Report of the National Eye Institute/Industry
`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 rubric to
`describe a variety ofconditions ofdiverse origin which affect the
`tear film and/or the ocular surface.‘ Recent findings show
`differences between Sjogrerfs-associated keratoconjunctivitis
`sicca (KCS) and non-S_jogren’s KCS.“ Neurotransrrrittersf-5
`viruses] and honnones” 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 International 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
`“academic/clinical practice/industry/govemmental effort to de-
`velop a consensus” was issued. ' ' In response to this, the National
`Eye Institute and leading industry groups sponsored a National
`Eye Institute/Industry 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 1994 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 was drafted 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 and/or 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 governmental
`agencies met. Individuals were invited to participate based on
`their clinical contributions to the field, corporate responsibili-
`
`ties, and/or 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:
`
`l. 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 epidemiologic data concerning dry
`eyes.
`'
`Participants were separated into three break-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
`again one year later to hearand discuss the committee reports and
`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 familiar term
`KCS was coined by Sjogren to define the ocular surface disorder
`accompanying the autoimmune exocrinopathy that he defined. ‘ 3
`This is how the term is used in some countries. However, inother
`
`* The term global in this context refers to the broad area of dry eye:
`encompassing all the subsets
`
`the CLAOjoumal
`III nnhtq rncnnlnd
`Copyright 1995 Contact Lana Association ot Ophthalrnologists
`
`' October 1995 - Volume 21, Number4
`221
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`ALL 2022
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01132
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`

`countries, the term Sjogren syndrome-KCS is used to define the
`ocular surface disease thatoccurs in 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 use ofthe 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 fordryeye. With
`this use, the [em is applied equally to disorders involving
`lacrimalinsufficiencyandthoseassociated 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.
`V Therefore, in the classification that follows, the broader defini-
`tion is used and KCS is taken to be synonymous with the general
`term dry eye.
`
`The global aspects of dry eye
`A GlobalDefinition: Dry eye is most frequently caused 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 or combinations have features in common which may
`be embraced by this single definition:
`
`Dry eye is a disorder of the tear film due to tear
`deficiencyorexcessive tearevaporation which causes
`damage to the interpalpebral ocular surface and is
`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 modifiedfor
`specific situations. Also, the definition is minimal, 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
`“intcrpalpebral” in dry eye. This is usually the case but
`should not be regarded as always so. Ocular surface
`damage in dry eye may spread beyond the interpalpebral
`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 diagnc»
`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 be excluded 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 rriight 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 fomis 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:
`1. 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 of dry eye include an assessment
`ofsymptoms, which include heaviness ofthe lids, foreign body
`sensation, burning, stinging. and photophobia.
`Validated questionnaires (in certain age groups) are avail-
`able which attempt to characterizedry eye in terms ofsymptoms
`and for which sensitivity and specificity information has been
`derived."-'5 It is proposed that a positive response to such a
`questionnaire be included witlnn the global criteria for dry eye.
`As noted by the Epidemiological Study Group, a ques-
`Iionnaire can be used to obtain data that would lead to a wider
`understanding ofthe demographics ofdry eye, as well as medical
`and other risk factors. These aspects are dealt with elsewhere.
`Demonstration ofOcular SurfaceDamage.' Ocular sur-
`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 Sj6gren’s and non-Sj6gren’s dry eye.“*‘3 Van
`Bijsterveld (1969) described a sco ' g system for rose bengal
`staining, which has high sensitivity and specificity.”
`Recently Lissamine Green has been offered as an altema-
`tive that is more readily tolerated.’°Fluorescein may 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 damage—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 the
`report of the Working Party on Diagnostic Tests.
`Other forms ofocular surface damage or reaction may be
`encountered in dry eye. The various indices of change are listed
`in Table 1. Most of these have not been incorporated into
` *_
`’‘Sensitivity andspecificityare specific to group studied(e.g., age, sex) and
`are dependent on actual criteria used to establish a diagnosis.
`
`the CLAO journal ' October 1995 - Volume 21, Number4
`222
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`

`

`TABLE I lndices of Surlace Damage in Dry Eye
`
`TABLE II Major classes of dry eye
`
`Fall in area of corneal epithelial cells
`Rise in area of conjunctival epithelial cells
`Fall in the nuclear/cytoplasmic ratio
`Presence of Snake chromatin
`
`Fall in goblet cell density
`Increased squamous metaplasia
`
`diagnostic tests.
`Demonstration of Tear Instability: Nom" and Lemp”
`recommended recording the break-up of the tear film after the
`instillation of fluorescein dye as a test of tear stability. The
`(fluorescein) tear break—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 tear surface
`tension,“ the BUT is also reduced.
`Goblet cell density is reduced in a number of forms of dry
`eye (e.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
`parameter to include within the diagnostic global criteria for dry
`eye.
`
`It should be noted that tear surface tension would make a
`
`reasonable surrogate test for tear stability as would direct 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.
`Demonstration of Tear Hyperosmolarity: Convincing
`arguments have been advanced which suggest
`that
`hyperosmolarity is the common denominator between all forms
`of dry eye. Tear hyperosmolarity has been demonstrated in
`experimental studies of tear deficient and evaporative dry eye;
`
`Tear-Deficient Dry Eye
`
`Non-Sjogren dry eye
`Sjégren syndrome dry eye
`
`Evaporative Dry Eye
`
`Blepharitis Associated
`Anterior Blepharitis
`Meibomian Gland Disease
`Ocular Mucin Deficiencies
`Blink Disorders
`
`Disorders of lid aperture and lid/globe oongruity
`Ocular Surlace Disorders
`
`Other Tear film disorders [Contact lens induced?]
`
`surface disease has been shown to be dependent on and propor-
`tional to increases in tear film osmolarity and duration of
`disease.23‘3'-‘5 It has been suggested that hyperosmolarity is the
`primary causative mechanism in this group of disorders, leading
`to discomfort, ocular surface damage, and inflanrrnationfiz
`For this reason, hyperosmolarity should be regarded as an
`important global criterion for the diagnosis of dry 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 osmolarity by the water vapor pres-
`sure method is simple, the technique must be sufficiently tested
`in dry eye conditions.” For this reason, measurement oftear film
`osmolarity will be regarded as a secondary test until such time
`as a prevailing test is available.
`It is recommended that hyperosmolarity 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.“
`
`NEI / mousrnv WORKSHOP
`1 995
`CLASSIFICATION OF DFIV EYE
`DRY EYE - K05
`
`Tear-deficient
`
`Sjogren
`Syndrome
`
`Non—Sjogren
`Tear Deficient
`
`Lacrknal
`
`Lacrimal
`
`9
`
`‘I
`
`2"
`
`Congenital Sarcoid
`RA.
`Yrnchoma.
`alacrimn.
`I-IIV
`SLE
`Clcatrieiul
`FLD
`in. Heat
`Syscl
`Ervlherrul
`Xeroomrralmla
`nrultltormu.
`-
`.
`= r...
`;
`.
`n.A. . mam»-run an:-nu
`Syid . Iyuhmkz udovullu
`SLE - -v-nun: up-an urvmuruouuu
`1- an - n-vn-v biurv ermro-b
`-w-9-urn pmummu.
`on... -eo..u.n.an.nm-ai-.u.-
`w.
`
`wowDru
`
`NP. kararm
`Contact Ions
`
`Deficient
`°"
`
`Related
`
`Lens
`
`Change
`"‘°°
`
`o
`
`2°
`
`PDGICIIH
`Anaanr
`Glands
`bIup'Il!ItIG.
`Dlslichinnls Obolmcllvo
`MGD
`
`Anterior
`no-prune
`7
`
`MP. imam. - uunpu-mu: hummi-
`noMar:
`.;.mr-ryrua-n-ruruuu-ng
`—nn§uvI‘n»uhndaon—o
`
`cum: —uuuo.—-nnuu
`new ..p—un-woman-u
`covusn.n..-v-a.o.am¢nn,
`
`Figure 1 Classification system and
`diagnostic algorithmfor dry eye. (See
`texrfarfirll discussion.)
`
`the CLAO journal - October 1995 - Volume 21. Number4
`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 H). Relation-
`ships may be more clearly seen in Figure 1, 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 lacrimal fluid into the
`conjunctiva] sac. This results in a reduction in the flow of
`tears and a fall in volume of tears in the conjunctival sac.
`Lacrimal disease is associated with a quantitative reduc-
`tion in secreted lacrimal proteins.” Tear—def'1cient 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 tear evaporation.” It may reasonably be termed
`evaporative dry eye.
`Each of the disorders listed in Table II is considered to be
`independently capable ofcausing dry eye. Some of the 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 obstructive meibornian 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 for the dry eye.
`The scarring of cicatricial conjunctivitis is one example. Such
`features help to make up the disease picture typical for this form
`of dry 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 sufferedby apatient with anteriorblepharitis with dry
`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
`trigeminal section are likely to be due to neural causes in addition
`to dry eye.
`
`It should also be recognized that diseases which can cause
`dry eye may at times cause changes in the external eye which are
`not sufficient to give rise to dry eye. Thus lacrimal function may
`be reduced as part of the aging process without producing the
`signs or symptoms of dry eye. Sarcoidosis of me 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 obstructive meibomian gland disease. The
`occurrence of disease or the demonstration of selected signs
`alone may be insufficient to make a diagnosis (Figure 2).
`Tear-deficientDry Eye: There are a number of fonns 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
`tear volume and tear flow. The standard measure is the Schirmer
`test, which has been validated by van Bijste'rveld” and is
`recommended by the Working Party on Diagnostic Tests.
`Other indicators of reduced tear function include the
`lacrimal thread test,” the Periotron test”, fluorophotometry, or
`thedemonstration ofreduced secretion oflacrimal proteins, such
`as lysozyme or lactofen-in.”“° This is discussed further by the
`Working Party on Diagnostic Tests.
`
`Figure 2 Dry eye diagnostic pinwheel. Criteriafor the diagnosis ofdry
`eye are presented The hub ofthe pinwheel represents the criteria applied
`to establish the globaldiagnosis ofdry eye. These characterize the disorder
`ofdry eye without specifying cause. Two or more are necessaryfor the
`identification ofdry eye state. The critedaforaqueous deficient dry eye are
`above the horizontal line; below the horizontal line are criteria for
`evaporative (aqueous suflicient) dry eye. Testsfor Sjdgren syndrome are
`at upper left, innersector; tesrsfor Non-Sjdgren aqueous deficient dry eye
`are at upper right, inner sector. See ten for full discussion. (PAN =
`polyaneritis nodosa; PLD= primary lacrimal gland disease; S!£ =
`systemic lupus erythematosus; WEG = Wegener‘s granulornazosis; Syst
`Scl = systemic sclerosis; Mixed CT: mixed-combined; Con Alac
`congenital alacrima; C vs. H: Grafi vs. Host disease; Cong. Defic. :
`congenital deficiency; Surface dis=surface disease.)
`
`Tests for a reduction in tear 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 lacrimal
`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 oflacrimal protein may be the earliest
`sign of aqueous-deficient dry eye.“
`TDDE may be divided into two major categories: Sjégren
`Syndrome Tear Deficiency (SSTD) and non-Sjtigren 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.
`
`SiockmSYNDROME Tr:AnDr:r1crr~:Ncv: Sjogren syndrome
`is anexocrinopathy affecting the lacrimal and/or salivary glands.
`The syndrome may be primary or secondary.
`Primary Sjogren syndrome consists of the features oftear-
`defrcient dry eye in combination with a dry mouth, the presence
`of autoantibodies and a positive focus score on minor salivary
`gland biopsy.”'“‘ Tests for dry mouth and for the presence of
`
`the CLAOjoumal - October 1995 - Volume 21. Number4
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`

`

`TABLE III Tests for dry mouth and salivary exocrinopathy"
`Salivary Features
`
`Focus score 5 1 on minor salivary gland biopsy
`Salivary scintigraphy
`Parotid sialography
`Unstimulated salivary flow (5 1.5ml in 15 minutes)
`Auto-Antibodies
`
`Anti Flo/SS—A or La/SS—B
`Antinuculear antibodies
`Rheumatoid factor
`
`‘From References 16, 17, 18
`
`autoantibodies and other serological evidence of connective
`tissue disease are given in Table III.
`Secondary Sjogren syndrome consists of the features of
`primary Sjogren syndrome in conjunction with overt clinical
`manifestations of an autoimmune connective tissue disease.
`Some of the autoimmune connective tissue diseases in which
`Sjogren Syndrome occurs are listed in Table IV. Of these,
`rheumatoid arthritis is the most common. Various criteria have
`been established for their diagnosis.
`NON-Srocru-2N TEAR DEFICIENCY: The various fonns of
`non-Sjfigren tear—defrcient dry eye are listed in Table V.
`1. Primary Lacrimal Deficiency (PLD)
`Congenital alacrima: Although its specific cause is not
`yet known, congenital alacrima is assumed to be a primary
`disorder of the lacrimal gland. The most prevalent form of PLD
`is acquired and sometimes referred to as non—Sj6gren 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 infi]tration.“’~‘3 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 Lacrimal Deficiency
`Sarcoidasis: 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% of a group of
`patients with AIDS, and in another study of AIDS patients with
`
`TABLE IV -Autoimmune connective tissue disease associated
`with secondary Sjogren syndrome
`
`Rheumatoid arthritis
`Polyarteritis
`Wegeners granulomatosis
`Systemic lupus erythematosus
`Systemic sclerosis
`Primary bilary cirrhosis
`Mixed connective tissue disease
`
`TABLE V Conditions associated with Non-Sjogren tear deficient
`dry eye__:____::_
`Lacrimal Disease
`_____..._:.____________.j
`Primary
`Congenital alacrima
`Acquired lacrimal disease‘
`Secondary
`Sarooidosis
`HIV
`Graft vs. Host disease
`Xerophthalmia
`Dacryoadenitis
`Lacrimal gland ablation
`___.j______.j___?_:_
`Lacrimal Obstructive Disease
`j——j
`Trachoma
`Cicatricial pemphigoid
`Erythema multifomie
`Burns
`Congenital lid deformity
`Trauma
`
`Atopic keratooonjunctivitis
`j.—j_:j
`Reflex Hyposecretion
`_____.j_______.__:_____j
`
`Neuroparalytic keratitis
`Chronic contact lens wear
`
`____::___::_j_:_j
`Proximal Vll Cranial Nerve Palsy
`Uncertain category .Z_:.:
`Multiple neuromatosis
`Crl cu Chat Syndrome
`‘Synonym; Non-Sjogren KCS
`
`xerostomia, there was a positive focus score on salivary gland
`biopsy of 2 or more.“ However, in this study, the predominant
`T-cell population was of suppressor lymphocytes (CD8), rather
`than the helper subset (CD4) characteristic of Sjogren syn-
`drome.
`
`Grafi versus Host Disease.‘ Associated with dry eye.
`VitaminA deficiency (Xerophthalmia): Reported to cause
`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 Glana'Ablarion: 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 conical sensation is a feature of contact lens wear
`and has been proposed as a mechanism for dry eye associated
`
`the CLAO joumal - October 1995 - Volume 21, Number 4
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`

`

`TABLE VI Causes oflcomeal and conjunctival sensory loss
` :____:_j
`infective
`
`
`Herpes simplex
`Herpes zoster
`Corneal Surgery
`.__.j___j
`Limbal incision
`Corneal graft
`Photoablative keratoplasty
`Refractive Keratoplasty
`Radial Keratoplasty
`______:__
`Neuroparalytlc Keratitis—j-——j
`
`Injection of trigeminal ganglion
`Tumor
`Section of seventh cranial nerve__
`Topical Medications
`___._..______:_._____:.__
`
`Topical anesthesia
`Beta blockers
`
`Atropine-like drugs
`______:__
`Other Causes
`
`
`Long-ten'n contact lens wear
`Diabetes Mellitus
`Aging
` _:_______jj
`
`(modified from Gilbard JP: Dry Eye Disorders in Principles and Practice oi
`ophrhalmology. Alben DM, Jackobic FA (eds): Philadelphia, WB.
`Saunders Company, 1994, pp. 257-276.)
`
`with long—standing contact lens wearfw particularly among
`hard and extended wear Contact lens users. Increased osmolality
`has been demonstrated in association with contact lens wear.”
`Neurolrophic keratitis, caused usually by unilateral sen-
`sory loss in the distribution ofthe first division ofthe fifth cranial
`nerve is associated with a severe ocular surface disorder. This is
`partly due to a loss of trophic function of the trigeniinal nerve.“
`The Bengal Rose staining, decreased conjunctiva] goblet cell
`density, and loss of corneal epithelial glycogen seen in experi-
`mental neurotrophic keratitis resembles that encountered in dry
`eye_s5
`
`Motor: Seventh nerve palsy involving the nervus
`intcrmedius (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 Lacrirnal Disease
`
`Cicatrizing conjunctiva] disease causes aqueous tear de-
`ficiency by scarring the orifices of the orbital and accessory
`lacrimal 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:
`Trachoma: Trachoma is one of the major causes of
`blindness on world-wide scale; and conjunctival and lid scarring
`contribute in a complex way, causing dry eye through cicanicial
`
`conjunctivitis, lid distortion, and cicatricial meibomian gland
`disease.
`
`Cicatricial pemphigoid: 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 lucida of the basement membrane of
`perilesional skin.” Subepidermal scarring affects the skin and
`conjunctiva and in the conjunctiva may be progressive and
`severe.
`
`Erythema multrforme.‘ Erytliema multiforrne is an acute,
`self-limited, blistering derrnatosis which is often, butnot 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 bums: Diffuse chemical or ther-
`mal bums may result in conjunctival scarring sufficient to cause
`dry eye_59
`
`These forms of tear-deficient dry eye are distinguished
`from 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 erythema multiforrne is charac-
`terized by the fcatures of tear-deficient dry eye, aclinical history
`typical of crythema 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 are exclusion
`criteria and there are no features suggestive of other cicatrizing
`conjunctiva] disorders.
`
`Evaporative Dry Eye (EDE) (TearSufficient): Dry eye
`can occur where lacrimal function is nomial and the volume and
`composition of the lacrimal fluid are adequate and regarded as
`sufficient, with the tear abnormality created by other periocular
`disease, usually leading to increased tear evaporation. The
`conditions are reasonably referred to as evaporative forms ofdry
`eye. Each ofthese disorders is independently capable ofproduc-
`ing dry eye.
`
`Blepharitis: It is known that anterior blepharitis may be
`associated with punctate keratitis. It is less clear that anterior
`blepharitis, independent of other fonns of lid disease, can cause
`dryeye. Skinlipid will break up the nomial tearfilrn.°° It has been
`postulated that desquarnated 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 CLAOjoumal
`
`‘ October 1995 - Volume 21,Number4
`226
`
`6
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