Dry eye is a multifactorial disease of the tears
and ocular surface that results in symptoms
of discomfort, visual disturbance, and tear
film instability with potential damage to the
ocular surface. It is accompanied by
increased osmolarity of the tear film and
inflammation of the ocular surface.
The presence of precorneal
layer of liquid was first
demonstrated by Fischer in
Rollet described it as 6th layer
Wolff was the first to describe
the structure of tear film.
Tear film is a 3 layered
Lacrimal secretory system
has been divided into 2
a. Basic secretors- goblet
cells, accessory lacrimal
glands, oil glands
B. reflex secretor- main
The concept of the 3 layer architecture has been replaced by the
concept of an integrated aqueous and mucin gel with a graded
concentration of mucins under a dynamic lipid layer.
The outer lipid layer is secreted by the meibomian glands. Lid
movement during blinking releases the lipid from the glands.
This layer prevents evaporation of the aqueous layer and also
acts as a surfactant allowing spread of the tear film. The
synthesis and secretion is influenced by hormones. Androgen
receptor and receptor proteins are found in the nuclei of the
Middle aqueous layer is secreted by the main and accessory lacrimal
Accessory lacrimal glands of Krause, Wolfring and Manz produce the
basal tear secretion. Androgen and Estrogen receptors have been
found on these glands, androgen function is more critical.
The main lacrimal gland produces the reflex secretion in response to
corneal and conj sensory stimulation, tear break up and ocular
inflammation mediated via the 5th cranial nerve. Responsible for 95%
of the aqueous component. It is decreased by topical anaesthesia and
during sleep. The innervation of the lacrimal gland is by
sympathetic, parasympathetic and sensory nerves.
The functions of this layer-
1. to provide oxygen from atmosphere to the cornea
2. anti bacterial function
3. to wash away debris and noxious stimuli and allow passage to
leucocytes after injury
4. to provide a smooth optical surface to the cornea.
The inner mucin layer is produced by the conjunctival and corneal
epithelial cells-goblet cells. Mucins are responsible for the
wetting of the corneal surface. Secretory mucins (MUC 5A) are
secreted by the goblet cells. The transmembrane mucins ( MUC
1 , MUC 4) form the glycocalyx and are produced by non goblet
Mucus is produced when the electrolyte composition of the tear
film changes from normal or when it becomes hyperosmolar.
Also sympathetic and parasympathetic nerves are located
adjacent to the conj goblet cells and sensory stimulation of the
cornea causes goblet cell mucus discharge.
The potassium concentration of the tear film is about 5 times
higher than in aqueous humor or serum. The normal osmolarity
is 306 +/- 2 mosm/l. it is lowest in the morning and increases as
the day progresses.
Dry eye is recognized as a disturbance of the Lacrimal Functional
Unit (LFU), an integrated system comprising -- the lacrimal glands,
ocular surface (cornea, conjunctiva and meibomian glands) and
lids, and the sensory and motor nerves that connect them.
This functional unit controls the major components of the tear film in
a regulated fashion and responds to environmental,
endocrinological and cortical influences.
CLASSIFICATION OF DRY
1. AQUEOUS TEAR
DEFICIENT DRY EYE–
lacrimal tear deficiency
a. Sjogren syndrome-
b. Non sjogren
---lacrimal gland duct
2. EVAPORATIVE DRY
A. Intrinsic- meibomian gland
-- disorders of lid aperture
--low blink rate
- Vit A deficiency
- Topical drugs-
- Contact lens wear
- Ocular surface disease-
Obstruction of the lacrimal gland ducts
Cicatricial pemphigoid and mucous membrane pemphigoid
Chemical and thermal burns
Reflex sensory block
Contact lens wear
Reflex motor block
VII cranial nerve damage
Age related dry eye
With increasing age, there is an increase in ductal pathology that
could promote lacrimal gland dysfunction by its obstructive effect.
These alterations include periductal fibrosis, interacinar
fibrosis, paraductal blood vessel loss and acinar cell
lymphocytic glandular infiltrates were found in 70% of lacrimal
glands studied and considered to be the basis of the fibrosis.
Appearances were likened to the less severe grades of Sjogren
It has been suggested
that the low-grade dacryoadenitis could be caused by
systemic infection or conjunctivitis or, alternatively, that
subclinical conjunctivitis might be responsible for stenosis
of the excretory ducts.
Congenital alacrimia- Triple A syndrome ( Allgrove syndrome) –
AC, alacrimia, addison‟s disease
Familial Dysautonomia- Riley day syndrome:
generalized insensitivity to pain accompanied by a
marked lack of both emotional and reflex tearing, within a
multisystem disorder. There is a developmental and
progressive neuronal abnormality of the cervical sympathetic
and parasympathetic innervations of the lacrimal gland and a
defective sensory innervation of the ocular surface, which
affects both small myelinated (Aδ) and unmyelinated (C)
Obstruction of the lacrimal ducts- can occur following any
condition causing cicatricing conjunctivitis. (
trachoma, ocp, erythema multiforme, sjs, chemical and
-Obstruction of the ducts of the main palpebral and accessory
lacrimal glands leads to aqueous-deficient dry eye.
-Lid deformity influences tear film spreading by
affecting lid apposition and dynamics.
1. reflex sensory block- in conditions of ocular sensory loss :
decreases reflex induced lacrimal secretion and reduces the
blink rate. In addition there is loss of trophic support to the ocular
surface due to deficient release of sub P / nerve growth factors.
Herpes simplex keratitis
Herpes zoster ophthalmicus
b. Corneal surgery
Limbal incision (extra-capsular cataract extraction)
c. Neurotrophic Keratitis
d. Topical anaesthesia – decreases blink rate by about 30% and tear
secretion by 60-75%
e. Systemic medications
f. Other causes
Chronic contact lens wear – hard and extended wear
Diabetes mellitus – (sensory or autonomic neuropathy or due to
microvascular changes in the lacrimal gland)
Evaporative dry eye
1. meibomian gland dysfunction (
posterior blepharitis)- mc
Causes include- acne rosacea,
seborrheic dermatitis, atopic
dermatitis, treatment of acne with
Shine and McCulley
have shown that constitutional
differences in meibomian lipid
composition exist in different
1. ocular surface diseases- imperfect
surface wetting, early tear film
breakup, tear hyperosmolarity, and
a. vit A deficiency- Vit A is essential for
development of goblet cells and
expression of mucins. Its deficiency
can also lead to lacrimal acinar
b. topical drugs and preservatives ( BAC)-
causes expression of inflammatory
cell markers leading to epithelial cell
damage, apoptosis and goblet cell
In subjects with high levels of
cholesterol esters , esterases and
lipases produced by normal lid
commensals release ffa‟s and
glycerides into the tear film which act
as source of iritation or soap
Therefore there is loss of the normal
tear film phospholipids and chol
esters which leads to evaporation. In
blepharitis these commensals are
increased in no.
2. disorders of lid aperture and lid/
ectropion, entropion, lagophthalmos,
2. Contact lens wear – 50%
correlation between hydration of CL and
dry eye symptoms is controversial.
3. Allergic conjunctivitis-
seasonal allergic conjunctivitis, vernal
keratoconjunctivitis, and atopic
- release of inflammatory cytokines lead to
loss of cell surface mucins.
- surface irregularities on the cornea and
conjunctiva lead to tear film instability .
- In chronic disease, MGD occurs.
3. low blink rate-
Physiological / extrapyramidal
- Lid swelling can interfere
with lid apposition and tear
- Use of antihistaminics also
contribute to dry eye.
CAUSATIVE MECHANISM OF
Reflex tear secretion is the initial compensatory mechanism in
response to the ocular irritation but with time the chronic inflammation
leads to decrease in corneal sensation which compromises the reflex
response and leads to an even greater tear film instability.
Ocular protection index-
TFBUT divided by Inter-blink interval (IBI)
If the OPI is <1.0, the patient has an exposed ocular surface, putting them
at risk for the development of the signs and symptoms of dry
eye, whereas if the OPI is ≥1.0, the patient's ocular surface is tear film
protected. The OPI has proven to be useful in assessing the factors
that may cause or exacerbate dry eye.
Most common symptoms include FB
sensation, burning, itching, dryness, soreness, heavy lids, photophobia, ocular
fatigue and reflex tearing.
These symptoms characteristically worsen during the day.
Stringy discharge, crusting of lids and transient blurring of vision can also
A history of exacerbation by reading, computer use, or in windy environment is
Enquire about contact lens use, ocular allergy, infections, and eyelid, corneal
and prior refractive surgery.
Medical history includes presence of any CTD/ autoimmune
disease, DM, thyroid eye disease, parkinson‟s, sarcoidosis, Bells‟s palsy, bone
marrow transplant, periorbital radiation or cranial tumors.
External observation of the face for acne rosacea.
Lids and lashes- examined for lagophthalmos, infrequent blinking, floppy
eyelids, lid retraction, ectropion, entropion, notching, trichiasis, distichiasis.
Lid margins- observation of meibomian gland architecture and openings,
presence of blepharitis, telangiectasia, scurf and position and siza of lacrimal
puncta. Enlargement of lacrimal gland is checked.
Function of 5th and 7th cranial nerve has to be checked.
Conjunctiva- may show mild redness and keratinization.
Tear film- marginal tear meniscus, presence of foam or debris suggestive of
MGD. In the dry eye, lipid contaminated mucin accumulates in the tear film as
particles and debris that move with each blink.
a. Punctate epithelial erosions in the interpalpebral
and inferior cornea.
b. Mucus filaments- stain with rose bengal
c. Mucus plaques- composed of mucus, epithelial
cells, proteinaceous and lipoidal material.
TESTS USED TO DIAGNOSE
AND MONITOR DRY EYE
The tests measure the following
A. tear film stability – Break up time
B. tear production – Schirmer test,
C. Ocular surface disease – corneal /
conjunctival stains and impression
it is the interval between the last complete blink and the
appearance of the first randomly distributed dry spot.
Flourescein 2% or a flourescein strip moistened with normal
saline is instilled in the lower fornix.
The patient is asked to blink several times.
Tear film is examined with broad beam in cobalt blue filter.
The time taken for the appearance of a dark spot is noted.
The established cut off for diagnosing dry eye is < 10 sec.
however, few authors have suggested a cut off of < 5 sec
when small volume of fluorescein is instilled.
Abnormal in ADDE and MGD
Fluorescein BUT has important limitations. Touching of the
filter paper strip to the conjunctiva can stimulate reflex
The Non-Invasive Tear Film Break-up Time Test
They are called Non Invasive because the eye is not touched.
Instruments such as a keratometer, hand-held keratoscope or
Tearscope are required to measure NIBUT. A prerupture phase that
precedes actual break up of the tear film can also be observed with
some techniques. This pre-rupture phase is termed Tear Thinning Time
(TTT). Measurement is achieved by observing the distortion (TTT)
and/or break up (NIBUT) of a keratometer mire (the reflected image of
keratometer grid). The clinician focuses and views the crisp mires, and
then records the time taken for the mire image to distort (TTT) and/or
break up (NIBUT). NIBUT measurements are longer than fluorescein
break up time. NIBUT values of less than 15 seconds are consistent
with dry eyes. TTT / NIBUT are considered to be more patient-
friendly, repeatable and precise.
Assesses the aqueous tear production.
No. 41 Whatmann filter paper is placed in the lower fornix for 5 min
and the amount of wetting is seen. The patient is instructed to look
forward and to blink normally during the course of the test. A negative
test (more than 10 mm wetting of the filter paper in 5 minutes) means
normal quantity of tears. Patients with dry eyes have wetting values of
less than 5 mm in 5 minutes.
Its main utility is in diagnosing patients with severe dry eyes.
Schirmer 1- is done without anaesthesia so it measures the basal and
the reflex secretion.
Schirmer 2- measures the basal secretion- after putting anaesthetic
Abnormal- <10mm without anaesthesia , for diagnosis- <5 mm
<6mm with anaesthesia
Sensitivity is poor : 10%- 25%
Many clinicians regard the Schirmer test as unduly invasive and
of little value for mild to moderate dry eyes. Other less invasive
methods to assess the adequacy of tear production have been
developed. The Phenol red thread test is one such test . A
cotton thread impregnated with phenol red dye is used. Phenol
red is pH sensitive and changes from yellow to red when wetted
by tears. The crimped end of a 70mm long thread is placed in
the lower conjunctival fornix. After 15 seconds, the length of the
color change on the thread - indicating the length of the thread
wetted by the tears -is measured in millimeters. Wetting lengths
should normally be between 9mm and 20mm. Patients with dry
eyes have wetting values of less than 9 mm.
Flourescein clearance test
5 microliter of fluorescein is placed on the ocular surface and the
residual dye is measured in a schirmer strip placed on the lower lateral
margin at intervals of 1, 10, 20, 30 minutes. At the end of the 30 min,
i.e., the last test, Schirmer strip is inserted after nasal stimulation.The
presence of flourescein on each strip is compared to a standard scale
or measured using flourophotometry. In normal eyes the value will
have fallen to zero after 20 minutes. Delayed clearance is observed in
all dry eye states.
It allows one to determine the basal tear secretion, reflex tear
secretion under nasal stimulation, and tear clearance, at the same
ATD- aq tear deficiency
DTC- delayed tear clearnce
A. Flourescein- synthesised by Baeyer in 1871
the intact corneal epithelium because of its high lipid content
resists penetration of water soluble flourescein and so is
not stained by it. Any break in the epithelial barrier permits
rapid penetration leading to staining of the areas with
B. Rose bengal stain- :
1% liquid rose bengal is instilled into the eye. The
examiner uses white light to assess the amount of staining.
VAN BIIJSTERVELD SCORING
Intensity scored in 2 exposed conjunctival zones and cornea
Score 0-3 for each zone. 0 for absent, 1 for just present, 2 for moderate staining and
3 for gross staining.
Maximum score 9.
Score more than 3.5 was considered abnormal.
Rose bengal stains the dead or devitalized epithelial layer which have lost or altered
C. Lissamine green- similar to rose bengal but
much less irritating.
Tear lysozyme levels- lysozyme is produced by the main
and accessory lacrimal gland. It represents 20% of the
protein content in tears. Its levels are decreased in early
stages of dry eye.
Tear lactoferrin levels- it is also secreted by the lacrimal
gland. Levels are decresed in dry eye. Immunoassay
kits are available to measure its levels. Like
It is a plate containing gel loaded with rabbit anti-human-
lactoferrin antiserum. Tear-moistened filter paper discs
containing lactoferrin were placed on the gel. The
lactoferrin concentration could be determined by
measuring the concentric ring of precipitate after 72
hours incubation at room temperature.
Tear film osmolarity- the recommended cut
off value is 316 mosm/ l (overall predictive
accuracy of 89% for the diagnosis). In the
past it has been offered as a gold standard in
dry eye diagnosis, but its general utility is
hindered because it needs expert technical
support, available in only a small no of
It is a non invasive technique of collection of the most superficial layers of the
ocular surface by applying different collecting device (usually
nitrocellulose filter papers) so that cells adherent to that surface are
subsequently removed from the tissue and further processed.
It was first introduced in 1977 by Egbert et al.
1. A piece of filter paper is applied to the conjunctival surface for
approximately 2-5 seconds.
2. The filter paper is removed from the conjunctiva in a peeling motion to
ensure maximal collection of surface cells.
3. The cells are fixed using fixatives like formaldehyde
, glutaraldehyde, ethanol and methanol.
4. The cells that are adherent to the filter paper are stained to enhance
the visibility of the goblet cells with counter staining of the epithelial
cells to increase the contrast of the goblet cells.
5. The specimen is examined under a light microscope and various
analyses of the visible cells are conducted.
Grade 0: small round epithelial cells with a eosinophilic
staining cytoplasm, large basophilic nuclei with an n/c
ratio of 1:2, abundant goblet cells( >5oo cells/mm2)
Grade 1: Slightly larger and more polygonal cells , smaller
nuclei,with n/c ratio of 1:3 , goblet cells are reduced in
number (350-500 cells/mm2), preserved plump , with
an intensely oval shape PAS positive cytoplasm.
Grade 2: even larger& polygonal epithelial
cells, occasionally multinucleated with variable staining
cytoplasm, small nuclei with n/c ratio 1:4- 1:5, goblet
cells markedly decreased in number (100-150 cells
mm2) , smaller and less intensely PAS positive.
Grade 3: large &polygonal with basophilic staining
cytoplasm small pyknotic nuclei ,occasionly completely
absent,n/c ratio >1:6, very few goblet cells(100
Squamous metaplasia involves 3 major steps- loss of
goblet cells, increase in cellular stratification and
Stage0- normal cellular structure
Stage 1 – partial loss of goblet cell, no keratinization
Stage 2- total loss of goblet cells, increase in sixe of epithelial
Stage 3- early and mild keratinization
Stage 4 – moderate keratinization
Stage 5- advanced keratinization
A. tear supplementation- Lubricants
B. tear retention- 1. punctal occlusion
2. moisture chamber
3. Bandage Contact lenses
C. Tear stimulation- Secretagogues
D. biological tear substitutes- 1. serum
2. Salivary gland
E. Anti- inflammatory therapy- 1. cyclosporine
F. essential fatty acids
G. environmental strategies
The foremost objectives in caring for patients
with dry eye disease are to improve the
patient‟s ocular comfort and quality of life, and
to return the ocular surface and tear film to the
normal homeostatic state. Although symptoms
can rarely be eliminated, they can often be
improved, leading to an improvement in the
quality of life.
The term artificial tears is a misnomer as they do not mimic the
composition of human tears. Most of them function only as lubricants.
Few recent ones mimic the electrolyte composition of tears.
The ideal artificial lubricant should be preservative-free, contain
potassium, bicarbonate, and other electrolytes and have a polymeric
system to increase its retention time.
The main variables in the formulation of ocular lubricants regard the
concentration of and choice of electrolytes, the osmolarity and the type
of viscosity/polymeric system, the presence or absence of preservative,
and, if present, the type of preservative.
A. Electrolyte composition- solutions containing electrolytes/ ions
have been shown to be beneficial in treating ocular surface
damage due to dry eye. Potassium and bicarbonate are most
Potassium is important to maintain corneal thickness, and
bicarbonate promotes recovery of the epithelial barrier function
and helps in maintaining the normal epithelial ultrastructure. (
hypotears , genteel eye drops)
B. Osmolarity- since the tear film in patients with dry eye is
hyperosmolar, these lubricants should be hypo-osmolar but with
a high colloidal osmolality. so compatible solutes like
glycerin, erythritol and levocarnitine.
C. Viscosity agents- macromolecule complexes added to
lubricants act as viscosity agents. They increase the residence
time, incresing the duration of action and penetration of the drug.
Viscous agents also protect the ocular surface epithelium. Eg.
CMC (mc), HPMC, HMC, polyvinyl alcohol, PEG, glycol
400, propylene glycol. Highly viscous agents have the
disadvantage that they cause blurring of vision and caking and
drying on eyelashes. Lower molecular wt viscous agents help to
minimize these problems. ( Systane contains HP- Guar which is
a gelling agent containing glycol 400 and propylene glycol.)
Hyaluronic acid has also been tried as a viscosity agent.
D. Preservatives- particularly BAK and disodium EDTA.
Most commonly used preservative in eye drops is BAK. It
has been found that its excessive use excites the
inflammatory cell markers like HLA-DR and ICAM 1 and
causes epithelial cell damage, apoptosis and decrease in
goblet cell density. Therefore leading to decrease in mucin-
MUC 5A. The toxicity is related to its
concentration, frequency of dosing and the severity of dry
eye. In mild dry eye it can be well tolerated even if used 4-
6 times a day but in mod- sev dry eye potential for toxicity
is high due to decreased tear secretion and decreased
Less toxic preservatives are now used more frequently.
Like polyquad, Na chlorite( purite), Na perborate.
These are „vanishing‟ preservatives. < Na chlorite - Na
and Cl on exposure to UV light, Na perborate- water
and oxygen on contact with tear film. >
Ointments and gels have a longer retention time as
compared to artificial tears.
It is of greatest value in patients with mod- sev KCS who have not responded to
topical treatment. Introduced by Beetham in 1935, he used electrocautery.
1. temporary occlusion- by inserting collagen plugs into the canaliculi that
dissolve in 1-2 wks. If patient is asymptomatic after 1-2 weeks permanent
occlusion can be done.
2. reversible occlusion- by inserting silicon or long lasting collagen plugs that
dissolve in 2-6 months. They include – FREEMAN silicon plug which is
dumbbell shaped and a HERRICK plug which is shaped like a golf tee.
3. permanent occlusion- is done in patients with severe dry with repeated
schirmer‟s test value less than 5 mm. it is done by coagulating the proximal
canaliculus with cautery, either thermal coagulation or diode laser cautery.
Beneficial outcome has been reported in 74-86% patients treated with
1. allergy to the materials used
2. punctal ectropion
3. pre existing NLD block
4. patients with clinical ocular surface inflammation
5. infection of lacrimal canaliculus or sac
1. spontaneous extrusion – mc , particularly with freeman style (50%)
2. internal migration of the plug
3. biofilm formation and infection and pyogenic granuloma
Tsubota et al reported an increase in periocular humidity in
subjects wearing these spectacles.
Bandage Contact lenses
They help to protect and hydrate the
corneal surface in severe dry eye
conditions. Silicone rubber lenses and
gas permeable scleral bearing hard
contact lenses can be used.
Tear stimulation- secretagogues
They increase the aqueous secretion or mucin
production or both.
These agents are currently under investigation
They include- diquafosol, rebamipide,
gefarnate, ecabet sodium, 15- HETE.
Cholinergic agonists- pilocarpine ( 5 mg qid) ,
Biological tear substitutes
Include serum or saliva.
They maintain the morphology and support the proliferation of
primary corneal epithelial cells better than tear substitues.
Serum has been used in the concentration ranging from 20% to
100%. The efficacy is dose dependant. It is not FDA approved
Salivary gland autotransplantation can be done. But since saliva
is hypo osmolar as compared to tears it can lead to microcystic
corneal edema. Therefore this is indicated only in end stage dry
eye disease, with schirmer test value </=1 mm, conjunctivalized
surface epithelium and persistent severe pain despite punctal
occlusion and hourly application of unpreserved lubricating
Anti inflammatory therapy
Hyperosmolarity of tear film is pro -inflammatory. Inflammation
leads to ocular surface disease. So, anti inflammatory agents
have been evaluated for use in dry eye. These include-
Cyclosporin is used in the concentration of 0.1% or 0.05%. Treated
eyes had approximately 200% increase in conjunctival goblet
cell density. It is used in moderate to severe aqueous
deficiency. Most common side effect includes burning on
instillation. Other is conjunctival hyperemia. Therapeutic benefit
is achieved in about a month.
Corticosteroids have been reported to decrease ocular
irritation, decrease corneal fluorescein staining and
improve filamentary keratitis. Low dose steroid therapy
can be used for short term (2 weeks) to suppress
discomfort and epithelial disease secondary to
inflammation. It is usually used along with or before
starting cyclosporin therapy.
TETRACYCLINES- they are attributed to have anti- bacterial
properties ( therefore decreasing the bacteria producing
lipases) , anti- inflammatory properties( by decreasing wbc
chemotaxis and phagocytosis and also decreasing the activity
of collagenase, phospholipase , MMP‟s and decreasing the
production of IL-1 and TNF alpha) and anti- angiogenic
They are therefore indicated in-
Posterior blepharitis – 100 mg doxycycline is given BD for the
first week and then OD for 6-12 weeks. Some studies have
suggested equal improvement with even 20 mg BD for 1-2
Essential fatty acids
Omega 6 fatty acids are precursors of arachidonic acid
and certain pro-inflammatory lipid mediators ( PGE2,
LTB4), whereas omega 3 fatty acids found in fish oil (
also in walnuts, flax seeds, soyabean, tofu) inhibit the
synthesis f these lipid mediators and block the
production of IL 1 and TNF alpha. So they have been
found to decrease the incidence of dry eye.