in the functioning of thelacrimal gland and/or lacrimal ducts may affect boththe quantity and quality of the secretions of thelacrimal gland that form the bulk aqueous com-ponent of the tear film [103,104]. Inflammationassociated with the ocular surface may be inducedthrough chronic irritation due to environmentalstress, ocular comorbidities, physiologic changesassociated with aging, or ocular manifestations ofsystemic conditions. Therapy with anti-inflamma-tory agents is recommended because of the strongcorrelation of inflammation with tear deficiency[4,6,105,106].

Cyclosporine A, a peptide derived from a fungalorigin, is an anti-inflammatory agent with immu-nosuppressive properties. Topical applicationof cyclosporine (0.05%) to the ocular surface isindicated to increase tear production in patientswho have decreased tear production due to inflam-mation associated with dry eye [107]. The precisemechanism of action of topically applied cyclospor-ine is unknown; however, the agent is believed toact as a T-cell immunomodulator in patients withtear deficiency [107].

Phase 3 clinical studies supporting the appro-val of topical cyclosporine for the treatment of dryeye indicated a significant increase in Schirmertest scores in individuals treated with cyclosporinetwice daily compared with those treated with



vehicle (level I). A significant decrease in fluor-escein corneal staining and improvement in sub-jective measures (e.g., blurred vision, need forartificial tear use, and global response to treat-ment) were also observed in the individuals treatedwith topical cyclosporine compared with thosetreated with vehicle [4,107,108]. An early responsetime ranging from 4 to 6 weeks to 3 months maybe observed in patients, and benefits may continueto improve for 2 years or more. Clinical improve-ments in the signs and symptoms of DED wereobserved in patients with severe manifestations ofthe disease following high-frequency adminis-tration (three to four times daily) of topical cyclo-sporine (level II) [109]. Ocular burning andstinging were the most commonly reportedadverse events in the individuals treated withtopical cyclosporine [108–110]. The authorsrecommend a dosage regimen of twice-daily appli-cation of topical cyclosporine to both eyes in thetreatment of tear deficiency for a minimum of6 months [111]. Patients should be assessed atfollow-up visits, and therapy is commonly main-tained indefinitely for this chronic condition, asappropriate. According to the judgment of theclinician, if the patient’s signs and symptoms havefully resolved, therapy with topical cyclosporinemay be discontinued or reduced to once-dailyadministration following 1 year of twice-dailytreatment. Clinical evidence indicates that once-daily administration following 1 year of twice-daily administration may still suppress the signsand symptoms of DED (level II) [112]. Members ofthe DTS Panel have used topical cyclosporinetherapy for 2 years or more for patients withaqueous deficiency. Limited safety information isavailable from the published studies evaluatinglong-term and/or a reduced administration regi-men of topical cyclosporine.

Topical lifitegrast

Activation and recruitment of immune cells, specifi-cally lymphocytes, occur in the development andperpetuation of DTS through the binding ofreceptors on the surface of immune cells with mol-ecules expressed on the epithelium of the ocularsurface and vascular endothelium. Lymphocytefunction-associated antigen-1 (LFA-1) is a memberof the integrin receptor family that is expressed onlymphocytes and binds to adhesion molecules, suchas intracellular adhesion molecule-1 (ICAM-1). Inhi-bition of the interaction between LFA-1 and ICAM-1by the integrin receptor antagonist lifitegrast (SAR1118) results in blocking the recruitment, acti-vation, and release of proinflammatory mediatorsby lymphocytes [113–115].


Topical application of a lifitegrast ophthalmicsolution (5.0%) is indicated for the treatment of thesigns and symptoms of DED [116]. Clinical evalu-ation of topical lifitegrast in the treatment of indi-viduals with dry eye (twice-daily administration)resulted in significant improvement in cornealand conjunctival staining as well as improvementsin ocular symptoms, including eye dryness, com-pared with placebo [115,117,118]. Adverse eventswere generally mild to moderate and transient innature, with the majority of ocular adverse eventsrelated to instillation in both treatment groups (e.g.,reduced visual acuity, irritation, and discomfort),whereas dysgeusia was the most common nonocularadverse event reported by individuals treated withlifitegrast [115,118,119].

The approved dosage regimen of topical lifite-grast is twice-daily application to both eyes (OU)[116]. Patient response to treatment should beassessed at follow-up visits, and therapy may bemaintained indefinitely, as appropriate.

Topical secretagogues

Secretagogues are agents that induce secretion as amechanism of action. Application of secretagoguesto the ocular surface are designed to stimulateaqueous and/or mucin secretion. Topical thera-peutic agents in the secretagogue class have beeninvestigated, but are not currently available in theUnited States [120,121]. Topical secretagogue for-mulations (e.g., 3% diquafosol sodium ophthalmicsolution and 2% rebamipide ophthalmic suspen-sion) are available internationally and indicatedfor the treatment of dry eye [122,123].

Topical steroids

Corticosteroids are anti-inflammatory compoundswith use in treating a range of ocular inflamma-tory conditions. In the United States, topicalophthalmic formulations of corticosteroids aregenerally indicated for the treatment of steroid-responsive inflammatory conditions affectingthe anterior segment. Clinical evidence frommultiple studies using different formulationsi

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