jurnal dry eye edit.doc

C L I N I C A L A N D E X P E R I M E N T A L

OPTOMETRY

REVIEW

Dry eye: an update on clinical diagnosis, management and promising new treatments

Julie M Albietz BAppSc(0ptom) (Hons) PhD School of Optometry, Queensland University of Technology

Dry eye conditions are prevalent with one in four to five patients presenting to eye care practitioners having dry eye signs and/or symptoms. An intimate relationship exists between the ocular surface and the tear film. The cycle of tear film instability and ocular surface damage characteristic of dry eye conditions suggests that dry eye represents a dysfunction of an integrated ocular surface-lacrimal gland unit. Therefore, dry eye is a multifactorial condition and ari approach based on clinical subtypes is required for diagnosis and management. There is increasing evidence that inflammation is a contributing and exacerbating factor in dry eye conditions and anti-inflammatory or immunomodulatory therapy for chronic dry eye conditions may facilitate ocular surface healing. Other promising new treatments for dry eye include new generation artificial tear polymers and preservative systems, secretagogues, topical androgen supplements and surgical techniques for ocular surface reconstruction. (Clin Exp Optom 2001; 84: 1 : 4-18)

Accepted for publication: 20 December 2000

Key words: artificial tear supplements, dry eye, dry eye treatments, evaporative dry eye, ocular surface disorders, tear deficient dry eye, tear film

The concept of the 'dry eye' was initially used to describe symptoms of ocular irritation due to insufficiency in lacrimal gland aqueous tear secretion and leading to ocular surface damage. Keratocon- junctivitis sicca was the term given to the ocular surface disease that develops in patients with aqueous tear deficiency. Over the past 30 years, knowledge of the pathogenic factors involved in dry eye states has grown significantly. Many patients with dry eye symptoms produce a normal quantity of aqueous tears hut have other tear film and/or ocular surface disorders.'.' The definition of dry eye has been expanded to include any anomaly in a gland associated with tear production or an anomaly in lid and/or

blinking function in which the quality and/or quantity of the tear film is ad- versely affected and there is an inability to maintain a healthy ocular surface.2s

The multifactorial nature of dry eye conditions has produced the term 'tear film and ocular surface disorders" as an alternative to the term dry eye. This recognises the intimate relationship between the om- lar surface and the tear film and the cycle of tear film instability and ocular surface damage characteristic of dry eye. It also acknowledges recent suggestions that dry eye represents a dysfunction of an integrated ocular surface-lacrimal gland unit."," The ocular sur fxe (conjunctiva, cornea, accessory lacrimal glands and meibomian glands), the lacrimal gland and the inter-

connecting neural reflex loops appear to comprise a tightly integrated functional unit, the parts of which ac.t together and not in isolation.' Decreased lacrimal gland secretion damages the ocular surhce , which creates a negative feedback loop resulting in damage to the lacrimal gland. There are probably several mechanisms by which this feedback occurs: 1. interruption or damage to the sensory

2. damage to the lacrimal gland 3. alteration of growth factor levels in the

lacrimal gland following corneal damage.

Contact lenses and corneal refractive surgery are additional factors that may create negative 'feedback to the lacrimal gland.'

corneal nerves

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Dry eye type Main Causes

Tear deficient dry eye 1. Sjbgren's syndrome 2. Non-Sjbgren's lacrimal disease

Ageing Menopause Medicamentosa Cicatricial disease Neurotrophic keratitis

Evaporative dry eye Meibomian gland disease Lid surfacing/blinking anomalies Contact lens related Chronic allergyhoxicity Cicatricial ocular surface disease

Table 1. Classification of dry eye: main subtypes and main causes (adapted from 3,

The National Eye Institute/Industry Workshop on Clinical Trials of Dry Eye3 has recommended a revision of the classification of dry eye, given its multifxtorial nature. The major dry eye categories proposed were tear deficient dry eye and evaporative dry eye. In the tear deficient category were Sjogren's syndrome and non-Sjogren's syndrome forms of aqueous tear deficiency. Evaporative forms of dry eye were oil deficient (meibomian gland anomalies), lid surfacing and blinking anomalies, chronic allergy/toxicity, contact lens-related anomalies and cicatricial ocular surface disease (Table 1).

Dry eye is a prevalent condition with one in four patients presenting for eye examination manifesting dry eye symp- toms7 and 10 to 18 per cent being diagnosed with dry eye depending on the diagnostic criteria The prevalence of dry eye has increased in recent years due to the general ageing of the population,'O increased medication use '('and increase in environmental allergens and irritants.".I2 It was estimated that there were 30 million dry eye sufferers in the United States of America in 1990 and the incidence of dry eye increased to 59 million in 1997." In addition to symptoms of chronic ocular surface irritation, dry eye is characterised by blurred vision,

increased risk of infecti~n, '~. ' ' medication contact lens intoleranceI6 and

progressive ocular surface disease, scarring and corneal morbidity.'"-"' Hence correct diagnosis and appropriate management of dry eye is essential.

THE TEAR FILM AND OCULAR SURFACE

The tear film is composed of an external lipid layer, an aqueous layer, a semi-solid conjunctival goblet cell mucous layer and the non-goblet epithelial mucin layer (the glycocalyx). The lipid layer is produced by the meibomian glands and its princi- pal role is to reduce tear film evaporation.2' The aqueous layer contains electrolytes, glucose, antibacterial proteins, antibodies and glycoproteins and is secreted primarily by the lacrimal gland.22 The inner layer of the tear film is composed of mucin secreted by the goblet cells of the c~njunctiva"~'~ and the non- goblet epithelial cells of the cornea" and c o n j ~ n c t i v a . ~ ~ ~ * ~ The superficial epithelial cells have microvilli and microplicae that are covered by the glycocalyx, a non-goblet cell mucin, which appears to anchor the goblet cell much to the underlying surface epithelium and may facilitate tear film spread and stabilisation.25 The thick-

ness of the tear film remains controver- sial. Interferometric estimates of 40 microns" (with the bulk of the tear film being mucin and the tear film thought to be a hydrated mucin gel) and more recently three microns" have been reported.

The ocular surface epithelium is non- keratinised and multi-layered with morphological variations in the corneal, limbal and conjunctival epithelia."","' The corneal and conjunctival epithelial barrier functions are formed and maintained by tight, intercellular desmosomes between the adjacent superficial cells.92,"" The limbal epithelium is thought to contain the stem cells of the corneal epithelium and serves as the junctional epithelium to prevent conjunctival epithelial ingrowth onto the corneal surface during the healing of a large corneal epithelial defe~t.: '~. ' '~ The limbal epithelium represents the true germinative zone for corneal epithelium. In normal conditions, the epithelial cells continuously migrate from the limbus toward the corneal centre. This process is accelerated in epithelial wound healing.'iti As the limbal epithelial stem cells have very slow cycling time, loss or damage to the limbal area from chemical or surgical trauma, chronic inflammation or contact lens-related pathology can result in limbal stem cell d.eficiency and a gradual conjunctivalisation of the ~ornea . '~ '

Numerous hormones, growth factors, retinoids, cytokines and reciprocal receptors for these factors have been identified in the lacrimal glands and on the ocular surface."-'2 The meibomian glands and lacrimal glands appear to require androgens to support their normal function.4'-"" Androgen loss may play a critical role in the initiation of meibomian gland dysfunction, and decreases in androgen, particularly evident in Sjogren's syndrome, may serve to lessen tissue function as well as to promote (but not cause) the autoimmune process in the lacrimal gland, 49.45 Programmed cell death (or apoptosis) of lacrimal gland acinar cells may be the primary event proceeding the damage to the lacrimal gland in tear deficient dry eye, even in the absence of autoimmune disease.'"

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DRY EYE SUBTYPES: CAUSES AND PREVALENCE

Tear deficient dry eye Aqueous tear deficient dry eye affects up to three per cent of the population and is more prevalent in females and the elderly."~''-"' The lacrimal gland abnormalities include lack of stimulation of tear secretion, inflammation and destruction of the lacrimal gland and accessory lacrimal glands and scarring or occlusion of the lacrimal gland secretory ducts."" The most severe forms of aqueous tear deficiency are due to destruction or absence of the lacrimal gland and include Sjogren's syndrome," human immunodeficiency syndrome," graft versus host disease"3 and congenital or surgical removal of the lacrimal gland.' Cicatricial diseases such as trachoma, chemical burns, Stevens- Johnson syndrome and ocular cicatricial pemphigoid can also cause a severe secondary aqueous tear deficiency through the scarring, narrowing and obliteration of the lacrimal gland and accessory lacrimal gland secretory ducts.'

AUTOIMMUNE AQUEOUS TEAR DEFICIENCY Sjogren's syndrome is the main cause of severe aqueous tear deficiency and has a prevalence of approximately one per cent, with the majority of sufferers being female." '' The condition is a slowly- progressing, chronic multi-system condition affecting excretory glands in all patients and extra-glandular organs in some patients with the major features being aqueous tear deficiency and xerostomia (dry mouth) .i4 Approximately half of the cases are associated with other connective tissue disorders, the most common being rheumatoid arthritis and others include systemic lupus erythematosis, scleroderma and polymyosis.55 The disease process is extremely complex and the ocular component is characterised by lacrimal gland inflammation, conjunctival inflammation and severe ocular surface desiccation, including punctate keratitis, mucous filaments, corneal ulceration and scleritis'h '' (Figure 1 ) . Although the exact mecha-

nism that triggers Sjogren's syndrome is unknown, it seems that some events cause changes in the cell membranes of the lacrimal and salivary glands and the immune system then attacks these glands as if they were f ~ r e i g n . ' ~ The infiltrative cells seen in lacrimal gland biopsy are specific to Sjogren's syndrome and they differ in type and number from the infiltration that occurs as a function of ageing.'" Recent research indicates that androgen deficiency may promote the progression of Sjogren's syndrome and associated lacrimal gland inflammation but does not cause Sjogren's syndrome or aqueous tear deficiency in human and animal model^.^' The relative roles of viral infections such as Epstein-Barr virus, cytornegalovirus and herpes virus-6 in the pathogenesis of Sjogren's syndrome have been suggested and there is evidence that these viruses activate or precipitate immune responses in the lacrimal glands, leading to increased inflammation."'-h'

NON-AUTOIMMUNE AQUEOUS TEAR DEFICIENCY Less severe forms of aqueous tear deficiency occur due to abnormalities of the regulation of tear secretion. These may be precipitated by ageing and age-related alterations in hormone level^."^"^ Diffuse fibrosis, diffuse atrophy and periductdl fibrosis predominantly found in elderly women suggest a relationship with aqiie- ous tear deficiency in post-menopausal women.' Many commonly-prescribed oral and topical medications may reduce aqire- ous tear production including topical and systemic anti-histamines, tricyclic anti- depressants, topical and systemic beta- blockers, the oral contraceptive pill and systemic and topical non-steroidal anti- inflammatory agents.'''

Loss of corneal sensitivity as is observed in diabetes,65 excimer laser photorefractive keratectomy and L.ASIK66 and contact lens wear,67 has been implicated in causing dry eye conditions through reduced reflex tearing'" and reduced blink rate.'' Re- duced tear secretion may actually lead to reduction in corneal sensitivity,6y thereby creating a cycle of declining sensitivity and declining tear production.

Evaporative dry eye

MEIBOMIAN GLAND ANOMALIES Meibomian gland anomalies cause the most prevalent form of evaporative dry eye with a prevalence of four per cent for lipid anomaly dry eye.* Approximately 40 per cent of the general population has signs of meibomian gland dysfunction'" and a 100 per cent incidence of poor tear film stability and ocular surface staining has been reported in subjects with chronic meib~mianitis.~' An increased prevalence of meibomian gland dysfunction occurs with age7" due to normal ageing changes in the lids and meibomian glands." The most common causes of meibomian gland dysfunction are damage or destruction of meibomian glands due to meibomian seborrhoea," meibomianitis" and senile or cicatricial meibomian gland changes.'' Less common causes of meibomian gland disease include congenital absence of meibomian glands,' replacement of meibomian glands due to congenital or acquired distichiasis" and meibomian ne~p las i a . ' ~ The dermatological conditions, acne rosacea and seborrhoeic dermatitis, have a 51 per cent and 74 per cent incidence of meibomianitis, respectively." Stagnation of the meibomidn gland lipids in meibomian gland dysfunction gives bacterial lipase an opportunity to break down the meibomian lipid into free fatty acids which cause increased tear film evaporation, an unstable tear film,'> marginal keratitis a n d a superficial punctate keratopathy7' (Figures 2, 3 arid 4).

CHRONIC ALLERGY Chronic allergy destabilises the tear film and can induce ocular surface di~ease.""~ An allergic history has been reported by 36 per cent of dry eye subject^.^ The allergic inflammatory mechanism in giant cell papillary conjunctivitis (GPC) causes ex- cessive mucin production through hyper- plasia of goblet cells and hypermitosis of non-goblet epithelial cells.7h 77 In addition, decrease in tear production has been reported in subjects who have nasal mucosal pathology following chemical destruction or chronic allergy resulting in reduction or loss of the nasolacrimal reflex." Vernal

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Figure 1. Chronic aqueous tear deficiency in Sjogrens syndrome. Corneal filaments and widespread staining are characteristic features. Inferior neovascular changes are secondary to aqueous tear deficiency and are due to chronic inflammation of the meibomian glands.

Figure 2. Marginal infiltrative keratitis associated with meibomii seborrhoea

Figure 3. Particulate meibomian gland debris in the tear film. The significant nasal pterygium will exacerbate the evaporative dry eye condition caused by the meibomian gland dysfunction.

Figure 4. Trichiasis, madarosis, lid thickening and telangectas associated with chronic meibomian gland dysfunction. Staphylococ blepharitis is also present.

Figure 5. Micro- and macropapillae in vernal kerato-conjunctivitis. The larger papillae can act as a foreign body, further disrupting the ocular surface.

Figure 6. Lid surfacing anomalies causing increased tear evaporatiot large fleshy pterygium and senile ectropion

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keratoconjunctivitis is associated with a 38 per cent incidence of dry eye7' (Figure 5).

OCULAR SURFACE TOXICITY Toxic effects of topical therapeutic agents can result in ocular surface damage, inflammation and tear film disruption.H" Preservatives such as benzalkonium chlo- rideX'.Hi . and cetrimideH4 are known to be toxic to the epithelium. Intrinsic toxicity ran also result from the active ingredient in the medication itself. For example, long-term use of topical anti-glaucoma medications can induce and/or exacerbate dry eye conditions through squamous metaplasia, loss of goblet cells and ocular surface inflanimation.K'X'

CONTACT LENS WEAR Dry eye is prevalent in contact lens weaF '' with 20 to 30 per cent of contact lens wearers having dry eye symptoms.q" Contact lens wear is associated with increased mucous production,' reduced blink fre- quency,'" blink inefficiency," 3 and 9 o'clock staining,'" reduced tear break-up time," increased tear evaporation" and increased tear osmolarity," all of which can produce and/or exacerbate dry eye signs and symptoms.

CICATRICIAL OCULAR SURFACE DISEASE Cicatricial ocular surface diseases, although rare, can result in gross tear film instability through destruction of ocular surface epithelia, loss of goblet cells and cicatricial changes such as symblepharon and scarring of lacrimal gland ductiiles.lq These conditions are potentially the most vision-threatening of all dry eye types with limbal stem cell loss and conjunctivalisation of the cornea being potential con- sequences of cicatricial disease.

LID SURFACING ANOMALIES Dry eye due to lid surfacing anomalies affects approximately two per cent of the population. Any anomaly preventing or restricting complete lid closure and normal blinking patterns can disrupt tear film stability, increase tear evaporation and in- iuce ocular surface staining."' Potential Iauses are ectropion, entropion, large >terygia,"+ facial palsies, symblepharon,'

incomplete blinking, nocturnal lagophthalmos,g6 lid retraction and proptosis in thyroid d i ~ e a s e , ~ ' involuniary blepharospasm,gH dermatochalasis,gq conjunctivochalasis,'"" lower lid laxity'"' and contact lens wear.L6~q1~10L? Extensions of the interblink period due to intense ion- centration during close work and computer work con~entration"'","'~ and in Parkin- son's disease may lead to dessication of the ocular surface." Reduction in lid ri- gidity and tonus occurs with age.lo5 Dellen occur in lid surfacing anomalies in association with pterygia, pingueculae and contact lens wear I H (Figure 6).

ENVIRONMENTAL INFLUENCES

Environmental factors such as dehydrat- ing temperature-controlled environments"' can cause or contribute to evaporative dry eye conditions. Several terms have been used to describe the ocular irritation, poor tear film stability and ocular surface desiccation associated with the poor indoor air-quality in tempcra- ture-controlled office environments. These include 'pollution keratoconjunctivitis',lL 'office dry eye syndrome' and 'sick building syndrome'."'" Studies irtdi- cate that 35 per cent to 48 per cent of in- dividuals working in such environments are afflicted by the ocular signs and/or symptoms. lo'' ""

The multifactorial nature of dry eye A dry eye condition can have multiple causative mechanisms."'" A common example is the elderly, post-menopausal, te ar-d e fi c i en t pa tie n t taking systemic medications that further reduce tear production.l"q~"" In chronic forms of dry eye, the complications from the primary condition can cause a secondary source of tear film instability and a further exacerbation of the ocular surface disease. An association between tear deficient dry eye and evaporative dry eye has been reported by several authors. McCulley and coworkers" reported a 25 per cent to 40 per cent incidence of aqueous tear deficiency in subjects with conditions of meibomian gland dysfunction. Chronic lid inflammation

from meibomian gland dysfunction may cause scarring of lacrimal and accessory lacrimal gland ductules, subsequently resulting in deficiency in aqueous tear pro- duction14 (Figure 4) . Alternatively, con- centration of tear proteins at the inferior lid margin resulting from reduced aqueous tear production can induce inflammation in meibomian glands." Meibomian gland anomalies are commonly reported in Sjogren's syndrome."'.11'

The tear film and ocular surface in dry eye Specific deficiencies of tear components have been identified in dry eye. These include deficiencies in tear proteins (for example, lactoferrin, lysozyme, preal- bumin) 114.114 and growth factors (for example, epidermal growth factor, transforming growth factors)'I5 and increase in inflammatory cells."l,"h

In all forms of dry eye, irrespective of the mechanism, the conjunctival ocular surface undergoes squamous metaplasia, a progressive transition to a non-secretory, keratinised epithelium.xi',l'7.'1X The loss of conjunctival goblet cells appears to he a very sensitive indicator of ocular surface disease.'""' Goblet cell loss occurs within weeks of the onset of dry eye There also appears to be an alteration to conjunctival mucin distribution and/or chemical properties in dry eye."' Inflam- matory mechanisms are the most likely cause for the loss of goblet cells in dry eye.l".ll9 Up regulation of immune- mediated markers of conjunctival ocular surface inflammation and infiltration of T-lymphocytes occur in the conjunctival epithelium in both Sjogren's syndrome and non-Sj(jgren's dry e Y e , ! i ~ , K l . l ? ? ~ 1 2 1 ~ The inflammatory mediators released as a result of cellular damage appear to exacerbate the ocular surface and lacrinial gland inflammation and damage in dry eye."7~1:"'

CLINICAL DRY EYE ASSESSMENT

While there are many tests for dry eye, there remains a great disparity among the symptoms and signs in many dry eye patients. Determining the cause of dry eye when minimal clinical signs are present

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is difficult and the diagnosis is compli- cated further when there is a lack of correlation between symptoms and objective tests1'' In an attempt to overcome these problems and to standardise the diagnostic criteria for dry eye, the National Dry Eye Institute/Industry report has produced the following global criteria' for clinical diagnosis of dry eye: 1. a validated test of dry eye symptoms 2. reduced tear film stability 3. ocular surface staining 4. tear hyperosmolarity.

Symptoms Although dry eye is represented by various dysfunctional states involving the tear film, ocular surface, lids and blinking, dry eye symptoms are generally not subtype specific. Commonly reported dry eye symptoms are grittiness, foreign body sen- sation, burning, soreness, stinging, scratchiness, dryness, blurry vision, a 'film over the eyes', paradoxical reflex tearing

Clinical evaluation of dry eye should include an assessment of subjective symptoms and functional lifestyle, through the use of a well-designed and validated dry eye questionnaire." Until recently, the McMonnies Dry Eye Symptom Survey was the only questionnaire to meet these requirements and provide a formal aid to dry eye history-taking in clinical prac- t i ~ e . " ' . ~ ~ ~ The recently introduced Ocular Surface Disease Index (OSDI)IS5 is a 12-item questionnaire designed to provide a rapid assessment of the symptoms of ocular irritation with dry eye disease and their impact on visual function. The OSDI correlates significantly with the McMonnies questionnaire and appears to be a valid and reliable method of measuring the severity of dry eye disease and pos- sesses the necessary psychometric properties to be used as an end point in clinical trials.136 While the OSDI has not yet been published, its advantage over the McMonnies Survey is that i t is not biased towards diagnosis of aqueous tear deficiency.

and photophobia,lH.20.Y~.."~

Tear film stability Tear film instability is a non-specific test for dry eye. All tear film stability tests have

poor repeatability and a mean of multiple measures is recommended."'A recent study indicated a significant correlation between ocular surface discomfort and tear film break-up time in dry eye subjects.'?" The most common clinical measure of tear film stability is fluorescein break-up time (FBUT) which has a refer- ence value of less than 10 seconds for dry eye."' As instillation of large volumes of fluorescein destabilise the tear film, an effort should be made to control the volume of fluorescein instilled in the eye. The Dry Eye Test (DETTM) is a newly- released thin fluorescein strip which de- livers only one microlitre of fluorescein into the eye, compared to 10 microlitres for a standard fluorescein strip, hence improving the accuracy and reproducibility of FBUT measurements."" It is not yet available in Australia. Non-invasive methods of tear film instability such as the keratometer mires and Keeler Tearscope PlusTu give longer tear film stability measures and a value less than 20 seconds war- rants further investigation.

Ocular surface staining Fluorescein and rose Bengal are the two most widely-used ocular surface stains. Rose Bengal stains dead and devitalised cells, mucous strands and areas where the mucous layer of the tear film is discon- tinuous."" Fluorescein lacks this ability to be blocked by tear constituents and dif- fuses rapidly into the stroma where cell to cell junc t ions a re disrupted."' Fluorescein acts as a vital stain adhering to devitalised cells.'"' Unlike rose Bengal, fluorescein does not stain mucus. Lissamine green B is an alternative to rose Bengal that is more easily t01erated.l~" Lissamine green B is identical to rose Ben- gal in its staining properties but it stains blue on the ocular surface and it is easier to distinguish against an inflamed con- jun~ t iva . "~ It is not yet available in Aus- tralia.

Fluorescein and rose Bengal staining are highly sensitive for dry eye diagnosis but mild staining has been found in 30 per cent to 40 per cent of normals."' Various semi- quantitative fluorescein and rose Bengal staining schemes have been described. The

most widely used staining grading schemes a re those proposed by Lemp,3 van Bji~terveldl~~ and the Oxford scores.14h

The location of ocular surface staining can be a significant indicator of the cause of a dry eye c ~ n d i t i o n . " ~ ~ ' ) Examples include: 1. Non-autoimmune aqueous tear defi-

ciency is characterised by interpalpebral staining, whereas in autoimmune aqueous tear deficiency the staining is more widespread and may be confluent'" (Figure 1 ) .

2. Meibomian gland anomalies are generally associated with staining along the inflamed lid margins and 4 and 8 o'clock corneal staining, where the inflamed lid margins meet.'47

3. Lid surfacing anomalies are associated with staining in the region of ocular surface exposure, which is generally inferior in senile and cicatricial ectropion, lower lid laxity and nocturnal lagophthalmos, interpalpebral in cases of incomplete blinking, large fleshy pterygia and pingueculae or widespread in thyroid eye

4. Staining of the plica semilunaris and caruncle is indicative of allergic conditions, where habitual eye rubbing and 'mucus fishing' may develop.5"

5 . Toxic papillary reactions are characterised by widespread corneal staining extending inferonasally to the conjunctiva in non-contact lens wearers. A simi- lar pattern of staining is seen in contact lens wearers with toxic papillary reactions. However, the staining is more intense in the superior limbal region."

6. Contact lens associated dry eye is most likely to be associated with a 3 and 9 o'clock or 4 and 8 o'clock staining in rigid gas permeable contact lens wear or inferior corneal exposure staining in soft contact lens wearers. Any type of contact lens can be associated with non-specific widespread staining when soiled lenses are worn."'

Tear film osmolarity Hyperosmolarity is a contributing mechanism in ocular surface damage and inflammation associated with aqueous tear deficiency and meibomian gland dys-

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function." However, in the absence of a simple clinical technique to measure tear osniolarity, this diagnostic test will remain a research tool for the present.' ""

Global dry eye diagnostic protocol Golding and Brennan"" researched the diagnostic accuracy of 20 common clinical tests for dry eye and determined that a protocol comprising the symptoms, stability arid staining tests of McMonnies dry eye symptom survey score equal to or greater than 14, rose Bengal staining score of one or greater and FBUT less than 10 seconds, gave an optimal dry eye diagnostic accuracy with sensitivity of 93 per cent and specificity of 100 per cent. Clinical differential diagnosis of dry eye types can h e made primarily o n the basis of biomicroscopic signs.x 'IiH

CLINICAL DIAGNOSIS OF TEAR DEFICIENT DRY EYE

Diagnostic work-up for tear deficiency should incorporate a detailed medication history (to identify medications inhibiting aqueous tear production), general health history (to identify related systemic conditions) and at least one test of tear secretion."' Tear secretion tests include the Schirmer and Jones tests, phenol red thread tear test (PRT) and fluorophotometry. These tests have only fair reproducability.'"'~''' Hence, tear deficiency diagnosis cannot be made on the basis of tear secretion alone. The Schirmer I test'"' and Jones testl"'measure basal and reflex tear secretion, respectively, and are the most commonly-used clinical tests."" The Jones test involves application of topical anaesthetic a few minutes before instillation of the Schirmer test strip into the lower fornix, whereas the Schirmer I test involves conjunctival stimulation and the Schirmer I1 test involves nasal stimulation.'% Normal values with and without anaesthetic are more than 5 mm over five minutes and more than 10 mm over five minutes, respectively.'54 Schirmer strips can cause significant patient discomfort and ocular surface disturbance when the poorly wetted strip fails to soften in a dry eye subject. lii

The PRT test has been described as a measure of tear volume and turnover rather than basal tear secretion."" PRT test values have not been found to correlate with Schirmer test values.'"; Evaluation is made by measuring the quantity of tears absorbed into a fine cotton thread placed in the inferior A normal value of 24 mm over 15 seconds has been re- corded for a Caucasian population.'"" A PRT test value of less than 11 mm in 15 seconds is diagnostic of aqueous tear deficiency."" The PRT test can effectively differentiate between tear deficient and non-tear deficient dry eye and between tear deficient dry eye and non-dry eye subjects. "Ix

A number of biomicroscopic signs are specifically associated with tear deficient dry eye. These include a scant inferior tear meniscus,"g dull pre-corneal tear film specular reflection,'"" lid parallel conjuiic- ti"al folds, ' l 7 ' , ' 6 ' particulate matter in the tear film,"'" tear film mucous debris and mucin filament^.'"^

Using fluorophotometry, tear flow and tear volume can he evaluated by measuring the decay of sodium fluorescein in the tear film after its topical application."" Tear turnover rate is approni- mately 42 per cent lower in dry eye subjects than in normals.""' The fluorescein clearance test has a higher predictive value for ocular irri tation than the Schirmer I t e ~ t . " ' ~

Several specific diagnostic criteria for primary Sjiigren's syndrome have heen proposed."? The European set of crite- rial"' is considered the most clinically applicable and has a high sensitivity and specificity. IP:!

The European criteria require four of the following six items for diagnosis of Sjogren's syndrome: 1. subjective complaint of dry eyes 2. subjective complaint of dry mouth 3 . pathological salivary gland biopsy 4. abnormal Schirmer I test o r van

Bjisterveld score 5 . abnormal unstimulated whole sialo-

nietry or sialography 6. presence of serum autoantibodies:

Ro/SS-A, La/SS-B, antinuclear antibodies, rheumatoid factor.

~~ ~

DIAGNOSIS OF EVAPORATIVE DRY EYE

Meibomian gland anomalies Various classification systems for meibomian gland dysfunction have been proposed. They have been based on biomicroscopic signs, tear film stability, ocular surface staining,':' morphologic characteristics of meibomian glands and their secretions," tear volume and secretion, osmolarity, meibomography"'!' and lipid tear interference patterns.17i',"' Char- acteristics of meibomian gland dysfunction include absent, cloudy, particulate or frothy meibomian gland excreta (Figures 3 and 7 ) , posterior lid inflammation and thickening, trichiasis, madarosis (Figure 4 ) , seborrhoeic blepharitis, meibomian gland dilation, capping, plugging, atrophy and chalazia.'.'" Lower lid eversion and transillumination enable meibomian gland morphology to be visualised and the extent of gland drop-out to be determined.'""

Chronic allergy and toxicity The symptom of itch is said to be strongly suggestive of an allergic condition"' but can occur in other forms of dry eye and mimicking conditions.2"."" A history ofsys- temic atopic conditions such as asthma, hayfever, eczema and/or atopic dermatitis is common.'7J Biomicroscopic features of chronic allergy and toxicity include lid oedema, contact dermatitis (toxicity), tar- sal papillae and giant papillae (allergy) (Figure 5 ) , conjunctival follicular response (toxicity), conjunctival chemosis and ropy mucous discharge."' Tear film stability is reduced in ocular allergic con- d i t ion~. '~ , ' '~ Ocular surface staining will occur in allergy, if there is an associated epitheliopathy in vernal keratoconjunctivitis or atopic keratoconjunctivitis"' or mechanical injury due to large papillae, chronic eye rubbing or 'mucus fishing'."'' I n giant papillary conjunctivitis and medication toxicity the staining is widespread."

Lid surfacing/blinking anomalies Diagnosis of lid surfacing anomaly dry eye is based on gross external examina-

Dry eye Albietz

Figure 7. Chronic meibomian gland dysfunction is often associated with significant oily debris in the tear film. Coloured interference fringes indicate a thickened lipid layer.

Figure 8. Insertion of collagen (temporary) punctal plug

tion and slitlamp biomicroscopic examination (Figure 6). A thorough examination of lid positioning, blinking patterns, punctal positioning, patency and apposition to the globe is recommended when lid surfacing anomalies are sus- pected.2,q1 Patients with inferior punctate erosions or epithelial defects, who com- plain of ocular pain or irritation on wdk- ing in the absence of a history of ocular trauma or surgery, may he suffering from nocturnal lagophthalmos.'" Assessment and monitoring of blinking patterns to avoid a n d / o r cor rec t contac t lens- related lid surfacing anomalies is essential for comfortable and safe contact lens wear.I7'See Table 2 for an overview of clinical diagnostic criteria for dry eye subtypes.

DRY EYE TREATMENTS

The primary goals of dry eye treatment should be to improve symptoms,3 reduce tear osmolarity, improve tear film stability and reverse ocular surface damage.""'g While artificial tear supplementation remains the main treatment for all forms of d ry eye,146.177.17X o the r t rea tments include tear conservation a n d tear stimulation for tear deficient dry eye,

anti-inflammatory agents in allergy/ toxicity related dry eye and surgical treatments for lid/blinking anomalies and ocular surface disease.

Tear supplements Commercially available topical artificial tear supplements a re composed of a blend of polymers, electrolytes and buff- ering systems. Frequent use of preserved topical medications exacerbates the ocular surface damage in dry eye by reduc- ing the epithelial barrier functionlHO.l"l and inducing cytotoxic changes to the ocular surface epithelia and increased cellular exfoliation.H4.'X2-'H3 Dry eye subjects are more susceptible to the toxic effects of topical medication due to inhibited tear clearance resulting in pro- longed residence time of potential tox- ins o n the ocular surface." Hence , artificial tear supplements to treat dry eye should be non-preserved, particularly if dosing at greater than four times per day is required.'"."' Bicarbonate appears to be an important component in an artificial tear because it facilitates restoration of epithelial harrier function.'""'"' Non- preserved methylcellulose-based artificial tear supplements with electrolyte composition resembling physiological condi-

tions reduce tear o~rnolarity, '~' reduce rose Bengal corneal staining, reverse conjunctival squamous metaplasia and increase goblet cell den~ity.'"',''~

Sodium hyaluronate significantly im- proved dry eye symptoms, tear film stability and corneal miningi"'-''' and reduced epithelial permeability in a group of dry eye subjects.'"' In addition, non-Newtonian polymers, such as hyaluronate and polyacrylic acid have enabled the production of artificial tear supplements with a viscosity that would not normally be toler- ated in Newtonian fluids such as methylcellulose, by prolonging corneal residence time, without causing trauma from shearing forces during blinking in tear deficient eye.Ig"

Non-toxic or minimally toxic preserved multi-dose artificial tears are gradually being released onto the market. This technology enables safe, frequent dosing with reduced costs compared to unit dose

Anti-inflammatory agents As inflammation is a significant feature of some dry eye conditions and the products of the inflammation exacerbate the disease process, medications targeting specific inflammatory ocular surface mecha-

Clinical and Expcrinieiital Optometry 84. I January-February 2001

11

Dry eye Albietz

Global dry eye diagnosis

Tear deficient dry eye subtype Non-Sjogren's tear deficiency

Primary Sjogren's syndrome

Secondary Sjogren's syndrome

Evaporative dry eye Meibomian gland disease

Lid surfacing/blinking anomalies

Chronic allergy/toxicity

McMonnies score 2 14 Fluorescein break-up time 4 0 s Rose Bengal or lissamine green staining Elevated tear osmolarity

Phenol red cotton thread tear test 4 1 mm/l5s Scant inferior tear meniscus Mucous debris/filaments Lid parallel conjunctival folds

Criteria for non-Sjogren's syndrome tear deficiency, plus Xerostomia Pathological salivary gland biopsy Abnormal saliography Abnormal serum antibodies

Criteria for Sjogren's syndrome, plus Collagen vascular disease Exclude lymphoma, sarcoidosis, graft vs host disease, HIV

Cloudy, particulate meibomian gland excreta Capped, plugged, atrophied glands Lipid interference fringes, froth in tear film Meibomian seborrhoea Meibomianitis Acne rosacea

Proptosis Ectropion Entropion Incomplete or infrequent blinking Pterygia/pingueculae Conjunctivochalsis Nocturnal lagophthalmos Bell's palsy

Atopic history and/or chronic topical preserved medication use Itch Ropy mucus Conjunctival chemosis Papillarylfollicular response Giant cell papillary conjunctivitis Widespread conjunctival staining in toxicity response

Cicatricial ocular surface disease Chemical burns Trachoma Xerophthalmia Ocular cicatricial pemphigoid Pseudopemphigoid

Table 2. Diagnostic criteria for dry eye types

nisms in dry eye have been recommended Topical non-preserved steroid (methyl prednisolone) used three or four times per day for two weeks, gave significanl short-term and in some cases long-term moderate or complete symptomatic relief in Sjogren's syndrome subjects with severe aqueous tear deficiency. A reduction in fluorescein staining was also noted."" Long-term use of topical steroid is discour- aged due to the potentiation For cataract formation, increased intraocular pressure and infection. Pulse therapy with non- preserved topical steroids for acute exacerbations of symptoms in Sjjijgren's syndrome has been suggested.'"3 N o n - preserved methylprednisolone has also been shown to reduce ocular surface inflammation in subjects with inhibited tear clearance.'""hti-inflammatory agents such as mast cell stabilisers and antihistamines have also been recommended in the treatment of allergy-related dry eye.7ti,"'

Novel tear stimulants and immuno-modulatory agents Several medications have shown promise in promoting lacrimal gland function in the treatment of tear deficient dry eye. Topical IBMX (isobutyl methyl xanthine) a n d a topical P,Y, agonist stimulate lacrimal gland function in humans.'$'','"x Oral pilocarpine tablets produce an improvement in tear volume and flow hut are most effective in increasing salivary flow.l"ln a mouse model of Sjiigren's syndrome, topical androgen treatment sup- presses inflammation and stimulates the function of the lacrimal gland.'.'

Topical cyclosporin A (CsA) ophthalmic emulsion has been found to be effective in the treatment of moderate to severe dry eye. This immuno-modulatory agent in 0.5 pe r cent a n d 1.0 per cent non- preserved form has produced significant improvements in dry eye symptoms, ocular surface staining and tear secretion.""'."!' Unlike topical steroids, it does not appear to produce any significant ocular or systemic side effects.

Initial treatment trials of Sjbgren's syndrome with autologous serum containing epidermal growth factor, vitamin A and transforming growth factor-beta indicate

Clirriral and Exprrimental Optomt.try 84.1 January-Fcbruary 'LOO 1

12

Dry eye Albietz

a significant reduction in rose Bengal and fluorescein staining and a significant improvement in the ocular surface mucin coating."'? Autologous serum has been demonstrated to heal 43.8 per cent of per- sistent defects within two weeks and 62.5 per cent within one month after com- mencement of treatment at a six to 10 times per day dosage.2o2

Tear preservation Occlusion of the lacrimal canaliculi im- proves the objective signs and symptoms of aqueous tear deficiency, where other conventional topical treatments have been ineffective or insufficient.2"9,"" Methods of canalicular occlusion include surgery, heat and use of a tamponade. Reversibil- ity is important and hence tamponade methods, such as collagen (temporary) (Figure 8) and silicone (semi-permanent) punctal plugs are currently favoured. However, silicone plugs can present problems including irritation, extrusion, migration along the canniculus, dacrocystitis and cannaliculitis.2""

Agents for meibomian gland dysfunction Lid hygiene procedures are a mainstay for treatment of meibomian gland anomalies.""'However, in recalcitrant conditions, such as those associated with acne rosacea, oral tetracycline produces significant improvement i n mean tear break-up time.2')' Tetracyclines improve the consist- ency of the meibomian gland oils, which aids the tear film stability and the antibacterial properties of the tears"" and re- duces tear evaporation. Topical androgen treatment appears to regulate the function of the meibomian glands, improving the quality of the secretion and break-up

'

'

'

~

Much Secretagogues The mucin secretagogue 15(s)-HETE alleviates corneal injury in a rabbit model of dry eye.2og P2Y2 receptors have been identified in the conjunctiva and there have been suggestions that stimulation of these receptors may increase mucin secretion with the potential to improve tear film stability.

Tear deficient dry eye subtypes

Non-Sjogren's tear deficiency

Primary Sjogren's syndrome

Secondary Sjogren's syndrome

Evaporative dry eye subtypes

Meibomian gland anomalies

Chronic allergyltoxicity

Lid surfacinglblinking anomalies

Cicatricial ocular surface disease

Low to medium viscosity non-preserved artificial tears Punctal plugs Non-preserved ointmentslgels

Treatments for non-Sjogren's tear deficiency, plus Topical androgen Topical cyclosporin Non-preserved steroid Submandibular gland transplantation Oral pilocarpine

Treatments for primary Sjogren's syndrome, plus Management of systemic collagen vascular disease or

immune dysfunction with specialist physician

Lid hygiene procedures Topical non-preserved artificial tears Oral tetracyclines Topical non-preserved steroid Topical androgens

Avoid allergens Topical non-preserved artificial tears Topical non-preserved antihistamine-decongestant Mast cell stabilisers Non-preserved steroids

Non-preserved artificial tearslointments Surgical repair: pterygium excision, blepharoplasty,

Botox injection for blepharospasm Lid tapinglmoisture chamber for nocturnal lagophthalmos

Mucous membrane transplant Amniotic membrane transplant Limbal stem cell transplant Corneal graft Lid repair Ocular surface reconstruction

ectropionlentropion repair

Table 3. Treatment options for dry eye subtypes

Clinical and Experimental Optometry 84.1 January-Fehruary 2001

13

Dry eye Albirtz

Surgery Transplantation of autologous submandibular gland is currently being trialed in subjects with severe tear deficient dry eye.?") The quality of the salivary tears is intermediate between normal tears and normal submandibular saliva. The effects of this solution on the ocular surface are currently being evaluated in clinical and laboratory studies. MUCOUS me m bra 11 e trans p 1 an tat i o r i , am n i o t i c membrane transplantation, limbal stem cell transplantation, penetrating keratoplasty and lid margin repositioning have been performed in severe cicatricial disease in order to re-establish a physiologic ocular surface." Functional goblet cells in the autologous nasal mucosa persist for up to 10 years after implantation, resulting in improvements in symptoms and visual acuity.'"

Significant relief of' dry eye symptoms has been reported when some lid surfacing anomalies were corrected surgically. Following upper lid blepharoplasty in subjects with dermatochalasis, subjective improvement was achieved in 87 per cent of subjects with symptoms of external ocular irritation."!' Local botoxalin A injection for involuntary blepharospasm results in significant relief of external ocular irritation in a group who had not achieved significant relief from other

Reduction of tear evaporation Moist chamber spectacles are prosthetic devices coupled to eyeglasses that slow the evaporation o f tears from the ocular stir- face. They provide relief from dry eye symptoms during wear""."" and can be an effective adjunctive treatment in the more severe dry eye cases. Humidifiers and wet gauze eye masks?" can be effective in re- ducing tear evaporation. Bandage contact lenses niinimise ocular surface desiccation and recurrent epithelial breakdown in severe dry eye"X.?i!l and can be an effective short- or long-term method of controlling symptoms and delaying or avoiding the need for ocular surface reconstructive surgery. Table 3 gives an overview of dry eye treatments.

- CONCLUSIONS

Dry eye is an increasingly prevalent niul- tifactorial condition. Clinical diagnosis can be made largely on the basis of syrnp- tom a to1 o gy and bi om i c ros c o pic signs . Recent advances in understanding the mechanisms involved in dry eye pathogenesis have enabled the development of new treatments with promising effectivenesj in treating chronic tear film and ocular stir- face disorders.

ACKNOWLEDGEMENTS

The author would like to thank Professor Leo Carney for his assistance in the prepa- ration of this manuscript.

The author has no commercial or pro- prietary interest in any of the products or tests referred to in this article.

REFERENCES 1.

2.

3.

4.

5.

6.

7.

8 .

9.

10

B r o n AJ. Non-Sjogrcn ' s d r y eye: pathogenesis, diagnosis and animal models. In: Sullivan DA, ed. Lacrirnal Gland, Tear Fihn and Dry Eye Syndromes. New York: Plenum Press, 1994: 471-488. Holly FJ, I x m p MA. Tear physiology and dry eyes. Surv Ophthalmol 1977; 22: 69-87. L x m p MA. Kepor t of t h e Nat ional Eye Institute/Indurtry Workshop on Clinical Trials in Dry Eyes. (YAOJ1995; 21: 221-212. Tseng SCG, Tsuhota K. Important concepts for treating ocular surface and tear. film disorders. h i Jf)/i)l,htlinlmollY97; 124: 825-835. Mathers WD. Why the cye heroines dry: a cornea and lacriinal gland feedback model functional unit concept. CIAOJ 2000; 26: 159-1 65. Stern ME, Bcurerman KM', Fox KI, G ~ ( J J, Mircheff AK, Plugf'elder SC. T h e patioloby of'dry eye: the interaction between the om- lar surface and lacrimal glands. Cornrn 19!48; 17: 584589. 1)oughty MJ, Fonn D, Richter L), Simpson T, Gaffer) H, Gordon K. A patient question- ilaire approach t o estimating the prevalence of dry eye symptoms in patients presenting to optornetric practices across Canada. Optom Vis Sri 1997; 74: (324-631. AIbietzJM. Prevalence of dry eye subtypes in clinical optometry practice. Optom Vi.r .Sci

McCarty CA, Barisal AK, 1,ioingston PM, Stanishvsky YL, Taylor HK. The epidemiology of' d r y eye in Melbourne, Australia. Oph- thidmology 1998; 105: 11 1 4 1 119. Schein OD, M u ~ i o z B, TielschJM, Bandeen- Roche K, U'est SK. An epidemiological study

11

of medication use and symptoms of dry eye.

Franck c. Fatty layer of the precorneal tear film in the 'office dry eye syndrome'. , 4 c h Ophthalmol199 1 ; 69: 737-743.

I121IPS1 ophlhalmol 145 sci 1997; 38: s213.

12. Norn M. Pollution keratoconjiinctivitis. Actn

1 3

14

15

I6

17

18

19

20

21

22

23

24

25

26

27.

28

29

O/~hlhiLlmol 1992; 70: 2ti9-27J. Kirchiier K, Editorial. News Review. hf Optom 1997; Oct: 7. Bowman RU', Dougherty J M , McCullry JI'. C h r o n i c b lephar i t i s a n d dry eyes. In( Ophthnlmol Clin 1987; 27: 27-35. Farris KL. Contact lenses and dry rye. 1111 O/ihthalmol Clin 199 1 ; 3 1: 83-90, McMonnies (:. Contact lens-rcl;ited tear tlefi- ciency. 15-ob1rm.c in Optomvtq 1990; 2: 584598. Wilson F. Adverse extcriial ocular effects (JI topical ophthalrnic therapy: an rpidernio- logical, laboratory and clinical stucly. h n 5 A m O/)hthnlmol Sor 1983; 81: 854-96.5. Baum J . Clinical manifestations of dry e ) e states. Trans Ophtliirlmol Sor UK 1985; 104: 415-423. Tseng SCG, Hirs t LM', Matiinenee A E , Kenyon KR, S u n T, G r e e n K. Poutible mechanisms for the loss of' goblet cells in mucin-deficient disorders. Ophthnlmoloa 1984; 91: 545-552. M'hitchei- JP. Clinical diagnosis o f the d r y eye. Int Ophlhalmol Clin 1987; 27: 7-24. Tiffany JM. T h e role of rneihomian secretion in the tears. fian, Ophthalmol So( ('A' 1985; 104: 396-401. Smoliii G, The role o f tears in the prevcn- tion of infectioii. Int Ophthcrlniol ( X n 1987: 27: 25-26. Kessing SV. Mucous gland system o f the conjunctiva. Arta f l / ~ h ~ h i d m o l .Suppl I 968; 46: I - 1 93. Marquardt R. Histological studies 0 1 goh1t.t cell counts in the hitman conjunctiva. In: Holly FJ, ed. T h e Prrocular Tear Film in Health, Disease and Con tac t Leiis Wt,;ir. Lubbock, Texas: D r y Eye Itistitiitc IN( : , 1986: 312-318. Wataiiahr H. Fahrincant M , Tisdale AS, Spurr-Michaitd SJ, Linhrrg K, (;ipsori IK. Hiunan corneal and conjunctival epithelia produce a mucin-like glycoproreiti fo r the apical surface. I n 7 d f ) /~h~l in lmol Vi.5 .Sri 1 $

Dilly PN. Coiiuibution of the epithcliiitii t o t h e s tabi l i ty of t h e t e a r f i lni . T r n n r Ophthnlmol Sor. CIA' 1985; 104: 381-389. liotet S, van Bijsterveld Ol', Koglx 0, liiroche I-. A new hypothesis on tear film stability O/)hllialmolr@ru 1987; 195: 119-124. Prydal .]I, Artal P, W'oori H, C:aniphell FW. Study of human precortieal tear film thickness and structure using laser interferom- etry. Invest Ophthalmol If/.\ Sr i IY92; 33: 2006-201 1. KingSmith PE, Fink BA, Fogt N, Nichols KK, Hill KM, M'ilson GS. T h e thickness of thc

-

Dry eye Alhictz

human precorneal tear film: evidence from reflection spectra. Invest Ophthalmol Vis Sci: 2000; 41: 3348-3359.

30. Kenyon KR. Anatomy and pathology of the ocular surface. Int Ophthalmol Clan 1979; 19: 169-1 95.

31. Bron AJ, Mengher LS, Davey CC. The normal conjunctiva and its response to inflammation. Trans Ophthalmol Soc UK 1985; 104: 424435.

32. Sugrue SP, Ziesle JD. ZO1 in corneal epithelium: association to the zonula occludens and adherens junctions. Exp Eye Res 1997;

33. Wanko T, Lloyd B, Matthews J. The fine structure of the human conjunctiva in the perilimhal zone. Invest Ophthalmol Vzs Sci 1994; 3: 285-301.

34. Kruse FE, Chen m, Tsai RFJ. Conjunctival transdifferentiations due to incomplete removal of limbal basal epithelium. Invest Ophthalmol Vis Sci 1990; 31: 1301-1314.

35. Huang AWJ, Tseng SCG. Corneal epithelial wound healing in the absence of limbal epithelium. Invest Ophthalmol Vis Sci 1991; 32: 96-105.

36. Lemp MA, Mathers WD. Corneal epithelial cell movement in humans. Eyr 1989; 3: 438- 445.

37. Puangsricharen V, Tseng SCG. Cytologic evidence of corneal diseases with limbal stem cell deficiency. Ophthalmolgy 1997; 102: 1476148.5.

38. Wilson SE, Li Q, Mohan RR, Tervo T, Vesaluoma M, Bennett GL, Schwa11 R, Tabor K, Kim J, Hargrave S, Cuevas KH. Lacrimal gland growth factors and receptors: lacrimal fibroblastic cells are a source of tear HGF. Adv Exp Med Bid. 1998; 438: 625-628.

39. Nakamura Y, Sotozono C, Kinoshita S. In- flammatory cytokines in normal human tears. CurrEye Re.< 1998; 17: 673-676.

40. Baudouin C, Brignole F, Pisella PJ, Becquet F, Philip PJ. Immunophenotyping the human dendriform cells from the conjunctival epithelium. CurrEyr&.s 1997; 16: 475-481.

41. Baudouin C, Brignole F, Becquet F, Pisella PJ, Goguel A. Flow cytometry in impression cytology specimens. A new method for evaluation of conjunctival inflammation. Invest Ophthamol Vzs Sri 1997; 38: 1458-1464.

42. Rocha EM, Wickham LA, da Silveira LA et al. Identification of androgen receptor pro- tein and 5alphareductase mRNA in human ocular tissues. BrJ Ophthalmol2000; 84: 6-84.

43. Sullivan DA, Krenzer KL, Sullivan BD, Tolls DB, Toda I, Dana MR. Does androgen insufficiency cause lacrimal gland inflammation and aqueous tear deficiency? Invest Ophthalmol Vzs Sci 1999; 40: 1261-1265.

44. Sullivan DA, Edwards JA. Androgen stimulation of lacrimal gland function in mouse models of Sjogrens syndrome. J Steroid Biochem Mol Biol 1997; 60: 237-245.

64: 11-20.

45. Sullivan DA, Wickham LA, Ullman MD et al. Androgen control of the meibomian gland. Invest Ophthalmol Vis Scz (Suppl) 1997; 38: s444.

46. Elkon B. Apotosis and autoimmunity. ,J Rheum 1997; 24: 67 .

47. de Roetth A. Hypofunction of the lacrimal gland and Sjogren syndrome. Lancet 1945;

48. Farris RL, Gilhard JP, Stuchell RN, Mandel ID. Diagnostic testS in keratoconjunctivitis sicca. CLAOJ1983; 9: 23-28.

49. Bjerrum KB. Keratoconjunctivitis sicca and primary Sjogrens syndrome in a Danish population aged 30-60 years. Acta Ophthalmol

50. Nelson JD. Diagnosis of keratoconjunctivitis sicca. Znt Ophthalmol Clin 1994; 34: 36-56.

51. Roetth de. Hypofunction of the lacrimal gland and Sjogrens syndrome. Lancet 1945;

52. Lucca JL, Farris RL. Keratoconjunctivitis sicca in male patients with human immunodeficiency virus type 1. Ophthalmology

53. Calissendorff B, el-Azazi M, Lonnquist B. Dry eye syndrome in long-term follow-up of hone marrow transplanted patients. Bonr Mawow Tran

Dry eye Albirtz

and other disorders by impression cytology. GrnPfrk Arch Clin Exp Ophthnlmol1992; 230: 329-334.

81. Baudouin C, Haouat N, Brignole F, Bayle J, Gastraud P. Imniunopathologica1 findings in conjunctival cells using inimunofluores- cence staining of impression cytology specimens. BrJ Ophthalmol 1992; 76: 545-549.

82. Giibbels M, Spitznas M. Effects of artificial tears on corneal epithelial permeability in dry eyes. Gr(zPfPT Arch Clin Exti Ophthnlmol

83. Tripathi BJ, Tripathi R, Kolli SP. Cytotoxic- ity of ophthalmic preservatives on human corneal epithelium. Lrns E y 7bx Kes 1992;

84. Diebold Y Herreras JM, Callejo S, Argueso P, Calonge M. Carbonier versiis cellulose- based artificial-tear formulations: morphologic and toxicologic effects on a corneal cell line. Cornea 1998; 17: 433-440.

85. Baudouin C, Pisella P j , Fillacier K et al. Ocular surface inflammatory changes induced by topical anti-glaucoma medications. Ophthnlmology 1999; 106: 556-563.

86. N u r i R, Finazm C , Cerruti A. Adverse effects of topical antiglaucomatous medications on the conjunctiva and lacrimal response. Int Ophthalmol 1998; 22: 31-35.

87. Turacli E, Budak K, b u r A, MiLrak R, Ekinci C. The effects of long term topical glaucoma medication on conjunctival impression cytology. Int Oph/hnlmoll997; 21: 27-33.

88. Caffery B, Richter D, Simpson T, Fonn D, Dougherty M, Gordon K. The prevalence of dry eye in contact lens wearers: part 2 of the Canadian dry eye epidemiology study (CANDEES) . I n z ~ ~ t Ophthnlmol vi .c Sci (Suppl)

89. Brennan NA, Efron N. Syniptomatology of HEMA contact lens wear. Optom Vis Sci 1989; 66: 834-838.

90. Osborn G, Zantos S. Practitioner survey- management of dry eyr symptoms in soft rontact lens wearers. Contact Lm.r Spclrurn

91. Lemp MA. Surfacing ahnormalies in the preocular tear film and dry eye syndromes. I n / Ophthnlmol Clin 1973; 13: IY l - IW.

92. Kline LA, DeImcca TJ. Effect of gel lens wear on the pre-corneal tear film. Int Con- tart Lrns Clin 1975; 2: 56-62.

93. Cedarstaff TH, Tomlinson AA. comparative study of tear evaporation rates and water content of soft contact lenses. Am,/ Optom Ihysiol Opt 1983; 60: 167-174.

94. Farris RL. Tear osmolarity and ocular surface disease in keratocoiijunctvitis sicca. Pans Am Ophthnlmol Soc 1985; 3: 501-545.

95. Hin t LW, Tseng SG, Tsubota K. Current Concepts o n Ocular Surface Disease. Allergan, 1993.

96. McMonnies CU. Key questions in a dry eye history.JAni Oyitom Assoc 198fi; 57: 512-517.

1991; 229: 345-349.

9: 361-375.

1996; 3: s72.

1989; Sept: 23-26.

97. GilbardIP, Farris lU. Ocular surface drying and tear film osmolarity in thyroid eye clis- ease. Actn Ophthalmol1983; 61: 108-1 16.

98. Tsubota K, Fujihara T, Kaido M, Mori A, Mimiura M, Kato M. Dry eye and Meiges syndrome. Rr] Ophthalmol1997; 81: 439-442.

99. Vold SD, Carroll RP, Nelson J.D. Dermato- chalasis and dry eye. A m JOplithulmol1903; 115: 216-220.

100. Mellor D, Tseng SC. Conjunctivochalasis literature review and possible pathop1i)si- ology. Suru Ophthnlmol 1998; 43: 225-232

1 0 1 . I a i D, Stasior OG. Lower eyelid laxity and ocular symptoms. Am,JOphth~~lmol1983; 95:

102. Lemp MA. The precorneal fluid and blirik- ing. Int ~ihthnlmol Clin 1981; 21: 55-64.

103. Hagan S, Lory B. Prevalence of dry eye among computer users. Optom Vis Sci 19518; 75: 712-713.

104. Tsubota K, Nakamori K. Dry eyes and video display terminals. NEngJMed 1993; 328: 584.

105. Patel S, FarrellJC. Age-related changes in precorneal tear film stability. Ofitom Vis .Sci 1989; 66: 175-178.

106. Backnian H, Haghighat F. Indoor air quality and ocular discomfort. J Am Optom Assoc 1999; 70: 309-316.

107. Somrner HJ, JohnenJ , Schongen P, Stolze HH. Adaptation of the tear film to work in air-conditioned rooms (office-eye syndrome). GprJ Ophthnlmol 1994; 3: 406-408.

108. Albietz JM, Golding TR. Differential diagnosis and management ofcommon dry eye subtypes. Clin Exp Optom 1994; 77: 244-260.

109. Schein OD, M u n o L R , Tielsch J M , Bandeen-Roche K, West S. Prevalence of dry eye among the elderly. Am,/Ophthnmol1997; 124: 723-728.

1 1 0 . Schein OD, Hochberg MCMunoz B et ;rl . Dry eye and dry mouth in the elderly: a population-based assessment. Arch Intrrn Mrrl 1999; 159: 1359-1363.

1 1 1 . Craig JP, Tomlinson A, Sturrock RU, Grierson DJ, Patel S. Tear physiology in rheumatoid arthritis. Invest Ophlhalmol Scz (Sup$) 1995; 36: S1043.

112. Shiniaraki J, Goto E, Ono M, Shimmura S, Tsubota K. Meibomian gland dysfunction in patients with Sjogrens syndrome. Oflh-

113. Seal DV, McGillJI, Mackie IA, Liakos GM, Jacobs P, Goulding NJ. Bacteriology and tear pro te in profiles of t he dry eye. Br J Ophthnlmol 1986; 70: 122-125.

114. Jaiinsen PT, van Bijsterveld OP. A simple test for lacrimal function: a tear lactoferrin assay by radial immunodiffusion. CrnQk Arch ClinExp Ophthalmoll983; 220: 171-174.

115. Wilson SE, Schultz GS, Chegini N, Weng J, He Y. Epiderinal growth factor, transformiirg growth factor, transforming growth factor hew, acidic fibroblast growth factor beta, basic growth factor and interleukin-1 proteins In

545-551.

thnlrnoloAy 1998; 105: 1485-1489.

the cornea. Exp Eye Kes 1994; 59: 63-70. 116. Norn MS. External Eye Methods ofExami-

nation. Copenhagen: Scriptor, 1983: 153. 117. Nelson J D . Impression cytology. Cornpa

1988; 7: 71-81. 118. Tseng SCG. Staging of conjunctival sqw-

nious metaplasia by impression cytolog). Ophthalrnolo~ 1985; 92: 728-733.

119. Adams GWC, Dilly P.N, Kirkness (IM. Monitoring ocular disease by impression cytology. Eyye 1988; 2: 506516.

120. (;ilhard,JP, Rossi SR, Gray KI,, Hanninrn LA. Natural history of tlisrasc in a rahbit model for keratoconjunctivitis sicca. A ~ N

121. Dmjo Y, Matanbe H, Tisdale AS, George M, Tsumura T. Alteration of mucin in human epithelia in dry eye. lnuest O~~hthnltriol Vi.$ Sci 1998; 39: 2602-2609.

122. Lemp MA. New strategies in the treatment of dry eye states. Cornra 1999; 18: 625-632.

123. Tsubota K, Fujihara T, Saito K, Xikeuchi T. Conjunctival epithelial expression of HW-DR in dry eye patients. OphthalmoloA$n 1999; 213: 16-19,

124. Smith JA, Stern ME, Gao J , Schwalb TA, Rupp DC, Whitecup SM. Conjunctival inflammation in Sjiigrens syndrome and non- Sjiigrens syndrome keratocoiij~inctivitis sicca. Inuest Ophthamol IJis Sci 2000; 41: S276.

125. Brignole F, Pisella PJ, Goldschild M, Dc SaintJean M, Goguel A. Baudouin C. Flow cytometric analysis of inflammatory markers in conjunctival epithelial cells ofpaticnts with dry eye. Invnt OjIh/hnlmol V i r S c i 2000; 41: 1356-1363.

126. Metz DP, Bacon AS, Holgate S, L.ightman SI.. Phenotypic characterization of T cells infiltrating the conjunctiva in chronic a1lc.r- gic disease. ,/Allergy Clin Immunol 11196; 98: 686-696.

127. Bron AJ. Eyelid secretions and the preveii- tion arid production of disease. Eye 1088; 2: 164-171.

128. Rocha EM, Wickham LA, Hiiang Z, Totla I, (;do], da Silveira IA, Sullivan 1)A. Pres- ence and testosterone influencc on the levels of anti- and pro-inflammatory cytokincs in lacrimal tissue o f a mouse model o f Sjogrens syndrome. Adu Exp M c d Bi(il1998; 438: 485-491.

129. Augustin AJ, Spirzrias M, Kaviani N, Meller D, Koch FH, Grus F, Gobbels MJ. Oxidative reaction in the tear fluid in paticnts suffering from dry eyes. Griirfri Arch Clin I:xjI

130. Trocrne SD, Hallberg CK, Gill KS, Gleich GJ, Tyring SK, Brysk MM. Effects of co+ nopliil granule proteins on human corneal epithelial cell viability and rnorpliology, / , I - vat Ophlhalmol \is Sri 1997; 38: 593-.599

131. Nelson.JD. Diagnoais and treatment oftii-y eye: A clinical perspective. Cornrn 2000; 19: S108.

Otihthdmol 1989; 67 SLlPpl 192: 95-101,

Clinical and Exprrirnrntal Optorncti-y 84.1 .lanuary-Fcbl.itar!. 2001

16

Dry eye Alhietz

132. Nichols KK, Begley CG, Caffery B, Jones IA. Symptoms ofocular irritation in patients diagnosed with dry eye. Optom Vis Sri 1999;

133. McMonnies CUT, Ho A. Responses to a dry eye questionnaire from a normal population, J A m Optom Atsoc 1987; 58: 588-591.

134. McMonnies CW, Ho A. Patient history in screening for dry eye conditions.jAm Optom Assoc 1987; 58: 296-301.

135. WaltJG, Rowe MM, Stern KL. Evaluating the functional impact of dry eye: the Ocu- lar Surface Disease Index. Drug Inf,] 1997; 31: 1436.

136. Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis B. Relkahility and validity of the Ocular Surface Disease Index. Arch Ophthalmol2000; 118: 615-621.

137. Cho P. Stability of the precorneal tear film: a review. Clin Exp Optom 1991; 74: 19-25.

138. Nally L, Ousler I11 GW, Albelson MA. Ocu- lar discomfort and tear film break-up time in dry eye patients: a correlation. Inupst Ophthalmol V i s Sci 2000 Suppl; 41 : S274.

139. Golding TR, Brennan NA. Diagnostic accuracy and intercorrelation of clinical tests for dry eye. Invest Ophthnlmol Vis Sri 1993; 34: 823.

140. Greiner JV, Finnemore VM, Exford JM, Herman JP, Glonek T, Bueno EA, Korh D. Effects of fluorescein instillation methods on the stability of the tear film lipid layer. Cornea 2000; 19 Suppl: S90.

141. Feenestra PG, Tsriig SCG. Comparison of fluorescein and rose Bengal staining. O p h thalmology 1992; 99: 605-61 7.

142. ydbery H. Dual appearance of fluorescein staining in vivo of diseased human corneal endothelium. A non-contact photomicro- graphic study. BrJ Ophthalmol 1992; 76: 43- 44.

143. Norn MS. Lisamin green. Vital staining of the cornea and conjunctiva. Artn Ophthdmol

144. Chodash J , Dix RD, Howell RC, Stroop WG, Tseng SC. Staining characteristics and antiviral activity of sulphorodanrine B and lissamine green B. Invest Ophthnlmol Vis Sci 1996; 35: 1046-1058.

145. van Bijsterveld OP. Diagnostic tests in the sicca syndrome. Arrh Ophthalmol 1969; 82: 10-14.

146. Bron AJ. The Doyne Lecture: Reflections on the tears. Eye 1997; 11: 583-602.

147. Catania LJ. Primary Care ofAnterior Seg- ment. Norwalk, Connecticut: Appleton and Lange, 1995.

148. Lamberts DW. Keratocorijunctivtis sicca. In: Smolin G, Thoft RA, eds. The Cornea. Scientific Foundations and Clinical Practice. Boston: Little, Brown & Company, 1983:

149. Gilbard JP, Farris RL. Tear osmolarity and ocular surface disease in keratoconjunctivi-

76: 838-844.

1973; 51: 483-491.

293-309.

tis sicca. Arch Ophthalvnol1979; 97: 1642-1648. 150. Little SA, Bruce AS. Repeatability of

phenol-red and tear thinning time tests for tear film function. Clzn Exp Optom 1994; 77: 6468.

51. Golding TR. Evaluation of tear film im- pairment in dry eye and hydrophilic contact lens wear. PhD Thesis: University of bfebourne, 1992.

52. Schirmer 0. Studien zur physiologie der tranenahsonderung und tranenahfuhr. Grnefek Arch Clin Exp Ophthnlmol 1903; 56: 197-291.

53 . Jones LT. The lacrimal secretory system and its treatment. A m JOphthalmoll966; 62: 47-60.

54. Nelson JD. Electrolytes in artificial tears mimic human tears, renew dry eyes. Ocular S u r g q N m s 1994; 5: 39-41.

5.5. Hamano H, Hori M, Hamano T et al. A new method for measuring tears. CIAOJ 1983; 9: 281-289.

56. Goren MB, Goren SB. Diagnostic tests in patients with symptoms of keratoconjunctivitis sicca. ArnJ Ophthalmol 1988; 106: 570- 574.

157. Sakamoto R, Bennett ES, Henry \A, Paragina S. The phenol red tear test: a cross- cultural study. Invest Ophthnlvnol Vis Sci 1992; 34: 3510-3514.

158. Patel S, Farrell J, Blades KJ, Grierson DJ. The value of a phenol red impregnated thread for differentiating between the aqueous and non-aqueous tear deficient dry eye.

159. Khurana AK, Chaudhary R, Ahluwalia BK, Gupta S. Tear film profile in dry eye. ,4ctn Ophthnlmol (Coppnh) 1991; 69: 79-86.

160. Jaanus S. Focus on pharmacology number 2: Managing the dry eye. Clin Eye Vision Carp 1990; 2: 142-145.

161. C k n e RB. Conjunctival pleating and kerate conjunctivitis sicca. Cornea 1991 ; 10: 367-368.

162. Hoh H, Schirra F, Kienecker C, Ruprecht KM. Lid-parallel conjunctival fold (LIPCOF) and dry eye: a diagnostic tool for the contactologist. Contartologicti 1995; 17E: 104-1 17.

163. Mackie IA, Seal D\: The questionably dry eye. BrJ Ophthalmol1981; 65: 2-9.

164. Wright P. Diagnosis and management of dry eyes. Trant Ophthnl Sor LK 1971; 91: 119-128.

165. Gijbhels M, Goehels G, Brithach R, Spitnas M. Tear secretion in dry eyes as assessed by objective fluorophotome try. G r J Ophthnlmol 1992; 1: 350-353.

166. Nelson JD. Simultaneous evaluation of tear turnover and corneal epithelial permeability by tluorophotometry in normal suh- jects and patients with keratoconjunctivitis sicca (KCS). Trans A m Ophthalmol Sac 1995; 93: 709-753.

167. Afonso AA, Monroy D, Stern ME, Feuer WJ, Tseng SC, Pflugfeldcr SC. Correlation

Ophthnl PhysiOl Opt 1998; 18: 471-476.

of tear fluorescein clearance and Schirrner test scores with ocular irritation symptoms. Ophthalmology 1999; 106: 805-810.

168. Vitali C, Moutsopulos HM, Bomhardiere S. The European Community Study Group on Diagnostic Criteria for Sjijgrens Syn- drome. Ann RheumDiseasP 1994; 53: 637-647.

169. Mathers WD, Sheilds WJ, Sachdev MS, Petroll WM, Jester JV. Meihomian gland dysfunction in chronic hlepharitis. Cornm

170. Yokoi N, Takehisay, Kinoshita S. Correla- tion of tear lipid layer interference patterns with the diagnosis and severity of dry eye. Am J Ophthalmol1996; 122: 818-824.

171. Josephson JE. Observations of the specular reflection from the anterior surface of the preocular tear film. In: Holly FJ, ed. The Preocular Tear Film in Health, Disease, and Contact Lens Wear. I.ubbock,Texas: Dry Eye Institute, Inc. 1986: 554563.

172. Jackson WB. Differentiating conjunctivitis of diverse origins. Surv Ophthnlmol Suppl 1993; 38: 91-104.

173. Christiansen SC. Evaluation and treatment of the allergic patient. Int Ophthnlmol Clin

174. Barsam PC, Sampson WG, Feldman GI,. Treatment of the dry eye and related problems. Ann Ophthalmol 1972; 4: 122-129.

175. Friedlander MH. Conjunctivitis of allergic origin: Clinical presentation and differential diagnosis. Surv Ophthalmol Suppl 1993; 38: 105-1 14.

176. Korb D. The role of blinking in successful contact lens wear. Int Contart Lens Clin 1974; 1 : 59-74,

177. Nelson J D , Drake MM, Brewer JT, Tuley M . Evaluation of a physiological tear suhsti- tute in patients with keratoconjunctivits sicca. In: Sullivan DA, ed. Lacrimal Gland, Tear Film, and Dry Eye Syndrome. NewYork: Plenum Press, 1994: 453-457.

178. Farris RL. Staged therapy for the dry eye.

179. Gilbard JP. Dry eye: pharmacological approaches, effects, and progress. CI,AOJ 1996; 22: 141-145.

180. Gijhhels M, Spitznas M. Influence ofarti- ficial tears on the conjunctival epithelium in dry eye syndrome. Cmpfpj Arch Clin Exp Ophthalmol1989; 227: 139-141.

181. Lopez Bernal D, Uhels JL. Artificial tear composition and promotion of recovery of the damaged corneal epithelium. Cornpa 1993; 12: 115-120.

182. Adams JL, Wilcox MJ, Trousdale MD, Chien D, Shimizu RW. Morphological and physiological effects of artificial tear formulations on corneal derived cells. Cmnpa 1992; 11: 234-241.

183. Doughty MJ. Twice-daily use o fa chlorbu- tanol preserved artificial tear on rabbit corneal epithelium assessed by scanning

1991; 10: 277-285.

1989; 29: 268-273.

c u q 1 9 9 1 ; 17: 207.215.

Clinical arid Experimrnral Optometry 84.1 January-February 2001

17

Dry eye AlbiPtz

electron microscopy. Ophthnl Physiol Opt 1992; 12: 457-466.

184. Doughty MJ. Acute effects of chlorobutanol- or benralkonium chloride-containing artificial tears on the surface features o f rabbit corneal epithelial cells. Optom \is Sci 1994;

185. Schaefer K, George MA, Ahelson MB, Garfofalo C. A scanning elrctron mirro- graphic comparison of th r effects of two preservative-free artificial tear solutions on the corneal epithelium as compared to a phosphate buffered saline and a 0.02% benzalkonium chloride control. Adu Mrd Biol 1994; 350: 459-4134,

186. UbelsJ, McCartney M, Lantz W, Beaird J, Dayalan A. Effects of preservative free tear solution on corneal epithelial structure and function. Arch Ophthnlrnol1995; 11

187. (XIhard.JP, Rossi SR. An electrolyte-based solution that increases corneal glycogen and conjunctival goblet cell density in a rabbit model for keratoconjunctivitis sicca. Oph- thnlmolog?. 1992; 99: 600-604.

188. Donshik PC, Nelson JD, Ahelson M, McCully JP. Effectiveness of Bion Tears, Celliifresh, Aquasite, and Refresh Plus for moderate to severe dry eye. In: Sullivan D et al, eds. I x r i m a l Gland, Tear Film, and Dry Eye Syndrome 2. New York: Plenum Press, 1998: 753-760.

1811. Shimmnra S, Ono M , Shinoraki K et al. Sodium hyaluronate eyedrops in the treatment of dry eyes. 131- J Ophthnlmul 1995; 79:

190. Mengher I S , Pandher KS, 13i-011 AJ, Davey CC. Effect of soditmi hyahironate (0.1 %) on break-up time (NIBUT) in patients with dry eyes. Br,J Ophthnlmol 1986; 70: 442-447.

191. Condon PI, McEwen CG, Wright M, Mac- intosh G, Prescott RJ, McDonald C. Double blind, randomised, placebo controlled, crossover, mnlticentre study to determine the efficacy of a 0.1 % (w/v) sodium hyaluronate solution (Fermavisc) in the treatment of dry eye syndrome. B t J Oplithnlmol 1999;

192. Yogi N , Komuro A, Nihida K, Kinoshita S. Effrctiveness of hyaluronan on corneal epithelial harrier function in dry rye. B r J Ophlhnlmol; 1997; 81 6.

193. Gurny R, RyserJE, Yabataby C, Martenet M , Edman P, Camber 0 . Precorneal resistencc times in humans of sodium hyaluronate as measured by gamma scintig- raphy. Gmrfps Arch (.h Exp Ophlhnlmol1990; 228: 510-512.

194. Chihert H, Goldsrhimdt P, Pouliquen Pe t al. Preservatives on the ocular surface: new technology (ABAK) able to capture irrevers- ibly hcnzalkoniurn chloride (BAK) for rye- drops. Invest Optnlinol Vis Sri (Suppl) 1996; 37: S576.

195. Marsh P, Pflngfelder S C . Topical

71: 562-572.

1007-1011,

83: 1121-1124.

nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjdgrens syndrome. Ophthalmoloa 1999; 106: 81 1-816.

196. Prabhasawat P, Tseng SCG. Frequent association of delayed tear clearance in orn- lar irritation. R r J Ophthnlmol 1998; 82: 6613.675.

197. GilbardJP, Rossi SR, Heyda KG. Stimula- tion of tear secretion and treatment of dry- eye disease with 3-isohutyl-methylxanthine. Arch Ophthalmol 1991; 109: 672-676.

198. Yerza BR, Mundasad M, Sylvester RN, Gordon J(;, Cooper M, Kellerman DJ. A double-masked randomized, placebo controlled, rising-dose study of multiple ocular instillations of INS365 ophthalmic solution in patients with mild to moderate dry eye disease. Cornm 2000; 19: S138.

199. Mathers WD, Dolney AM. Objective dem- onstration of tear stimulation with oral pilocarpine in dry eye patients. Invesl

200. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicentre, randomised studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. Ophthalmology 2000; 107: 631-639.

201. Stevenson D, TauberJ, Reis BL. Efficacy and safety of cyclosporin A ophthalmic emulsion in the treatment of moderate-to- severe dry eyr disease: a dose-ranging, randomised trial. Ophthalmology 2000; 107: 967-974.

202. Tsubota K, Goto E, Shimmima S. Treat- ment of dry eye by autologous serum application in Sjiigrens syndrome. Br J Ophthalmol 1999; 83: 390-395.

203. MurubeJ, Muruhe E. Treatment of dry eye by blocking the lacrimal canaliculi. Surv Ophthnlmol 1996; 40: 463-480.

204. Gilbard JP, Rossi SR, Azar DT, Heyda KG. Effect of punctal occlusion by Freeman silicone plug insertion on tear osmolarity in dry rye disorders. CI,Aq]l989; 15: 216-218.

205. Rumelt S, Remidla H, Rubin PA. Silicone punctal plug migration resulting in dacryo- cystitis and canaliculitis. Cornvn 1997; 16: 377-379.

206. Driver PJ, Lemp MA. Meibomian gland dysfunction. Surv Ophthnlmol1996; 40: 343-347.

207. Quarterman MJ, Johnson LIW, Abele DC et al. Ocular rosacea: Signs, symptoms and tear studies before and after treatment with doxycycline. Arrh llermatol1997; 133: 49-54.

208. Sullivan DA, Wickham LA, Rocha EM et al. Androgens and dry eye in Sjdgrens syndrome. Ann W A t a d Sci 1

209. Gamache DA, Wei Z-y, Weimer I,, SpellrnanJM, YanniJM. Preservation of corneal integrity by the mucin secretagogue I5(s)-HETE in a rabbit model of desiccation induced dry eye. Cornea 2000; 19: S88.

210. Geerling G, Honnicke K, Schroder C et al. Quality of salivary tears following autolo-

i (Suppl) 2000; 41: S60.

gous submandibular gland transplantation for severe dry eye. GraeJes Arch Clin Exp Ophthalmol2000; 238: 45-52.

211. Wenkel H, Rummelt V, Naumann GO. Long term results after autologoris nasal mucosal transplantation in severe mucous deficiency syndromes. BrJ Ophthelmol2000;

212. Chiou AG, Florakis GJ, &rim M. Mariage- ment of conjunctival cicatrizing diseases and severe ocular surface func t ion . Surv Ophthalmol1998; 43: 19-46.

213. Tseng SC, Prabhasawat P, Barton K, Gray T, Meller P. Amniotic membrane transplant with or without limbal allografts for corneal surface reconstruction in patients with limbal stem cell disease. Arch Ophthalmol

214. Tsai RJF, Tseng SCG. Human allograft limbal transplantation for corneal siirf;lcr reconstruction. Cornea 1994; 13: 389-400.

215. Farris RI,, Kornfield S, Hart DE. The efficacy of moisture chamber eyeglasses are an efficacious treatment of severe dry eyes. In.orsf Ophthnlmol V2.r Sci (Suppl) 2000; 41: S273.

216. Tsubota K. Tear dynamics and dry eye. Ir(~g Kvtin Eye Re.r 1998; 17: 565-596.

217. Kurihashi K. Moisture aid duringsleep for treatment of treatment of dry eye: wet g a u x eye mask. Ophthalmulogicn 1994; 208: 216219.

218. Kuckelkorn R, Berti-am B, Redbrake (;, Remi M. Therapeutic hydrophilic bandage lenses after perforating keratoplasty i n srvere chemical burns . Klin Monlntbl AugenhPiNzd 1995; 207

219. Lemp MA. Contact lensev and the dry-eye patient. Int O f i h t h ~ ~ ~ ~ l Clin 1986; 26: 63-71,

84: 279-284.

1998; 116: 431-441.

Authors address: Dr Julie Albietz Centre for Eye Research School of Optometry Queensland University of Technology Victoria Park Road Kelvin Grove QLD 4059 AUSTRALIA

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