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

Accepted for publication: 20 December

2000

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)

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. Keratoconjunctivitis 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 b e e n e x p a n d e d 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 adversely 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 omlar 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 s u r f x e (conjunctiva, cornea,
accessory lacrimal glands and meibomian
glands), the lacrimal gland and the inter-

connecting neural reflex loops appear t o

comprise a tightly integrated functional
unit, the parts of which ac.t together and
not in isolation.' Decreased lacrimal gland
secretion damages the ocular s u r h c e ,
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
corneal nerves
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.'

Clinical arid Expcrimental Opromrtry 84.1 January-Febi-uary 2001

Dry eye Albietz

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 symptoms7 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 intoleranceI6and
progressive ocular surface disease, scarring a n d 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 principal role is to reduce tear film evaporation.2'The aqueous layer contains electrolytes, glucose, antibacterial proteins,
antibodies a n d glycoproteins a n d 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 nongoblet epithelial cells of the cornea" and
conj~nctiva.~
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 m u c h to the underlying surface epithelium and may facilitate tear
film spread and stabilisation.25The thick-

ness of the tear film remains controversial. 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 nonkeratinised 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 a n d a gradual
conjunctivalisation of the ~ o r n e a . ' ~ '
Numerous hormones, growth factors,
retinoids, cytokines a n d 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.'"

Clinical and Experimental Optometry 84.1 January-February 2001

Dry eye Alhietz

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, StevensJohnson syndrome and ocular cicatricial
pemphigoid can also cause a severe secondary aqueous tear deficiency through
the scarring, narrowing and obliteration
of the lacrimal gland a n d 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." '' T h e condition is a slowlyprogressing, 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.55The 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 t h e 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 aqiieous tear deficiency in post-menopausal
women.' Many commonly-prescribed oral
and topical medications may reduce aqireous tear production including topical and
systemic anti-histamines, tricyclic antidepressants, topical and systemic betablockers, the oral contraceptive pill and
systemic and topical non-steroidal antiinflammatory agents.'''
Loss of corneal sensitivity as is observed
in diabetes,65excimer laser photorefractive
keratectomy and L.ASIK66and contact lens
wear,67has been implicated in causing dry
eye conditions through reduced reflex
tearing'" and reduced blink rate.'' Reduced tear secretion may actually lead to
reduction in corneal sensitivity,6ythereby
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 d u e to meibomian
seborrhoea," meibomianitis" and senile
o r 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
n e ~ p l a s 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 excessive mucin production through hyperplasia of goblet cells and hypermitosis of
non-goblet epithelial cells.7h77 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

Clinical and Experimental Optometry 84.1 January-FehrudI-y 2001

Dry eye Albz

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

Clinical and Experimental Optometry 84.1 January-Fchrudry 200 I

Dry eye Albietz

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 chlorideX'.Hi .and cetrimideH4are 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 w e a F ''

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 frequency,'" 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 consequences 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 iniuce ocular surface staining."' Potential
Iauses are ectropion, entropion, large
>terygia,"+facial palsies, symblepharon,'

incomplete
blinking,
nocturnal
lagophthalmos,g6lid 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 ioncentration during close work and computer work con~entration"'","'~
and in Parkinson's disease may lead to dessication of
the ocular surface." Reduction in lid rigidity and tonus occurs with age.lo5Dellen
occur in lid surfacing anomalies in association with pterygia, pingueculae and
contact lens wear I H (Figure 6).

ENVIRONMENTAL INFLUENCES
Environmental factors such as dehydrati n g temperature-controlled environments"' can cause o r 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 tempcrature-controlled office environments.
These include 'pollution keratoconjunctivitis',lL 'office dry eye syndrome' and
'sick building syndrome'."'" Studies irtdicate that 35 per cent to 48 per cent of individuals 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 e n 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 production14 (Figure 4 ) . Alternatively, concentration 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, prealb u m i n ) 114.114 a n d growth factors (for
example, epidermal growth factor, transforming growth factors)'I5and 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."' Inflammatory mechanisms are the most likely
cause for the loss of goblet cells in dry
eye.l".ll9 U p regulation of immunemediated 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

Clinical and Exprririirntdl Optometry 84.1 January-February 200 I

Dry eye Albietr

is difficult and the diagnosis is complicated 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 sensation, burning, soreness, stinging,
scratchiness, dryness, blurry vision, a 'film
over the eyes', paradoxical reflex tearing
and photophobia,lH.20.Y~.."~
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 pract i ~ e . " ' .The
~ ~ ~recently introduced Ocular
Surface Disease Index (OSDI)IS5is a
12-itemquestionnaire designed to provide
a rapid assessment of the symptoms of
ocular irritation with dry eye disease and
their impact on visual function. T h e
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 possesses the necessary psychometric properties to be used as an end point in clinical
trials.136While the OSDI has not yet been
published, its advantage over the
McMonnies Survey is that it is not biased
towards diagnosis of aqueous tear deficiency.

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 reference 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 newlyreleased thin fluorescein strip which delivers 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
PlusTugive longer tear film stability measures and a value less than 20 seconds warrants 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 discontinuous."" Fluorescein lacks this ability to
be blocked by tear constituents and diffuses rapidly into the stroma where cell
to cell j u n c t i o n s a r e disrupted."'
Fluorescein acts as a vital stain adhering
to devitalised cells.'"' Unlike rose Bengal,
fluorescein does n o t stain mucus.
Lissamine green B is an alternative to rose
Bengal that is more easily t01erated.l~"
Lissamine green B is identical to rose Bengal in its staining properties but it stains
blue on the ocular surface and it is easier
to distinguish against an inflamed conj u n ~ t i v a . "It~ is not yet available in Australia.
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 semiquantitative fluorescein and rose Bengal
staining schemes have been described. The

most widely used staining grading schemes

a r e 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 deficiency is characterised by interpalpebral staining, whereas in autoimm u n e 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 a n d 4 a n d 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 a n d pingueculae o r 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 similar 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-

Clinical and Experimental Optometry 84.1 January-February 2001

Dry eye Albirtz

~~

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 a n d Jones tests, phenol red
thread tear test (PRT) a n d 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.'54Schirmer 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 recorded 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 conjuiicti"al folds,
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 appronimately 42 per cent lower in dry eye subjects than in normals.""' The fluorescein
clearance test has a higher predictive
value for o c u l a r irritation t h a n t h e
Schirmer I t e ~ t . " ' ~
Several specific diagnostic criteria for
primary Sjiigren's syndrome have heen
proposed."? The European set of criterial"' 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 sialonietry or sialography
6. presence of serum autoantibodies:
Ro/SS-A, La/SS-B, antinuclear antibodies, rheumatoid factor.
'l7','6'

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',"'Characteristics 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 ofsystemic atopic conditions such as asthma,
hayfever, eczema and/or atopic dermatitis is common.'7JBiomicroscopic features
of chronic allergy and toxicity include lid
oedema, contact dermatitis (toxicity), tarsal 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 cond i t i o n ~ . ' ~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 a n d
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

Figure 8. Insertion of collagen (temporary) punctal plug

fringes indicate a thickened lipid layer.

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 suspected.2,q1
Patients with inferior punctate
erosions o r epithelial defects, who complain of ocular pain or irritation on wdking 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 c o r r e c t c o n t a c t lensrelated 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,3reduce
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 r y eye,146.177.17X o t h e r t r e a t m e n t s
include tear conservation a n d tear
stimulation for tear deficient dry eye,

tions reduce tear o~rnolarity,'~'

reduce
rose Bengal corneal staining, reverse conjunctival squamous metaplasia a n d
increase goblet cell den~ity.'"',''~
Sodium hyaluronate significantly improved dry eye symptoms, tear film stabilTear supplements
Commercially available topical artificial
ity and corneal miningi"'-''' and reduced
tear supplements a r e composed of a
epithelial permeability in a group of dry
eye subjects.'"' In addition, non-Newtonian
blend of polymers, electrolytes and buffering systems. Frequent use of preserved
polymers, such as hyaluronate a n d
polyacrylic acid have enabled the productopical medications exacerbates the ocular surface damage in dry eye by reduction of artificial tear supplements with a
ing the epithelial barrier functionlHO.l"l viscosity that would not normally be tolerand inducing cytotoxic changes to the
ated in Newtonian fluids such as
ocular surface epithelia and increased
methylcellulose, by prolonging corneal
cellular exfoliation.H4.'X2-'H3
Dry eye subresidence time, without causing trauma
from shearing forces during blinking in
jects are more susceptible to the toxic
effects of topical medication due to intear deficient eye.Ig"
hibited tear clearance resulting in proNon-toxic or minimally toxic preserved
longed residence time of potential toxmulti-dose artificial tears are gradually beins o n t h e ocular surface." H e n c e ,
ing released onto the market. This technology enables safe, frequent dosing with
artificial tear supplements to treat dry eye
should be non-preserved, particularly if
reduced costs compared to unit dose
dosing at greater than four times per day
is required.'"."' Bicarbonate appears to
be an important component in an artifiAnti-inflammatory agents
As inflammation is a significant feature of
cial tear because it facilitates restoration
of epithelial harrier function.'""'"' Nonsome dry eye conditions and the products
of the inflammation exacerbate the dispreserved methylcellulose-based artificial
ease process, medications targeting spetear supplements with electrolyte composition resembling physiological condicific inflammatory ocular surface mechaanti-inflammatory agents in allergy/
toxicity related dry eye a n d surgical
treatments for lid/blinking anomalies
and ocular surface disease.

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

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

Primary Sjogren's syndrome

Criteria for non-Sjogren's syndrome tear deficiency, plus

Xerostomia
Pathological salivary gland biopsy
Abnormal saliography
Abnormal serum antibodies

Secondary Sjogren's syndrome

Criteria for Sjogren's syndrome, plus

Collagen vascular disease
Exclude lymphoma, sarcoidosis, graft vs host disease, HIV

Evaporative dry eye

Meibomian gland disease

Cloudy, particulate meibomian gland excreta

Capped, plugged, atrophied glands
Lipid interference fringes, froth in tear film
Meibomian seborrhoea
Meibomianitis
Acne rosacea

Lid surfacing/blinking anomalies

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

Chronic allergy/toxicity

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 discouraged due to the potentiation For cataract
formation, increased intraocular pressure
and infection. Pulse therapy with nonpreserved topical steroids f o r 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 suppresses 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 p e r c e n t a n d 1.0 p e r c e n t nonpreserved 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 persistent defects within two weeks and 62.5
per cent within one month after commencement of treatment at a six to 10
times per day dosage.2o2

Tear deficient dry eye subtypes

Non-Sjogren's tear deficiency

Low to medium viscosity non-preserved artificial tears

Punctal plugs
Non-preserved ointmentslgels

Primary Sjogren's syndrome

Treatments for non-Sjogren's tear deficiency, plus

Topical androgen
Topical cyclosporin
Non-preserved steroid
Submandibular gland transplantation
Oral pilocarpine

Secondary Sjogren's syndrome

Treatments for primary Sjogren's syndrome, plus

Management of systemic collagen vascular disease or
immune dysfunction with specialist physician

Tear preservation
Occlusion of the lacrimal canaliculi improves 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. Reversibility 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""

Evaporative dry eye subtypes

Meibomian gland anomalies

Lid hygiene procedures

Topical non-preserved artificial tears
Oral tetracyclines
Topical non-preserved steroid
Topical androgens

Chronic allergyltoxicity

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

Lid surfacinglblinking anomalies

Non-preserved artificial tearslointments

Surgical repair: pterygium excision, blepharoplasty,
ectropionlentropion repair
Botox injection for blepharospasm
Lid tapinglmoisture chamber for nocturnal lagophthalmos

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 consistency of the meibomian gland oils, which
aids the tear film stability and the antibacterial properties of the tears"" and reduces tear evaporation. Topical androgen
treatment appears to regulate the function
of the meibomian glands, improving the
quality of the secretion and break-up

Cicatricial ocular surface disease Mucous membrane transplant

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

Table 3. Treatment options for dry eye subtypes

Much Secretagogues
The mucin secretagogue 15(s)-HETE
alleviates corneal injury in a rabbit model
of dry eye.2ogP2Y2 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.
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 o n the ocular
surface are currently being evaluated in
clinical and laboratory studies. MUCOUS
me m bra 11e trans p 1an 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 stirface. 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 reducing 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 niultifactorial condition. Clinical diagnosis
can be made largely on the basis of syrnptom a to1o gy and bi om i c ros c opic 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 stirface disorders.
ACKNOWLEDGEMENTS
The author would like to thank Professor
Leo Carney for his assistance in the preparation of this manuscript.
The author has no commercial or proprietary interest in any of the products or
tests referred to in this article.
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Authors address:
Dr Julie Albietz
Centre for Eye Research
School of Optometry
Queensland University of Technology
Victoria Park Road
Kelvin Grove QLD 4059
AUSTRALIA