Report of the National Eye Institute/Industry
`Workshop on Clinical Trials in Dry Eyes
`
`Chairman: "lichael A. Lemp, MD
`
`"
`
`Introduction
`Over the last 20 years our knowledge of the pathogenetic
`factors invo lved in dry eye states has grown significantly. It is
`now genera ll y recognized that the term .. dry eye·· is a rubric to
`describe a variety ofconditionsofdiverse origin which affect the
`tear film ancl/or the ocular sUii'ace. 1 Recent findings show
`differences between Sjogren 's-associated keratoconjunctivitis
`sicca (KCS ) and non-Sjogren's KCS .24 Neurotransmitters,5
`viruses. 7 and hormonesK.Y are im portant in regulating tear pro(cid:173)
`duction and immune activity in the lacrimal glands and the
`ocular surface. Finally, meibomian gland dysfunction can in(cid:173)
`crease tear· evaporation with an increase in tear film osmolarity
`and resultant ocular surface disease. 111
`Despite these advances. there has been a lack of consensus
`on the appropriate diagnostic criteria. cla~sification of disease
`states, the aim of specific diagnostic tests, the role of subjective
`assessment, clinical trial designs, and interpretation of resulh.
`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/governmental effort to de(cid:173)
`velop a consensus" was issued. 11 In response to thi s. the National
`Eye Institute and leading industry groups ~pon~ored a Nationa l
`Eye Institute/Industry Workshop on Clinical Triah in Dry Eyes.
`The workshop was organized and chaired by the author. Two I
`and one-ha lf day meetings in December 1993 and again in
`December 1994 were held on the campu~ of the National
`ln~titutes of Health . The aim of the work~hop<, was to provide
`clin ical instruments for the conduct of epidemiological studies
`and cli nical trial s. This report was drafted in accordance with the
`recommendat ions of the American Medical Association con(cid:173)
`cerning consensus conferences. 12
`The objective of the workshop was to identify areas of
`con,e nsus ancl/or disagreement in the design and interpretation
`of cli n1cal trials in dry eyes. To thi s end, a group of individuals
`from academic and clinical fielJs, industry, and governmental
`agenuc-, met. Individuals were invited to participate based on
`the ir clin ical contributions to the field, corporate responsibili -
`
`ties. <tncllor regulatory function s. 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:
`I. 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 repons. Two separate commit(cid:173)
`tees were formed to address the first two issues, and these
`committees met during the following year. The large group met
`again one year laterto hear and discuss the commi ttee reports and
`any additional epidemiologic information.
`
`Report of the Classification Study Group
`The purpose of the group was to develop a practical
`c lassification of dry eye disorde rs and to consider which catego(cid:173)
`ries of diagnostic tests might be used to discriminate between
`different disorders. The Standardization of Clinical Tests Group
`paid particular attention to the prec ision and accuracy of the
`recommended tests and their avai lability to clinicians and the
`research community.
`The aims of the Classification Study Group were:
`I. To produce a global * defi niti on 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 hetween different countries. The fami liar term
`KCS was coined by Sjogren to define the ocular surface disorder
`accompanying the autoimm une exocrinopathy that he defined. 11
`This is how the term is used in some countries. However, in other
`
`* The term global in this co111ext refers to the broad area of dry eves
`encompassing all the subsets
`
`~~PY'!.~~t-~ ~~5 C~ntact Lens Association of Ophthalmologists
`
`the CLAO journal • October 1995 • Volume 2 1, Number 4
`221
`
`APOTEX 1036, pg. 1
`
`

`

`counted for in certain protocols.
`
`Global criteria for dry eye
`The global definition recognizes a commonality among
`all fonns 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
`fonns 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:
`I. 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
`of symptoms. which include heaviness of the lids, foreign body
`sensation. burning, stinging. and photophobia.
`Validated questionnaires (in certain age groups) are avail(cid:173)
`able which attempt to characterize dry eye in tenns of symptoms
`and for which sensitivity and specificity infonnation has been
` It is proposed that a positive response to such a
`derived. 14
`·
`questionnaire be included within the global criteria for dry eye.
`As noted by the Epidemiological Study Group, a ques(cid:173)
`tionnaire can be used to obtain data that would lead to a wider
`understanding of the demographics of dry eye, as well as medical
`and other risk factors. These aspects are dealt with elsewhere.
`Demonstration of Ocular Surface Damage: Ocular sur(cid:173)
`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 ·sand non- Sjogren ·s dry eye. 1
`R Van
`1
`6-
`Bijsterveld ( 1969) described a scoring system for rose bengal
`staining, which has high sensitivity and specificity. 19
`Recently Lissamine Green has been offered as an alterna(cid:173)
`tive that is more readily tolerated 2 ° Fluorescein may also be used
`as an alternative if the fluorescence from the ocular surface or
`conjunctiva and cornea is viewed through yellow filters. ~ 1
`It is recommended that surface damage-assessed by
`staining with vital dyes-be used as a global criterion of dry eye.
`Details of the rose bengal and other tests are described in the
`report of the Working Party on Diagnostic Tests.
`Other fonns of ocular surface damage or reaction may be
`encountered in dry eye. The various indices of change are listed
`in Table I. Most of these have not been incorporated into
`
`1'
`
`' Sensiriviryand specificiryare specific ro group srudied (e.g .. age. sex) and
`are dependenr on acrual crireria used ro esrablish a diagnosis.
`
`countries, the tenn Sjogren syndrome-KCS is used to define the
`ocular surface disease that occurs in Sjogren syndrome, and non(cid:173)
`Sjogren KCS is used to define ocular surface disease due to
`primary, age-related lacrimal insufficiency. This is an accept(cid:173)
`able use of the tenn KCS as long as it is understood that there are
`other fonns of lacrimal insufficiency that give rise to dry eye,
`such as that due to sarcoidosis, AIDS, or graft-versus-host
`di sease.
`The tenn KCS is also used as a synonym for dry eye. With
`this use, the tenn is applied equally to disorders involving
`lacrimal insufficiency and those associated with excessive evapo(cid:173)
`ration of tears, such as meibomian gland disease.
`Because of this varied use of the tenn KCS, it is not
`possible to justify one particular use as opposed to another.
`Therefore, in the classification that follows, the broader defini(cid:173)
`tion is used and KCS is taken to be synonymous with the general
`tenn dry eye.
`
`The global aspects of dry eye
`A Global Definition: Dry eye is most frequently caused by
`a decrease of lacrimal gland function but may also occur when
`lacrimal gland function is nonnal. 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
`deficiency or excessive tear evaporation which causes
`damage to the interpalpebral ocular surface and is
`associated with symptoms of ocular 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 minimal, and it should
`not be concluded that the features of dry eye are limited to this
`definition. Thus:
`I. The definition states that ocular surface damage is
`"interpalpebrar· 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.
`2. Dry eye usually causes symptoms, but the possibility is
`acknowledged that in some patients in whom the diagno(cid:173)
`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.
`3. In the same way, a dry eye condition could exist, sup(cid:173)
`ported by symptoms and signs (e.g., reduced tear secre(cid:173)
`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-
`
`the CLAO journal • October 1995 • Volume 21, Number 4
`222
`
`APOTEX 1036, pg. 2
`
`

`

`TABLE I Indices of Surface 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: Norn" and Lemp''
`recommended recording the break-up of the tear film after the
`instillation of tluore~cein dye a~ a test of tear stabi lity. The
`(fluorescein ) tear break -up time (BUT or FBUT) has been
`shown to be depende nt on the reduction of tear surface tens ion
`by mucins.'" When tear mucin is reduced. as reflected by a fall
`in conjuncti val goblet cell dens it y'' or a ri se in tear suti.ace
`
`te nsion. 2" the BUT is also reduced .
`Goblet cell density is reduced in a number of forms of dry
`eye (e.g .. in di sorder~ of the lacrimal and of the meibomian
`g lands ) with resultant reduction in BUT. It is not known to what
`ex tent ocular su d'acc mucin .'- as opposed to goblet ce ll mucin.
`contributes to the reduced BUT of dry eye. or whether there arc
`other contributing factor,. Howe ,·er. BUT offers a valuable
`parameter to include '' ithin the d i ag n o~tic g lobal critetia for dry
`eye.
`
`It should be noted that tear ~urfacc tension would make a
`reasonable sutTogate test for tear stabilit y as would direct tesh of
`tear mucin. which arc currently under development. Unfortu (cid:173)
`nately, neither of these tests is currently avail able 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 Hyperosmo/nrity: Convincing
`a rguments have bee n advanced which suggest that
`hyperos mo larity is the common denominator between all form s
`of dry eye. Tear hype rosmo larity has been demonstrated in
`experimental studies of tear defic ient and evaporat ive dry eye:
`
`Tear-Deficient Dry Eye
`
`Non-Sjogren dry eye
`Sjogren syndrome dry eye
`
`Evaporative Dry Eye
`
`Blepharitis Associated
`Anterior Blepharitis
`Meibomian Gland Disease
`Ocular Mucin Deficiencies
`Blink Disorders
`Disorde rs of lid aperture and lid/globe congruity
`Ocu lar Surface Disorde rs
`Other Tea r film disorders [Contact lens induced?]
`
`surface di sease has been shown to be depende nt on and propor(cid:173)
`tio nal to increases in tear film osmolarity and duration of
`disease.'' 'L" It has been suggested that hyperosmolarity is the
`primary causative mec hanism in thi s group of disorders. leading
`to di scomfon. ocular su rface damage. and intlammation. ' 2
`For thi s reason. hyperosmolarity should be regarded as an
`imponant g loba l criterion fort he di agnos is of dry eye. However.
`a simple technique to measure tear hyperosmolarity is not yet
`read il y avai lable to a ll researchers and c lini cians. The freezing
`point depression method is expensi,·c and techn icall y difficult. ''
`Although measurement of osmo larit y by the water vapor pres(cid:173)
`sure method is simpl e. the technique must be sufficientl y tested
`in dry eye conditions. 11 Forth is reason. measure ment of tear film
`osmolarity wi ll be regarded as a secondary test until suc h time
`as a prevailing te st is available.
`It is recommended that hyperosmo larity be used as a
`g lobal criterio n of dry eye by those researc hers who have an
`accurate means of testing available.
`Other criteria for the g lobal diagnosis of dry eye may a lso
`be considered. such as the tear feming test. which has been used
`for diagnostic purposes and to identify deg ree of severity. '"
`
`NEl l INDUSTRY WORKSHOP
`1995
`CLASSIFICATION OF DRY EYE
`
`Tra choma.
`Contact len s
`C tc atnc ta l
`pem p htg o•d. vu •tr pa l s y
`Erythem a
`mult•l orm e
`!:::c::=:-='lA<>lalu"'------,,c',:"'"~·'"""~''~ ... =m::-o ='5<"1'e<"O._,.,
`
`• pr1mary o~oary corrr.o"'"
`1c Bll
`Ott>e• - <>fher 8ul c•m.nuno Clo!Ooa"o"
`
`N p
`PLD
`MGO
`
`r> .. LHC>PAflllyl.; l<flr•l 11"
`l<8fA io llt> •
`.. p rtmary lac;.'"""' ul:o'>d <I<&A•'""
`~ melbomo<tn 01•and d'"'"'"'"
`
`tllor.l< "hnO< JnJOIIIOf .. <
`Ul..NI(
`A. PERl = apO<"'urc <tt>•,<lr,..,..AI•toe'\
`CONGR '" hd su<1aco noonQ"-'•ty
`
`Figure 1 C!assijicarion s\·sfem and
`dia ~n osric al ~ orirhm f or dn· ere. (See
`rexr f orfu/1 discussion. )
`
`the CLAO joumal • Octobe r 1995 • Volume 21 . Numhc r 4
`223
`
`APOTEX 1036, pg. 3
`
`

`

`Major classes of dry eye
`Dry eyes may be assigned to two major classes: Tear(cid:173)
`deficient dry eye and evaporative dry eye (Table II). Relation(cid:173)
`ships may be more clearly seen in Figure I, which is a
`diagnostic algorithm based on this classification.
`I. In tear-deficient dry eye, there is a disorder of lacrimal
`function or a failure of transfer of lacrimal fluid into the
`conjunctival 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(cid:173)
`tion in secreted lacrimal proteins. 36 Tear -deficient dry eye
`is the largest category of dry eye.
`2. In tear-sufficient dry eye, lacrimal function is normal, and
`in most cases if not all, the tear abnormality is due to
`increased tearevaporation.31 lt may reasonably be termed
`evaporative dry eye.
`Each of the disorders listed in Table II is considered to be
`independently capable of causing 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(cid:173)
`deficient disease with obstructive 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 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 of these accessory factors to the dry eye picture and
`they may act as a confounding influence in diagnosis. Thus the
`symptoms suffered by a patient with anterior blepharitis 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 the lacrimal gland
`need not decrease tear secretion if damage to lacrimal function
`is limited. Cicatrizing conjunctival 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-deficient Dry Eye: There are a number of forms of
`tear-deficient dry eye (TDDE). This category requires the dem(cid:173)
`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 Bijsterveld 19 and is
`recommended by the Workin_g Party on Diagnostic Tests.
`Other indicators of reduced tear function include the
`, fluorophotometry, or
`lacrimal thread test, 37 the Periotron test 38
`the demonstration of reduced secretion oflacrimal proteins, such
`40 This is discussed further by the
`as lysozyme or lactoferrin. 39
`·
`Working Party on Diagnostic Tests.
`
`... _ -
`
`KCS -DRYEYE
`A DIAONOST1C PINWHEEL
`
`Figure 2 Dn· ere diagnosTic pinwheel. CriTeria for The diagnosis of dry
`ere are presemed. The hub of The piml"i1eel represenTs The criTeria applied
`To esTablish The global diagnosis of dn eve. These characTerize The disorder
`of dn- eve wiT hour specifving cause. Two or more are necessary for The
`idenTificaTion ofdry eve slaTe. The criTeria for aqueous deficienT dry eye are
`ahm·e The hori~mual line; below The hori~onral line are criTeria fur
`emporaTi1·e (aqueous sufficienT) dry eve. TesTs for Sjbgren syndrome are
`aT upper left. inner secwr: TesTs for Non-Sjiigren aqueous deficienT dry eye
`are aT upper righT. inner secfOr. See TexT for full discussion. (PAN =
`polmrreriTis nodo.m: PLD= priman· lacrimal gland disease: SLE =
`srsTemic lupu .~ eryThemaTosus; WEG = Wegener's granulomafOsis; SysT
`Sci = srsTemic sclerosis: Mixed CT= mixed-combined; Con Alae =
`congeniTal alacrima: G vs. H= Graft 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(cid:173)
`tion since they do not initiate ocular surface damage. It has been
`suggested that deficiency of lacrimal protein may be the earliest
`sign of aqueous-deficient dry eye.•1
`TDDE may be divided into two major categories: Sjogren
`Syndrome Tear Deficiency (SSTD) and non-Sjogren Tear De(cid:173)
`ficiency (NSTD). In NSTD there are none of the systemic ~i g n \
`or clinical manifestations of autoimmune disease, which are the
`hallmarks of SSTD.
`SJOGREN SYNDROME TEAR DEFICIENCY: Sjogren syndrome
`is an exocrinopathy affecting the lacrimal and/or salivary gland-..
`The syndrome may be primary or secondary.
`Primary Sjogren syndrome consists of the feature~ of tear(cid:173)
`deficient dry eye in combination with a dry mouth, the pre ~ence
`of autoantibodies and a positive focus score on minor salivary
`18 Tests for dry mouth and for the presence of
`gland biopsy. 17
`
`·
`
`the CLAO journal • October 1995 • Volume 21, Number 4
`224
`
`APOTEX 1036, pg. 4
`
`

`

`TABLE Ill Tests for dry mouth and salivary exocrinopathy•
`
`Salivary Features
`
`Focus score s; 1 on minor salivary gland biopsy
`Salivary scintigraphy
`Parotid sialography
`Unstimulated salivary flow (5 1.5ml in 15 minutes)
`
`Auto-Anti bod ies
`
`Anti Ro/SS-A or La/SS-B
`Antinucu lear antibodies
`Rheumatoid factor
`
`'From References 16, 17. 18
`
`autoantibodies and other serological ev idence of connecti ve
`ti ssue disease are given in Table Il l.
`Secondary Sjogren syndrome consists of the features of
`pri mary Sjogren sy ndrome in conjunction with overt clinical
`mani fes tations of an autoimmune connecti ve ti ssue di sease .
`Some of the autoimmune connecti ve ti ss ue di seases in which
`Sjogren Syndrome occ urs are listed in Table IV. Of these,
`rheumatoid anhritis is the most common. Various criteria have
`been establi shed for their diagnos is.
`No:--;-S.Jii<au::--; T EA R DEFICJE:\ c Y: The various fo rms of
`non-Sjogren tear-de ficient dry eye are listed in Table V.
`I. Primary Lac ri mal Defi ciency ( PLD)
`Congenital alacrinw: Although its speci fi c cause is not
`yet known. congenital alacrima i-, a''umed to he a primary
`di sorder of the lac rimal gland. The most prevalent form of PLD
`is acquired and -,o mctimcs referred to as non-Sjogren KCS. It is
`more com mon in women. and its frequency increases with age.
`It results from a gradual destruction of lacrimal gland and ductal
`tissue by a round-cel l infi ltration "'"' An im mune mec hanism of
`lacrimal tissue destruction is not excluded. Since the mec hani sm
`for gland de\! ruction is unknown. it is appropriate to refer to thi s
`conditi on as acquired PLD. PLD shows the features of aqueous(cid:173)
`de ficient dry eye in the absence of signs of autoimmune disease
`or featu res of other forms of aq ueous-deficient dry eye (Table
`V).
`
`2. Secondary Lacrimal Deficiency
`Sarcoidosis: Infiltration of the lacrimal glands with sarcoid
`granulomata may cause dry eye. 44
`Lnnphonw: In the same way, infi ltrati on of the lacrimal
`glands wi th lymphomatous cells may cause dry eye."'
`H!Vinfection: Dry eye was detected in 21 0't: of a group of
`JXtlie nts with AIDS, and in another study of AIDS patients with
`
`TAB LE IV Autoimmune connective tissue disease associated
`w1th secondary Sjogren syndrome
`
`Rheumatoid arthritis
`Polyarteritis
`Wegener's granulomatosis
`Systemic lupus erythematosus
`Systemic sclerosis
`Pnmary bilary cirrhosis
`M1xed connective tissue disease
`
`TABLE V Conditions associated with Non-Sj6gren tear deficient
`dry eye
`
`Lacrimal Disease
`
`Primary
`Congenital alacrima
`Acquired lacrimal disease·
`Secondary
`Sarcoidosis
`HIV
`Graft vs. Host disease
`Xerophthalm ia
`Dacryoadenitis
`Lacrimal gland ablation
`
`Lacrimal Obstructive Disease
`
`Trachoma
`Cicatricial pemphigoid
`Erythema multiforme
`Burns
`Congenital lid deformity
`Trauma
`Atopic keratoconjunctivitis
`
`Reflex Hyposecretion
`
`Neuroparalytic keratitis
`Chronic contact lens wear
`Proximal VII Cranial Nerve Pal sy
`
`Uncertain Category
`
`Multiple neuromatosis
`Cri cu Chat Syndrome
`
`·synonym. Non-Sjogren KCS
`
`xe rostomi a, there was a positi ve foc us score on sali vary gland
`biopsy of 2 or more.46 However, in thi s study. the predominant
`T -cell populat ion was of suppressor lymphocytes (CD8 ), rather
`than the helper subset (C D4) characteristic of Sjogren syn(cid:173)
`drome.
`C rqft l'erstts Host Disease: Associated with dry eye.
`Viwmin A deficiency (Xerophthalmia): Reported to cause
`dry eye by two di stinct mec hani sms. Loss of conjuncti val goblet
`cells and probably other surface mucin sources are responsible
`for one form of dry eye with normal lacrimal function . This is
`di scussed below. A tear-defi cient form of dry eye has also been
`reported. 4
`K
`utcrimal Gland Ablation: Removal of the main lacrimal
`gland is a further cause of tear loss.""
`3. Refl ex (neural) Causes of Evaporati ve Dry Eye (Table
`
`VI )
`
`SensorY: Tear secretion is in pan, if not wholl y. refl ex in
`origin. Reduced sensory fu nction fac ilitates dryi ng by two
`mec hanisms: sensory loss causes decreased tear secretion50 and
`when bilateral. reduces the blink rate. For instance, topical
`proparacaine app lied bilaterally decreases the bl ink rate by
`about 30Cj,- ' 1 and causes a decrease in tear sec retion of60-75%.5"
`Loss of corneal sensation is a feature of contact lens wear
`and has been proposed as a mechani sm for dry eye associated
`
`the CLAO journal • October I '.1\15 • Volume 21. Number 4
`225
`
`APOTEX 1036, pg. 5
`
`

`

`TABLE VI Causes of corneal and conjunctival sensory loss
`
`Infective
`
`Herpes simplex
`Herpes zoster
`
`Corneal Surgery
`
`Limbal incision
`Corneal graft
`Photoablative keratoplasty
`Refractive Keratoplasty
`Radial Keratoplasty
`
`Neuroparalytic Keratitis
`
`Injection of trigeminal ganglion
`Tumor
`Section of seventh cranial nerve
`
`Topical Medications
`
`T apical anesthesia
`Beta blockers
`Atropine-like drugs
`
`Other Causes
`
`Long-term contact lens wear
`Diabetes Mellitus
`Aging
`
`(modified from Gilbard JP: Dry Eye Disorders in Principles and Practice of
`Ophthalmology, Albert OM. Jackobic FA (eds): Philadelphia. W.B.
`Saunders Company. 1994, pp. 257-276.)
`
`with long-standing contact lens wear,525 1 particularly among
`hard and extended wear contact lens users. Increased osmolality
`has been demonstrated in association with contact lens wear. 12
`Neurotrophic keratitis, caused usually by unilateral sen(cid:173)
`sory loss in the distribution of the first division of the fifth cranial
`nerve is associated with a severe ocular surface disorder. This is
`partly due to a loss of trophic function of the trigeminal nerve.5
`"
`The Bengal Rose staining, decreased conjunctival goblet cell
`density, and loss of corneal epithelial glycogen seen in experi(cid:173)
`mental neurotrophic keratitis resembles that encountered in dry
`eye.ss
`
`Motor: Seventh nerve palsy involving the nervu s
`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.56
`Other: Dry eye has also been reported with multiple
`neuromatosis. 57
`4. Obstructive Lacrimal Disease
`Cicatrizing conjunctival disease causes aqueous tear de(cid:173)
`ficiency by scarring the orifices of the orbital and accessory
`lacrimal glands. Among the several causes of conjunctival
`scarring. those disorders that are associated w1th 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 cicatricial
`
`conjunctivitis, lid distortion, and cicatricial meibomian gland
`disease.
`Cicatricial pemphigoid: Cicatricial pemphigoid is a
`dermatosis characterized by blistering skin and mucosal lesions
`and the presence of deposits of IgG (and complement compo(cid:173)
`nents) in the lamina Iucida of the basement membrane of
`perilesional skin. 58 Subepidermal scarri ng affects the skin and
`conjunctiva and in the conjunctiva may be progressive and
`severe.
`Erythema multiforme: Erythema multiforme is an acute.
`self-limited, blistering dermatosis which is often, but not always,
`precipitated by drugs, infection or malignancy. It is character(cid:173)
`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 thennal burns: Diffuse chemical or ther(cid:173)
`mal bums may result in conjunctival scarri ng sufficient to cause
`dry eye. 59
`These forms of tear-deficient dry eye are distinguished
`from each other and from idiopathic dry eye by spec ific criteria.
`It is sufficient here to give an example of such criteria for one
`disorder. The dry eye caused by erythema multi forme is charac(cid:173)
`terized by the features of tear-deficient dry eye, a clinical history
`typical of erythema multiforme, and cicatricial conjunctival
`change~ involving the orifices of the lacrimal gland ductules.
`Serological and immunoh istological features could be accepted
`in addition.
`In establishing po~itive criteria for any disorder. it i~ abo
`implied that exc lusion criteria are establi shed. These are often in
`an opposite sense to the inclusion criteria. In thi s instance. it is
`implied that positive features of Sjogren syndrome are exclusion
`criteria and there are no features suggestive of other cicatri1ing
`conjunctival disorders.
`Evaporative Dry Eye (EDE) (Tear Sufficient): Dry eye
`can occur where lacrimal function is normal and the volume and
`composition of the lacrimal fluid are adeq uate 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 form s of dry
`eye. Each of these disorders is independently capable of produc(cid:173)
`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 forms of lid disease, can cau~e
`dry eye. Skin lipid will break up the normal tearfilm.60 lt has been
`postulated that desquamated cells derived from the lid margin in
`squamous blepharitis may deliver such lipid to the tear fil m and
`give rise to punctate keratitis by causing tear instabili ty and
`increased tear evaporation. However, there is also the view that
`qualitatively altered meibomian lipid may directly damage the
`ocular surface.oo..e·' in which case the surface damage arises h) a
`different mechanism.
`It can be seen that the diagnosis of dry eye based solel y on
`the administration of a questionnaire and on the presence of
`interpalpebral staining could be vulnerable to confounding.
`
`the CLAO journal • October 1995 • Volume 21 , Number 4
`226
`
`APOTEX 1036, pg. 6
`
`

`

`TAB LE VII Meibomian gland diseases
`
`1. Reduced number
`2. Replacement
`
`Congenital Deficiency54
`Distichiasis5'
`Metaplastic
`Secondary
`3. Hyposecretory·
`4 . Obstructive meibomitis35 36 45 46 49
`Focal or diffuse5
`'
`Primary , or secondary to:
`Local Disease
`Anterior Blepharitis;
`ConJunctivitis , e.g. , Trachoma; Pemphigoid; Atopy;
`Chem ical Burns
`Systemic Disease
`Seb. Dermatitis49
`Acne Rosacea49
`Atopy'9
`lchthyosis51
`Psoriasis43
`
`Anhydrotic Ect. Dyspl
`Ectrodactyly Syndrome55 56
`Turner Syndrome
`Fungal57 56
`Toxic :
`13-Cis Ret. Acid50·5960
`Polychlorinated Biphenyls6' 62 63
`(Rabbit) Epinephrine53
`
`Other
`Internal Hordeolum
`Chalazion
`Concretions
`5. Hypersecretory·
`6. Neoplastic
`7 . Suppurative
`
`Me1bom1an Seborrhoea32 33 34
`
`'Hypothetical: Evidence IS not yet available for pnmary hyposecretion
`'Although there IS evidence for an accumulation of me1bom1an oils within
`the glands. there IS none yet for overproduction
`
`However. this would be avoided if hypcro\molarity were incor(cid:173)
`porated into the global diagnostic schema. The dem o n ~tration of
`excessive evaporative loss in the prese nce of anteri or blepharit i ~
`wou ld clarify the mechanism.
`Meihomian Gland Disease: It is recognized that various
`forms of meibomian gland disease can independently cause dry
`eye . The mechanism is assumed to be insufficient tear oi l for
`resurfacing the tear film with each blink ancl!or a qualitative
`alteration of the meibomian lipid in such a way as to destabilize
`the tear film. A list of meibomian gland disorders is given in
`Table VII.
`It is assumed that the occurrence of dry eye is dependent
`on the severity and extent of gland dys function . The most
`common f01m of meibomian gland disease is obstructive. Ob(cid:173)
`\tructive me