This document discusses dry eye syndrome, its causes, and pathophysiology. It begins by describing the three layers of the tear film and how deficiencies or issues with the layers can cause dry eye. The main causes discussed are deficient aqueous production, which can be due to non-Sjogren's syndrome related issues or Sjogren's syndrome, and evaporative loss, often due to meibomian gland dysfunction. The document provides details on the frequency, risks, and classifications of dry eye conditions.

1. Dry Eye SyndromeDry Eye Syndrome
Dr Humberto ValbuenaDr Humberto Valbuena

2. INTRODUCTIONINTRODUCTION
BackgroundBackground:: Dry eye is a common disorder of the tearDry eye is a common disorder of the tear
film that results from decreased tear production,film that results from decreased tear production,
excessive tear evaporation, or abnormality in mucin orexcessive tear evaporation, or abnormality in mucin or
lipid components of the tear film. Generally, it islipid components of the tear film. Generally, it is
accepted that the tear film is made up of 3 intertwinedaccepted that the tear film is made up of 3 intertwined
layers, as follows:layers, as follows:
1-1- A superficial thin lipid layerA superficial thin lipid layer is produced by theis produced by the
meibomian glands, and its principal function is to retardmeibomian glands, and its principal function is to retard
tear evaporation and to assist in uniform teartear evaporation and to assist in uniform tear
spreading.spreading.

3. 2-2- A middle thick aqueous layerA middle thick aqueous layer is produced by theis produced by the
main lacrimal glands (reflex tearing), as well as themain lacrimal glands (reflex tearing), as well as the
accessory lacrimal glands of Krause and Wolfringaccessory lacrimal glands of Krause and Wolfring
(basic tearing).(basic tearing).
3-3- An innermost hydrophilic mucin layerAn innermost hydrophilic mucin layer is producedis produced
by both the conjunctiva goblet cells and the ocularby both the conjunctiva goblet cells and the ocular
surface epithelium and associates itself with thesurface epithelium and associates itself with the
ocular surface via its loose attachments to theocular surface via its loose attachments to the
glycocalyx of the microplicae of the epithelium.glycocalyx of the microplicae of the epithelium.

4.  Mucin deficiency, as seen inMucin deficiency, as seen in Stevens-Johnson syndromeStevens-Johnson syndrome or after aor after a
chemical burnchemical burn, leads to poor wetting of the corneal surface with, leads to poor wetting of the corneal surface with
subsequent desiccation and epithelial damage.subsequent desiccation and epithelial damage.
 Keratoconjunctivitis sicca (KCS)Keratoconjunctivitis sicca (KCS) is the name given to the ocularis the name given to the ocular
surface disorder that develops in patients withsurface disorder that develops in patients with aqueous tearaqueous tear
deficiency (ATD),deficiency (ATD), and it is the most common cause of dry eye.and it is the most common cause of dry eye.
 KCS is subdivided intoKCS is subdivided into Sjögren syndromeSjögren syndrome (SS)(SS) associated KCSassociated KCS
and non-SS associated KCS. Evaporative loss is due predominantlyand non-SS associated KCS. Evaporative loss is due predominantly
toto meibomian gland dysfunction (MGD).meibomian gland dysfunction (MGD).
 Patients withPatients with primary SSprimary SS have evidence of a systemic autoimmunehave evidence of a systemic autoimmune
disease as manifested by the presence of serum autoantibodies anddisease as manifested by the presence of serum autoantibodies and
very severe ATD and ocular surface disease.very severe ATD and ocular surface disease. Secondary SSSecondary SS isis
defined as KCS associated with a diagnosable connective tissuedefined as KCS associated with a diagnosable connective tissue
disease, most commonly rheumatoid arthritis.disease, most commonly rheumatoid arthritis.

5. PathophysiologyPathophysiology
A genetic predisposition in SS associated
KCS exists as evident by the high
prevalence of human leukocyte antigen
B8 (HLA-B8) haplotype in these patients.
This condition leads to production
of autoantibodies, antinuclear
antibody (ANA), rheumatic factor,
or SS-specific antibodies (eg, anti-
RO [SS-A], anti-LA [SS-B]), and
lymphocytic infiltration (ie, CD4+
cells) of the lacrimal and salivary
gland
Glandular degeneration
and induction of
apoptosis in the
conjunctiva.

6. Androgen receptors are located in
lacrimal glands and in meibomian
glands.
At menopause, a decrease in circulating
sex hormones (ie, estrogen, androgen)
occurs, possibly affecting the functional
and secretory aspect of the lacrimal
gland.
It has been postulated that in MGD a deficiency in
androgens results in loss of the oil layer, exacerbating the
evaporative tear loss.

7. - Various proinflammatory cytokines that may cause cellular
destruction, including interleukin 1 (IL-1), interleukin 6 (IL-6), and
interleukin 8 (IL-8), are altered in patients with KCS.
- Additionally, adhesion molecules, such as intercellular adhesion
molecule-1 (ICAM-1), important in cellular diapedesis, are up-
regulated in the conjunctiva of patients with KCS.
- Normal production of tear proteins, such as lysozyme, lactoferrin,
lipocalin, and phospholipase A2, is decreased in KCS. Decreased
polar lipids, phosphatidyl ethanolamine (PE) and sphingomyelin (SM),
are present in obstructive MGD.

8.  Mucin synthesizing genesMucin synthesizing genes, designated, designated MUC1-MUC8MUC1-MUC8, have been, have been
isolated, and their role in hydration and stability of the tear film areisolated, and their role in hydration and stability of the tear film are
being investigated in patients with dry eye syndrome.being investigated in patients with dry eye syndrome.
 Particularly significant isParticularly significant is MUC5AC,MUC5AC, expressed by stratifiedexpressed by stratified
squamous cells of the conjunctiva and whose product is thesquamous cells of the conjunctiva and whose product is the
predominant component of the mucous layer of tearspredominant component of the mucous layer of tears
 AA defect in this genedefect in this gene may be a factor in dry eye syndromemay be a factor in dry eye syndrome
development.development.

9. Frequency:Frequency:
In the USIn the US:: Dry eye is a very common disorderDry eye is a very common disorder
affecting a significant percentage of the population,affecting a significant percentage of the population,
especially those older than 40 years. The estimatedespecially those older than 40 years. The estimated
number of people affected ranges from 10-14 million innumber of people affected ranges from 10-14 million in
the US.the US.
InternationallyInternationally :: The frequency of dry eye in otherThe frequency of dry eye in other
countries closely parallels that of the US.countries closely parallels that of the US.

10.  Mortality/Morbidity:Mortality/Morbidity: Dry eye may be complicated byDry eye may be complicated by sterilesterile
or infectious corneal ulcerationor infectious corneal ulceration. Occasionally, corneal perforation. Occasionally, corneal perforation
may occur. In rare cases, sterile or infectious corneal ulceration inmay occur. In rare cases, sterile or infectious corneal ulceration in
dry eye syndrome can cause blindness.dry eye syndrome can cause blindness.
 Race:Race: No known racial predilection exists.No known racial predilection exists.
 Sex:Sex: Dry eye may be slightly more common in women. KCSDry eye may be slightly more common in women. KCS
associated with SS (a type of dry eye) is believed to affect 1-2% ofassociated with SS (a type of dry eye) is believed to affect 1-2% of
the population, and 90% of those affected are women.the population, and 90% of those affected are women.

11. CausesCauses
 A classification system formulated by the National Eye InstituteA classification system formulated by the National Eye Institute
distinguishes 2 main categories (or causes) of dry eye states, andistinguishes 2 main categories (or causes) of dry eye states, an
aqueous deficiency state and an evaporative state.aqueous deficiency state and an evaporative state.
 Deficient aqueous productionDeficient aqueous production
 Non-Sjögren syndromeNon-Sjögren syndrome
– Lacrimal disease (primary or secondary)Lacrimal disease (primary or secondary)
 Systemic vitamin A deficiency (xerophthalmia)Systemic vitamin A deficiency (xerophthalmia)
 Lacrimal ablationLacrimal ablation
 Congenital alacrima (Riley-Day syndrome)Congenital alacrima (Riley-Day syndrome)
 Primary lacrimal deficiencyPrimary lacrimal deficiency
 Graft-versus-host diseaseGraft-versus-host disease

12. – Infiltrative processesInfiltrative processes
 LymphomaLymphoma
 AmyloidosisAmyloidosis
 HemachromatosisHemachromatosis
 SarcoidosisSarcoidosis
– Infectious diseasesInfectious diseases
 HIV diffuse infiltrative lymphadenopathy syndromeHIV diffuse infiltrative lymphadenopathy syndrome
 TrachomaTrachoma
– Lacrimal obstructive diseaseLacrimal obstructive disease
 TrachomaTrachoma
 Ocular cicatricial pemphigoidOcular cicatricial pemphigoid
 Erythema multiforme and Stevens-Johnson syndromeErythema multiforme and Stevens-Johnson syndrome
 Chemical burnsChemical burns
 Endocrine imbalanceEndocrine imbalance

13. – Anticholinergic medicationsAnticholinergic medications
– Decreased corneal sensationDecreased corneal sensation
 Neurotrophic keratitisNeurotrophic keratitis
 Corneal surgeryCorneal surgery
 Herpes simplexHerpes simplex
 Contact lens wearContact lens wear
 Cranial nerve VII (CN VII) palsyCranial nerve VII (CN VII) palsy
 DiabetesDiabetes
 AgingAging

14.  Sjögren syndromeSjögren syndrome
– PrimaryPrimary (no associated connective tissue disease [CTD])(no associated connective tissue disease [CTD])
– SecondarySecondary (associated CTD)(associated CTD)
 Rheumatoid arthritisRheumatoid arthritis
 Systemic lupus erythematosusSystemic lupus erythematosus
 Progressive systemic sclerosis (scleredema)Progressive systemic sclerosis (scleredema)
 Primary biliary cirrhosisPrimary biliary cirrhosis
 Interstitial nephritisInterstitial nephritis
 Polymyositis and dermatomyositisPolymyositis and dermatomyositis

15.  Evaporative lossEvaporative loss
– Blepharitis-associated - Obstructive meibomian gland diseaseBlepharitis-associated - Obstructive meibomian gland disease
– Blink disordersBlink disorders
– Disorders of eyelid aperture and eyelid/globe congruityDisorders of eyelid aperture and eyelid/globe congruity

16. CLINICALCLINICAL
 Ocular irritation of dry sensation, burning, itching,Ocular irritation of dry sensation, burning, itching,
foreign body sensation, photophobia, and blurred visionforeign body sensation, photophobia, and blurred vision
are common in patients with dry eye.are common in patients with dry eye.
 In KCSIn KCS, symptoms tend to be worse toward the end of, symptoms tend to be worse toward the end of
the day, with prolonged use of the eyes, or withthe day, with prolonged use of the eyes, or with
exposure to extreme environmental conditions.exposure to extreme environmental conditions.
 Patients with MGDPatients with MGD may complain of redness of themay complain of redness of the
eyelids and conjunctiva, but, in these patients, theeyelids and conjunctiva, but, in these patients, the
symptoms are worse on awakening in the morningsymptoms are worse on awakening in the morning..

17.  ParadoxicallyParadoxically, some patients with dry eye syndrome, some patients with dry eye syndrome
complain ofcomplain of too much tearingtoo much tearing. When evidence of dry eye. When evidence of dry eye
syndrome exists, this symptom often is explained bysyndrome exists, this symptom often is explained by
excessive reflex tearing due to severe corneal surfaceexcessive reflex tearing due to severe corneal surface
disease from the dryness.disease from the dryness.
 Certain systemic medications also decrease tearCertain systemic medications also decrease tear
production, such as antihistamines, beta-blockers, andproduction, such as antihistamines, beta-blockers, and
oral contraceptives.oral contraceptives.

18. PhysicalPhysical
 Signs of a dry eye include the followingSigns of a dry eye include the following::
– Bulbar conjunctival vascular dilationBulbar conjunctival vascular dilation
– Decreased tear meniscusDecreased tear meniscus
– Irregular corneal surfaceIrregular corneal surface
– Decreased tear break-up timeDecreased tear break-up time
– Punctate epithelial keratopathyPunctate epithelial keratopathy
– Corneal filamentsCorneal filaments
– Increased debris in the tear filmIncreased debris in the tear film
 Symptoms often do not correlate with signs.Symptoms often do not correlate with signs.
 In severe cases, there may be anIn severe cases, there may be an epithelial defect or a sterileepithelial defect or a sterile
corneal infiltrate or ulcercorneal infiltrate or ulcer. Secondary infectious keratitis also can. Secondary infectious keratitis also can
develop. Both sterile and infectious corneal perforations can occur.develop. Both sterile and infectious corneal perforations can occur.

19. GRADO 1: OJO SECO LEVEGRADO 1: OJO SECO LEVE
Lo característico del
grado 1 es la presencia
de síntomas de ojo seco
lesiones de superficie
reversibles, no
diagnosticables por
biomicroscopia, de
síntomas ligeros de
sequedad ocular: picor,
sensación de sequedad
y raspado, deseo de
cerrar los ojo.

20. GRADO 2: OJO SECO MEDIOGRADO 2: OJO SECO MEDIO
Lo característico del grado 2
es la existencia de lesiones
de superficie reversibles,
diagnosticables por
biomicroscopia Tinción
corneal o conjuntival
positiva con fluoreceína o
rosa de Bengala, filamentos
corneales, TBUT muy bajo.

21. GRADO 3: OJO SECO SEVEROGRADO 3: OJO SECO SEVERO
Lo característico del grado 3
es la presencia de lesiones
corneales y conjuntivales
persistentes
leucomas cicatriciales,
opacidades corneales,
neovascularización corneal,
borramiento de pliegues
lacunares, simbléfaros

22. WORKUPWORKUP
Lab Studies:Lab Studies:
 Conjunctival impression cytology can be used to monitor the progression ofConjunctival impression cytology can be used to monitor the progression of
ocular surface changes.ocular surface changes.
 Serology for circulating autoantibodies, including ANA or SS antibodies (ie,Serology for circulating autoantibodies, including ANA or SS antibodies (ie,
SS-A, SS-B), may be indicated.SS-A, SS-B), may be indicated.
Other Tests:Other Tests:
 Dry eye is essentially aDry eye is essentially a clinical diagnosisclinical diagnosis , combining information, combining information
obtained from both the history and the examination and performing 1 orobtained from both the history and the examination and performing 1 or
more tests to lend some objectivity to the diagnosis. No one test ismore tests to lend some objectivity to the diagnosis. No one test is
sufficiently specific to permit an absolute diagnosis of dry eye.sufficiently specific to permit an absolute diagnosis of dry eye.
 Tear break-up test (TBUT)Tear break-up test (TBUT) is determined by measuring the time lapseis determined by measuring the time lapse
between instillation of fluorescein and appearance of the first dry spots onbetween instillation of fluorescein and appearance of the first dry spots on
the cornea. Decreased TBUT of less than 10 seconds is consideredthe cornea. Decreased TBUT of less than 10 seconds is considered
abnormal, indicative of tear instability.abnormal, indicative of tear instability.

23.  Use rose bengal and fluoresceinUse rose bengal and fluorescein staining to evaluatestaining to evaluate
epitheliopathy. Rose bengal stains not only dead and devitalized cells butepitheliopathy. Rose bengal stains not only dead and devitalized cells but
also healthy cells that are protected inadequately by a mucin coating.also healthy cells that are protected inadequately by a mucin coating.
Fluorescein pools in epithelial erosions and stains exposed basementFluorescein pools in epithelial erosions and stains exposed basement
membrane.membrane.
– Early or mild cases of KCSEarly or mild cases of KCS are detected more easily with roseare detected more easily with rose
bengal than with fluorescein staining, and the conjunctiva usually isbengal than with fluorescein staining, and the conjunctiva usually is
stained more intensely than the cornea. Interpalpebral staining of thestained more intensely than the cornea. Interpalpebral staining of the
nasal and/or inferior paracentral cornea is seen in KCS. A linear patternnasal and/or inferior paracentral cornea is seen in KCS. A linear pattern
of inferior conjunctiva and corneal staining by rose bengal isof inferior conjunctiva and corneal staining by rose bengal is
characteristic of MGD.characteristic of MGD.
– Van Bijsterveld developedVan Bijsterveld developed a scoring system for rose bengala scoring system for rose bengal thatthat
evaluates the intensity of staining based on a scale of 0-3 in 3 areas:evaluates the intensity of staining based on a scale of 0-3 in 3 areas:
nasal conjunctiva, temporal conjunctiva, and cornea. With this system,nasal conjunctiva, temporal conjunctiva, and cornea. With this system,
the maximum possible score is 9. According to this system, a score ofthe maximum possible score is 9. According to this system, a score of
3.5 or greater is considered positive for KCS.3.5 or greater is considered positive for KCS.

24.  Use the Schirmer test to test aqueousUse the Schirmer test to test aqueous
tear productiontear production .. Traditionally, the basic secretion test isTraditionally, the basic secretion test is
performed following the instillation of topical anesthetic and theperformed following the instillation of topical anesthetic and the
placement of a thin strip of filter paper in the inferior cul-de-sac.placement of a thin strip of filter paper in the inferior cul-de-sac.
Measurement of less than 5 mm is abnormal; 5-10 mm is equivocal.Measurement of less than 5 mm is abnormal; 5-10 mm is equivocal.
– The Schirmer I testThe Schirmer I test ,, which measures both basic andwhich measures both basic and
reflex tearing, consists of the same test without the use of areflex tearing, consists of the same test without the use of a
topical anesthetic agent. Less than 10 mm of wetting after 5topical anesthetic agent. Less than 10 mm of wetting after 5
minutes is diagnostic of ATD. The test is relatively specific, but itminutes is diagnostic of ATD. The test is relatively specific, but it
is poorly sensitive.is poorly sensitive.
– The Schirmer II testThe Schirmer II test measures reflex tearing.measures reflex tearing. It isIt is
performed similar to the basic secretion test, with the addition ofperformed similar to the basic secretion test, with the addition of
nasal mucosal irritation with a cotton tip applicator. Wetting ofnasal mucosal irritation with a cotton tip applicator. Wetting of
less than 15 mm after 5 minutes is consistent with abnormalitiesless than 15 mm after 5 minutes is consistent with abnormalities
of reflex secretionof reflex secretion

25.  Additional tests include tear film osmolarityAdditional tests include tear film osmolarity, tear, tear
lysozyme, and tear lactoferrin. Tear film osmolarity haslysozyme, and tear lactoferrin. Tear film osmolarity has
been shown to be elevated in patients with dry eyes.been shown to be elevated in patients with dry eyes.
 It is a very sensitive test for identifying a dry eye butIt is a very sensitive test for identifying a dry eye but
lacks specificity. The test often is not used because oflacks specificity. The test often is not used because of
the lack of commercially available equipment for itsthe lack of commercially available equipment for its
measurementmeasurement..

26. Procedures:Procedures:
 Lacrimal gland or minor (salivary) gland biopsy may beLacrimal gland or minor (salivary) gland biopsy may be
performed to aid in diagnosing SS.performed to aid in diagnosing SS.
Histologic FindingsHistologic Findings :: Histopathologically, squamousHistopathologically, squamous
metaplasia with loss of goblet cells, cellular enlargement,metaplasia with loss of goblet cells, cellular enlargement,
and increase in cytoplasmic/nuclear ratio of theand increase in cytoplasmic/nuclear ratio of the
superficial conjunctival epithelial cells are present insuperficial conjunctival epithelial cells are present in
patients with KCS.patients with KCS.

27. TREATMENTTREATMENT
 Medical Care:Medical Care:
 MildMild
– Artificial tears with preservatives up to 4 times dailyArtificial tears with preservatives up to 4 times daily
– Lubricating ointment at bedtimeLubricating ointment at bedtime
– Hot compresses and eyelid massage, especially if associatedHot compresses and eyelid massage, especially if associated
with MGDwith MGD
 ModerateModerate
– Artificial tears without preservatives 4 times daily to hourlyArtificial tears without preservatives 4 times daily to hourly
– Lubricating ointment at bedtimeLubricating ointment at bedtime
– Doxycycline 100 mg qd/bid if indicated for MGDDoxycycline 100 mg qd/bid if indicated for MGD
– Lower punctal occlusionsLower punctal occlusions

28.  SevereSevere
– Perform all of the above treatmentsPerform all of the above treatments
– Punctal occlusions (lower and upper)Punctal occlusions (lower and upper)
– Moist environment (humidifier, moisture shield)Moist environment (humidifier, moisture shield)
– Lateral tarsorrhaphyLateral tarsorrhaphy
 Emerging therapyEmerging therapy
– Immunomodulatory agents (eg, topical cyclosporine A)Immunomodulatory agents (eg, topical cyclosporine A)
– Topical androgensTopical androgens
– Secretagogues (substance that increases acinar cell activity andSecretagogues (substance that increases acinar cell activity and
protein synthesis, eg, oral pilocarpine)protein synthesis, eg, oral pilocarpine)
– Cytokine-blocking agentsCytokine-blocking agents
 Consultations:Consultations: A rheumatologist can be consulted if aA rheumatologist can be consulted if a
systemic collagen vascular disease is suspected.systemic collagen vascular disease is suspected.

29. Further Outpatient Care:Further Outpatient Care:
 Follow-up care is based on the severity of symptoms.Follow-up care is based on the severity of symptoms.
Complications:Complications:
 Decreased visual acuityDecreased visual acuity
 BlindnessBlindness
Prognosis:Prognosis:
 In general, prognosis for visual acuity in patients with dryIn general, prognosis for visual acuity in patients with dry
eye syndrome is good.eye syndrome is good.

30. Gracias………Gracias………