`Workshop on Clinical Trials in Dry Eyes
`
`Chairman: Michael A. Lemp, MD
`
`Introduction
`
`Over the last 20 years our knowledge of the pathogenetic
`factors involved in dry eye states has grown significantly. It is
`now generally recognized that the term “dry eye“ is a nihric to
`describe a variety ofconditions ofdiverse origin which affect the
`tear fiim andlor the ocular surface.‘ Recent findings show
`differences between Sjogren’s-associated keratoconjunctivitis
`sicca (KCS} and non—Sji:igren‘s KCS.“ Neurotransmitters,’-°
`viruses,’ and hormones” are important in regulating tear pro-
`duction and immune activity in the lacrimal glands and the
`ocular surface. Finally, meibomian gland dysfunction can in-
`crease tear evaporation with an increase in tear film osmolarity
`and resultant ocular surface disease. ‘°
`Despite these advances, there has been a lack ofconsensus
`on the appropriate diagnostic criteria, classification of disease
`states, the aim of specific diagnostic tests, the role of subjective
`assessment, clinical trial designs, and interpretation of results.
`This has led to the use of diverse clinical trial designs, which
`hampers treatment comparisons and leads to confusion over
`desirable end-points.
`At the lntemational Symposium on the Lacrimal Gland,
`Tear Film. and Dry Eye Syndromes in 1992 (Proceedings.
`Plenum Press, New York and London, 1994), a call for an
`“academic2'clinical practicelindustrylgovernmental effort to de-
`velopaconsensus“ was issued. " In response to this, the National
`Eye Institute and leading industry groups sponsored a National
`Eye Institute’! ndustry Workshop on Clinical Trials in Dry Eyes.
`The workshop was organized and chaired by the author. Two 1
`and one-half day meetings in December 1993 and again in
`December I994 were held on the campus of the National
`Institutes of Health. The aim of the workshops was to provide
`clinical instruments for the conduct of epidemiological studies
`and clinical trials. This report wasdrafted in accordance with the
`recommendations of the American Medical Association con-
`
`-
`cerning consensus conferences.”
`The objective of the workshop was to identify areas of
`consensus andfor disagreement in the design and interpretation
`of clinical trials in dry eyes. To this end, a group of individuals
`from academic and clinical fields, industry, and govemmental
`agencies met. Individuals were invited to participate based on
`their clinical contributions to the field, corporate responsibili-
`
`ties, andlor regulatory functions. The format of the meeting was
`as follows:
`
`A brief overview of various factors concerning dry eyes
`was given. This was followed by discussion. Three areas of
`critical interest were identified:
`1. The development of a classification system for dry eyes.
`_ 2. The standardization of clinical tests used to diagnose dry
`eye states and assess treatment effects.
`3. The development of epidetnioiogic data concerning dry
`eyes.
`
`Participants were separated into th.ree brealt—out groups,
`each of which submitted interim reports. Two separate commit-
`tees were formed to address the first two issues, and these
`
`committees met during the following year. The large group met
`againoneyearlatertohearanddiscussthe committee reportsand
`any additional epidemiologic information.
`
`Report of the classification Study Group
`The purpose of the group was to develop a practical
`classification of dry eye disorders and to consider which catego-
`ries of diagnostic tests might be used to discriminate between
`different disorders. The Standardization of Clinical Tests Group
`paid particular attention to the precision and accuracy of the
`recommended tests and their availability to clinicians and the
`research community.
`The aims of the Classification Study Group were:
`1. To produce a global‘ definition of dry eye.
`2. To define the major classes. subclasses, and types of dry
`eye.
`
`3. To recognize the existence of dry eye states of mixed
`etiology.
`4. To define the diagnostic tests, with examples, which
`might be applied.
`The current terminology of dry eye is complicated by
`different usage between different countries. The farniliat‘ term
`KCS was coined by Sjogren to define the ocular surface disorder
`accompanying the autoimmune exocrinopathy that he defined. ' 3
`This is how the ten-n is used in somecountries. However. in other
`
`“ The term global‘ in this context refers to the broad area of dry eyes
`encompassing all‘ the subsets
`
`E:|z:m9119I§GoIIlLe1Lan|AIIontltiorIo!Opri'fl\ak1Io|ogls1:
`
`the CLAO journal
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`- October 1995 - Volume 21,Num.ber4
`221
`
`1
`
`ALL 2022
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01129
`
`
`
`countries, the tenn Sjogren syndrome-KCS is used to define the
`ocularsurfaoe disease thatoecursin Sjogren syndrome. and non-
`Sjogren KCS is used to define ocular surface disease due to
`primary. age-related lacrimal insufficiency. This is an accept-
`able useofthe term KCS as long as it is understood that there are
`other forms of lacrimal insufficiency that give rise to dry eye.
`such as that due to sarcoidosis. AIDS. or graft-versus-host
`disease.
`
`The term KCS is also used as a synonym fordry eye. With
`this use. the term is applied equally to disorders involving
`lacrimalinsufficiency and thoseassociated withexcessiveevapo-
`ration of tears, such as meibomian gland disease.
`Because of this varied use of the term KCS, it is not
`possible to justify one particular use as opposed to another.
`Therefore. in the classification that follows, the broader defini-
`tion is used and KCS is taken to be synonymous widt the general
`termdryeye.
`
`The global aspects of dry eye
`A GlobalDefinition: Dry eyeis mostfrequentlycaused by
`a decrease of lacrimal gland function but may also occur when
`lacrimal gland function is normal. The various etiologies may
`act independently or may interact to cause dry eye. These
`disorders orcombinations have features in common which may
`be embraced by this single definition:
`
`Dtyeyerlsadisarderofflzetetarfibuduerarear
`deficiencyorexcessivetearempomnbn whichcauses
`damage to the interpalpebvalocular surface andis
`associated with symptoms ofocular discomfort
`Because the definition is global. it is appropriate for any
`etiology of dry eye and does not describe a specific cause.
`Although it embraces most causes, it must be recognized that it
`is an operational definition that may need to be modified for
`specific situations. Also. the definition is rrtinimal, and it should
`not be concluded that the features of dry eye are limited to this
`definition. Thus:
`
`1. The definition states that ocular surface damage is
`"interpalpebral" in dry eye. This is usually due case but
`should not be regarded as always so. Ocular surface
`damage in dry eye may spread beyond the interpalpcbral
`region of the globe to affect the superior surface of the
`globe.
`. Dry eye usually causes symptoms, but the possibility is
`acknowledged that in some patients in whom the diagno-
`sis is strongly suggested on the basis of signs, symptoms
`could be absent. Since the operational criteria usually
`employed for the diagnosis of dry eye would ordinarily
`include a symptom score, a small fraction of individuals
`will beexcluded by the above definition. This would have
`to be acknowledged in certain protocols.
`. In the same way. a dry eye condition could exist, sup-
`ported by symptoms and signs (e.g., reduced tear secre-
`tion), and yet it might not be possible to show ocular
`surface damage by current methods. This possibility
`should be recognized and again would need to be ac-
`
`counted for in certain protocols.
`
`Global criteria for dry eye
`The global definition recognizes a commonality among
`all forms of dry eye which can be used to develop diagnostic
`tests. Global criteria are required for the diagnosis of dry eye
`which. like the global definition, do not necessarily identify a
`particular etiology. The working group considered that most
`forms of dry eye will exhibit the following features:
`I. Symptoms
`2. Interpalpebral surface damage
`3. Tear instability
`4. Tear hyperosmolarity
`
`Global tests for dry eye
`The above features are embodied in the following tests.
`which are proposed as global tests for dry eye:
`1. Validated questionnaire of symptoms
`2. Demonstration of ocular surface damage
`3. Demonstration of tear instability
`4. Demonstration of tear hyperosmolarity
`A Validated Questionnaire of Symptoms.‘ Because an
`important therapeutic goal‘ is to improve symptoms. all clinical
`trials concerning the treatment ofdry eye include an assessment
`of symptoms. which include heaviness ofthe lids. foreign body
`sensation. binning, stinging. and photophobia.
`Validated questionnaires (in certain age groups)areavail-
`able which attempt to characterizedry eye in tenns ofsymptoms
`and for which sensitivity and specificity information has been
`derived. "-" It is proposed that a positive response to such a
`questionnaire be included within the global criteria for dry eye.
`As noted by the Epidemiological Study Group, a ques-
`tionnaire can be used to obtain data that would lead to a wider
`underslandingofthedemographics ofdryeye. as well as medical
`and other risk factors. These aspects are dealt with elsewhere.
`flemonstrnn‘onafOcularSu:1'aceDamage.- 0cularsur-
`face damage may be demonstrated in several ways. Ocular
`surface damage can be quantified using vital dyes. Rose bengal
`staining has been incorporated into international standards for
`the diagnosis of Sjogren‘s and non-Sj6gren‘s dry eye. ‘H’ Van
`Bijsterveld (1969) described a scoring system for nose bengal
`staining. which has high sensitivity and specificity."-'
`Recently Lissamine Green has been offered as an altcma-
`tive that is rnorereadily tolet-ated."'Fluoresceinmay alsobeused
`as an alternative if the fluorescence from the ocular surface or
`conjunctiva and cornea is viewed through yellow filters."
`—
`It is recommended that surface darnage—assessed by
`staining with vital dyes—be used as a global criterion ofdry eye.
`Details of the rose bengal and other tests are described in die
`report of the Working Party on Diagnostic Tests.
`Other forms of ocular surface damage or reaction may be
`encountered in dry eye. The various indices ofchange are listed
`in Table l. Most of these have not been incorporated into
`
`'3ett.ritr'vr'.t3«mtdspecificilyarespecific togroup srudiea‘(e.g.. age. .rex)a.r:d‘
`are dependent on actual criteria used to establish rt diagnosis.
`
`2
`
`
`
`TABLE I Indioes of Surface Damage in Dry Eye
`
`TABLE Ii Maior classes at dry eye
`
`Fall in area oi corneal epithelial cells
`Flise in area of conjunctival epithelial cells
`Fall in the nucleadcytoplasmic ratio
`Presence of Snake chromatin
`
`Fall in goblet cell density
`Increased squamous metaplasia
`
`diagnostic tests.
`Demonstration of Tear Iostabr'lt'r_y.- Nom" and Lamp”
`recommended recording the break-up of the tear film after the
`instillation of fluorescein dye as a test of tear stability. The
`(fluorescein) tear brealr—up time (BUT or FBUT) has been
`shown to be dependent on the reduction of tear surface tension
`by mucins.” When tear mucin is reduced, as reflected by a fall
`in conjunctival goblet cell density” or a rise in tw surface
`tension.” the BUT is also reduced.
`Goblet cell density is reduced in a number of forms of dry
`eye Ife.g., in disorders of the lacrimal and of the meibomian
`glands) with resultant reduction in BUT. It is not known to what
`extent ocular surface mucin,” as opposed to goblet cell mucin.
`contributes to the reduced BUT of dry eye, or whether there are
`other contributing factors. However. BUT offers a valuable
`parameterto include within the diagnostic global criteria for dry
`eye.
`
`It should be noted that tear surface tension would make a
`
`reasonable surrogate testfortearstability aswoulddirect tests of
`tear mucin. which are currently under development. Unfortu-
`nately. neither of these tests is currently available for routine
`clinical use.
`
`It is recommended that a test of tear stability (BUT) be
`used as a global criterion of dry eye.
`Demonstmlion of Tear Hypenismohzrfly: Convincing
`arguments have been advanced which suggest
`that
`hyperosmolarity is the common denorninator between all forms
`of dry eye. Tear hyperosmolaiity has been demonstrated in
`experimental studies of tear deficient and evaporativc dry eye;
`
`Tear-Deficient Dry Eye
`
`Non-Sifigran dry eye
`Siogren syndrome dry eye
`
`Evaporatlvo Dry Eye
`
`Blepharitis Associated
`Anterior Blepharitis
`Meibomian Gland Disease
`Ocular Mucin Deficiencies
`Blink Disorders
`
`Disorders of lid aperture and lidlglobe congruity
`Ocular Surface Disorders
`
`Other Tear iilm disorders [Contact lens ind=uced'?]
`
`surface disease has been shown to be dependent on and propor-
`tional to increases in tear film osrnolarity and duration of
`disease."""—” It has been suggested that hyperosmolarity is the
`primary causative mechanism in this group of disorders, leading
`to discomfort, ocular surface damage. and inflamrnation.”
`For this reason, hyperosmolariry should be regarded as an
`important global criterion forthc diagnosis ofdry eye. However,
`a simple technique to measure tear hyperosmolarity is not yet
`readily available to all researchers and clinicians. The freezing
`point depression method is expensive and technically difficult.”
`Although measurement of osmolarlty by the water vapor pres-
`sure method is simple, the technique must be sufficiently tested
`in dry eye conditions.” For this reason. meastuement oftear film
`osmolarity will be regarded as a secondary test until such time
`as a prevailing test is available.
`It is recommended that liyperosmolarity be used as a
`global criterion of dry eye by those researchers who have an
`accurate means of testing available.
`Other criteria for the global diagnosis of dry eye may also
`be considered. such as the tear feming test, which has been used
`for diagnostic purposes and to identify degree of severity.“
`
`us: / mousrav wnnrcsnop
`1 995
`CLASSIFICATION OF DRY EYE
`DRY EYE - KGB
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`0 October 1995 0 Volume 2l.Numbcr4
`223
`
`3
`
`
`
`Major classes of dry eye
`Dry eyes may be assigned to two major classes: Tear-
`deficient dry eye and evaporative dry eye (Table 1]). Relation-
`ships may be more clearly seen in Figure l. which is a
`diagnostic algorithm based on this classification.
`1. In tear—deficient dry eye, there is a disorder of lacrimal
`function or a failure of transfer of lacritnal fluid into the
`conjunctiva] sac. This results in a reduction in the flow of
`tears and a fall in volume of tears in the conjunctiva] sac.
`Lacrimai disease is associated with a quantitative reduc-
`tion in secreted lacrimal pmteins.” Tear-deficient dry eye
`is the largest category of dry eye.
`. In tear-sufficient dry eye, lacrimal function is normal, and
`in most cases if not all. the tear abnormality is due to
`increased tcarevaporation.” It may reasonably be termed
`evaporative dry eye.
`Each of the disorders listed in Table I] is considered to be
`independently capable ofcausingdryeye. Some ofthe disorders
`may occur together and act in concert to cause dry eye. An
`example of the latter is the common association of aqueous-
`deficient disease with obstmctive meibomian gland disease.
`Each of these disorders is considered from the dry eye
`aspect only, although many of them may cause changes to the
`external eye in addition to those that are the basis forthe dry eye.
`The scarring of cicatricial conjunctivitis is one example. Such
`features help to make up the disease picture typical for this form
`ofdry eye. In some instances there may be uncertainty as to the
`contribution ofthese accessory factors to the dry eye picture and
`they may act as a confounding influence in diagnosis. Thus the
`symptoms suffered byapatient with anteriorblepliaritis withdry
`eye are likely to be due to the inflammatory lid disease as well
`as to the dry eye and the signs of interpalpebral staining after
`ttigeminal sectionarelikely tobedue to neuralcausesinaddition
`to dry eye.
`It should also be recognized that diseases which can cause
`diyeye may at times cause changes in theexternal eye whichare
`not sufficient togive rise to dry eye. Thus lacrirnal function may
`be reduced as part of the aging process without producing the
`signs or symptoms ofdry eye. Sarcoidosis ofthe lacrimal gland
`need not decrease tear secretion if damage to lacrimal function
`is limited. Cicatrizing conjunctiva] disease does not always lead
`to dry eye. nor does obsuuctive meibomian gland disease. The
`occurrence of disease or the demonstration of selected signs
`alone may be insufficient to make a diagnosis (Figure 2).
`Tear-deficr'em‘Dry Eye: There are a number of forms of
`tear-deficient dry eye (TDDE). This category requires the dem-
`onstration of defective lacrimal function. Defective lacrimal
`function is usually demonstrated by showing reduced aqueous
`tearvolume and tear flow. The standard measure is the Schin-ner
`test. which has been validated by van Bijsterveld” and is
`recommended by the Working Party on Diagnostic Tests.
`Other indicators of reduced tear function include the
`lacrimai thread test,” the Periotron test“, fluorophotometry, or
`thedemonstrationofreducedsecretion oflacrimal proteins, such
`as lysozyme or lactoferrin.”»‘" This is discussed further by the
`Working Party on Diagnostic Tests.
`
`Figure 2 Dry eye diagnosticpirtwheel. Cr-r'ten'.ofor the diagrrosir ofclry
`eye are presented. The hub ofthe pin wheel represents the criteria applied
`to csrabfish theglobaldiagnosis ofdry eye. These characterize the discrete r
`ofdry eye without specifying coarse. Two or more are necessoryfizr the
`.idenrr_'fico:ion ofdry eye state. Thecrireriofor oqueonsdeficientdry eye are
`above the horizontal line; below the horizontal lit-re are criteria for
`evopomtive (aqueous sufiicienrl dry eye. Tcrrsfor Sjéignen xyrrdmrrre are
`or upper left. irmer sector; resrsfor Non-Sjogren aqueous deficient dry eye
`are or upper right.
`inner sector. See text for full discussion. (PAN =
`polyor1err'ri.r nodoro; PU): primary lacrirrrol gland o‘iseo.re.- .S'i'..E =
`iyrrenric lupus eryrfrerrrarosrtr: WEG = Wegemn-'.r grarrulonIal'asl$.' Sysr
`St‘! = systemic sclerosis; Mixed Cl": mireol-combined: Con Ala: =
`congenital olocnirno; C vs. ll: Graft vs. Hour disease.’ Cong. Defic.
`congenital deficiency; Surface di.t=.rrr:)"oce disease. ) .j
`
`Tests for a reduction in tea: secretory rate or volume may
`be regarded as the primary tests for the aqueous-deficient dry
`eye, since they are most directly related to the presumed damage
`mechanism. It is thought that tests for deficiency of lacrirnal
`proteins can be regarded as surrogate tests of lacrimal dysfunc-
`tion since they do not initiate ocular surface damage. It has been
`suggested that deficiency oflacrimai protein may be the earliest
`Sign of aqueousdeficient dry eye."
`TDDE may be divided into two majorcategories: Sjogren
`Syndrome Tear Deficiency (SSTD) and non-Sjiigren Tear De-
`ficiency (NSTD). In NSTD there are none of the systemic signs
`or clinical manifestations of autoimmune disease. which are the
`hallmarks of SSTD.
`
`Siociuavsvnneoiae Tern DEfiClENC‘|': Sjogren syndrome
`is anexocrinopathy affecting the lacrimalandlorsalivary glands.
`The syndrome may be primary or secondary.
`Primary Sjogren syndrome consists of the features oftear-
`deficient dry eye in combination with a dry mouth, the presence
`of autoantibodies and a positive focus score on minor salivary
`gland biopsy."-*5 Tests for dry mouth and for the presence of
`
`the CLADjoI.Il'ltal * October 1995 0 Volume 21. Number 4
`224
`
`4
`
`
`
`TABLE III Tests for dry mouth and salivary entocrlnopathy‘
`Salivary Features
`
`Focus score 5 1 on minor salivary gland biopsy
`Salivary scintigraphy
`Parotid sialography
`Unstirrtulated salivary flow (5 1.5m| in 15 minutes)
`Auto-Antibodies
`
`Anti Flcu'SS-A or La!SS-B
`Anlinuoulear antibodies
`Rheumatoid factor
`
`'Fl'Dl".l'l Fl'e!ersncas 16‘, 17. F8
`
`autoantibodies and other serological evidence of connective
`tissue disease are given in Table 111.
`Secondary Sjogren syndrome consists of the features of
`primary Sjbgren syndrome in conjunction with overt clinical
`manifestations of an autoimmune connective tissue disease.
`Some of the autoimmune connective tissue diseases in which
`Sjiigren Syndrome occurs are listed in Table IV. Of these.
`rheumatoid arthritis is the most common. Various criteria have
`been established for their diagnosis.
`NON-Sroctutn Tsut DEFICIENCY: The various forms of
`non-Sjiigten tear-deficient dry eye are listed in Table V.
`1. Primary Lacrimal Deficiency (PLD)
`Congenital alacrimm Although its specific cause is not
`yet known, congenital alacrima is assumed to be a primary
`disorder of the lactimal gland. The most prevalent form of PLD
`is acquired and sometimes referred to as non-Sjiigren KCS. it is
`more common in women. and its frequency increases with age.
`It results from a gradual destruction of lacrimal gland and ductal
`tissue by a round-cell infiltration .“-’-‘-‘ An immune mechanism of
`lacrimal tissue destruction is not excluded. Since the mechanism
`for gland destruction is unknown, it is appropriate to refer to this
`condition as acquired PLD. PLD shows the features of aqueous-
`deficient dry eye in the absence of signs of autoimmune disease
`or features of other forms of aqueous-deficient dry eye (Table
`V).
`
`2. Secondary Lactimal Deficiency
`Sarcoi'dorr'.r: Infiltration ofthelacrimal glands with sarcoid
`granulomata may cause dry eye.“
`Lymphoma: In the same way, infiltration of the lacrimal
`glands with lymphomatous cells may cause dry eye.“
`HIV infection: Dry eye was detected in 21 ‘F: of a group of
`patients widt AIDS. and in another study of AIDS patients with
`
`TABLE N Autoimmune connective tissue disease associated
`with secondary Siogran syndrome
`
`Rheumatoid arthritis
`Polyanaritis
`wegeners granulornatosis
`Systemic lupus erythematosus
`Systemic sclerosis
`Primary bilary cirrhosis
`Mixed connective tissue disease
`
`Congenital alacrima
`Acquired lacrimal disease‘
`Secondary
`Sarooidosis
`HIV
`Graft vs. Host disease
`Xerophthalmia
`Dacrycadenilis
`Lacrimal gland ablation
`_.j_j_j_____j_j_j
`Lacrimal Obstructive Disease
` .j__j_j_
`Trachoma
`Cicatricial pemphigoid
`Erythema multitomte
`Bums
`Congenital lid deformity
`Trauma
`
`Atoplc lteratoconjunctivitis
`
`Reflex I-fypooeeretlon
`
`Nouroparalytic keratitis
`Chronic contact lens wear
`
`Proximal VII Cranial Nerve Palsy
`Uncertain Category_
`Multiple neuromatosis
`Crl cu Chat Syndrome
`‘Synonym: Non-Sjdgrsn K05‘
`
`xetostomia, there was a positive focus score on salivary gland
`biopsy of 2 or more.“ However, in this study. the predorninant
`T-cell population was of suppressor lymphocytes (CD8). rather
`than the helper subset (CD4) characteristic of Sjogren syn-
`drome.
`
`Graft versus Hort Dllfeale.’ Associated with dry eye.
`Vitamin}! deficiency t’Xerophthalmio): Reported tocause
`dry eye by two distinct mechanisms. Loss ofconjunctival goblet
`cells and probably other surface mucin sources are responsible
`for one form of dry eye with normal lacrimal function. This is
`discussed below. A tear-deficient form of dry eye has also been
`reported.“
`Lacrimal Glartrli-iblariou: Removal of the main lacrimal
`gland is a further cause of tear loss.”
`
`3. Reflex (neural) Causes ofEvaporative Dry Eye (Table
`
`VI)
`
`Sensory: Tear secretion is in part, if not wholly. reflex in
`origin. Reduced sensory function facilitates drying by two
`mechanisms: sensory loss causes decreased tear secretion” and
`when bilateral. reduces the blink rate. For instance. topical
`proparacaine applied bilaterally decreases the blink rate by
`about 30%" and causes adecrease intearsecretion of60-75%.”
`Loss of corneal sensation is a feature of contact lens wear
`and has been proposed as a mechanism for dry eye associated
`
`llIcCLAOjut:mal 0 October 1995 0 Volurne 21. NI.Imber4
`225
`
`5
`
`
`
`?__j_j,_,___j___j__j
`TABLE VI Causes of corneal and conjunctiva] sensory loss
`
`-
`
`Herpes simplex
`Herpes zostor
`corneal Surgery:j__
`Limbal incision
`Corneal graft
`Fhotoablalive keratoplasty
`Refractive Keratoplasty
`Radial Karatop-tasty_:___j_
`Nauroperalytlc Keratltis?
`
`Injection of trigeminai ganglion
`Tumor
`
`Section of seventh cranial nenre
`_%j.____
`Topical Medicationsmm
`Topical anesthesia
`Beta blockers
`
`Atropine-like drugs
`_.j.j.j+_:____j___j._?
`other Causes
` _j_
`
`Long-_tem1 contact tans wear
`Diabetes Mollitus
`Aging_%...j.f
`(modified from GMWIJ‘ JP.‘ Dry Eye Disorders in Principles and Practice of
`Ophthalmology. A.lborrDM, Jaaltobic FA (eds): Phfladelprila. W.B.
`Saunders Gmmany, 1.994. pp. 257-2711)
`
`with long-standing contact lens wear,"-*3 particularly a.mong
`hardandextendedweareontact lens users.1ncI'eascdosmolality
`has been demonstrated in association with contact lens wear.”
`Neurotrophic lceratitis, caused usually by unilateral sen-
`soryloss inthe distribution of the first division ofthe fifth cranial
`nerveisassociated with asevere ocular surfacedisorder. This is
`partly due to a loss oftrophic function of the trigeminal nerve."
`The Bengal Rose staining, decreased conjunctival goblet cell
`density, and loss of corneal epithelial glycogen seen in experi-
`mental neurotrophjc keratitis resembles that encountered in dry
`eye}:
`.
`
`Motor: Seventh nerve palsy involving the ncrvus
`intermedius (as in posterior fossa tumors) interferes with the
`secretomotor fibers to the lacrimal gland and may cause dry eye
`in association with a facial nerve palsy.“
`Other: Dry eye has also been reported with multiple
`neuromatosis.”
`4. Obstructive Lacrimal Disease
`
`Cicatrizing conjunctiva! disease causes aqueous tear de-
`ficiency by scarring the orifices of the orbital and accessory
`lacrirnal glands. Among the several causes of conjunctiva]
`scarring. those disorders that are associated with dry eye are
`listed in Table V and include the following:
`Tradtorrta: Trachoma is one of the major causes of
`blindness on world-wide scale;a.nd conjunctiva] and lid scarring
`contribute in acomplex way. causing dry eye through cicatricial
`
`conjunctivitis, lid distortion. and cicatricial rneibomian gland
`disease.
`
`Cicorrictal‘ pentphigor'd.' Cicatricial pemphigoid is a
`derrnatosis characterized by blistering skin and mucosal lesions
`and the presence of deposits of IgG (and complement compo-
`nents) in the lamina Iucida of the basement membrane of
`periiesional skin.“ Subepidetmal scarring affecm the skin and
`conjunctiva and in the conjunctiva may be progressive and
`severe.
`
`Erythema rmtt't{fom-r.e.- Erythema multiforme is an acute,
`self-limited. blistering dennatosis which isoftcmbutnot always,
`precipitated by drugs. infection or malignancy. It is character-
`ized clinically by typical target lesions in the skin which show
`central arteriolar and venular necrosis resembling those seen in
`hypersensitivity reactions. There are IgM and complement
`deposits in the skin
`Chemical and thermal brrms: Diffuse chemical or ther-
`mal bums may result in conjunctival scarring sufficient to cause
`dry eye.”
`
`These forms of tear-deficient dry eye are distinguished
`front each other and from idiopathic dry eye by specific criteria.
`It is sufficient here to give an example of such criteria for one
`disorder. The dry eye caused by crythema multiforme is charac-
`terized by the features oftear-deficient dry eye. a clinical history
`typical of erythema multiforme, and cicatricial conjunctival
`changes involving the orifices of the lacrimal gland ductules.
`Serological and immunohistological features could be accepted
`in addition.
`
`In establishing positive criteria for any disorder. it is also
`implied that exclusion criteria are established. These are often in
`an opposite sense to the inclusion criteria. In this instance. it is
`implied that positive features ofSjogren syndrome areexclusion
`criteria and there are no features suggestive of other cicatrizing
`conjunctiva] disorders.
`Evqpomtive Dry Eye (EDE) (Tear Sufliciem): Dry eye
`can occur where lacrimal function is nomtal and the volume and
`composition of the lacrirnal fluid are adequate and regarded as
`sufficient, with the tear abnormality created by other periocular
`disease. usually leading to increased tear evaporation. The
`conditionsarcrcasottably referred toasevaporative forms ofdry
`eye. Each ofthese disorders is independently capable ofproduc-
`ing dry eye.
`
`Blephar-iris: It is known that anterior blepharitis may be
`associated with punctatc lteratitis. It is less clear that anterior
`blepharitis. independent of other forms of lid disease. can cause
`dryeye. Sltinlipid wi|lbreakupthenon'naltearfilm."“Ithas been
`postulatedthat desquamated cells derived from the lid margin in
`squamous blepharitis may deliver such lipid to the tear film and
`give rise to punctate keratitis by causing tear instability and
`increased tear evaporation. However, there is also the view that
`qualitatively altered meibomian lipid may directly damage the
`ocular surface?" in which case the surface damage arises by a
`different mechanism.
`
`It can be seen that the diagnosis ofdry eye based solely on
`the administration of a questionnaire and on the presence of
`interpalpebral staining could be vulnerable to confounding.
`
`the CLAOjoumai - October 1995 - Volume 2l,Number4
`226
`
`6
`
`
`
`TABLE VII Meibomian gland diseases
`1. Reduced number
`2. Replacement
`
`Congenital Deficiency“
`Distic-l1iasis5‘
`Mataplastic
`Secondary
`3. Hyposecretory‘
`4. Obstructive maibomitis°‘~“-‘5-“-‘°
`Focal or dlftuse“
`Primary. or secondary to:
`Local Disease
`Anterior Blepharitis;
`Conjunctivitis, e.g.. Ttachoma; Pernphigoid; Atopy:
`Chemical Bums
`Systernic Disease
`Seb. Demtatitis"
`Acne Hosacea“
`Atopy“
`lchthyosiss‘
`Psoriasis“
`
`Anhydrotic Eet. Dyspl
`Ectrodactyly Syndromes‘-55
`Turner Syndrome
`Fungal”-5'
`Toxic:
`13-Cis Ftet Acid5"“°-‘°
`Polychlorinated Bipher'ry|s"-"-
`(Rabbit) Epinephrine”
`'
`
`Meibomien Seborrhoea*’«“‘~"‘
`
`Other
`
`Internal Hordeolum
`Chalazion
`Concretiorts
`
`5. Hypersecretoryl
`6. Neoplastic
`7. Suppurative
`
`Disorders ofLidAperture andLr'aIv‘Globe Congnury: The
`increased width of the palpebral aperture which occurs with
`proptosis in thyroid disease is associated with ocular drying and
`tear hyperosmolarity."
`Drying of the ocular surface due to lid deformity and poor
`resurfacing of the ocular surface with tears. is generally ac-
`cepted. but has received little study.”
`Ocular Surface Disorder: Although any elevation of the
`ocular surface is associated with local surface drying, the cre—
`ation of such dry spots is rarely confused with dry eye.
`However, in one disorder. xerophthalrnia, aqueous-ad-
`equate and aqueous-deficient dry eye can both occur. with
`defective surface wetting (xerosis) associated with surface meta-
`plasia.“ Ocular sLu'face changes have been well documented and
`include goblet cell loss.” Although the mctaplasia could be due
`emirelytogobletcell loss. it isalso possible that itisdue to a more
`subtle abnormality of the surface glycocalyx caused by the
`vitaminAdeficiency itself."‘Itisforthis reason thatthiscategory
`is retained.
`
`Other Tear Filrn Disorders: This category is inserted in
`recognition that there may be other, as yet undetemri ned. causes
`of dry eye. This will include those disorders which cause ocular
`surface damage in the presence ofmortal lacritnal function, and
`whose mechanism is as yet unclear. This could include some
`ocular surface disorders due to contact lens wear. including
`drying of the ocular surface under a high water content soft
`lens.“
`
`Combined Disorder: Any of the disorders discussed
`above. whether aqueousdeficient or aqueous -adequate may
`occur in conjunction with any other, and several of them
`commonly do. Lacrirnal gland deficiency may be accompanied
`by meibornian gland deficiency and cicatricial conjunctival
`disease may cause dry eye both by occlusion of the lacrimal
`gland ductules. and by causing a lid incongruity which interferes
`with tear resurfacing with each blink.
`When the signs of more than one form of dry eye are
`present. it may not always be possible to differentiate their
`relative contribution to the dry eye state.
`
`Report of the Standardization of Clinical Test Study
`Group (Tables VIII and IX)
`It has been found that lacrima] kinetics. tear secretion rate.
`age, questionnaire results, and non-invasive tear breakup time
`are not correlated in non-dry eye subjects." In clinical treatment
`trials, correlation between Schirmer tests. rose bengal staining.
`and impression cytology have not been found.” If the results of
`these testsdonotcorrelate with each other, findingasingle“gold
`standar ” may not be possib